HEALTH AND HUMAN DEVELOPMENT

CANNABIS
MEDICAL ASPECTS

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 HEALTH AND HUMAN DEVELOPMENT
JOAV MERRICK - SERIES EDITOR
NATIONAL INSTITUTE OF CHILD HEALTH
AND HUMAN DEVELOPMENT,
MINISTRY OF SOCIAL AFFAIRS, JERUSALEM

Adolescent Behavior Research: Poverty and Children:

International Perspectives A Public Health Concern
Joav Merrick and Hatim A. Omar (Editors) Alexis Lieberman and Joav Merrick (Editors)
2007. ISBN: 1-60021-649-8 2009. ISBN: 978-1-60741-140-6

Complementary Medicine Systems: Living on the Edge: The Mythical,

Comparison and Integration Spiritual, and Philosophical
Karl W. Kratky Roots of Social Marginality
2008. ISBN: 978-1-60456-475-4 (Hardcover) Joseph Goodbread
2008. ISBN: 978-1-61122-433-7 (E-book) 2009. ISBN: 978-1-60741-162-8

Pain in Children and Youth Alcohol-Related Cognitive Disorders:

Patricia Schofield and Joav Merrick Research and Clinical Perspectives
(Editors) Leo Sher, Isack Kandel and Joav Merrick
2008. ISBN: 978-1-60456-951-3 (Editors)
2009. ISBN: 978-1-60741-730-9 (Hardcover)
Challenges in Adolescent Health: 2009. ISBN: 978-1-60876-623-9 (E-book)
An Australian Perspective
David Bennett, Susan Towns, Advances in Environmental Health
Elizabeth Elliott Effects of Toxigenic Mold
and Joav Merrick (Editors) and Mycotoxins- Volume 1
2009. ISBN: 978-1-60741-616-6 (Hardcover) Ebere Cyril Anyanwu
2009. ISBN: 978-1-61668-240-8 (E-book) 2010. ISBN: 978-1-60741-953-2

Behavioral Pediatrics, 3rd Edition Children and Pain

Donald E. Greydanus, Dilip R. Patel, Patricia Schofield and Joav Merrick
Helen D. Pratt and Joseph L. Calles, Jr. (Editors)
(Editors) 2009. ISBN: 978-1-60876-020-6 (Hardcover)
2009. ISBN: 978-1-60692-702-1 (Hardcover) 2009. ISBN: 978-1-61728-183-9 (E-book)
2009. ISBN: 978-1-60876-630-7 (E-book)
Chance Action and Therapy.
Obesity and Adolescence: The Playful Way of Changing
A Public Health Concern Uri Wernik
Hatim A. Omar, Donald E. Greydanus, 2010. ISBN: 978-1-60876-393-1 (Hardcover)
Dilip R. Patel and Joav Merrick (Editors) 2011. ISBN: 978-1-61122-987-5 (Softcover)
2009. ISBN: 978-1-60456-821-9
 International Aspects of Rural Child Health:
Child Abuse and Neglect International Aspects
Howard Dubowitz and Joav Merrick Erica Bell and Joav Merrick (Editors)
(Editors) 2011. ISBN: 978-1-60876-357-3 (Hardcover)
2010. ISBN: 978-1-60876-703-8 (Hardcover) 2010. ISBN: 978-1-61324-005-2 (E-book)
2010. ISBN: 978-1-61122-049-0 (Softcover)
2010. ISBN: 978-1-61122-403-0 Understanding Eating Disorders:
(E-book) Integrating Culture,
Psychology and Biology
Positive Youth Development: Yael Latzer, Joav Merrick
Implementation of a Youth Program in a and Daniel Stein (Editors)
Chinese Context 2011. ISBN: 978-1-61728-298-0
Daniel T.L Shek, Hing Keung Ma and Joav
Merrick (Editors) Positive Youth Development: Evaluation
2010. ISBN: 978-1-61668-230-9 (Hardcover) and Future Directions in a Chinese
2010. ISBN: 978-1-61209-091-7 (E-book) Context
Daniel T.L. Shek, Hing Keung Ma and Joav
Advanced Cancer Pain Merrick (Editors)
and Quality of Life 2011. ISBN: 978-1-60876-830-1 (Hardcover)
Edward Chow and Joav Merrick (Editors) 2010. ISBN: 978-1-61668-376-4 (E-book)
2010. ISBN: 978-1-61668-207-1
(Hardcover) Self-Management and
2010. ISBN: 978-1-61668-400-6 (E-book) the Health Care Consumer
Peter William Harvey
Bone and Brain Metastases: Advances in 2011. ISBN: 978-1-61761-796-6 (Hardcover)
Research and Treatment 2011. ISBN: 978-1-61122-214-2 (E-book)
Arjun Sahgal, Edward Chow
and Joav Merrick (Editors) Sexology from a
2010. ISBN: 978-1-61668-365-8 (Hardcover) Holistic Point of View
2010. ISBN: 978-1-61728-085-6 (E-book) Soren Ventegodt and Joav Merrick
2011. ISBN: 978-1-61761-859-8 (Hardcover)
Environment, Mood Disorders 2011. ISBN: 978-1-61122-262-3 (E-book)
and Suicide
Teodor T. Postolache and Joav Merrick Principles of Holistic Psychiatry:
(Editors) A Textbook on Holistic Medicine
2010. ISBN: 978-1-61668-505-8 for Mental Disorders
Soren Ventegodt and Joav Merrick
Narratives and Meanings 2011. ISBN: 978-1-61761-940-3 (Hardcover)
of Migration 2011. ISBN: 978-1-61122-263-0 (E-book)
Julia Mirsky
2010. ISBN: 978-1-61761-103-2 (Hardcover)
2010. ISBN: 978-1-61761-519-1 (E-book)
Clinical Aspects of Psychopharmacology The Dance of Sleeping and Eating
in Childhood and Adolescence among Adolescents: Normal and
Donald E. Greydanus, Pathological Perspectives
Joseph L. Calles Jr., Dilip P. Patel, Yael Latzer and Orna Tzischinsky (Editors)
Ahsan Nazeer and Joav Merrick (Editors) 2011. ISBN: 978-1-61209-710-7 (Hardcover)
2011. ISBN: 978-1-61122-135-0 (Hardcover)
2011. ISBN: 978-1-61122-715-4 (E-book) Social and Cultural Psychiatry
Experience from the Caribbean Region
Climate Change and Rural Hari D. Maharajh and Joav Merrick
Child Health (Editors)
Erica Bell, Bastian M. Seidel 2011. ISBN: 978-1-61668-506-5 (Hardcover)
and Joav Merrick (Editors) 2011. ISBN: 978-1-61728-088-7 (E-book)
2011. ISBN: 978-1-61122-640-9 (Hardcover)
2011. ISBN: 978-1-61209-014-6 (E-book) Human Development: Biology
from a Holistic Point of View
Rural Medical Education: Søren Ventegodt, Tyge Dahl Hermansen and
Practical Strategies Joav Merrick (Editors)
Erica Bell, Craig Zimitat 2011. ISBN: 978-1-61470-441-6 (Hardcover)
and Joav Merrick (Editors)
2011. ISBN: 978-1-61122-649-2 (Hardcover) Drug Abuse in Hong Kong:
Development and Evaluation of a
Advances in Environmental Prevention Program
Health Effects of Toxigenic Daniel TL Shek, Rachel CF Sun
Mold and Mycotoxins and Joav Merrick (Editors)
Ebere Cyril Anyanwu 2011. ISBN: 978-1-61324-491-3 (Hardcover)
2011. ISBN: 978-1-60741-953-2 (Hardcover)
Building Community Capacity:
Public Health Yearbook 2009 Minority and Immigrant Populations
Joav Merrick Rosemary M Caron
2011. ISBN: 978-1-61668-911-7 (Hardcover) and Joav Merrick (Editors)
2012. ISBN: 978-1-62081-022-4 (Hardcover)
Child Health and Human Development
Yearbook 2009 Building Community Capacity:
Joav Merrick Skills and Principles
2011. ISBN: 978-1-61668-912-4 Rosemary M Caron
(Hardcover) and Joav Merrick (Editors)
2012. ISBN: 978-1-61209-331-4 (Hardcover)
Alternative Medicine Yearbook 2009
Joav Merrick (Editor) Textbook on Evidence-Based Holistic
2011. ISBN: 978-1-61668-910-0 (Hardcover) Mind-Body Medicine: Basic Principles
of Healing in Traditional Hippocratic
Medicine
Søren Ventegodt and Joav Merrick
2012. ISBN: 978-1-62257-094-2 (Hardcover)
 Human Immunodeficiency Child Health and Human Development
Virus (HIV) Research: Yearbook 2010
Social Science Aspects Joav Merrick (Editor)
Hugh Klein and Joav Merrick (Editors) 2012. ISBN: 978-1-61209-789-3
2012. ISBN: 978-1-62081-293-8 (Hardcover)
Public Health Yearbook 2010
Adolescence and Chronic Illness. Joav Merrick (Editor)
A Public Health Concern 2012. ISBN: 978-1-61209-971-2 (Hardcover)
Hatim Omar, Donald E. Greydanus,
Dilip R. Patel The Astonishing Brain and Holistic
and Joav Merrick (Editors) Consciousness: Neuroscience and
2012. ISBN: 978-1-60876-628-4 (Hardcover) Vedanta Perspectives
2012. ISBN: 978-1-61761-482-8 (E-book) Vinod D. Deshmukh
2012. ISBN: 978-1-61324-295-7
Our Search for Meaning in Life: Quality (Hardcover)
of Life Philosophy
Soren Ventegodt and Joav Merrick Randomized Clinical Trials and
2012. ISBN: 978-1-61470-494-2 Placebo: Can You Trust the Drugs are
(Hardcover) Working and Safe?
Søren Ventegodt and Joav Merrick
Child and Adolescent Health Yearbook 2012. ISBN: 978-1-61470-067-8 (Hardcover)
2009
Joav Merrick Alternative Medicine Yearbook 2010
2012. ISBN: 978-1-61668-913-1 (Hardcover) Joav Merrick (Editor)
2012. ISBN: 978-1-62100-132-4 (Hardcover)
Applied Public Health: Examining AIDS and Tuberculosis:
Multifaceted Social or Ecological Public Health Aspects
Problems and Child Maltreatment Daniel Chemtob
John R. Lutzker and Joav Merrick (Editors)
and Joav Merrick (Editors) 2012. ISBN: 978-1-62081-382-9 (Hardcover)
2012. ISBN: 978-1-62081-356-0
(Hardcover) Public Health Yearbook 2011
Joav Merrick (Editor)
Translational Research 2012. ISBN: 978-1-62081-433-8 (Hardcover)
for Primary Healthcare
Erica Bell, Gert P. Westert Alternative Medicine Research
and Joav Merrick (Editors) Yearbook 2011
2012. ISBN: 978-1-61324-647-4 (Hardcover) Joav Merrick (Editor)
2012. ISBN: 978-1-62081-476-5 (Hardcover)
Child and Adolescent Health Yearbook
2010
Joav Merrick (Editor)
2012. ISBN: 978-1-61209-788-6 (Hardcover)
 Textbook on Evidence-Based Holistic Conceptualizing Behavior in Health and
Mind-Body Medicine: Research, Social Research:
Philosophy, Economy and Politics of A Practical Guide to Data Analysis
Traditional Hippocratic Medicine Said Shahtahmasebi and Damon Berridge
Søren Ventegodt and Joav Merrick 2013. ISBN: 978-1-60876-383-2
2012. ISBN: 978-1-62257-140-6 (Hardcover)
Adolescence and Sports
Textbook on Evidence-Based Holistic Dilip R. Patel, Donald E. Greydanus,
Mind-Body Medicine: Basic Philosophy Hatim Omar and Joav Merrick (Editors)
and Ethics of Traditional Hippocratic 2013. ISBN: 978-1-60876-702-1 (Hardcover)
Medicine 2013. ISBN: 978-1-61761-483-5 (E-book)
Søren Ventegodt and Joav Merrick
2012. ISBN: 978-1-62257-052-2 (Hardcover) Pediatric and Adolescent Sexuality and
Gynecology: Principles for the Primary
Textbook on Evidence-Based Care Clinician
Holistic Mind-Body Medicine: Holistic Hatim A. Omar, Donald E. Greydanus,
Practice of Traditional Hippocratic Artemis K. Tsitsika, Dilip R. Patel
Medicine and Joav Merrick (Editors)
Søren Ventegodt and Joav Merrick 2013. ISBN: 978-1-60876-735-9
2013. ISBN: 978-1-62257-105-5 (Hardcover)
Living on the Edge: The Mythical,
Textbook on Evidence-Based Spiritual, and Philosophical Roots of
Holistic Mind-Body Medicine: Healing Social Marginality
the Mind in Traditional Joseph Goodbread
Hippocratic Medicine 2013. ISBN: 978-1-61122-986-8
Søren Ventegodt and Joav Merrick (Softcover)
2013. ISBN: 978-1-62257-112-3 (Hardcover)
Health Risk Communication
Textbook on Evidence-Based Holistic Marijke Lemal and Joav Merrick (Editors)
Mind-Body Medicine: Sexology and 2013. ISBN: 978-1-62257-544-2 (Hardcover)
Traditional Hippocratic Medicine
Søren Ventegodt and Joav Merrick Bedouin Health:
2013. ISBN: 978-1-62257-130-7 (Hardcover) Perspectives from Israel
Joav Merrick, Alean Al-Krenami
Health and Happiness from and Salman Elbedour (Editors)
2013. ISBN: 978-1-62948-271-2 (Hardcover)
Meaningful Work: Research in
Quality of Working Life
Building Community Capacity: Case
Søren Ventegodt and Joav Merrick (Editors)
2013. ISBN: 978-1-60692-820-2 (Hardcover) Examples from Around the World
Rosemary M. Caron
and Joav Merrick (Editors)
2013. ISBN: 978-1-62417-175-8 (Hardcover)
 Managed Care in a Public Setting Pain Management Yearbook 2011
Richard Evan Steele Joav Merrick (Editor)
2013. ISBN: 978-1-62417-970-9 (Softcover) 2013. ISBN: 978-1-62808-970-7 (Hardcover)

Bullying: A Public Health Concern Food, Nutrition and Eating Behavior

Jorge C. Srabstein Joav Merrick and Sigal Israeli (Editor)
and Joav Merrick (Editors) 2013. ISBN: 978-1-62948-233-0 (Hardcover)
2013. ISBN: 978-1-62618-564-7 (Hardcover)
Pain Management Yearbook 2012
Health Promotion: Joav Merrick (Editor)
Community Singing as a 2013. ISBN: 978-1-62808-973-8 (Hardcover)
Vehicle to Promote Health
Jing Sun, Nicholas Buys Public Health Concern: Smoking,
and Joav Merrick (Editors) Alcohol and Substance Use
2013. ISBN: 978-1-62618-908-9 (Softcover) Joav Merrick and Ariel Tenenbaum (Editor)
2013. ISBN: 978-1-62948-424-2 (Hardcover)
Public Health Yearbook 2012
Joav Merrick (Editor) Mental Health from
2013. ISBN: 978-1-62808-078-0 (Hardcover) an International Perspective
Joav Merrick, Shoshana Aspler
Alternative Medicine Research and Mohammed Morad (Editor)
Yearbook 2012 2013. ISBN: 978-1-62948-519-5 (Hardcover)
Joav Merrick (Editor)
2013. ISBN: 978-1-62808-080-3 (Hardcover) Suicide from a Public
Health Perspective
Advanced Cancer: Managing Symptoms Said Shahtahmasebi
and Quality of Life and Joav Merrick (Editor)
Natalie Pulenzas, Breanne Lechner, Nemica 2014. ISBN: 978-1-62948-536-2 (Hardcover)
Thavarajah, Edward Chow,
and Joav Merrick (Editors) India: Health and
2013. ISBN: 978-1-62808-239-5 (Hardcover) Human Development Aspects
Joav Merrick (Editor)
Treatment and Recovery 2014. ISBN: 978-1-62948-784-7 (Hardcover)
of Eating Disorders
Daniel Stein and Yael Latzer (Editors) Alternative Medicine
2012. ISBN: 978-1-61470-259-7 (Hardcover) Research Yearbook 2013
2013. ISBN: 978-1-62808-248-7 (Softcover) Joav Merrick (Editor)
2014. ISBN: 978-1-63321-094-3 (Hardcover)
Health Promotion:
Strengthening Positive Public Health Yearbook 2013
Health and Preventing Disease Joav Merrick (Editor)
Jing Sun, Nicholas Buys 2014. ISBN: 978-1-63321-095-0 (Hardcover)
and Joav Merrick (Editors)
2013. ISBN: 978-1-62257-870-2 (Hardcover)
 Public Health: Improving Health Cancer: Bone Metastases, CNS
via Inter-Professional Collaborations Metastases and Pathological Fractures
Rosemary M. Caron and Joav Merrick Breanne Lechner, Ronald Chow, Natalie
(Editors) Pulenzas, Marko Popovic, Na Zhang,
2014. ISBN: 978-1-63321-569-6 (Hardcover) Xiaojing Zhang, Edward Chow, and Joav
Merrick (Editors)
Alternative Medicine 2016. ISBN: 978-1-63483-949-5 (Hardcover)
Research Yearbook 2014
Joav Merrick (Editor) Cancer: Spinal Cord, Lung, Breast,
2015. ISBN: 978-1-63482-161-2 (Hardcover) Cervical, Prostate, Head and Neck
Cancer
Pain Management Yearbook 2014 Breanne Lechner, Ronald Chow, Natalie
Joav Merrick (Editor) Pulenzas, Marko Popovic, Na Zhang,
2015. ISBN: 978-1-63482-164-3 (Hardcover) Xiaojing Zhang, Edward Chow, and Joav
Merrick (Editors)
Public Health Yearbook 2014 2016. ISBN: 978-1-63483-904-4 (Hardcover)
Joav Merrick (Editor)
2015. ISBN: 978-1-63482-165-0 (Hardcover) Cancer: Survival, Quality of
Life and Ethical Implications
Forensic Psychiatry: Breanne Lechner, Ronald Chow, Natalie
A Public Health Perspective Pulenzas, Marko Popovic, Na Zhang,
Leo Sher and Joav Merrick (Editor) Xiaojing Zhang, Edward Chow, and Joav
2015. ISBN: 978-1-63483-339-4 (Hardcover) Merrick (Editors)
2016. ISBN: 978-1-63483-905-1 (Hardcover)
Leadership and Service Learning
Education: Holistic Development Cancer: Pain and Symptom
for Chinese University Students Management
Daniel TL Shek, Florence KY Wu Breanne Lechner, Ronald Chow, Natalie
and Joav Merrick (Editors) Pulenzas, Marko Popovic, Na Zhang,
2015. ISBN: 978-1-63483-340-0 (Hardcover) Xiaojing Zhang, Edward Chow, and Joav
Merrick (Editors)
Mental and Holistic Health: Some 2016. ISBN: 978-1-63483-864-1 (Hardcover)
International Perspectives
Joseph L. Calles Jr., Donald E Greydanus, Alternative Medicine Research
and Joav Merrick Yearbook 2015
2015. ISBN: 978-1-63483-589-3 (Hardcover) Joav Merrick (Editor)
2016. ISBN: 978-1-63484-511-3 (Hardcover)
Cancer: Treatment, Decision Making
and Quality of Life Public Health Yearbook 2015
Breanne Lechner, Ronald Chow, Natalie Joav Merrick (Editor)
Pulenzas, Marko Popovic, Na Zhang, 2016. ISBN: 978-1-63484-514-4 (Hardcover)
Xiaojing Zhang, Edward Chow, and Joav
Merrick (Editors)
2016. ISBN: 978-1-63483-863-4 (Hardcover)
 Quality, Mobility and Globalization in
the Higher Education System: A
Comparative Look at the Challenges of
Academic Teaching
Nitza Davidovitch, Zehavit Gross,
Yuri Ribakov, and Anna Slobodianiuk
(Editors)
2016. ISBN: 978-1-63484-986-9 (Hardcover)

Cannabis: Medical Aspects

Blair Henry, Arnav Agarwal, Edward Chow,
Hatim A. Omar, and Joav Merrick (Editors)
2016. ISBN: 978-1-53610-510-0 (Hardcover)
HEALTH AND HUMAN DEVELOPMENT

CANNABIS
MEDICAL ASPECTS

BLAIR HENRY
ARNAV AGARWAL
EDWARD CHOW
HATIM A. OMAR
AND
JOAV MERRICK
EDITORS

New York
Copyright © 2017 by Nova Science Publishers, Inc.

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 CONTENTS

Foreword xvii
Blair Henry, Arnav Agarwal, Edward Chow,
Hatim A Omar and Joav Merrick
Section one: Introduction 1
Chapter 1 Plants as medical tools 3
Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski,
Paul Kerrigan, Phineas Samuel and Jeremy Friedberg
Chapter 2 History of medical cannabis 17
Andrew Hand, Alexia Blake, Paul Kerrigan,
Phineas Samuel and Jeremy Friedberg
Chapter 3 Cannabis or marijuana 27
Donald E Greydanus and Joav Merrick
Section two: Plant pharmacology 63
Chapter 4 Pharmacology of cannabis 65
Mandakini Sadhir
Chapter 5 The pharmacological properties of cannabis 71
Istok Nahtigal, Alexia Blake, Andrew Hand,
Angelique Florentinus-Mefailoski, Haleh Hashemi Sohi
and Jeremy Friedberg
Section three: Clinical applications 83
Chapter 6 Medical cannabis use in an outpatient palliative care clinic 85
Noah Spencer, Erynn Shaw and Marissa Slaven
Chapter 7 Four patient perspectives on medical cannabis 95
Jeremy Friedberg
xiv Contents

Chapter 8 Safety concerning medical cannabis 99

Bonnie Cheung and Hance Clarke
Chapter 9 Medical cannabis in the treatment of chemotherapy-
induced nausea and vomiting 105
Jordan Stinson and Carlo DeAngelis
Chapter 10 Medical marijuana, cancer anorexia and cachexia 113
Meiko Peng, Minhaz Khaiser, Michael Lam, Soha Ahrari,
Mark Pasetka and Carlo DeAngelis
Chapter 11 Medical cannabis dosing strategies in pain related conditions 129
Minhaz Khaiser, Meiko Peng, Michael Lam, Soha Ahrari,
Mark Pasetka and Carlo DeAngelis
Chapter 12 How to administrate cannabis and efficacy 147
Stephanie Stockburger
Chapter 13 Cannabis and pain 155
Jonathan K Hwang and Hance Clarke
Chapter 14 Medical cannabis for pain in adolescence 179
Barry Knishkowy
Section four: Policy, ethics and social commentary 187
Chapter 15 Medical cannabis from the pain physician’s perspective 189
Ainsley M Sutherland, Judith Nicholls and Hance Clarke
Chapter 16 Ethical and policy implications concerning medical cannabis 199
Sally Bean and Maxwell J Smith
Chapter 17 Adverse effects of cannabis use 207
Amy L Burnett
Chapter 18 Cannabis and the role of our schools 211
Venus Wong and Alissa Briggs
Chapter 19 Canada and medical marijuana 221
Blair Henry, Rachel McDonald, Stephanie Chan,
Edward Chow and Leigha Rowbottom
Chapter 20 Medical cannabis and palliative care 227
Noah Spencer, Erynn Shaw and Marissa Slaven
Section five: Acknowledgments 233
Chapter 21 About the editors 235
Chapter 22 About the Rapid Response Radiotherapy Program at the
Odette Cancer Centre, Sunnybrook Health Sciences Centre,
Toronto, Canada 237
 Contents xv

Chapter 23 About the National Institute of Child Health

and Human Development in Israel 239
Chapter 24 About the book series “Health and human development” 243
Section six: Index 247
Index 249
 FOREWORD

MEDICAL CANNABIS: TO USE OR NOT TO USE?

Blair Henry, D(Bioethics)1,, Arnav Agarwal, MD(C)1, Edward

Chow, MBBS1, Hatim A Omar, MD, FAAP2 and Joav Merrick, MD,
MMedSc, DMSc2-6
Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada,
1
2
Division of Adolescent Medicine and Young Parents Program, Kentucky Children’s
Hospital, UK Healthcare, Department of Pediatrics, University of Kentucky College of
Medicine, Lexington, Kentucky, United States of America,
3
National Institute of Child Health and Human Development, Jerusalem,
4
Office of the Medical Director, Health Services, Division for Intellectual and
Developmental Disabilities, Ministry of Social Affairs and Social Services, Jerusalem,
5
Division of Pediatrics, Hadassah Hebrew University Medical Center, Mt Scopus
Campus, Jerusalem, Israel and 6Center for Healthy Development, School of Public
Health, Georgia State University, Atlanta, US

INTRODUCTION
Cannabis has a long history of medicinal use, dating back thousands of years (1). However,
with the discovery of morphine, hypodermic needles and other fast acting synthetic opioids in
the ninetieth and the turn of the twentieth century- cannabis use declined as a medication (2).
For most of the past six decades, cannabis has been considered a recreational drug, and was
considered illegal in many jurisdictions. Yet in the past few years its association with medicine
has made a dramatic comeback. As illustrated in figure 1, over the past six years (2010-2016)
the terms “medical cannabis” and “medical marijuana” has seen a 4 to 5 fold increase in
references based on a historical trend analysis of the terms noted in the PubMed database. It


Correspondence: Mr Blair Henry, Senior Ethicist, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue,
Toronto, ON Canada. E-mail: Blair.Henry@sunnybrook.ca.
xviii Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al.

would appear that the term medical cannabis is most often used over medical marijuana, in the
emerging literature.

700

600

500
Frequency of citations

400

Term Medical Cannabis

300
Term Medical Marijuana

200

100

0
1960 1980 2000 2020
Year of Pulication Search

Figure 1. Number of article titles using the terms: medical cannabis and medical marijuana in PubMed

In the past several years, claims on the potential for cannabis to treat, cure and prevent a
number of diseases and conditions has led some to query whether these claims are overstated.
A game changer for medical cannabis has been the ability to consume it without a need to
actually inhale it along with other negative products of combustion. Newer technologies that
allow for the vaporization of the full plant has made it less of a health concern (3).
Noticeably the evidence on medical cannabis is lacking in both quality and quantity. To
date most of the research has been conducted in Israel, however, with cannabis set to be
legalized for use in Canada (4) and in a recent move in the United States, by the Obama
administration (5), to remove barriers should allow researchers greater access to medical
cannabis for testing in well-designed clinical trials.
In Canada, the federal marijuana regulations were updated in the summer of 2016 with the
introduction of the Access to Cannabis for Medical Purposes Regulations (ACMPR).
The aim of this newly update regulation (ACMPR) is to treat marijuana like other psychoactive
drugs used for medical purposes. Many of the Colleges (eight provincial) in Canada prohibit or
at best strongly discourage its members from dispensing, providing or accepting delivery of
marijuana for medical purposes (6). Of major concern for most Colleges has been a lack of
good evidence on both medical risks and therapeutic benefits of marijuana- intimating that
 Foreword xix

physicians’ currently prescribing cannabis may be falling short of a fulsome informed consent
process.
The typical recommendation for Canadian physicians is that medical cannabis should not
be a first line therapy and that documentation should outline that conventional therapies were
attempted but were not successful (6). The legal defense organization for physicians practicing
in Canada- the Canadian Medical Protective Association (CMPA), updated its guidance
document following the passing of ACMPR regulations- a cursory read through this document
quickly identifies a less than positive endorsement for physicians, highlighting mainly potential
risks and limitations to physicians potentially interested in adding medical cannabis to their
treatment recommendations.
As the medical community has been slow to start- noticeable in the grey literature is the
proliferation of website by patient and advocacy groups making claims that cannabis has the
potential to treat ailments and symptoms ranging from AIDS related illness, Asperger’s,
Bulimia, carpal tunnel syndrome to whiplash- making the differentiation between the
miraculous and mere hype all the more challenging to identify (7-9).

REFERENCES
[1] Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical
cannabis. Pharmacotherapy 2013;33(2):195–209.
[2] Kritikos PG, Papadaki SP. The history of the poppy and of opium and their expansion in antiquity in the
eastern Mediterranean area, 1967. URL: https://www.unodc.org/unodc/en/data-and-analysis/bulletin/
bulletin_1967-01-01_3_page004.html
[3] Grant I, Atkinson JH, Gouaux B, Wilsey B. Medical marijuana: Clearing away the smoke. Open Neurol
J 2012;6(1):18–25.
[4] Philpott J. Plenary statement for the Honourable Jane Philpott, Minister of Health - UNGASS on the
World Drug Problem. United Nations General Assembly Special Session on the World Drug Problem.
URL: http://news.gc.ca/web/article-en.do?nid=1054489
[5] Saint Louis C, Apuzzo M. Obama administration set to remove barrier to marijuana research. New York
Times 2016 Aug 16 August.
[6] Canadian Medical Protective Association. Medical marijuana: Considerations for Canadian
doctors, 2014. URL: https://www.cmpa-acpm.ca/en/legal-and-regulatory-proceedings/-/asset_publisher/
a9unChEc2NP9/content/medical-marijuana-new-regulations-new-college-guidance-for-canadian-
doctors
[7] United Patient’s Group. Illnessess treatable with medical cannabis, 2016. URL: https://
unitedpatientsgroup.com/
[8] Walia AQ. Twenty medical studies that show cannabis can be a potential cure for cancer, 2013. URL:
http://www.collective-evolution.com/2013/08/23/20-medical-studies-that-prove-cannabis-can-cure-
cancer/
[9] Harding A. Medical marijuana, 2013. URL: http://www.webmd.com/pain-management/features/medical-
marijuana-uses
SECTION ONE: INTRODUCTION
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 1

PLANTS AS MEDICAL TOOLS

Haleh Hashemi, PhD, Andrew Hand, MSc,

Angelique Florentinus-Mefailoski, MSc,
Paul Kerrigan, BSc, Phineas Samuel, BSc
and Jeremy Friedberg*, PhD
MedReleaf Corp, Markham Industrial Park, Markham, Ontario, Canada

Cannabis has been used for centuries for its fiber, food and as medicine. This review
highlights the history of cannabis, its uses as a medical tool and the active ingredients found
in this versatile plant. Many pain management pharmaceuticals widely accepted and used
today, such as opioids and aspirin, contain plant derived extracts. The evolving cannabis
story is paralleled to the history of current plant extracts used as pharmaceuticals. Usage,
side effects and mortality rates of current pain medications are compared to cannabis and
reveal great potential for cannabis as a safe and effective alternative in pain management.

INTRODUCTION
One of the primary sources of difficulty for doctors to explore the use of cannabis as a medical
tool stems from the idea that they are prescribing a “plant” and not an individual compound.
Although this plant contains a predominant family of active ingredients, the cannabinoids, it is
still a mixture of all the components in the plant tissue or plant extract. To compound this
apprehension, this particular plant has had long and sorted cultural and social-political history
in western civilization that is slowly, yet with difficulty, on the path to a resolution. However,
in the annals of western medicine, the story of this plant’s journey is not new or unique and
there is much to learn from the journey other plants have gone through from obscurity to
common use. The purpose of this chapter is to chronicle two historical plant’s journeys in
modern medicine and what comparisons and differences can be drawn to the story of cannabis.

*
Correspondence: Jeremy Friedberg, PhD, MedReleaf Corp, Markham Industrial Park, POBox 3040, Markham,
Ontario, L3R 6C4, Canada. E-mail: jfriedberg@medreleaf.com.
4 Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al.

CURRENT PLANT EXTRACTS USED AS PHARMACEUTICALS

AND USED IN PHARMACEUTICAL PRODUCTION

Secondary metabolites, also referred to as natural products (NP), are organic compounds that
are not directly involved in the natural growth, development, or reproduction of an organism,
and typically result from the activities of biosynthetic pathways. The vast biodiversity of earth’s
flora and fauna have been a tremendous and variable source of useful and medically relevant
compounds and in many cases compounds that cannot be synthesized in vitro (1). The
mechanism by which an organism synthesizes secondary metabolites is often found to be
unique to each organism or it is an expression of the individuality of a species. They are
produced for different reasons from a result of the organism’s adapting to its external
environment, to acting as a possible defense mechanism against predators, or simply in assisting
in the survival of the organism (2, 3).

Medicinal plants

Plants and their extracts have been used as medicinal compounds for thousands of years. Their
unique properties are the result of their evolution. This has resulted in the production of unique
and structurally diverse secondary metabolites. These unique pharmacological properties and
their application by different cultures and regions made them great candidates for new drug
discovery research (4). According to the World Health Organization (WHO), 80% of people
still rely on traditional plant-based medicine for primary health care and 80% of plant derived
drugs were related to their historical application(5). In recent years, advancements in molecular
biology in association with traditional medicine has promoted further investigations and
yielded new drug candidates for the pharmaceutical market (6).

HISTORY OF PLANT EXTRACTS USED AS PHARMACEUTICALS

The oldest records for the usage of medicinal plants dates back to 2400 BCE on clay tablets
(Mesopotamia). The Greek physician Dioscorides (100 AD), recorded the collection, storage
and the uses of medicinal herbs, whilst the Greek philosopher and natural scientist,
Theophrastus (~300 BCE) collected similar information in a series of books available to this
day. The monasteries in England, Ireland, France and Germany preserved this Western
knowledge whilst scholars in the Middle East preserved the Greco-Roman knowledge and
expanded the uses of their own resources, together with Chinese and Indian herbs unfamiliar to
the Greco-Roman world during the Dark and Middle Ages. In the Middle East, Avicenna, a
Persian pharmacist, physician and philosopher contributed much to the sciences of pharmacy
and medicine through works such as the Canon Medicine book, which directly aided people in
the middle east to establish privately owned pharmacies as early as the 8th century (7).
 Plants as medical tools 5

CURRENT STATUS OF NATURAL PRODUCTS (NP) INCLUDING

MEDICINAL PLANT EXTRACTS

In 2014, the global market for plant-derived drugs was valued at $23.2 billion. It is expected
that this market will reach $35.4 billion by 2020, representing a significant share of the
global pharmaceutical market (8). This increase is a result of (1) the interest expressed by
pharmaceutical companies in new and lower price drugs especially for psychosomatic,
metabolic, and minor disorders and (2) the tendency of people to use modern traditional
medicine. Traditional medicine has been widely used in different types of medication, dietary
products and nutritional supplements since ancient times. Many of them currently are registered
pharmaceuticals through regulatory offices such as the Food and Drug Agency (FDA) once
they surpass clinical trials and demonstrate efficacy and safety (6, 8, 9). To date, 60,000 species
of plants have been screened to yield the 135 known drugs. Considering the number of
unscreened plant species, (approximately >300,000) there is a potential to find 540–653 new
drug candidates in the years to come (10).

Table 1. Plant-derived natural products approved for therapeutic use

in the last thirty years (1984–2014)

Generic name Scientific name Trade name Indication (mechanism of

(year of action)
introduction)
Artemisinin Artemisia annua Artemisinin Malaria Treatment (radical
L. (1987) formation)

Arglabin Artemisia Arglabin Cancer Chemotherapy

glabella (1999) (farnesyl transferase
inhibition)

Capsaicin Capsicum Qutenza (2010) Post therapeutic

Annum L., neuralgia(TRPV1activator)

Colchicine Colichicum SPP Colcrys (2009) Gout (tubulin binding)

6 Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al.

Table 1. (Continued)

Generic name Scientific name Trade name Indication (mechanism of

(year of action)
introduction)
Delta -9- Cannabis Sativa Sativex a Chronic neuropathic pain
Tetrahydrocannbinol L, (2005) (CB1 and CB 2Receptor
(THC) activation)

Cannabidiol (CBD)

Galanthiamine Galanthus Razadyne Dementia associated with

Caucasicus (2001) Alzheimer’s disease (ligand
of human Nicotinic acetyl
choline receptors (nAChRs)

Ingenol mebutate Euphorbia Picato (2012) Actinic keratosis (inducer of

peplus L. cell death)

Masoprocol Larrea Actinex (1992) Cancer chemotherapy

tridentata (lipoxygenase inhibitor)

Omacetaxine Cephalotaxus Synribo (2012) Oncology (protein

mepesuccinate harringtonia translation inhibitor)
(Homoharringtonine)
 Plants as medical tools 7

Generic name Scientific name Trade name Indication (mechanism of

(year of action)
introduction)
Paclitaxel Taxus brevifolia Taxol (1993), Cancer chemotherapy
Nutt. Abraxanec b (mitotic
(2005), inhibitor)
Nanoxelc
(2007)

Solamargine Solanum spp Curadermd Cancer chemotherapy

(1989) (apoptosis triggering)

Resources: (Ref 53), www.clinicaltrials.gov, and www.drugs.com.

a
Mixture of the two compounds
b
Paclitaxel nanoparticles.
c
Containing not just solamargine but also other solasodine glycosides

PLANT EXTRACTS WIDELY USED IN PHARMACEUTICAL PRODUCTION

The plant extracts utilized as pharmaceutics vary greatly from country to country. Due to the
rapid development in the understanding of plant chemistry, and the advancing ability to isolate
and purify natural compounds, there are now a diversity of plant extracts on the market, either
synthetic or directly derived from plants. Morphine, purified from opium by Serturner (1806),
was the first alkaloid with high biological efficacy. This event was subsequently followed by
the isolation of many other alkaloids including strychinine from Strychnos mux-vomica, and
quinine from Cinchona spp. The most widely used breast cancer drug is paclitaxel (Taxol®),
was isolated from the bark of Taxus brevifolia (Pacific Yew). It is now produced synthetically
and is one of the main tools to treat breast cancer.
Cannabis (Cannabis sativa) was traditionally used to alleviate severe headaches, a
treatment for degenerative bone and joint diseases, ophthalmitis, general edema,
infectious wounds, gout, and pelvic pain. Sativex, a titrated extract containing delta-9-
tetrahydrocannabinol (psychoactive) and cannabidiol (anti-inflammatory), has been approved
in a few countries (e.g., Canada, The United Kingdom, Germany and New Zealand) since 2005.
This botanical prescription drug is an oromucosal spray containing cannabinoid medicine for
the treatment of spasticity due to multiple sclerosis and neuropathic pain of various origins.
Marinol (dronabinol) and Cesamet (nabilone) are available in North-America for the treatment
of vomiting and nausea associated with the use of chemotherapy to treat cancer (11).
Several FDA approved botanicals currently are available in the global market like Veregen
(Tea catechins) for the treatment of external genital and perianal warts (12) and Fulyzaq (extract
from the red sap of Croton lechleri) for the treatment of diarrhea in HIV patients. In 2012 the
Dutch Medicines Evaluation Board approved a dry extract of Dioscorea nipponica, a traditional
Chinese botanical to relief headache, muscle pain and cramps (12). This was the first time that
a Traditional Chinese Medicine (TCM) product was introduced into a European Union country.
The list of plant species, which are processed in a relatively large scale, and their respective
8 Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al.

bioactive agents has been shown in table 1. A list of plant-derived products that has been used
in clinical tials are shown in table 2.

Table 2. Plant derived natural products in clinical trialsa

Generic name and chemical Number of recruiting clinical trialsb:

structure indications (potential mechanism of
action)
Haplophragma 1 trial: Solid tumors (E2F1 pathway
adenophyllum activator)

Curcumin Curcuma longa L. 26 trials: Cognitive impairment, different

(Turmeric) types of cancer, familial adenomatous
polyposis, schizophrenia, cognition,
psychosis, prostate cancer, radiation
therapy, acute kidney injury, abdominal
aortic aneurysm, inflammation, vascular
aging, bipolar disorder, irritable bowel
syndrome, neuropathic pain, depression,
somatic neuropathy, autonomic
dysfunction, Alzheimer's disease, plaque
psoriasis, fibromyalgia, cardiovascular
disease (NF-κB inhibition)
Epigallocatechin-3-O-gallate Camellia sinensis 14 trials: Epstein-Barr virus reactivation
(L.) in remission patients with nasopharyngeal
carcinoma, multiple system atrophy,
Alzheimer's disease, cardiac amyloid
light-chain amyloidosis, Duchenne
muscular dystrophy, cystic fibrosis,
diabetic nephropathy, hypertension,
fragile X syndrome, different types of
cancer, obesity, influenza infection (cell
growth arrest and apoptosis induction
Genistein Genista tinctoria 5 trials: Colon cancer, rectal cancer,
L. colorectal cancer, Alzheimer's disease,
non-small cell lung cancer,
adenocarcinoma, osteopenia, osteoporosis
(protein-tyrosine kinase inhibitor,
antioxidant)
 Plants as medical tools 9

Generic name and chemical Number of recruiting clinical trialsb:

structure indications (potential mechanism of
action)
Gossypol Gossypium 2 trials: B-cell chronic lymphocytic
hirsutum L. leukemia, refractory chronic
lymphocytic leukemia, stage III
chronic lymphocytic leukemia, stage
IV chronic lymphocytic leukemia, non-
small cell lung cancer (Bcl-2 inhibitor)
Picropodophyllotoxin Podophyllum 1 trial: Glioblastoma, glio sarcoma,
hexandrum anaplastic astrocytoma,
Royle, replaced anaplastic oligo dendroglioma,
by anaplastic oligo L.astrocytoma,
Sinopodophyllum anaplastic ependymoma (tubulin
hexandrum binding/IGF-1R Inhibitor)

Quercetin Allium cepa L. 9 trials: Chronic obstructive pulmonary

disease, Fanconi anemia, different
types of prostate cancer, diabetes
mellitus, obesity diastolic heart failure,
hypertensive heart disease, heart failure
with preserved ejection fraction,
hypertension, oxidative stress,
Alzheimer's disease, pancreatic ductal
adenocarcinoma, plaque
psoriasis (NF-κB inhibition)
Resveratrol Vitis vinifera L. 22 trials: Pre-diabetes, vascular system
injuries, lipid metabolism disorders
(including non-alcoholic fatty liver
disease), endothelial dysfunction,
gestational diabetes, cardiovascular
disease, type 2 diabetes mellitus,
inflammation, insulin resistance,
disorders of bone density and structure,
metabolic syndrome, coronary artery
disease, obesity, memory impairment,
mild cognitive impairment, diastolic
heart failure, hypertensive heart
disease, heart failure with preserved
ejection fraction, hypertension,
oxidative stress, polycystic ovary
syndrome, Alzheimer's disease (NF-κB
inhibition)
a
Resources: (Ref 53), www.clinicaltrials.gov, and www.drugs.com.
b
Determined from www.clinicaltrials.gov on 22nd of October, 2014, including trials in which the
respective natural product is applied alone or as a mixture with other constituents, excluding studies
with unknown status.
10 Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al.

THE OPIOIDS STORY

Opiates have had a similar, long standing role to Cannabis in both management of disease and
recreational use. The Greek word for juice “opos”was chosen due to the latex liquid that seeps
from cuts in immature seed capsule. Modern usage of the word applies to all alkaloid and
peptide compounds that can bind to opioid receptors (15). It is widely accepted that opium
poppies were first cultivated in lower Mesopotamia, with the Sumerians referring to it as “hul
gil,” which translates to “joy plant” (16). In the same geographical region, civilizations such as
the Babylonians, Assyrians and Egyptians all have documented use of the plant for both pain
management and ritualistic use (17). The Ebers Papyrus, an Egyptian medical document from
ca. 1500 BCE also was mentioned about use of opium soaked sponges to manage pain during
surgery, and for the prevention of excessive crying from children. From there, opium spread
through the eastern world, with documented evidence of opium use by Greek culture in the
third century BCE, and both India and China in the eighth century AD (18). With the
introduction of opium came addiction and abuse, particularly in China during the seventeenth
century after the banning of tobacco smoking led to an increased rate in the smoking of opium.
Pharmacist Friedrich Sertürner first isolated morphine from opium poppies in 1806, the
name being derived from Morpheus, the Greek GOD of dreams (19). Morphine saw regular use
in the nineteenth century for pain, as well as other ailments such as respiratory problems and
anxiety (20). With the invention of the hypodermic needle in 1853, use of morphine for minor
surgical procedures, management of chronic pain and as an anesthesia during operations
increased (16, 20). During the American Civil War, many soldiers were given morphine for
injuries sustained during battle, and thus many suffered from opiate addiction after the war
ended (21). To help combat morphine addiction, heroin was synthesized in 1898 as a more
effective, less addictive and generally safer alternative. Saint James Society even provided free
heroin through the mail to morphine addicts in an attempt to curb their usage. Between 1898
and 1910 Bayer marketed heroin as an analgesic and cough suppressant, before discovering
that the drug did indeed induce considerable dependence in the user, and was very hazardous
(22).
All opioids act by interacting with opioid receptors, which are distributed throughout both
the central and peripheral nervous systems, as well as some other organs such as the heart, liver
and kidney (23). Multiple opioid receptors classifications exist- μ, κ, σ, nociception receptor,
each with similar but different tissue location and function (24). Opioid receptors located on
sensor nerves in the peripheral nervous system regulate analgesia and inflammation, the later
due to cytokines produced during inflammation inducing the release of endogenous compounds
that interact with opioid receptors. Similar to the endocannabinoids endogenously produced by
the human body, endo-opioids such as endorphins and enkephalins interact with the same
opioid receptors as plant derived opioids (25).

THE ASPIRIN STORY

Humans have benefitted from the use of plant derived salicylates for millennia.
Recommendations for treatment are described among the Ebers papyrus in Egypt (1500-3000
BCE) and also in Greece (500 BC) by the physicians Hippocrates and Galen (26). Patients
 Plants as medical tools 11

would be treated with a preparation including the leaves or bark of the willow tree, Salix alba,
which alleviated inflammation, fever, and pain.
To test historical observations, scientific validation is needed to confirm true relationships.
In 1763, the first scientific description of Salix alba as a treatment for malarial fever in 50
patients is performed by Reverend Edward Stone (27). At the end of his account, Stone states
his hopes; “that it (Salix alba bark powder) may have a fair and full trial in all its variety of
circumstances and situations, and that the world may reap the benefits accruing from it” (27).
Advances in organic chemistry in the 1820s allowed for the isolation of Salicin from
willow bark (28). Salicin is used successfully to treat rheumatic fever, notably by TJ Maclagan
and Sir William Osler until the end of the 19th century (29).
In 1838, salicylic acid was derived from Salicin. Pharmaceutical chemists began to
investigate the useful derivatives of salicylic acid which reduced such side effects as
gastrointestinal irritation, resulting in over a dozen such compounds being synthesized by 1908
(26). In 1897, acetylsalicylic acid is synthesized in pure form and by 1899 is being sold
worldwide as Aspirin by Bayer. Current worldwide production of acetylsalicylic acid is
estimated to be 40,000 tons a year, and the number of clinical trials involving the drug is
estimated to be 700-1000 annually (30). Certainly, the powdered bark of Salix alba has had its
advantages and many people continue to reap benefit from its acetylated and pure cousin,
acetylsalicylic acid.

THE EVOLVING CANNABIS STORY

In the Western world cannabis was used only as a fiber source until the mid-1800s. However,
once introduced for its pharmacological benefits, it quickly played an important role in
medicine as early as the 20th century (31). Early in its introduction, cannabis was included in
numerous over the counter and prescription drugs and referenced in many medical texts (32).
However, in the mid-20th century, the use cannabis underwent a major cultural shift going from
a medication to the status of being an illicit drug and its therapeutic applications were soon
deterred by as a result of changes in the law (33).
As a medication, cannabis had many strengths and potential applications, however, one of
the main reasons of its initial decline was the growing use of alternative analgesics (33).
Initially the decline in cannabis medicinal uses were practical: It was insoluble in water making
it incompatible with hypodermic needles, and it’s delayed onset of at least an hour when
consumed, posed a challenge for new quick acting analgesics (32). Another significant practical
dilemma involved the sizable variation in effects both between different batches of cannabis
and from person to person leading to inconsistent results. Ultimately, physicians found it
difficult to work around these issues and analgesics such as aspirin, heroin and chloral hydrate,
which were easily administered, fast acting and consistent, began to phase out cannabis (33).
Though there where legitimate reasons for physicians to move towards other analgesics,
cannabis had major advantages that were lost as a result: the reduced risks of developing
physical dependence associated with cannabis, its low toxicity and that is had little to no
disturbance in vegetative functions (32). These advantages over other analgesics warrant efforts
to solve the practical obstacles to the medical uses of cannabis in modern day approaches. The
main issue of inconsistency with Cannabis can be addressed far more effectively in modern day
12 Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al.

medicine than it could have been in the past. The main method used to determine the strength
of a dose during the late 1800s was to administer cannabis to animals and observe the reaction
(33). Today, laboratory analysis can be far more precise in measurement, using modern
chemical analysis techniques to determine the exact chemical composition of the plant. By
providing this information to physicians it is now possible for them to gauge the dose they are
prescribing the patient (34). Another cause of inconsistency was that cannabis was most likely
obtained from many sources growing different plants (32). Even if the source was the same,
each plant would have a different potency due to genetic variation between seeds and as a
results, acquiring a supply of cannabis that was consistent in composition was nearly impossible
(35). Today this issue can be addressed through the application of clonal propagation and
growing many daughter plants using prunings from a single mother plant. The advantage of
this method is that all daughter plants will be genetically identical and so patients can continue
to have access to consistent and identical medication (36).
In light of these developments and based off growing evidence of the medical application
of Cannabis, the perception of cannabis is once again changing. We are seeing a general trend
towards cannabis once again becoming a part of western medicine as evidenced by its legal
status for medicinal use in Canada (37). Use of Cannabis as a medicine should be re-evaluated
using modern approaches of science and medicine to determine its true value as a therapeutic
agent.

COMPARISON OF CURRENT PAIN MEDICATIONS

The use of prescription pain medications such as opioids, corticosteroids and anticonvulsants
has dramatically increased over the past decades. These prescription pain medications provide
effective pain management but often come with risk of abuse, physical dependence, addiction
and other serious side effects and are routinely used in combination with other medications (38-
44) (see table 3).
Opioids, including morphine, codeine and oxycodone, are the most commonly used
prescribed medication to treat acute or chronic moderate to severe pain. Opioids are used to
control pain in cancer, neuropathy, fibromyalgia and other sources of pain. Patients taking
prescription opioids need to be observed closely to monitor pain management and the physical
reaction to the medication prescribed. Long term use brings adverse effects such as tolerance,
risk of overdose, dependence and addiction and even death. Other side effects with short or
long time use include brain damage, heart disease, liver disease, breathing problems and
psychiatric effects (45).
 Table 3. Comparison of current pain medications

Medication Utility Common drugs Target Physical dependance Side effects Mortality rate

Cannabis Cancer, HIV Cannabis Sativa Endocannabinoid receptor Rare Cognitive and memory impairment Not reported
Neurological disorders Increased heart rate, fluctuation in blood pressure. Rare: Stroke, heart infarct
Immunity Anxiety, panic, depression
Mood and behaviour Suppressed immune system, growth disorders, apathy, mood/personality changes, hormonal changes
Appetite and metabolism

Opioids Pain (dental, injury, surgery) Morphine Opioid receptor Yes Addiction, brain damage, death <28,000 (9 per 100,000 persons) in USA in 2014 [8]
Cough, serious diarrhea Codeine Weakened immune systetm, hallucinations, coma, breathing problems
Neuropathy Oxycodone Sedation, anxiety, hormonal inbalance
Sickle cell disease Tramadol
Headache, migrane Fentanyl
Fybromyalgia Methadone
Anxiety Hydromorphone
Cancer

Corticosteroids Cancer Dexamethasone Steroid hormone receptor Yes Liver disease, infertility, heart attack, high blood pressure, cancer, depression, psychiatric effects, damage to gonads Prednisone: 666 of 5626 RA patients in USA over 25 years [4]
Arthritis Cortisone Insomnia, muscle weakness, suppress immune system
Hydrocortisone Glaucoma, osteoporosis
Prednisone

Anti-convulsant Seizures Carbamazepine GABA receptor Yes Dizziness, suicidal thoughts/actions, depression Carbamazepine: 16 per 100,000 cases per year [7]
Neuropathy Ethosuximide PPAR receptor Liver problems, kidney disease, drug interactions, fatigue, drowsiness, nausea, rash, tremor, weight gain Gabapentin: 14 of 725 cases in France 1995-2009 [6]
Personality disorders Gabapentin Heart disease, depression, confusion, anxiety, constipation, mania
Mood
Brain disorders (bipolar, mania, depression)
Fybromyalgia
Insomnia
14 Haleh Hashemi, Andrew Hand, Angelique Florentinus-Mefailoski et al.

In the United States, 47,000 people died of drug overdose in 2014 and 61% of deaths
associated with drug overdose involved prescription opioids of which oxycodone and
hydrocodone being the most frequently prescribed (45-47). Every year, the number of people
dying from drug poisoning increases exponentially. There is a large demand for an effective
and more safe alternative for relief pain.
Cannabis has been used for centuries to treat pain, neurological disorders, immunity,
metabolism, mood and behavioural disorders (see table 3) (48, 49). Side effects of Cannabis
use are often mild and reversible with low acute toxicity and no recorded deaths by the Centers
for Disease Control and Prevention (50). Common side effects of cannabis use include euphoria
and temporary cognitive and memory impairment. Hypotension might cause a risk for patients
with cardiovascular diseases (51). In recent studies, data was obtained from patients using
medical cannabis and/or prescription pain medication (PPM) for pain management. Patients
using PPM found medical cannabis to be more efficient in controlling pain than PPM. Patients
on PPM used medical cannabis to significantly reduce opioid intake and improved their quality
of life (52). Overall, cannabis offers a low risk profile and effective alternative in pain
management.

CONCLUSION
The medical cultural apprehension surrounding utility of Cannabis in clinical practice is
understandable. In comparison, the parallels to the stories of plant extracts becoming
pharmaceuticals, and the benefits and associated risks, explains the state of cannabis acceptance
today. Many of these stories have evolved without controversy, while others have been fraught
with social and cultural challenges as well as significant health risks. However, in the case of
cannabis and in comparison to the story of opioids, history is showing us a reasonable and
feasible path forward. The difference, however, in the cannabis story is that the final clinical
utility resides in the plant itself and not just a single compound. Cannabis will continue to be a
viable and beneficial clinical tool, but with ongoing education and research, there is great
potential for further discoveries to the application of cannabis in medicine.

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In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 2

HISTORY OF MEDICAL CANNABIS

Andrew Hand, MSc, Alexia Blake, MSc, Paul Kerrigan, BSc,

Phineas Samuel and Jeremy Friedberg*, PhD
MedReleaf Corp, Markham Industrial Park, Markham, Ontario, Canada

Understanding the cultural and medical history of cannabis use is an important component
to the successful integration of cannabis in modern clinical practices. This chapter
chronicles over six thousand years of documented cannabis use in cultural practices,
medical applications, breeding practices to enhance the pharmacological properties, and
the various methods by which people have consumed the plant.

INTRODUCTION
Today there is much discussion and debate over cannabis and its use in healthcare. But what is
often left out of the dialogue is the over 6000 years of documented experience people have had
with this plant. Historically, cannabis’ medical applications appear to have been realized by
most cultures, however, it appears that much of our modern day cultural perspectives on
cannabis is based neither on historical evidence nor recent discovery. As with many scientific
disciplines, much can be learned from our collective history. To help with our modern
understanding about cannabis, this chapter provides the reader with a historical account of this
plants’ use, a perspective into the effects of millennia of selective breeding, and insight into the
many ways in which cannabis can be administered.

HISTORY OF CANNABIS USE

The earliest evidence of cannabis cultivation comes from China, in the form of pollen deposits
found in the village site of Pan-p’o, dated to 4000 BCE (1). At the time, cannabis was regarded

*
Corresponding author: Dr. Jeremy Friedberg, MedReleaf Corp., Markham Industrial Park, Markham, Ontario,
Canada, L3R 6C4, P.O. Box 3040. E-mail: jfriedberg@medreleaf.com.
18 Andrew Hand, Alexia Blake, Paul Kerrigan et al.

among the ‘five grains’ and was farmed as a major food crop, also playing a major role in the
production of textiles, rope, paper, and oil (2). The first record of its use in medicine comes
from the Pen-ts’ao ching, the world’s oldest pharmacopoeia (3). Although compiled between
0-100 AD, the Pen-ts’ao has been attributed to Emperor Shen-nung, who ruled during 2700
BCE (3). It recognizes cannabis as being useful for over 100 ailments, including rheumatic
pain, gout and malaria (4). The Pen-ts’ao ching also mentions the psychoactive effects of
cannabis stating that “ma-fen (fruit of cannabis), if taken over the long term, it makes one
communicate with spirits and lightens one’s body” (1). Between 117 and 207 AD, Hua T’o, a
physician of the time and the founder of Chinese surgery, described cannabis as an analgesic
(5). He is reported to have used a mixture of cannabis and wine to anesthetize his patients before
surgery (1). As cannabis use increased in China, it spread westward, reaching India by 1000
BCE (2, 3).
Cannabis spread quickly throughout India and was used extensively, both recreationally
and medicinally (3). It was also adopted and integrated into religious practices, earning mention
in the Atharva Veda, one of the Vedic scriptures of Hinduism, as being among the five sacred
plants of Hinduism, and teaching that a guardian angel lives within its leaves (3). Cannabis is
mentioned within the Vedas as a “source of happiness,” a “joy-giver,” and “bringer of freedom”
(2, 3). The Raja Valabba states that the gods created cannabis out of compassion for humans
(2). In Hinduism, cannabis was smoked during the daily devotional service (2). Due to religious
use in India, it was possible to explore the medicinal benefits of cannabis, which led to the
discovery that cannabis can be used to treat a plethora of diseases and ailments (2). The general
uses in India included use as an analgesic, anticonvulsant, anesthetic, antibiotic, and anti-
inflammatory (3). These properties allowed for the treatment of many diseases, including
epilepsy, rabies, anxiety, rheumatism and even respiratory conditions such as bronchitis and
asthma (3). Cannabis use continued to spread throughout the world and was adopted by many
different cultures (3).
The Assyrians were aware of cannabis’ psychotropic effects since at least 900 BCE (3). By
450 BCE, cannabis had reached the Mediterranean, as evidenced by a first-hand account from
Herodotus (3). Herodotus writes of a Scythian funeral ceremony, where cannabis seeds were
burned ritually for its euphoric effect (3). In Tibet, cannabis was considered to be sacred, used
extensively in medicine and in Tantric Buddhism to facilitate meditation (3). In Persian
medicine, cannabis’ biphasic effects were clearly noted, emphasizing the distinction between
cannabis’ initial euphoric effects and the dysphoric effects that follow (2). The Persian
physician Avicenna (980 – 1037 AD), one of the most influential medical writers of the
medieval period, published ‘Avicenna’s Canon of Medicine’, a summary of all medical
knowledge of the time (6). His canon was widely studied in western medicine from the
thirteenth to the nineteenth century, having a lasting impact on western medicine (6). Avicenna
recorded cannabis as an effective treatment for gout, edema, infectious wounds and severe
headaches (6). In Arabic medicine, cannabis was regarded as an effective treatment for epilepsy
(7). Recorded first by al-Mayusi, between 900-1000 AD (13), followed by al-Badri, in 1464
AD, who wrote of the chamberlain’s epileptic son who was cured using cannabis leaves (6). In
the 1300s, Arab traders brought cannabis from India to Africa, where it was used to treat
malaria, fever, asthma and dysentery (3). The 1500s saw cannabis reach South America via the
slave trade, which transported Africans along with seeds, from Angola to Brazil (3). In Brazil,
cannabis was used extensively in the African community, including religious rituals such as the
‘Catimbo’ which used cannabis for magical and medical purposes. From Brazil, cannabis
 History of medical cannabis 19

travelled north to Mexico where it was used recreationally by individuals of low-socioeconomic

class (3).
Cannabis’ therapeutic uses were first introduced to Western medicine in 1839, when the
Irish physician William O’Shaughnessy published ‘On the preparations of Indian hemp, or
gunjah’ (3). In the first paragraph of his work he highlights that “…in Western Europe,
[cannabis’] use either as a stimulant or as a remedy is equally unknown”, indicating British
unfamiliarity with the drug (3). O’Shaughnessy first encountered cannabis while working as a
physician in India, with the British East India Company (3). Interested, he studied the existing
literature on cannabis, and conferred with elders and healers to understand the recreational and
medicinal uses of cannabis in India (3). O’Shaughnessy then proceeded to test the effects of
different forms of cannabis on animals to evaluate the toxicity of the drug (3). Confident that
the drug was safe, he provided extracts of cannabis to patients and discovered it had both
analgesic and sedative properties (5). The immediate results impressed him enough to begin
prescribing the drug and he was rewarded with positive results (5). His greatest success
came when he managed to calm the muscle spasms caused by tetanus and rabies (5).
O’Shaughnessy’s initial results, followed by those of other physicians, led cannabis to spread
rapidly through Western medicine in both Europe and into North America.
In 1860, the Committee on Cannabis Indica, of the Ohio State Medical Society, reported
success for the use of cannabis to treat many ailments including gonorrhea, asthma, rheumatism
and intense stomach pain (9). Cannabis’ use in medicine continued to grow, peaking in the late
eighteenth, early nineteenth century, when it could be readily found in over the counter
pharmaceuticals such as “Piso’s cure” and the “One day cough cure” (5). This rapidly
increasing popularity of the new medication sparked the publication of more than 100 papers
on its therapeutic uses (3). In 1924, Sajous’s Analytic Cyclopedia of Practical Medicine
summarized what, at the time, were believed to be the main therapeutic uses of cannabis (10).
They concluded that cannabis was useful in the treatment of migraines, coughing and
inflammation, along with diseases such as tetanus, rabies, and gonorrhea.
Following this rapid rise of use within 1900s medicine, cannabis use began to decline due
to a variety of factors (3). Vaccines for diseases such as tetanus made cannabis’ previous role
in treating these diseases obsolete (3). Furthermore, development of synthetic analgesics such
as chloral hydrate, antipyrine (5) and aspirin filled some of the demand for analgesics (3).
However, it was the development of the hypodermic needle and its application to opiates that
could be considered the greatest factor to the decline of cannabis use (3). These factors led to
an overall decrease in the prevalence of cannabis and its necessity as an analgesic, making it
more susceptible to the political influences to follow.
At the beginning of the 1900s, cannabis’ recreational use in the United States of America
was in large restricted to Mexican and African minority groups whom had immigrated into the
country (3). By the 1930’s there was an increase in recreational use among all US citizens,
leading narcotics officers to push for restrictive legislation on both the recreational and
medicinal use of cannabis (5). The American Medical Association advised that cannabis
remains a medical agent, citing its medicinal use, low toxicity and absolutely no evidence “…to
show that its medicinal use is leading to the development of cannabis addiction” (5). However,
despite the protests, in 1937 the Marijuana Tax Act was enacted, essentially ending the already
diminished use of cannabis as a therapeutic (5). In 1941 cannabis was removed entirely from
the American pharmacopeia (5). Over the next couple decades, cannabis use in medicine was
essentially non-existent, and it was not until the 1970s that medical interests were revived (5).
20 Andrew Hand, Alexia Blake, Paul Kerrigan et al.

The prevalence of recreational cannabis use rose significantly in the early 1970s, spiking
from only 5% of people reporting to have used cannabis in 1967, to 44% in 1971 (3). This
massive increase in recreational use brought cannabis into the spotlight, and with the discovery
of cannabis’ active component, Δ9-THC, by Gaoni and Mechoulam in 1964, it became possible
to isolate the principle component, making studying and quantifying its effects possible (3). In
1988, the receptor CB1 was identified (11). It was found to be the binding site of THC, and to
be the most abundant neurotransmitter receptor in the central nervous system (11). This
discovery was followed by the identification of a second cannabinoid receptor, CB2, localized
primarily in the peripheral nervous system and on immune cells (12). The presence of
cannabinoid receptors, concentrated in neural and immune cells, alluded to a possible mode of
action that could be the source of cannabis’ analgesic, sedative and immunoregulatory
properties.

THE GENETICS AND SELECTIVE BREEDING OF CANNABIS

Since human cultures first began cultivating cannabis, selective breeding has been employed to
improve wild cannabis as a source of seeds, fiber and drug. However, cannabis is not a very
simple plant to breed, as two primary complications have made controlled selective breeding a
challenge. Firstly, cannabis is typically a dioecious plant, indicating that individual plants are
distinctly male or female. Therefore, cannabis plants are predisposed to outcrossing as opposed
to self-pollination, which is the primary means of fixing desirable traits in other species. In
addition to this, the valuable components of cannabis are produced and harvested from female
plants, and thus it is a challenge to identify males with favourable genetically regulated
traits. Secondly, cannabis is a wind-pollinated plant and therefore will very easily pollinate
surrounding females, making selective crosses difficult to control. Due to the challenges
outlined above, it is typical of cannabis growers to utilize clonal propagation as opposed to
seeds, as this will produce identical “offspring”. Regardless of these limitations, cannabis
breeders have improved upon the concentration of psychotropic compounds and yield, whereas
hemp breeders have continuously worked to improve the textile characteristics of fiber-type
cannabis cultivars. Understanding the inheritance of chemical phenotype (chemotype) for the
most clinically relevant cannabinoids has been central to modern medicinal cannabis and hemp
breeding. Modern molecular techniques have allowed for a greater ability to screen for elite
cultivars, greatly increasing the rate at which desired traits can be identified and bred into new
cultivated varieties
Figure 1. A timeline of cultural and medical milestones in cannabis.
22 Andrew Hand, Alexia Blake, Paul Kerrigan et al.

Primarily through the research of de Meijer at HortaPharm B.V., four loci, O, A, B

and C, have been found to genetically regulate cannabinoid content (13, 14). Cannabinoids
are terpenophenolic compounds, produced primarily with the monoterpenoid precursor
geranylpyrophosphate (GPP), and one of two phenolic precursors, olivetolic acid or divarinolic
acid, both of which are resorcinolic acid homologs produced by the polyketide pathway (15,
16). Production of the phenolic precursors can be disrupted by a mutant null allele o, at locus
O. In a homozygous state, synthesis of either resorcinolic acid precursor is blocked, while O/o
heterozygous phenotypes typically have one-tenth the cannabinoid content. This indicates that
allele o acts as a dominant repressor of the polyketide pathway that generates both olivetolic
acid and divarinolic acid (17).
Synthesis of either olivetolic acid or divarinolic acid is regulated by locus A, which
according to de Meijer (18) is likely polygenic, with the alleles Ape1 to n encoding olivetolic acid
synthase, and alleles Apr1 to n encoding divarinolic acid synthase. These phenolic precursors,
along with GPP, are utilized by the enzyme geranylpyrophosphate:olivetolate transferase to
produce either CBGA or CBGVA, depending on the phenolic precursor present (19). The
synthesis of the two most clinically relevant cannabinoids, THC and CBD, is then controlled
by co-dominant alleles present at Locus B. THCA/THCVA or CBDA/CBDVA will be
produced if alleles BT or BD is present and functional, respectively, while homozygous
individuals will produce significant quantities of both metabolites. Variations in the sequence
of BT and BD can lead to enzymes with reduced function, so THC: CBD ratios are commonly
found to deviate from 1:1 (14). Mutant alleles BT0 and BD0 significantly reduce THCA and
CBDA production, while leading to considerable accumulation of the precursor CBGA (14).
Lastly, an independent gene at Locus C produces the enzyme CBCA synthase, which competes
with CBDA synthase and THCA synthase for CBGA precursor, producing the cannabinoid
CBCA or CBCVA (see Figure 2).

Figure 2. Cannabinoids biosynthetic pathways.

 History of medical cannabis 23

Many of the genes mentioned above have been sequenced, and molecular markers
detectable via PCR have been developed and validated to correlate with specific chemotypes.
Modern breeders can take advantage of this simple molecular technique in order to expedite
breeding objectives, while using classical breeding techniques in order to select for
other favourable traits, such as yield, disease resistance and flowering time requirements, all
aspects that greatly impact the output of a medical cannabis facility. In the near future more
advanced molecular breeding techniques, such as transgenic gene expression or substitution of
gene promoters with knockdown/overexpression variants could yield dramatically different
chemotypes with potentially novel medical application.

MODERN METHODS OF CANNABIS CONSUMPTION

Most commonly, the flower of the plant is dried, ground, and smoked. The main benefit of
smoking is that it provides rapid relief on the timescale of minutes (20). Furthermore, this
instant feedback allows users to adjust their dosing to either increase or maintain a steady
state of relief. This control also reduces the risk of experiencing adverse effects due to
overconsumption, such as dizziness, paranoia, or anxiety.
Similarly, vaporization also provides rapid onset of effects, with the added benefit of
being considered a much safer and more efficient means of cannabis consumption compared
to smoking. Pyrolysis of cannabis has been shown to generate over 2000 new compounds,
including hazardous components such as carbon monoxide and polycyclic aromatic
hydrocarbons (21, 22). In addition, some studies have shown that 30 - 50% of THC is lost
during burning (23). Since vaporization involves heating dried cannabis to temperatures below
combustion, the production of smoke is avoided, and fewer harmful combustion by-products
are created (24, 25). Thus, vaporization is a very efficient method of consumption that allows
for rapid relief of symptoms, and is overall a superior and healthier means of consuming
cannabis compared to smoking.

Oral administration

Oral administration through either ingestion or sublingual absorption are also popular methods
of cannabis consumption. Similar to vaporization, oral consumption avoids exposure to smoke
and other hazardous pyrolysis by-products. However, cannabis must be decarboxylated prior
to ingestion.
Oral administration often involves the consumption of a cannabis extract, rather than the
actual plant material. For oral sprays, such as Sativex, the extract is often mixed with a
diluting/carrier agent, such as propylene glycol (26). Alcohol, flavouring, and sweeteners may
also be added to adjust the viscosity and taste. Application of the product under the tongue
results in rapid absorption due to the high vascularity of the sublingual region. However, taste
is obviously a concern with such products, and a titrated spray dispenser is required for
consistent dosing.
Alternatively, an infusion can be made by soaking decarboxylated cannabis in butter or
edible oil. This infusion can be used for cooking or baking applications. However, making this
24 Andrew Hand, Alexia Blake, Paul Kerrigan et al.

infusion is a time consuming and highly-tedious process that, if completed at home, will
produce extracts with unknown and highly variable THC concentrations. Because of this dosing
challenge, capsules may be a safer and more convenient method of cannabis administration,
resulting in higher patient compliance and a lower risk of experiencing adverse effects.
Despite being a popular historical method of consuming cannabis, tea preparations are not
very popular or recommended for several reasons (27). First, cannabinoid extraction during
steeping will be very low due to the low water solubility of cannabinoids. However, the addition
of cream or non-skim milk may aid in this. Secondly, water temperatures may not be sufficient
to completely decarboxylate cannabinoids. Thirdly, the final concentration of cannabinoids in
the tea will be unknown (and low), making tea a very inefficient way of consuming cannabis.
Compared to sublingual administration or inhalation, there is a noticeable delay in the onset
of therapeutic action following ingestion (21, 28). For this reason, ingestion may not be a
preferred means of consumption if instant relief is desired.

Other methods of consumption

While inhalation and oral administration are the most common (and therefore the most studied)
methods of cannabis consumption, rectal, transdermal, and ophthalmological administration
are also possible. All of these methods are commonly used for drugs that are not suitable for
oral administration, often due to their potential to irritate the stomach or gastrointestinal tract,
and more commonly due to their low oral bioavailability (21). For cannabis, these methods also
avoid the generation and consumption of smoke and other hazardous combustion by-products.
Transdermal application may be achieved by incorporating decarboxylated cannabis oil
into topical products, such as lotions, gels, or transdermal patches. Such products may be
most useful for individuals seeking to treat localized, physical pain. Ophthalmological and
suppository products are less common, but animal studies have demonstrated their potential as
alternative methods of cannabis consumption offering rapid absorption (24, 28-30).

CONCLUSION
Cannabis use both culturally and medically has had a long and well documented history.
Cannabis has been used medicinally in many different cultures and upon exposure to western
medicine in the 19th century quickly gained popularity as an analgesic, anticonvulsive, and
hypnotic. These medical properties are innately part of cannabis biology, and over time
selective breeding projects have amplified these traits. The medical properties of this plant
combined with an understanding of the effective methods of consumption help make cannabis
the powerful medication it is today. Much can be learned from this historical record but what
is most salient, is that the use of cannabis to treat clinical symptoms is not new. The challenge
is education, and policy changes to incorporate the nature of cannabis’ atypical consumption
requirements in modern clinical methodology.
 History of medical cannabis 25

ACKNOWLEDGMENTS
We thank Dean Pelkonen for assistance with graphic design for Figure 1.

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[14] De Meijer EPM, Hammon KM. The inheritance of chemical phenotype in Cannabis sativa L. (II):
Cannabigerol predominant plants. Euphytica 2005; 145: 189-98.
[15] Fellermeier M, Eisenreich W, Bacher A, Zenk MH. Biosynthesis of cannabinoids: incorporation
experiments with 13C-labeled glucoses. FEBS J 2001; 268: 1596-604.
[16] Rahajo TJ, Chang WT, Choi YH, Peltenburg-Looman AMG, Verpoorte R. Olivetol as product of a
polyketide synthase in Cannabis sativa L. Plant Sci 2004;166:381-5.
[17] De Meijer EPM, Hammond KM, Sutton A. The inheritance of chemical phenotype in Cannabis sativa
L. (IV): cannabinoid-free plants. Euphytica 2009; 168: 95-112.
[18] De Meijer EPM. The chemical phenotypes (chemotypes) of cannabis. In: Pertwee RG, ed. Handbook of
cannabis. Oxford: Oxford University Press, 2011: 89-110.
[19] Fellermeier M, Zenk MH. Prenylation of olivetolate by a hemp transferase yields cannabigerolic acid,
the precursor of tetrahydrocannabinol. FEBS Lett 1998; 427: 283-5.
[20] Grotenhermen, Franjo. Pharmacokinetics and pharmacodynamics of cannabinoids. Anesthesiology.
1997; 86(4): 24–33.
[21] Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers 2007; 4(8): 1770–804.
[22] Abramovici H. Information for health care professionals: cannabis (marihuana, marijuana) and the
cannabinoids. Health Canada 2013. URL: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/
marihuana/med/infoprof-eng.pdf.
[23] Sharma P, Murthy P, Bharath MMS. Chemistry, metabolism, and toxicology of cannabis: Clinical
implications. Iran J Psychiatry 2012; 7(4): 149–56.
26 Andrew Hand, Alexia Blake, Paul Kerrigan et al.

[24] Gieringer DH. Cannabis “vaporization ”: a promising strategy for smoke harm reduction. J Cannabis
Ther 2001; 14(9): 153–70.
[25] College of Family Physicians of Canada. Authorizing dried cannabis for chronic pain or anxiety:
preliminary guidance from the College of Family Physicians of Canada. Mississauga, ON: College of
Family Physicians of Canada, 2014.
[26] GW Pharmaceuticals. Product Monograph - Sativex. GW Pharmaceuticals 2015. URL: http:// www.
gwpharm.com/sativex.aspx.
[27] Hazekamp A, Bastola K, Rashidi H, Bender J, Verpoorte R. Cannabis tea revisited: a systematic
evaluation of the cannabinoid composition of cannabis tea. J Ethnopharmacol 2007; 113(1): 85-90.
[28] Ben Amar M. Cannabinoids in medicine: a review of their therapeutic potential. J Ethnopharmacol 2006;
105: 1–12.
[29] Green K, Kearse E, McIntyre O. Interaction between Delta-9-tetrahydrocannabinol and indomethacin.
Ophthalmic Res 2001; 33(4): 217–20.
[30] Brenneisen R, Elsohly M. The effect of orally and rectally administered ∆ 9-tetrahydrocannabinol on
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In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 3

CANNABIS OR MARIJUANA

Donald E Greydanus1,*, MD, Dr. HC (ATHENS)

and Joav Merrick2-6, MD, MMedSci, DMSc
Department of Pediatric and Adolescent Medicine,
1

Western Michigan University School of Medicine, Kalamazoo, Michigan, US

2
National Institute of Child Health and Human Development, Jerusalem, Israel
3
Office of the Medical Director, Health Services,
Division for Intellectual and Developmental Disabilities,
Ministry of Social Affairs and Social Services, Jerusalem, Israel
4
Division of Pediatrics, Hadassah Hebrew University Medical Center,
Mt Scopus Campus, Jerusalem, Israel
5
Kentucky Children’s Hospital, University of Kentucky College
of Medicine, Lexington, United States
6
Center for Healthy Development, School of Public Health,
Georgia State University, Atlanta, US

Though use of phytocannabinoids are being increasing linked to improvement of some

health conditions, frequent users of cannabis are at increased risk for adverse effects which
can lead to additional health problems. Marijuana (cannabis) remains a controversial drug
in the 21st century. This chapter considers current research on use of cannabis sativa and
its constituents such as the cannabinoids. Topics reviewed include prevalence of cannabis
(pot) use, other drugs consumed with pot, the endocannabinoid system, use of medicinal
marijuana, medical adverse effects of cannabis, and psychiatric adverse effects of cannabis
use. Treatment of cannabis withdrawal and dependence is difficult and remains mainly
based on psychological therapy; current research on pharmacologic management of
problems related to cannabis consumption is also considered. The potential role of specific
cannabinoids for medical benefit will be revealed as the 21 st century matures. However,
potential dangerous adverse effects from smoking marijuana are well known and should
be clearly taught to a public that is often confused by a media-driven, though false message
and promise of benign pot consumption.

* Correspondence: Donald E Greydanus, MD, DrHC (Athens), Professor and Founding Chair, Department of
Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine,
1000 Oakland Drive, D48G, Kalamazoo, MI 49008-1284, United States. E-mail: Donald.greydanus
@med.wmich.edu.
28 Donald E Greydanus and Joav Merrick

INTRODUCTION
A number of chemicals are inhaled for the development of euphoria, including marijuana
(cannabis, pot), methamphetamine, heroin, crack cocaine, phencyclidine, and nitrites (amyl and
butyl) (1). Marijuana (cannabis, pot) has been known to Homo sapiens for thousands of years
and concern has been raised over the past two centuries regarding its potential adverse effects-
--leading to various laws in the United States and other countries to control its production and
use (2). The psychoactive chemical, delta-9-tetrahydrocannabinol (THC) was isolated in the
mid-1960s while other aspects of the endocannabinoid system (cannabinoid receptors [CB1
and CB2] and key endogenous cannabinoids [2-arachidonoyl glycerol and anandamide]) were
identified over 20 years later. Though use of phytocannabinoids are being increasing linked to
improvement of some health conditions, frequent users of cannabis are at increased risk for
adverse effects which can lead to additional health problems (3). Research is identifying
components of cannabis which are not psychoactive and may become established parts of the
pharmacopoeia as the 21st century continues.

Cannabis sativa plant

The products of cannabis are made from the easily grown hemp plant, Cannabis sativa, and the
psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), is at the heart of the complex
cannabis controversy in this and the past century. The euphoria can last minutes to hours. The
enzyme, Δ1-tetrahydrocannabinolic acid synthase, catalyzes the oxidative cyclization of
cannabigerolic acid (CBGA) into Δ1-tetra-hydrocannabinolic acid, which is the precursor of
THC (4). This enzyme controls the psychoactivity of Cannabis sativa (4) due to THC, which
is present in the C. sativa’s dried leaves, seeds, stems, flowers (sensimilla), and oil (5). The pot
of the 1960s-1970s contained 1-2% THC, while the Hawaiian sensimilla product was 3%; this
is in contrast to current versions with much higher THC percentage as measured by the Potency
Monitoring Project and other research (5, 6). A recent survey in Japan revealed an average
potency of 11.2% with a maximum potency of 22.6% (7). High-potency cannabis is referred to
as “skunk.”
Cannabis remains a popular global drug that is easily obtained around the world.
Movements are increasing to legalize this drug, because of the research noting positive medical
benefits as well as the intense euphoria it produces along with a popular, though false
impression that this is a “safe” drug (8, 9). Cannabis remains a controversial drug, because its
illegal status places it in conflict with the popular notion that pot is a harmless chemical—a
notion made fashionable or trendy by many media and Hollywood personalities who may
promote its use to enhance their joie de vivre. Such promotions seem to be effective as noted
by the popularity of this illicit drug. However, marijuana (cannabis) has been prohibited in the
United States since the 1937 Marijuana Tax Act as a federal law and is classified by the US
Drug Enforcement Agency (DEA) as an illegal Schedule I drug. The use, sale and possession
of cannabis (marijuana) in the United States is illegal under federal law. However, some states
have created exemptions for medical cannabis use, as well as decriminalized non-medical
cannabis use. In four states, Alaska, Colorado, Oregon and Washington, the sale and possession
 Cannabis or marijuana 29

of marijuana is legal for both medical and non-medical use, while Washington DC has legalized
personal use, but not commercial sale.

Prevalence

Prevalence data for cannabis can be determined in various ways such as self-report data, waste
water (sewage) analysis, and sales of cigarette paper (10, 11). Research notes that marijuana is
the most commonly used illicit drug on earth (12, 13). The most frequently used substances
among American adolescents are tobacco, alcohol, and marijuana. Marijuana (“weed, pot, hash,
BC Bud, Ganja, grass, smoke, doobs,” others) is an illicit schedule I drug that constitutes about
three-fourths of the illegal drug utilization in the United States (14-16).
Many studies have been done to confirm the high use of cannabis among adolescents and
young adults of the world. The 2007 European School Survey Project on Alcohol and other
Drugs (ESPAD) reported that lifetime use of cannabis among students (age 15-16 years) in
Europe ranged from 3% in Armenia to 45% in the Czech Republic with an average of 19%
among 35 countries (see table 1). One-third of Canadian university students used cannabis (17).
The United States Centers for Disease and Prevention (CDC) YRBS (Youth Risk
Behavioral Surveillance) reported a lifetime use (once or more times) among US high school
students of 31.3% in 1991 that increased to 47.2% in 1999 and was 36.8% in 2009 (18). Use of
marijuana by US high schools students that occurred 30 days before the survey ranged from
14.7% in 1991 to 26.7% in 1999 and 20.8% in 2009. Other studies note marijuana use by
adolescents that range from 28% in New York City versus 38% across the United States (19).
Prevalence of cannabis use disorders have increased in veterans in the United States and were
higher in states which allowed cannabis for medical purposes (20).

Consumption of cannabis (marijuana)

Marijuana is typically smoked as a joint, but can be taken orally in various foods, teas or
capsules which may be used as “medicinal” marijuana. It can be prepared in food for oral
consumptions, as in brownies, cookies, or spaghetti. Various oral consumptions are found in
different countries. For example, in eastern Iran, there is a special solid “pie” called Majoon
Birjandi, which is consumed by adolescents to reach a cannabis-induced euphoria (21).
The marijuana (bhang) cigarette is rolled from the C sativa plant (upper leaves, tops, and
stems) that is cut and dried. Hashish refers to dried exudate that comes from the top and
underside of the plant leaves while concentrated hashish distillate is called hashish oil.
Sensimilla is another potent marihuana product that is made from the seedless female flower
of the cannabis plant. The “typical” marijuana cigarette includes about 20 mg of THC that is
produced from a gram of C sativa leaves and buds; however, much variation in potency can be
found (vida supra). THC can be found in the body for up to 2 weeks after use of a single pot
cigarette. A blunt is a cigarette or cigar form made from tobacco and filled with marijuana in a
process called boosting; this can be used to boost the effects of other drugs such as alcohol (22).
30 Donald E Greydanus and Joav Merrick

Table 1. Lifetime use of marijuana: 2007 ESPAD* (15-16 year olds)

Armenia: 3%
Austria: 17%
Belgium (Flanders): 24%
Bulgaria: 22%
Croatia: 18%
Cyrus: 5%
Czech Republic: 45%
Estonia: 26%
Faroe Islands: 6%
Finland: 8%
France:31%
Germany: 20%
Greece: 6%
Hungary: 13%
Iceland: 9%
Ireland: 20%
Isle of Man: 34%
Italy: 23%
Latvia: 18%
Lithuania: 18%
Malta: 13%
Monaco: 28%
Netherlands: 28%
Norway: 6%
Poland: 16%
Portugal: 13%
Romania: 4%
Russia: 19%
Slovak Republic: 32%
Slovenia: 22%
Sweden: 7%
Switzerland: 33%
Ukraine: 14%
United Kingdom: 29%
AVERAGE: 19%
* Hibell B, Guttormsson U, Ahlström S, Balakireva O, Bjarnason T, Kokkevi A et al. ESPAD (The
European School Survey Project on Alcohol and Other Drugs) report 2007. Substance use among
students in 35 European countries. Stockholm, Swedish Council Information Alcohol Other Drugs,
2009.

Cannabis and other drug use

Pot is often combined with consumption of alcohol or diazepam which increases cannabis
sedative effects. Addition of various other drugs enhances the euphoric effects. For example,
marijuana is often mixed with various drugs such as nicotine, cocaine, opioids, or hallucinogens
(as LSD [lysergic acid diethylamide]). It is also mixed with drugs such as phencyclidine (PCP)
in which the joint is dipped (hand-rolled) into PCP dissolved in an organic solvent (as
formaldehyde); after drying it is smoked---called “water, wet, or Sherms.” Such additions add
to the complications of pot use. Other additives include glutethimide and methaqualone, which
have been popularized in the past. Persons abusing marijuana who also take disulfiram due to
 Cannabis or marijuana 31

alcohol abuse can develop increased psychoactive effects of cannabis due to THC blockage by
the disulfiram (23).
Cannabis users also smoke tobacco and research claimed that this occurs for a variety of
reasons, including shared genetic factors, the similar cue of smoking for both, and withdrawal
symptoms that are seen to some extent in both (24). One study of 467 adults who regularly
smoked both cannabis and tobacco found that one-third started with cannabis first, nearly half
initiated tobacco before cannabis, and most cannabis smokers who stopped tobacco did so after
taking up regular cannabis consumption (25).
As noted, those who consume marijuana also tend to use other drugs and it may serve as
a gateway drug from early experimentation in adolescence to other drug use (26, 27). For
example, two different studies reported that 45% of college students who illegally used
prescription drugs also abused marijuana, while 24 to 57% also abused alcohol (28). Cannabis
initiation usually follows alcohol use though cannabis use can start before alcohol use and
African-Americans (versus European-Americans) have an increased risk for this cannabis-first
trend (29). Other research notes increased risk for cannabis-related problems in African-
American females versus European-Americans (29). Some research identifies declining
socioeconomic position from childhood to adulthood as a risk factor for cannabis as well as
tobacco consumption (30).
Some researchers reported that patients seen in a pain clinic were at increased risk for use
of marijuana; for example, one study of these patients with 21, 746 urine specimens found
13.0% incidence of urine with cannabis (tetrahydrocannabinol); also, 4.6% were positive for
cocaine and 1.07% were positive for methamphetamine. (31). A case-crossover research design
study noted that cannabis was a trigger for onset of cocaine use even when genetic influences
and various environmental conditions were held constant (32).

Cannabinoids

Cannabis sativa contains over 60 cannabinoids as well as over 400 other chemicals including
benzopyrene, a known carcinogen. Table 2 lists some of the known cannabinoids (33). The
cannabinoids of the Cannabis sativa plant include cannabidiol (CBD), cannabigerol (CBG), and
cannabinol (CBN) which, in contrast to THC, are not psychoactive. Cannabidiol (CBD) may
activate central nervous system (CNS) limbic and paralimbic regions which can reduce
autonomic arousal and feelings of anxiety; this is in contrast to THC which can be anxiogenic
(34). Cannabigerol is found in higher concentrations in hemp and has been used to lower
intraocular pressure.
Other research also notes that THC and cannabidiol influence different CNS regions and
thus, have different effects on cannabis users (35). In addition to anxiolytic effects, cannabidiol
has been shown to have anti-emetic, anti-inflammatory, and antipsychotic effects (36). There
is no effect on vital signs (i.e., blood pressure, pulse, body temperature), gastrointestinal transit,
or psychological functioning. Doses up to 1,500 mg per day as well as chronic use of CBD
have been reported as being well tolerated by humans (36). There can be hepatic drug
metabolism inhibition, reduced activities of some drug transporters (i.e., p-glycoprotein), and
lowered capacity of fertilization (36).
32 Donald E Greydanus and Joav Merrick

Euphoria is produced from effects of this lipophilic drug on cannabinoid receptors (ECS:
CB 1 and CB 2) in mesocortical and limbic systems; THC also effects the striatum and lateral
prefrontal cortex. Cannabinoid receptors are also found in the liver, gastrointestinal tract,
skeletal tissue, and adipose tissue. There are endogenous ligands for cannabinoid receptors (i.e.,
N-palmitoethanolamide and anandamide) that act like neurotransmitters (26). Part of the
complexity of the cannabis issue is the presence of the endogenous endocannabinoid system
and this system is now reviewed.

Endocannabinoid system

The endocannabinoid system consists of CNS cannabinoid receptors and their endogenous
ligands; ligands (Latin: binding) refers to triggering molecules that bind to a target protein site
(37). Endocannabinoids (endogenous cannabinoid receptor agonsts) include arachidonic acid
derivatives: 2-AG (2-arachidonoyl glycerol) and anandamide (arachidonoyl ethanolamide
[AEA]) (see table 2) (38, 39). AEA and 2-AG are the two most researched endocannabinoids.
The complex effects of this system on emotional and cognitive behavior may be strongly
influenced by various environmental factors (40).

Table 2. Types of cannabinoids

Endogenous cannabinoid agonists

2-AG (2-arachidonoyl glycerol)
Anandamide (arachidonoyl ethanolamide)
Cannabidiol (CBD) (isomer of THC)
Cannabinol (CBN) (metabolite of THC)
Cannabigerol (CBG) (alpha-2-adrenergic receptor agonist)
Tetrahydrocannabinolic acid (THC biosynthetic precursor)
Synthetic cannabinoid agonists
WIN 55,212-2
JWH-133
HU-210
CP-55940

The endocannabinoid system is identified both as a cause of psychiatric disorders but also
research suggests that proper manipulation of this system may be pharmacologically useful in
management of some psychiatric disorders---such as depression, anxiety, anorexia nervosa, and
others (41). For example, cannabidiol may be beneficial in treatment of psychiatric disorders
(41).
The endocannabinoid system is involved in processes of brain reward that are related to
drug abuse—as noted in animal and human research; this includes cue-induced relapse of drug
abuse (42). This CNS system is involved in various functions involving memory, emotions,
movement, cell proliferation, and other important cell functions (43). Key neuron classes that
express high levels of CB1 receptors are GABAergic interneurons in such CNS areas as the
cerebral cortex, amygdala, and hippocampus; these areas also contain cholecystokinin, an
important neuropeptide (44).
 Cannabis or marijuana 33

The cannabinoid CB (1) receptor (CB1R) is mainly found in the central nervous system
and the CB (2) receptor is expressed in immune system cells and recent research has shown the
importance of this receptor, not only concerning the immune system; both receptors are G-
protein coupled receptors and are involved in adenylate cyclase inhibition (45, 46). The CB1R
is a G-protein coupled receptor that is associated with most of the CNS endocannabinoid
signaling (47). CB1R, also known as CNR1 and CB2R, also known as CNR2 are of importance
and future research will most likely show us new information. It is widely found in the
cerebellum, basal ganglia, and limbic system; the hippocampus has the highest concentration
of cannabinoid receptors. Cannabinoid receptors are found in other tissues including the heart,
lungs, endocrine glands, arteries, immune system, sympathetic ganglia, gastrointestinal tract,
and reproductive tract (38).
The activation of CB1 receptors can inhibit amino acid and monoamine neurotransmitter
release. Certain lipid derivatives (i.e., 2-arachidonoylglycerol [2-AG] and anandamide [AEA])
can function as endogenous ligands for CB 1 receptors and lead to excitation in such areas as
the cerebellum and hippocampus by inhibition suppression (44). Most drugs of abuse alter brain
levels of endocannabinoids. Since blockade of this system can change the reward behavior
associated with some drugs of abuse, the CNS endocannabinoid system is under active research
to develop medications that may be helpful in treatment of drug abuse—including drug relapse
(42). Cannabis as potential medication (“medicinal marijuana”) is now considered.

Use of medical cannabis

Conclusions regarding the “benign” or “malignant” effects of cannabis use influence different
countries’ policies regarding legalization or criminalization of cannabis use (48). This is also
complicated by use of cannabis products in a “medicinal” manner and thus, effects to find the
most “appropriate” variety (varieties) of cannabis that are available (49, 50). A plethora of
medicinal benefits have been identified with marijuana use over past centuries (51-53) (see
table 3).
In Israel the private company Tikun Olam Ltd was the first, largest and foremost supplier
of medical cannabis in Israel and one of leading medical cannabis companies in the world.
Tikun Olam has been operating under license from the Israel Ministry of Health since 2007. In
2016 medical cannabis is set to hit pharmacy shelves in Israel in the form of cigarettes, cookies
and oil, while the number of doctors permitted to prescribe the natural painkiller and the number
of farmers allowed to grow it will substantially increase, according to a new Health Ministry
reform. At the same time, the entire production and supply chain will be strictly supervised to
ensure that medical cannabis is kept out of the recreational drug market.
The concern over the addictive and psychomimetic qualities of THC placed active research
on potential medical benefits of this plant on the backburner until recently (53). However,
increased understanding of the cannabinoid signaling system has led to increased research on
potential medicinal uses of cannabis (54); this endocannabinoid system, for example, is being
analyzed for use in treatment of various neuropsychiatric diseases (43).
Studies are looking at potential benefits of cannabinoids (phytocannabinoids) in
management of neuropathic pain, hypertension, post-stroke neuroprotection, multiple sclerosis,
epilepsy, cancer, and other disorders (55-62). Cancer research, for example, has identified that
cannabinoids can inhibit cancer growth, angiogenesis, and metastasis (62). Cannabinoid-like
34 Donald E Greydanus and Joav Merrick

anti-inflammatory products may be useful as material for wound dressing due to anti-
inflammatory effects (63). Cannabidiol is under research as a new class of anti-inflammatory
bowel disease drug (64).

Table 3. Potential benefits of cannabis based on research studies (See text)

Remedy for inflammation

Remedy for pain (including chronic pain & neuropathic pain)
Remedy for diarrhea (as in Crohn’s disease)
Treatment for dystonia
Treatment for multiple sclerosis
Treatment for rheumatoid arthritis
Treatment for glaucoma
Treatment for emesis due to chemotherapy
Treatment for epilepsy
Improvement of anorexia in AIDS patients
Treatment for Huntington’s Disease
Management of inflammatory bowel disease
Beneficial effect on atherosclerosis
Reduce brain infarct size
Block negative memories in posttraumatic stress disorder
Reduce cardiac reperfusion injury
Adjuvant treatment for prostate carcinoma
Others

A number of cannabis products are being manufactured by pharmaceutical companies,

including Sativex (THC + cannabidiol), Marinol (dronabinal; THC; Schedule III drug), and
Cesamet (THC, Schedule II) (53). The latter two have been approved for use in the anorexia-
cachexia syndrome as well as for nausea and vomiting (53). Dronabinol is a synthesized gelatin
capsule which has been used to treat glaucoma by lowering intraocular pressure or relieve
chemotherapy-induced emesis (vida infra) (65). Marijuana has been used to treat the wasting
syndrome associated with HIV/AIDS (9). A newer tablet formulation of THC is Namisol
(>98% THC) which has been studied to ameliorate pain and spasms in adults with multiple
sclerosis as well as relieve nausea, and emesis in HIV or cancer patients (66).
Though cannabis users noted lowering of anxiety and feelings of anxiety, much research
remains to be accomplished to identify which if any cannabinoid products may be
therapeutically and safely used as pharmacologic management of individuals with anxiety
disorders (67). Current research is looking at such anxiety disorders as social anxiety disorder,
post-traumatic stress disorders, panic disorder, and obsessive-compulsive disorder (68, 69).
Research suggests that the phytocannabinoid chemical, cannabidiol, may be useful in
blocking negative or fear memory associated with posttraumatic stress disorder in a process
called reconsolidation blockage (70). Some research notes a lower mortality rate among adults
with schizophrenia and related psychotic disorders in those who smoked cannabis versus those
who did not smoke cannabis (71), while research on smoked, vaporized, and oral cannabis
products for potential improvement of health are continuing (72).
 Cannabis or marijuana 35

Synthetic cannabinoids (cannabinoid designer drugs; cannabimimetics)

A number of designer drugs have become available in the 21st century and cannabis has become
involved in this trend as well. These synthetic cannabinoids (called “legal highs,” “Spice
drugs,” “K2” drugs) are similar to THC found in the C. sativa plant and produce similar effects
to smoking cannabis since they bind to the same cannabinoid brain and peripheral organ
receptors as THC (73-79). These herbal blends have been noted since 2008 in various “herbal”
smoking products sold via the internet and in retail outlets (called “head shops”) that focus on
drug paraphernalia sold for cannabis and other drug use; brand names include such exotic
names as Aroma, Yucatan Fire, Spice Gold, and others (73, 80).
Though available in some countries, advertised as “safe,” (since they do not resemble the
chemical structure of THC) and considered legal in various locations, they are potentially
dangerous drugs---having up to 10 times the strength of delta-9-THC (74, 81, 82). In a moving
and dangerous cat and mouse game, sellers change the synthetic cannabinoids in attempts to
avoid putting up for sale a specific product identified as illegal in a specific country or area. As
one synthetic cannabinoid is banned, others are produced to take their place as there are over
140 different Spice drugs that are produced (73). They may be marked as some type of
“incense” or “herbal” product and even “air fresheners” but potential adverse reactions remain
(76, 77). Toxicology screens looking at THC may miss the presence of these cannabinoid
designer drugs (76, 78).
They are typically tobacco and cannabis free but produce similar cannabis effects that can
include withdrawal symptoms, anxiety, intoxication, psychosis, death, and others (vida infra)
(73, 83). Some reports suggest that increased hallucinations and paranoia are noted with these
“spice” synthetic cannabinoids (78). Part of the potential danger is that they can contain various
added but often unknown chemicals that are part of the manufacturing process. However, some
of the products found on the internet do not have significant amounts of impurities and adverse
effects are due to the synthetic cannabinoids themselves and the potential additives (84).

CANNABIS LAB TESTING

Those smoking 3.55% pot develop a peak plasma level near 160 mg/ml 10 minutes after
beginning to ingest this product; the THC is removed from the plasma to body tissues leading
to its euphoric effects and then to body fat as long-term storage (6). THC is then eliminated
over several weeks in the urine and feces. Urine tests can be used to establish the presence of
cannabinoid metabolites and can be positive in casual users for up to 10 days versus 14 to 30
days for chronic pot users (26). Current drug testing (using high-performance liquid
chromatography with diode-array detection) can identify low THC content in cannabis
seedlings right after germination; however, chemotype determination of THC can occur as the
plant ages--at 3 weeks and beyond (85).
Cannabis testing can be used to verify past pot use but not the presence of cannabis
intoxication, dependence, or abuse. Testing may also note suppression of testosterone and
luteinizing hormone (LH), though it is unclear what such tests actual mean from a clinical
viewpoint. Passive inhalation of cannabis does not result in a positive urine test for THC. Urine
testing for THC does not identify the presence of synthetic cannabinoids.
36 Donald E Greydanus and Joav Merrick

THC-COOH (11-nor-9-carboxy-THC) is the main secondary THC metabolite developed

after cannabis is taken; it is not psychoactive but has a long-half life and can be detected for
days and in heavy cannabis users, for weeks after consumption. It is an important metabolite
used in blood or urine testing for identification of cannabis; urine THC-COOH testing has been
used to identify cannabis abstinence and a positive test can be confirmed with gas
chromatography-mass spectrometry THC blood testing that indicates recent cannabis exposure
(6). Whole blood and plasma testing can also reveal 11-hydroxy-THC after smoking cannabis.
Polymerase chain reaction (PCR) testing is available to police to identify where specific C
sativa samples came from in order to assist with forensic studies and investigations (86). In
addition to urine as well as blood testing, saliva and hair testing for cannabis are possible—the
latter for evaluation of chronic cannabis exposure (87, 88).

MEDICAL ADVERSE EFFECTS

Though some authors question the data on negative effects of cannabis use, most authors
conclude that use of cannabis has significant risks for the user in a dose-dependent and/or
idiosyncratic fashion (89, 90). Identifying adverse effects of cannabis is challenging because
studying an illicit drug can be problematic as can separating out cannabis effects from other
drugs that are often taken simultaneously, such as tobacco or alcohol; also, there is variation in
techniques of cannabis consumption (89, 91-93).
A case of an infant with altered consciousness after exposure to cannabis smoke (passive
inhalation) has been reported (94). Another 10-month-old infant consumed oral cannabis and
presented with cannabis poisoning---drowsiness, generalized hypotonia, and restlessness; this
infant had high blood as well as urine levels of cannabis products and recovered with
symptomatic management that included clinical monitoring for the first 24 hours after the
ingestion (95).
A number of side effects are possible for the cannabis consumer including increased
mortality rates (see table 4). Chronic use can lead to weight gain from overeating and reduced
physical activity. Acute pot use can lead to suppression of rapid eye movement (REM) and
diffuse slowing of background EEG activity (26). The smoke of cannabis can be irritating to
conjunctival, nasopharyngeal, and bronchial tissue leading to injected conjunctiva, chronic
cough, sinusitis, pharyngitis, and (chronic) bronchitis (96). Adolescents or young adults who
present with chronic cough should be screened for cannabis use in addition to more classic
causes, such as asthma, gastroesophageal reflux, respiratory tract infections, and others (97,
98).
Chronic use of cannabis has not been shown to effect thyroid function (99). Acute
pancreatitis linked to cannabis use has been reported in a 22-year old male who presented with
epigastric pain, nausea, and emesis (100). Abdominal pain due to colonic perforation and
subsequent peritonitis has been reported as a complication of cannabis body packing in attempts
to illegally smuggle illicit drugs from one country to another (101).
 Cannabis or marijuana 37

Table 4. Potential adverse effects of marijuana* (see text)

Addiction (Physiologic)
Withdrawal syndrome
Dependence (Psychological) and with heavy use, tolerance
Variety of negative psychological reactions:
(anxiety, hallucinations, violent behavior, depression, fear)
Overt precipitation of psychosis or depression
Insomnia (can be chronic and improved with trazodone)
Memory spans that are impaired
Blunted reflexes
Flu-like reaction (after stopping this drug after 24 to 60 hours, lasting up to 2 weeks)
Confusion and cognition impairment
Alteration of time perception
Amotivational syndrome (lose interest in school or work success)
Physiologic responses can include cough, bronchospasm, bronchitis
Amenorrhea
Immunologic dysfunction
*Used with permission from Greydanus DE, Feucht CL, Hawver EK. Substance abuse disorders. In:
Greydanus DE, Patel DR, Omar HA, Feucht C, Merrick J, eds. Adolescent medicine:
Pharmacotherapeutics in general, mental, and sexual health. Berlin: DeGruyter, 2012:180.

Cannabis hyperemesis

Cannabinoid hyperemesis is noted in some cannabis users who present with usually sudden,
severe, and cyclic (intractable) emesis which resolves with intravenous fluids, antiemetics, and
cannabis cessation. There can be cyclic nausea and abdominal pain as well and after a careful
evaluation, the cause is linked to cannabis use (102). It was first described in Australia in 2004
and may be missed in patients presenting with hyperemesis and abnormal patterns of bathing
(103). Though cannabinoids have been used to treat chronic nausea and emesis, a paradoxical
effect on the gastrointestinal tract in noted in cannabis hyperesis syndrome and three parts are
described: prodromal, hyperemetic, and recovery phases (104).
The hyperemesis phase is usually resolved in 48 hours. Patients may report temporary
symptomatic improvement with prolonged hot showers or bath exposure and thus, compulsive
hot water bathing has become part of the cannabis (cannabinoid) hyperemesis complex (102,
105-107). Diagnostic confusion with the cyclic vomiting syndrome may occur (104). If
cannabis use resumes, the hyperemesis complex may recur (104, 105, 108).

Dental effects of cannabis

Pot users tend to have increased risks for dental caries, oral infections, and periodontal disease
(109-111). Dysplastic changes and premalignant lesions can be identified in oral mucosa of
cannabis users (109). Use of local anesthetics in patients intoxicated with cannabis intensifies
and prolongs pot-induced tachycardia (109).
38 Donald E Greydanus and Joav Merrick

Exposure to smoking (cannabis or tobacco) leads to contact with many carcinogens (pro-
carcinogens) such as polycyclic aromatic hydrocarbons (112). Cannabis users often smoke
tobacco and drink alcohol which increases carcinogen exposure and risk of oral squamous cell
carcinoma which represent 95% of malignant lesions in the mouth (112).

Pulmonary effects

Some research identifies an anti-inflammatory effect from consumption of the C. sativa plant.
For example, one study of 5,115 adult males that took place over 20 years noted that occasional
and low cumulative cannabis use was not associated with adverse effects on pulmonary
function (113). Murine studies suggest that cannabidiol has an immunosuppressive and anti-
inflammatory effect on acute lung injury because of an increase in extracellular adenosine
(114).
However, it is known that marijuana, as well as tobacco, contains a toxic combination of
gases and other substances that can be injurious to the pulmonary system (115). Marijuana
smokers usually smoke fewer “joints” than tobacco smokers consume cigarettes; however,
methods of cannabis smoking may place more cannabis particulate matter into the lungs
than noted with typical cigarette smoking (115). Those with cannabis dependence will continue
to use it despite chronic cough, excessive sedation, or other marijuana-related problems.
Combining marijuana with tobacco leads to known tobacco-effects via second-hand smoke.
Pot use can induce some bronchodilation, but regular or heavy cannabis consumption can
result in generalized airway inflammation with evidence of respiratory epithelial cell injury and
damage to alveolar macrophages which can lead to pulmonary infection (115). Sharing of
cannabis water pipes has led to the development of pulmonary tuberculosis (TB) (116).
Smoking cannabis that contains fungal spores can result in pulmonary aspergillosis in those
with immune-compromised conditions (116, 117).
There is a dose-related large airway dysfunction with hyperinflation and obstruction of
airflow; one cannabis joint has been noted to be equivalent to 2.5 to 5 cigarettes in terms of this
pulmonary dysfunction (118). Macrophage injury can result in cytokine and nitric oxide
impairment. Smokers of cannabis are typically exposed to more carbon monoxide and tar than
cigarette smokers; this effect is not related to the THC content (119).
Heavy and/or chronic users of cannabis may have persistent cough, bronchitis, (bullous)
emphysema (chronic obstructive lung disease [COPD]), pulmonary dysplasia, pneumothorax,
tuberculosis (TB), and other respiratory infections (26, 115, 116, 120). Cannabis can lead to
increased airway resistance and large airway inflammation though causal links to COPD or
macroscopic emphysema remain controversial and unproven (92, 93, 118, 121). Smoking both
tobacco and marijuana increases risks for abnormal tracheobronchial histopathology and COPD
(121).

Cannabis and cancer

Marijuana smoke contains toxic chemicals in amounts similar to or higher than that found in
tobacco and is linked as a potential respiratory tract carcinogen (26, 93, 96, 120,). Chronic
inflammatory and precancerous airway changes in a dose-dependent relationship as well as
 Cannabis or marijuana 39

increase in airway cancer are reported in cannabis users (90). Anecdotal reports of upper and
lower respiratory airway cancer have been published (116, 122). For example, a case of small-
cell lung cancer was reported in a 22-year old male who smoked one marijuana joint three times
a week for three years (123). However, specific link of cannabis to lung cancer remains
unproven (92, 93, 124). Current literature suggests that cannabis-only smokers are at lower risk
of lung cancer than tobacco-only smokers (125). However, some epidemiologic data does place
an independent role of cannabis smoking in the development of lung cancer (126, 127).

Cardiovascular effects

Cannabinoids have complex and varying effects on blood pressure depending on which
cannabinoid is being studied (33). Acute effects of cannabis include increase in heart rate along
with an increase (usually mild) in blood pressure and then decreased vascular resistance-
induced orthostatic hypotension (55, 128). Individuals with coronary heart disease may have
increased cardiovascular adverse effects from cannabis use (89). Cannabis-induced ST segment
elevation mimicking the Brugada syndrome has been reported (129, 130). Other drugs, both
licit and illicit (i.e., cocaine), have been linked with the Brugada syndrome as well (131).
Reported cardiovascular effects linked to cannabis include anecdotal cases of acute
coronary syndrome, congestive heart failure, and arrhythmias (55, 96, 129, 132-135). Patients
with angina may have decreased time with chest pain onset due to the acute effects of cannabis
use; also, myocardial infarction may be triggered by the acute effects of cannabis use (55).
Patients at high risk for coronary heart disease should be advised to avoid using cannabis (55).
Studies on cannabis also provide evidence of positive or “neutral” effects from cannabis
consumption. For example, though inhalation of marijuana may induce acute coronary
symptoms, ingestion of cannabinoids may have a positive effect on atherosclerotic heart disease
via effects on the endocannabinoid system (134). Also, cannabis use has not been specifically
linked to increased hospitalization due to cardiovascular disease or increased mortality from
cardiovascular etiology (55). If a patient has a cardiac death and has a positive urine test for
cannabinoid, a plasma THC level should also be done before seeking to link the cannabis
history with the cardiac death.

Motor vehicle accidents

Adolescents and young adults who drive vehicles under the influence of pot (often combined
with alcohol) are at increased risk (two-times) of motor vehicle accidents leading to potential
death and injury (89, 90, 96, 136, 137). Those who consume cannabis without other drugs also
place themselves at increased risk for motor vehicle crashes (137). Individuals driving under
marijuana influence may experience distortion of on-coming vehicle headlights resulting in
motor vehicle crashes. Driving impairment worsens with increasing amounts of cannabis
consumed (138). The problem of driving while under cannabis influence is increasing and in
some areas of California, for example, the rate of nighttime weekend drivers who tested positive
for THC was nearly 20% (139). Unfortunately, tests used in the field to identify if cannabis is
involved in motor vehicle accidents may not be sensitive enough to detect the precise presence
40 Donald E Greydanus and Joav Merrick

of this drug (140). Cannabis consumption is also involved in non-traffic injuries, especially
falls in the older adult population (141).

Sports doping

Those involved in sports should understand that cannabis is a drug banned by the World Anti-
Doping Agency despite history of pot use in the Olympics and it has been on the list of
prohibited drugs of the International Olympic Committee since 1989 (75, 142). Cannabis
smoking results in reduced exercise test duration during maximal exercising and increased heart
rate at less than maximal exercise levels (55). Cannabis-induced increase in blood pressure and
reduced psychomotor activity can also decrease overall athletic performance. Management of
urine samples from athletes can be problematic because of the intricacies of interpreting urine
samples due to the complexities of prolonged cannabis excretion (143).

ADVERSE EFFECTS: PSYCHIATRIC

Cannabis and neurodevelopment effects

Adverse neuropsychological effects of cannabis use must be separated out from the acute
effects of cannabinoids, effects of heavy cannabis consumption, and psychiatric disorders
worsened or even caused by cannabinoids (144). Specific effects in individual cannabis users
are difficult to predict because of the heterogeneity or non-uniformity of different studies that
have been done to seek neuroimaging effects in cannabis use; some authors have concluded it
is difficult to prove major effects of cannabis on brain structure (145, 146). Some research
suggests that identified cannabis-related neurocognitive performance defects disappear after 25
days of cannabis abstinence (147).
However, other recent research studies are noting that cannabis users demonstrate
important deficits in prospective memory and executive functioning that exist beyond acute
cannabis intoxication (148). The presence of cannabis and nicotine use disorders in parents
appears to increase the risk for major depressive disorder in their late adolescent offspring
(149). Studies in animals and humans suggest a subtle (versus gross) effect on cognitive
functioning with later development of hyperactivity, reduced attention span, impulsivity,
depression, and substance use disorders (150). Most frequently reported adverse effects of
cannabis use include mental slowness, reduced reaction times, and increased anxiety (89).
Dysfunction occurs to dopamine and opioid neurotransmitter systems (151).
Animal and human research concludes that the developing brain, with its high neuronal
plasticity, is vulnerable to exposure to exogenous cannabinoids, particularly in the
perinatal/prenatal period and during young adolescence (43, 151-154). Animal and human
studies suggest that early onset of cannabis use (i.e., early adolescence) can increase risks for
cognition dysfunction, CNS changes (i.e., low striatal dopamine release), neuropsychiatric
disorders, cannabis dependence, and consumption of additional illict drugs (152, 155).
Persistent or problematic marijuana use can lead to major interference with daily life activities
whether at work, in school, or in one’s home.
 Cannabis or marijuana 41

Cannabis use often develops in adolescence and early adulthood which, as noted, is a
vulnerable time for subsequent adverse brain effects (47). For example, cannabinoid receptors
are abundant in the CNS white matter in adolescence as well as young adulthood; long-term
cannabis use during this time period can lead to impaired axonal fiber connectivity with
negative effects on the white matter of the brain (156). Cannabis use in early adolescence may
alter CB1R signaling with potentially increased risk for development of psychiatric disorders
(47). Early adolescent cannabis use has been linked with adolescent drop-out behavior in some
research (157).
Some research links other CNS problems with heavy cannabis use. For example, one study
identified regional brain abnormalities (in the hippocampus and amygdale) in long-term, heavy
pot users—data found in both human and animal studies (158). Animal studies noted
hippocampal-dependent short-term memory deficits that occurred in some but not all rats given
chronic cannabinoid administration (159).

Cannabis and ADHD

One report of 162 adolescents studied during inpatient management of problems related to drug
dependence (i.e., marijuana, heroin, alcohol, or cocaine abuse) revealed attention deficit
hyperactivity disorder (ADHD) in 34% of them (160). A study from different medical centers
that focused on 600 adolescents (ages 13 to 16 years of age) who were undergoing management
for marijuana-related problems reported that 38% also had ADHD (161). Such studies support
the theory that ADHD and adolescent substance abuse disorder (including cannabis
dependence) can be seen as a developmental disorder with similar underlying physiologic
mechanisms (19).

Cannabis dependence

Psychological dependency and tolerance are classically described in pot smokers. The
American Psychiatric Association’s DSM-IV-TR describes two cannabis use disorders
(cannabis dependence and abuse) and six categories of cannabis-induced disorders (see table
5) (26), while DSM-V has included cannabis withdrawal. Some have placed the dependence
rate at 7-10% of regular users (90), while a susceptibility gene, NRG1, has been associated with
cannabis dependence in African Americans (162).

Table 5. DSM-IV-TR Cannabis use and induced disorders (26)

Cannabis use disorders

Cannabis Dependence
Cannabis Abuse
Cannabis-induced disorders
Cannabis Intoxication
Cannabis Intoxication Delirium
Cannabis-induced Psychotic Disorder, with Delusions
Cannabis-induced Psychotic Disorder, with Hallucinations
Cannabis-Induced Anxiety Disorder
Cannabis-Related Disorder Not Otherwise Specified
42 Donald E Greydanus and Joav Merrick

Those with cannabis dependence can consume cannabis in potent forms for years and spend
several hours a day in finding as well as taking it; there can be physiologic dependence and also
psychologic dependence (26). Cannabis intoxication may last longer with oral cannabis versus
smoking it. Intoxication may even last up to 24 hours due to effects of enterohepatic circulation
and/or slow release of fat soluable THC and other cannabinoids from fatty tissue. Cannabis use
disorders are more common in males versus females and are most prevalent in the 18 to 30 year
old group (26).
Depersonalization and derealization episodes are described in pot users (APA, 26).
Anecdotal cases of cannabis-induced depersonalization in adolescents have been reported
(163). A history of conduct disorder in childhood or adolescence and antisocial personality
disorder are risk factors for substance use disorder including cannabis-related disorders (26).
Differentiation of cannabis-induced disorders from primary mental health disorders can be
difficult. Ataxia and aggression are more likely to be seen with phencyclidine (PCP)
intoxication versus cannabis intoxication; aggression with nystagmus or ataxia is more likely
to be from alcohol intoxication (26).
Demonstrating a direct link between cannabis use and the development of overt depression
has been problematic and not clearly proven (164). Regular cannabis consumption (particularly
daily use) in adolescence has been linked with increased risks for anxiety disorders in
adolescents and young adults, even after the cannabis was stopped (154). Anxiety is linked to
regular or heavy use of cannabis and further research is needed to unravel this connection in
more detail (165). For example anxiety can arise due to fear of being discovered by law
enforcement officials; there can be episodes resembling panic attacks.

Cannabis withdrawal syndrome

Chronic pot users can develop psychological addiction and a withdrawal syndrome comparable
to heroin addiction (8). A heavy marijuana user, whether an adolescent or adult, who suddenly
stops this drug can develop a recognizable withdrawal syndrome as reported by various
research studies (166-172). Withdrawal symptoms can develop within 48 hours of cessation
and include irritability, restlessness, anxiety, aggression, and sleep difficulties. (89).
Withdrawal symptoms tend to subside in 2 to 12 weeks after cannabis abstention (89). As noted,
a CNR1 gene has been linked with abstinence-induced withdrawal symptoms (173). Heavy
cannabis use has been linked with a smaller amygdala and hippocampus while those with CNR1
may be predisposed to smaller hippocampal volume following heavy cannabis use (173). Some
smoke pot to control problems with anger (169-172).
Withdrawal symptoms are due to the cessation of THC and are relieved with taking delta-
9-THC or simply smoking marijuana (166, 174). Adolescents undergoing treatment for
cannabis dependence experience withdrawal symptoms most acutely during the first week of
cannabis absence and this tends to ease over the next month of abstinence (166, 175). Research
notes that the majority of heavy pot users report several symptoms after stopping cannabis and
this can complicate effective management, especially since cannabis dependent users may
resort to consuming various others drugs to relieve the symptoms of cannabis withdrawal (166,
176). Diagnostic criteria for a formal cannabis withdrawal syndrome (CWS) have been
included in the 5th edition of the American Psychiatric Association’s Diagnostic and Statistical
Manual of Mental Disorders (DSM-V) (177).
 Cannabis or marijuana 43

Addiction

The identification and isolation of THC in 1964 enhanced specific research into effects of
cannabis on humans and animals (43). Endogenous cannabinoids (particularly CB1 receptor
activation) activate neural mechanisms in the central nervous system (CNS) similar to how
other reward-enhancing drugs induce drug addiction (178-180). This core reward system is part
of the addiction mechanism that use of cannabis develops in the unwary pot smoker as well as
in users of other illict drugs of addiction (181, 182). This mechanism involves the meso-
accumbens reward circuitry of the CNS as well as neural firing of the neurotransmitter,
dopamine. Some research notes that THC can induce striatal effects on dopamine as noted with
other drugs of abuse (183). Though some studies suggest dependence develops faster in cocaine
versus cannabis users, recent research concludes there is no such difference (184).
Addiction also involves prefrontal cortex (PFC) dysfunction with frontostriatal dysfunction
and the erosion of the ability to stop the addiction; more research is needed to identify potential
impact of cannabinoids in the PFC and its potential role in cannabis dependence (185-187). A
nucleotide polymorphism has been identified in a cannabis receptor-1 gene (CNR1)---
rs2023239-- that is associated with cannabis dependence, cannabis craving, and withdrawal
symptoms due to cannabis abstinence (173). Some neuropeptides called orexins (hypocretins)
originate in the lateral hypothalamus and are linked to features of drug addiction (i.e., cannabis,
nicotine) that include drug craving, relapse, and withdrawal (188).

Cannabis and psychosis

Chronic use of cannabis, particularly with the newer synthetic cannabis products, is associated
with increased rates of psychosis (189-191). Frequent cannabis use increases the risk by two
times for schizophrenia and psychotic symptoms, perhaps by cannabis-induced disruption of
the endocannabinoid system in which the normal signaling and functioning of this endogenous
system is disturbed (192). Cannabis (marijuana) is commonly used by those with schizophrenia
and can cause paranoia in approximately 40% of persons experimenting with this drug (193).
Patients with schizophrenia who consume cannabis are hospitalized at rates higher than those
who do not use cannabis (194).
Cannabis-induced schizophrenia is currently theorized as being due to dysfunction of late
postnatal brain maturation in which glutamatergic transmission dysfunction leads to abnormal
prefrontal neurocircuitry (195). Exposure of adolescents to cannabis at certain times in
adolescence and at certain doses may lead to prefrontal cortical circuitry abnormalities with the
result of inducing schizophrenia in susceptible adolescents (195).
One research group reports a mean time of 7.0 +/- 4.3 years between onset of cannabis use
and onset of psychosis (190). Those at risk for psychosis may be vulnerable to brain volume
loss (i.e., cerebellum, prefrontal cortex, and cingulate) due to use of cannabis (196). Self-
mutilation can also occur with cannabis-induced psychosis (197). Those with psychosis who
use cannabis may not notice improved psychotic symptoms with cessation of their cannabis
(198).
Most cannabis users do not develop psychosis and this cannabis-psychosis link appears to
be via a complex environmental-genetic-molecular interaction possibly involving anandamide
dysfunction and other biological factors (191, 199, 200). Most research suggests a link between
44 Donald E Greydanus and Joav Merrick

cannabis use and risk for suicide in patients with psychosis and also those without psychosis
(201). The development of schizophrenia and use of cannabis share a variety of similarities,
including neuropsychological deficits, reduced motivation, hallucinations, and initiation in late
adolescence (202).
Cannabis is also a very common illicit drug for individuals with psychosis and disruptive
disorders to consume (13, 203). Those with psychosis have a higher rate of cannabis use than
the general population, probably in attempts to utilize the cannabis-induced euphoria to deal
with negative aspects of schizophrenia, such as boredom and depression (12). Cannabis can
also prompt the onset of psychotic symptoms in otherwise healthy people as well, and this
includes paranoia and/or delusional thinking due to effects of THC on striatal and prefrontal
function.
Thus, use of marijuana can have opposite effects on different users. Some research fails to
find a clear association between use of cannabis and symptoms of psychosis, especially with
low or moderate cannabis use (204). A major component of cannabis, cannabidiol (CBD), has
been shown by some research to have anti-psychotic effects (205). The presence of CBD may
explain the lack of psychosis development in many cannabis users. Studies with cannabidiol
(versus THC) suggest a modulating effect based on functional MRI brain imaging (206).
Schizophrenic patients using cannabis may be particularly sensitive to brain damage from the
cannabis though cannabidiol (CBD) may provide a protective effect from brain volume loss
(202).

MANAGEMENT
Behavioral therapies

The “hedonic” CNS dysregulation seen in drug addiction studies in animals and human subjects
underscores the concept of drug addiction as a brain disease and the necessity of prevention
before this complex brain dysfunction arises (12, 182, 207). Indeed, it is difficult to convince
an addicted cannabis user to stop smoking this plant and thus, prevention via intensive and
comprehensive education is the best option currently available. Unfortunately cannabis
dependence is difficult to treat successfully and few who seek to stop their cannabis addiction
succeed in long-term cessation (180). One of the ironic reasons for this is that chronic cannabis
consumers classically have cognitive impairments which lead to defects in their decision
making skills (208).
However, there are steps therapists can take in helping this phenomenon of a nation and a
world obsessed with smoking pot. Continued education of the dangers of cannabis should take
place on a persistent and relentless basis. It should be understood that some literature and some
people conclude that the negative impact of smoking cannabis is limited (209). Cannabis
consumers may be cognizant of such literature, which may encourage them to continue to use
this so-called” safe illicit drug. Thus, teaching about the potential problems of cannabis should
always be provided by healthcare providers to help offset this destructive message of “benign”
pot consumption.
Treatment specifically for cannabis use is needed as management of other or co-existing
drug dependence (such as heroin, tobacco, or alcohol, for example) does not necessarily reduce
 Cannabis or marijuana 45

levels of cannabis consumption (210). Comprehensive school-based prevention programs

teaching about drug use, including cannabis, can be beneficial in lowering youth drug
experimentation and addiction (211, 212). Increased education about high-risk adolescent
behaviors for adolescents and their parents can be useful in prevention efforts (213). Intense
education is needed for groups at high risk for drug abuse, such as males, young adults, and
individuals with increased psychological stress (214).
Behavioral principles for management in adolescence can be directed by factors shown to
suggest higher risk for cannabis use including genetic factors, family history, minimal parental
supervision, drug availability, high-risk peer group, and those with a need for higher thrill-
seeking activities (215, 216). Groups at high risk of mental health problems are those with
combined drug use, such as comorbid cannabis and methamphetamine; thus, this group should
receive intense management (217). Comprehensive behavioral management can also be of help
in reducing cannabis use in those arrested for cannabis possession (218). Screening of these
persons for suicide risk is recommended and lower cannabis use can reduce risks for suicide in
those with and without psychosis (201). Patients with psychosis and cannabis smoking should
undergo behavioral therapies to improve both problems and not just one (219).
If life-time abstinence from cannabis is not possible, delaying its use (especially heavy use)
as long as possible after adolescence and young adulthood, may result in less white matter
damage from cannabis consumption than noted during cannabis smoking in the second and
third decade of life (156). Management can also focus on reducing cannabis use if abstinence
is not possible, since adverse effects tend to be increased with heavy use of cannabis (91).
Therapy should seek underlying factors in use of cannabis or other drugs. For example, research
notes that socially anxious males are at increased risk for use of cannabis as part of a mechanism
to deal with or avoid social situations (220). Thus, therapy can be directed at reasons for this
avoidance behavior and the acquisition of successful strategies to improve their social anxiety
which may reduce the need for ongoing cannabis consumption.
Often recommended behavioral management strategies (such as cognitive behavioral
therapy and contingency management) have their limitations and combination of these
techniques does not increase success in helping those with cannabis dependence (221).
However, research notes that youth with cannabis use disorder benefit more from CBT (versus
family therapy) if they are older teenagers (i.e., 17-18 yrs of age) and do not have pre-existing
psychiatric disorders; in the same study, multidimensional family therapy was more helpful
(versus CBT) for those who were younger (i.e., under age 17) and/or had a past year history of
disruptive disorders (i.e., opposition defiant or conduct disorder) (222).
However, one should continue to provide the cannabis consumer with hope and
encouragement that overcoming this drug addiction is possible despite its wide acceptance in
society. Research does show that such benefit is more likely with intensive or prolonged
behavioral therapy, especially cognitive-behavioral therapy and motivational interviewing
(223). Also, it should be understood that even brief (i.e., four) sessions of motivational
interviewing with cognitive behavioral therapy delivered via telephone can be beneficial, at
least in the short run, for motivated cannabis users who called in seeking help with treatment
(224).
Behavioral therapies can be useful in the motivated cannabis addict and such counseling
seeks to help the cannabis consumer gain control over their addiction at the CNS level by
enhancing neuroanatomical progression from ventral striatal (nucleus accumbens) to dorsal
46 Donald E Greydanus and Joav Merrick

striatal control (182). Even brief interventions may have positive benefit in less cannabis use at
3 month follow-up (3) and another study at 12-month follow-up (17).
Also, therapy seeks to help the addict deal with cannabis craving and relapse triggers, such
as becoming re-exposed to various drugs of addiction; it is also important to help this person
deal with stress and also with finding and avoiding old clues in his/her milieu, such as key
persons, places, or objects (182, 207). Genetic factors also have a role in why some develop
addiction and are recalcitrant to management strategies (207). Involvement of families, schools,
communities, and peer groups are critical in seeking to reduce and prevent cannabis smoking
in adolescents. It is unclear what the interactions are between abuse of illicit drugs and use of
prescription drugs, but the potential drug interactions should be considered in prevention and
treatment plans (225).

PHARMACOLOGIC THERAPIES
There are currently no FDA-approved pharmacologic agents for management of cannabis
dependence. Traditionally, pharmacologic agents have not been specifically beneficial in
treating marijuana addiction whether dependence or withdrawal symptoms (226). However, a
careful assessment of each patient is necessary and a reduction in cannabis use can be noted in
some patients under standard pharmacotherapy for mental illness (223). There is no evidence
that one anti-depressant, anxiolytic, or antipsychotic is more effective than another. Cannabis
use disorders are common in those with schizophrenic spectrum disorders; however, there is
no current literature that guides clinicians in the best treatment approaches for this dual
diagnosis (227). Knowledge, however, is slowly emerging to guide pharmacologic therapies
for cannabis-induced problems in the 21st century.
Individuals with co-occurrence of cannabis and tobacco use tend to have higher abstinence
rates if treatment includes measures aimed at dual abstinence (24). Thus, pharmacotherapy for
nicotine addiction may help the individual stop marijuana use as well by removing use of and
thus, influence of tobacco. Pot-associated persistent insomnia may be improved with use of
trazodone. Research is looking at new methods of treatment that will emerge from the study of
the genetics of addiction including gene-milieu interplay and role of genetic variation (228).

CANNABIS INTOXICATION
Pharmacologic management typically centers on use of benzodiazepines or atypical
antipsychotics. Propranolol and rimonabant (vida infra) have been reported to be beneficial in
management of acute, physiologic effects of cannabis intoxication; use of flumazenil and
cannabidiol is under current study in this regard (229).

CANNABIS WITHDRAWAL
Oral THC (dronabinol) may relieve cannabis withdrawal symptoms but not relapse (230, 231).
Adding dronabinol and lofexidine (alpha-adrenergic receptor agonist) can lower the severity of
 Cannabis or marijuana 47

withdrawal and lower relapse rates in those with cannabis dependence (232). The anti-
depressant mirtazapine can also help those undergoing cannabis withdrawal.

CANNABIS-ASSOCIATED PSYCHOSIS
Cannabidiol has been shown in animal and human studies to have anti-psychotic effects and it
may become a useful pharmacotherapeutic agent for schizophrenia management (205).
Research has therapeutically targeted the cannabinoid (CB1) receptor since delta-9-THC is a
partial CB1 receptor agonist. Treatment of patients with psychotic disorders and cannabis use
should include seeking to reduce or stop the cannabis use, perhaps using cannabinoid agonist
medication (219). Those with psychosis can be provided with appropriate anti-psychotic
medications.

CANNABIS DEPENDENCE
Nabilone is a synthetic THC analogue with improved bioavailability over dronabinol and is
under current research as a potential medication for marijuana dependence as it may lead to a
positive mood and limited adverse cognitive effects in marijuana smokers (233) (see chapter
5). Olanzapine can reduce psychomimetic effects of THC in some individuals and its potential
benefit is under study (234). Rimonabant and the anxiolytic buspirone have provided
some efficacy in cannabis addicts on maintenance therapy. Rimonabant is a CB1-selective
cannabinoid receptor antagonist/inverse agonist that has been under research for obesity
treatment as well as treatment of nicotine and marijuana addiction. It is not available in the
United States and was pulled from the European market in October of 2008 due to a high risk
to benefit ratio; concerns have been identified regarding major psychiatric adverse effects (i.e.,
depression and suicide) as well as overall efficacy (166).

Oxytocin

Animal research notes that various drugs, including cannabis, can induce chronic changes in
markers of oxytocin function with resultant social behavior dysfunction. Oxytocin is a
neurohypophyseal hormone that has been under research in the regulation of drug abuse (235).
This neuropeptide may serve as a neuromodulator on neurotransmission of dopamine in the
nucleus accumbens as well as effects on the hippocampus (235). Central nervous system
oxytocin pathways may offer a way of improving mood and social deficits found in some
individuals with drug addiction (236). Research suggests that use of intranasal oxytocin may
be useful in correcting the negative cannabis (and other illicit drug) effect on social behavior
and perhaps protect the individual from addictive disorders. (237).
NAC

N-acetylcysteine (NAC) has been shown to be useful in management of cannabis-dependent

adolescents and young adults due to modulation of glutamate in the nucleus accumbens; it is
48 Donald E Greydanus and Joav Merrick

suggested as an adjuvant treatment (1,200 mg per day) along with psychological management
(238).

Others

Research has failed to validate the use of naltrexone for the treatment of cannabis dependence.
Entacapone is a member of the drug class called nitrocatechols that is used in the management
of Parkinson’s disease. It is an inhibitor of COMT (catechol-O-methyltransferase) and is under
research as a possible drug for cannabis dependence.
Other drugs under research include lithium, dronabinol, URB597 (fatty acid amide
hydrolase [FAAH] inhibitor), methyllycaconitine or MLA (nicotinic alpha-7-receptor
antagonist), and endocannabinoid metabolizing enzymes (239).

CONCLUSION
Research must provide more specific information on how cannabis and products derived from
cannabis can be useful in medical management of illness or if the cannabis risks simply
outweigh any potential benefit (240). Does cannabis have advantages over specific
cannabinoids? Can the psychotropic effects of cannabis be reduced, while utilizing potential
medicinal benefits of CB1 receptors activation? Oral cannabis undergoes changes which
produce a narrower therapeutic window and raises questions regarding whether or not
medicinal cannabis products can be given orally or must be used as a mist or smoke for positive
and optimal benefit. It is difficult to find an oral dose that benefits most without induced
unacceptable or unwanted adverse effects in many unwary consumers (240).
Generalized consumption of the unprocessed Cannabis sativa plant can lead to
considerable public health risks including increased schizophrenia, psychosis, dependence, and
other risks as noted in this review (241). A medical role for specific cannabinoid compounds
remains under active medical research (242, 243). What is well-known is that there are many
potential medical and psychiatric adverse effects to smoking cannabis and its synthetic
derivatives. Links between use of alcohol, cannabis, and other illicit drugs continues to be
unveiled by research (244). Research is identifying new techniques of cannabis identification
to assist the police and other authorities in forensic investigation (245). Finally, treatment of an
individual with cannabis dependence is very difficult and requires more research in the 21st
century (246, 247). Indeed, Cannabis sativa, a controversial plant known for thousands of
years, remains disputatious and contentious in the 21st century (248).

Medical cannabis

In recent years medical cannabis has been used for patients with cancer, PTSD (post traumatic
stress syndrome), Crohn disease, colitis, Tourette syndrome, Parkinson disease, ALS
(amyotropic lateral sclerosis), MS (multiple sclerosis), epilepsy, Alzheimer disease and AIDS.
 Cannabis or marijuana 49

Health Canada has approved a new regulation on medical marijuana/cannabis, the

Marihuana for Medical Purposes Regulations (249): The production of medical cannabis by
individuals is illegal. Health Canada, however, has licensed authorized producers across the
country, limiting the production to specific licenses of certain cannabis products. There are
currently 26 authorized licensed producers from seven Canadian provinces offering more than
200 strains of marijuana and recent literature indicates that currently available cannabinoids are
modestly effective analgesics that provide a safe, reasonable therapeutic option for managing
chronic non-cancer-related pain (249).
A recent review looked at the use of medicinal marijuana in the treatment of posttraumatic
stress disorder (PTSD) (250). It was concluded that while the literature to date was suggestive
of a potential decrease in symptoms with the use of medicinal marijuana, there was a lack of
large-scale trials, making conclusions difficult to confirm at this time (250).
A German review (251) of cannabis and inflammatory bowel diseases (IBD), irritable
bowel syndrome (IBS) and chronic pancreatitis found that cannabis may be useful for symptom
relief in Crohn's disease such as pain, nausea, and loss of appetite, but studies with high
methodological quality, sufficient sample size and study duration were lacking.
The Guideline Development Subcommittee of the American Academy of Neurology (252)
looked at the efficacy of medical marijuana in several neurologic conditions, such as treatment
of symptoms of multiple sclerosis (MS), epilepsy and movement disorders. The following were
studied in patients with MS: 1) spasticity: oral cannabis extract (OCE) was effective, and
nabiximols and tetrahydrocannabinol (THC) were probably effective, for reducing patient-
centered measures; it is possible both OCE and THC were effective for reducing both patient-
centered and objective measures at one year, 2) central pain or painful spasms (including
spasticity-related pain, excluding neuropathic pain): OCE was effective; THC and nabiximols
were probably effective and 3) urinary dysfunction: nabiximols was probably effective for
reducing bladder voids/day; THC and OCE were probably ineffective for reducing bladder
complaints, 4) tremor: THC and OCE were probably ineffective; nabiximols was possibly
ineffective and 5) other neurologic conditions: OCE was probably ineffective for treating
levodopa-induced dyskinesias in patients with Parkinson disease (252).
Oral cannabinoids were of unknown efficacy in non-chorea-related symptoms of
Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy (252). it seems that
current data are limited and there is a need for randomized controlled trials investigating the
symptom-alleviating and neuroprotective potential of cannabinoids.
Studies in Alzheimer disease, HIV, AIDS and palliative care showed that cannabinoids can
lead to an increase in appetite in patients with HIV wasting syndrome, but the therapy with
megestrol acetate was superior to treatment with cannabinoids (253). Again in this review of
108 studies with 1,561 participants (253) it was found that the studies were not of sufficient
duration to answer questions concerning the long-term efficacy, tolerability and safety of
therapy with cannabis or cannabinoids.
50 Donald E Greydanus and Joav Merrick

ACKNOWLEDGMENTS
This paper is an adapted and revised version of an earlier publication: Greydanus DE, Hawver
EK, Greydanus MM, Merrick J. Marijuana: Current concepts. Front Public Health 2013 Oct
10. doi: 10.3389/fpubh.2013.00042.

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SECTION TWO: PLANT PHARMACOLOGY
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 4

PHARMACOLOGY OF CANNABIS

Mandakini Sadhir*, MD
Division of Adolescent Medicine, Department of Pediatrics, University of Kentucky,
Lexington, Kentucky, United States of America

Cannabis has been used for recreational purposes around the world. It is derived from the
plant cannabis sativa which has various other compounds known as cannabinoids. Most
common form of cannabis used for recreational purpose is marijuana, which is prepared
from dried flowering tops and leaves. The primary psychoactive component is delta 9-
tetrahydrocannabinol (δ-9THC), which exerts its physiological and psychological effects
through its interaction with CB1 and CB2 receptors. Smoking is the most commonly used
method with onset of effects within minutes after inhalation. Oral ingestion of cannabis has
varied absorption with delayed onset but longer duration of action. Urine drug screen is the
most common method for detecting cannabis use. Other cannnabionoids such as
cannabidiol have been utilized for medicinal purpose and research is ongoing to fully
understand its role in treatment of various health conditions. Synthetic cannabis has
emerged as drug of abuse over recent years and poses greater challenge due to serious
physiological and psychological effects and inability to be detected in standard screening
tests. This chapter describes main cannabinoids, their mechanism of action and metabolism
in humans.

INTRODUCTION
Cannabis has been used for recreational purpose around the world for many decades. Its use
however has increased in recent years among adolescents and young adults. Much of this
increase seems to correlate with low risk perception (1, 2). The primary psychoactive
constituent of cannabis is delta 9-tetrahydrocannabinol (δ-9THC) known to have various
physiological and psychological effects. Chronic use leads to dependence and behavioral
disturbances (3). Multiple studies have explored effects of cannabis on various health
conditions, but its medicinal use is currently limited (3, 4). Debate exits over decriminalization

*
Correspondence: Mandakini Sadhir, MD, Division of Adolescent Medicine, Department of Pediatrics, University
of Kentucky, Lexington, KY 40536-0284, United States. E-mail: m.sadhir@uky.edu.
66 Mandakini Sadhir

and legalization of cannabis with potential to have varied consequences (5). The cannabinoids
are mainly classifed as phytocannabinoids, endocannbinoids and synthetic cannabinoids. The
chapter describes these main cannabinoids, their mechanism of action and metabolism in
humans.

PHYTO-CANNABINOIDS
Cannabis is derived from a female plant Cannabis sativa which contains many compounds
known as phyto-cannabinoids or commonly cannabinoids. The principal cannabinoids are delta
9-tetrahydrocannabinol (δ-9THC), cannabidiol (CBD) and cannabinol (CBN) (4). THC initially
isolated in 1964, is a primary psychoactive agent and has been widely studied (6, 7).Over the
years, many new cannabinoid and non- cannabinoid compounds in the plant have been
discovered (4). The number of cannabinoids identified since 2005 has increased from 70 to
104. Other known compounds in the plant have also increased from 400 to 650 (4). The content
of THC varies in different sources and preparations of cannabis. Its content is highest in the
flowering tops and subsequently declines in the leaves, stem and seeds of the plant (8). Most
common form of cannabis that is used for recreational purpose is Marijuana with THC content
from 0.5 % to 5%. It is prepared from the dried flowering tops and leaves (6-8). Another form
of cannabis is hashish with THC content 2–20% and is derived from dried cannabis resin and
compressed flowers (9). The potency of cannabis products has increase significantly from
approx. 3% to 12-16% or higher (percent THC weight/per dry weight of cannabis) over the past
decades due to sophisticated cultivation and plant breeding techniques. The concentration of
THC can also reach about 80% using butane hash oil (4). In the 1960’s and 1970’s, a cannabis
product for example contained about 10 mg of THC. But, in recent years a joint made of other
subspecies of cannabis may contain about 150 mg of THC. Current generation of cannabis user
may be exposed to higher concentrations of THC as compared to those who used cannabis
decades earlier (8).
Cannabidiol (CBD) is a non-psychoactive cannabinoid obtained from the plant. Over the
years, it has drawn much attention due to its pharmacological activity and therapeutic use (10).
CBD is found to have neuroprotective, analgesic, sedative, anti-emetic, anti-spasmodic, anti-
anxiety and anti-inflammatory properties. Research is ongoing to understand its role in
treatment of various health conditions (10, 11).

MECHANISM OF ACTION
Cannabinoids are known to exert their physiological action through G protein coupled receptors
known as CB1 and CB2. These receptors were initially identified in 1990s and have been
extensively studied (12). Activation of these receptors leads to inhibition of adenylyl cyclase
resulting in decreased production of cAMP and changes in ion channel activity. Through these
receptors, cannabinoids hyperpolarize neurons by closing voltage-dependent calcium channels
and activate potassium channels (13). CB1 receptors are present in both central and peripheral
nervous system. They are mostly present in region of brain associated with memory, cognition,
reward, anxiety, pain perception, movement (12-14). These include cortex, hippocampus,
 Pharmacology of cannabis 67

olfactory area, basal ganglia, cerebellum and spinal cord. Few CB1 receptors are found
in the brainstem and thus administration of cannabinoids is not associated with respiratory
depression unlike opioids (8, 13, 14). CB1 receptor activation has also shown to modulate
neurotransmitters in the brain, including glutamate, γ-amino butyric acid (GABA), opioids,
dopamine, and serotonin, resulting in varied effects (8, 9). Role of serotonin receptor 5-HT2A
in causing some of specific effects of THC such as memory deficits, anxiolytic-like effects, and
social interaction has been reported (15). CB2 receptors are present in the cells of immune
system predominantly in the spleen and macrophages and appear to play role in modulation of
cytokine release and immune cell migration (14).

ENDOCANNABINOIDS
Endocannabinoids are endogenous compounds discovered in the 1990s that interact with
cannabinoid receptors and produce similar effects as cannabis (10). The two main endogenous
compounds are anandamide (from the Sanskrit word ananda, meaning bliss) and 2-
arachidonoylglycerol (2AG) (10). These are derivative of the fatty acid arachidonic acid related
to the prostaglandins. Anandamide is partial agonist for both CB1 and CB2 receptors with CB1
efficacy higher than CB2. It produces similar effects to δ-9THC, but is less potent and has
shorter half-life due to rapid metabolism (9, 16). 2-Arachidonoylglycerol was originally
identified in intestinal tissue and is found at much higher levels than anandamide in the brain.
2-AG is thought to be the main endogenous agonist for both CB1 and CB2 receptors (16).
Endocannabinoids also interact with other G protein coupled receptor and ion channels. Some
of the known ion channel are vanilloid receptor-type 1 (TRPV1) activated by anandamide.
Other receptors are several types of potassium channels, alpha7 nicotinic receptors and 5-HT3
receptors (10, 11). The endocannabinoid system comprised of endocannabinoids and its
receptors is thought to mediate various physiological processes and are implicated in health and
disease (16).

ABSORPTION OF CANNABIS
The tetrahydrocannabinol and other cannabinoids have varied absorption and effects depending
on dose, route of administration and vehicle. Further physiological factors such as metabolism
and excretion can influence drug concentrations and its subsequent effects (11). Smoking is
most common and widely used method. After inhalation, THC is rapidly absorbed through
lungs and reaches brain quickly with physiological and psychological effects becoming
apparent within seconds to minutes (10, 17). The effects then reach a plateau that can last 2–4
h before slowly declining. While, the amount of THC absorbed is higher with inhalation, the
bioavailability varies according to the depth of inhalation, puff duration and breath-hold (17).
Absorption of THC is variable when ingested. When taken orally, some of the THC is degraded
by liver due to first pass metabolism and converted to 11-hydroxy δ-9THC, which is also a
psychoactive agent (10, 17). The concentration of 11-hydroxy δ-9THC is thus higher in blood
after ingestion than inhalation and may contribute to some of the psychological effects (17).
With oral ingestion, onset of effect and peak concentration of THC in blood is much delayed
68 Mandakini Sadhir

(1-2h) (11). Slow gastrointestinal absorption prolongs the duration of action that may last
several hours (8, 9, 11). Other routes of administration for cannabis such as oro-mucosal, rectal
and transdermal have been explored and studied. These routes of administration increase
bioavailability of THC by avoiding first pass metabolism in the liver. Such forms may be
beneficial for therapeutic uses but further research is needed (11).

DISTRIBUTION
Cannabinoids are highly lipophilic and get distributed in adipose tissue, liver, lung and spleen
(9). Following assimilation in blood, concentration of THC in plasma decreases due to
peripheral redistribution particularly in adipose tissues. Sequestration in adipose tissue
prolongs elimination half- life that can last for several days (8, 11). From the adipose tissue,
THC gets slowly released into the blood stream and other body compartments including the
brain. Cannabinoids also cross the placenta, entering into fetal circulation and secreted in breast
milk (9).

METABOLISM AND ELIMINATION

THC is metabolized in the liver by microsomal hydroxylation and oxidation using enzymes
of Cytochrome P 450 Complex generating more than 100 metabolites (18, 19). As a result
of hydroxylation, THC generates a psychoactive compound 11-hydroxy δ 9_Tetra
hydrocannabinol (11-OH-THC). Further, 11-OH-THC is oxidized by microsomal alcohol
dehydrogenase and aldehyde oxygenase to produce the non-psychoactive metabolite,
THCCOOH (11). The majority of cannabinoids (80-90%) are excreted within five days as
hydroxylated and carboxylated metabolites (18). The elimination of metabolites is mostly
through feces (65%) and approximately 20% in urine (17). Among the major metabolites, 11-
OH-THC is predominantly excreted in feces and THCCOOH is excreted in urine mainly as a
glucuronic acid conjugate. This particular metabolite has been utilized for diagnostic purposes
for detection of cannabis in urine (17).

DETECTION AND ANALYSIS OF CANNABIS

Cannabinoids can be detected in urine, blood, saliva, hair and nail using various analytical
techniques (20). These techniques are utilized to measure cannabinoids for research studies,
drug treatment and employment related drug screening. Various chromatographic techniques
such as thin layer chromatography (TLC), high performance thin layer chromatography
(HPTLC), gas chromatography-mass spectrometry (GC-MS), high performance liquid
chromatography-mass spectrometry (HPLC- MS) have been utilized for detection and
quantitation of cannabis metabolites (17). The preferred sample for screening is urine to
check for presence of urine metabolites particularly glucuronic acid conjugate of THCCOOH
(20). The main techniques utilized for urine drug screening are immunoassay and gas
chromatography-mass spectrometry (GC-MS). Immunoassays are the most common method
 Pharmacology of cannabis 69

for initial screening while GC-MS is used for confirmation (21, 22). The cut off limit for
cannabis metabolites in immunoassay is 50ng/ml; it is 15 ng/ml for GC-MS. Detection of
metabolites in urine varies depending on frequency and duration of cannabis use. It can be
detected anywhere from 3 days (single use) up to 30 days or longer (long term heavy smoker)
(22).
Detection of THC and its metabolites is influenced by various other factors in addition to
sensitivity and specificity of assays. These factors include route of administration, amount of
cannabinoids consumed and absorbed, body fat content, rate of metabolism and excretion, time
of specimen collection (9, 20).
There has been growing interest in utilization of oral fluids as an alternative biological
specimen for detection of drugs in forensic and clinical settings (23). Studies have shown oral
fluids to be simple, non-invasive method of specimen collection with advantages of observed
specimen collection, making adulteration difficult. It has shown to have stronger correlation
with blood than urine concentration of cannabis metabolites and can detect recent exposure
(23). It also offers ease of multiple sample collections and lower biohazard risk of specimen
collection. Currently, research on oral fluids in ongoing and further evaluation is needed before
implementing it as a drug screening test (23).

SYNTHETIC CANNABINOIDS
Synthetic cannabinoids are a heterogeneous group of compounds originally synthesized for
research purpose to explore endogenous cannabinoid system for possible therapeutic use (24).
However, these compounds became drugs of abuse and were marketed as “designer drugs”. In
the 2000s, synthetic cannabinoids were sold under brand names such as “spice” and “K2,”
labeled as herbal incense. These became very popular drugs of abuse as they could not be
detected by standard screening tests (25).
The synthetic cannabinoids act on cannabinoid receptors and have greater affinity to CB1
than CB2 receptors. Both animal and in vitro studies have shown that synthetic cannabinoids
are 2-100 times more potent than THC (25). Synthetic cannabinoids are metabolized in the liver
via conjugation and oxidation pathways and have longer elimination half- life (24, 25). Use of
synthetic cannabinoids has resulted in medical and psychiatric emergencies due to their intense
physiological and psychological effects. Some of the common adverse effects include seizures,
myocardial infarction, acute renal failure, anxiety, agitation, psychosis, suicidal ideation, and
cognitive impairment. Long-term or residual effects are currently unknown (26, 27).

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70 Mandakini Sadhir

[3] Ammerman S, Ryan S, Adelman WP, Committee on Substance Abuse, Committe on Adolescence. The
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[4] Madras BK. Update on cannabis and its medicinal use. Belmont, MA: McLean Hospital, Alcohol Drug
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[5] Haase H, Eyle N, Schrimpf J. The international drug control treaties: How important are they to US
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[6] Robson P. Cannabis. Arch Dis Child 1997;77(2):164-6.
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cannabinoids. Anaesthesia 2001;56(11):1059-68.
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tetrahydrocannabinol, cannabidiol and cannabinol. Handb Exp Pharmacol 2005;168:657-90.
[12] Hirst R, Lambert D, Notcutt W. Pharmacology and potential therapeutic uses of cannabis. Br J Anaesth
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[13] Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol 2008;20(Suppl
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serotonin 5-HT2A Receptors. PLoS Biol 2015;13(7):e1002194.
[16] Maccarrone M, Bab I, Bíró T, Cabral GA, Dey SK, Di Marzo V, et al. Endocannabinoid signaling at
the periphery: 50 years after THC. Trends Pharmacol Sci 2015;36(5):277-96.
[17] Sharma P1, Murthy P, Bharath MM. Chemistry, metabolism, and toxicology of cannabis: clinical
implications. Iran J Psychiatry 2012;7(4):149-56.
[18] Jiang R, Yamaori S, Takeda S, Yamamoto I, Watanabe K. Identification of cytochrome P450 enzymes
responsible for metabolism of cannabidiol by human liver microsomes. Life Sci 2011;89(5-6):165-70.
[19] Watanabe K, Yamaori S, Funahashi T, Kimura T, Yamamoto I. Cytochrome P450 enzymes involved
in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci
2007;80(15):1415-9.
[20] Musshoff F, Madea B. Review of biologic matrices (urine, blood, hair) as indicators of recent or
ongoing cannabis use. Ther Drug Monit 2006;28(2):155-63.
[21] Chiarotti M, Costamagna L. Analysis of 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol in biological
samples by gas chromatography tandem mass spectrometry (GC/MS-MS). Forensic Sci Int
2000;114(1):1-6.
[22] Moeller KE, Lee KC, Kissack JC. Urine drug screening: practical guide for clinicians. Mayo Clin Proc
2008;83(1):66-76.
[23] Lee D, Huestis MA. Current knowledge on cannabinoids in oral fluid. Drug Test Anal 2014;6(1-2):88-
111.
[24] Wiley J, Marusich J, Huffman J. Moving around the molecule: relationship between chemical structure
and in vivo activity of synthetic cannabinoids. Life Sci 2014;97(1):55-63.
[25] Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, Huestis MA. Synthetic
cannabinoids: epidemiology, pharmacodynamics, and clinical implications. Drug and Alcohol
Dependence. Drug Alcohol Depend 2014;144:12-41.
[26] Castellanos D, Gralnik LM. Synthetic cannabinoids 2015: An update for pediatricians in clinical
practice. World J Clin Pediatr 2016;5(1): 16-24.
[27] National Institute on Drug Abuse. Synthetic cannabinoids: Drug facts. URL:https:// www.drugabuse.
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In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 5

THE PHARMACOLOGICAL PROPERTIES OF CANNABIS

Istok Nahtigal, MSc, Alexia Blake, MSc,

Andrew Hand, MSc, Angelique Florentinus-Mefailoski, MSc,
Haleh Hashemi Sohi, PhD and Jeremy Friedberg*, PhD
MedReleaf Corp, Markham Industrial Park, Markham, Ontario, Canada

The efforts to understand the nature of how the consumption of cannabis affects the human
body are ongoing, complex, and multifaceted. Documentation on the use of cannabis dates
back thousands of years; however, it is only now with the recent softening of legal
restrictions that modern research approaches have been able to initiate an appropriate level
of detailed investigations. For clinicians, researchers and policy makers, this chapter
reviews the general structure of cannabinoids, the current understanding of cannabinoids
on cellular systems, the diference between inhalation and oral consumption on cannabinoid
bioavailability, the variance among purified cannabinoids versus whole plant extract, and
the potential activities of another prominent family of secondary metabolites found in
cannabis, the terpenes.

INTRODUCTION
The efforts to understand the nature of how the consumption of cannabis affects the human
body is an ongoing and complex process. Although documentation of cannabis’ use dates back
thousands of years, it was only in the recent amelioration of legal restrictions that allowed
modern research approaches to initiate an appropriate level of detailed investigations, as with
other plant species. For clinicians, researchers and policy makers, this chapter reviews the
general structure of cannabinoids, the current understanding of cannabinoids within cellular
systems, the differences of inhalation and oral consumption on cannabinoid bioavailability, the
therapeutic efficacy of purified cannabinoids versus whole plant extract, and the potential
activities of another prominent family of secondary metabolites found in cannabis, the terpenes.

*
Correspondence: Jeremy Friedberg, PhD, MedReleaf Corp, Markham Industrial Park, POBox 3040, Markham,
Ontario, L3R 6C4, Canada. E-mail: jfriedberg@medreleaf.com.
72 Istok Nahtigal, Alexia Blake, Andrew Hand et al.

STRUCTURE, EXPRESSION AND PRODUCTION

OF KNOWN CANNABINOIDS

Phytocannabinoids are represented by a number of compounds that exhibit potent bioactivities

on human physiology (1) and make up the most studied group of chemicals from the Cannabis
sativa plant (see Table 1 for a list of predominant cannabinoids). Phytocannabinoids have also
been discovered in plants from the genus Radula (liverworts) and Helichrysum (sunflower
family) (2). Notwithstanding the long history of cannabis use and research, the cannabinoid
biosynthesis pathways have only been recently elucidated. Cannabigerol type compounds
(CBG, CBGa) were the first cannabinoids identified (3) and it is CBGa that is converted into
THCa, CBDa and CBCa via the action of oxidocyclase THCa-, CBDa- or CBCa-synthase (4).
Cannabigerol is synthesized from olivetolic acid (OLA) and geranyl diphosphate (GPP),
products of the polyketide and non-mevalonate pathways, respectively. The cannabinoids THC,
CBD and CBC possess a C5 side chain, versions also exist wherein a C3 group is substituted
and the compounds are otherwise identical. These analogous cannabinoids are THCVa,
CBDVa and CBCVa, whose precursors are divarinolic acid (DVA) and GPP.
Cannabinoids are not present plant-wide. They are produced and primarily localized to
specialized structures called trichomes. Trichomes are epidermal protuberances which cover
the flower, leaves and parts of the stem (1, 5). The cannabinoids are synthesized in secretory
cells and translocated to a storage cavity within the trichome (6). Compartmentalization is
necessary due to the cytotoxic nature of cannabinoids. It is from these trichomes that the
cannabinoids are harvested or vaporized, depending on the end use or mode of consumption.
The natural form of the cannabinoids as they exist in the trichome are the acid forms, however,
neutral cannabinoids are the pharamacologically active forms responsible for the partial
agonistic effects on both the CB1 and CB2 type receptors. Consequently, moderate heating is
required to drive a decarboxylation reaction where the carboxylic acid moiety of the acid
cannabinoids is removed, leaving the neutral forms (7).

KNOWN CANNABINOIDS AND THEIR EFFECTS ON CELLULAR AND

SYSTEM PHYSIOLOGY

Cannabis sativa produces a wide range of secondary metabolites, with the total number of
identified and reported compounds increasing steadily since Gaoni and Mechoulam first
isolated (-)-trans-delta-9-tetrahydrocannabinol (Δ9-THC) in 1964 (8). In total, 545 different
compounds have been isolated, of which 104 belong to a group of compounds unique to
Cannabis sativa, referred to as cannabinoids (9-17) (see Table 1). However, this number is
considered by many researchers to be dynamic and is a subject of debate, with the number of
cannabinoid-like compounds possibly exceeding 130 (18). Most of these compounds are
typically present only in trace quantities, and the pharmacological value of only a small number
has been researched. The focus of this paper on the pharmacological action of Δ9-THC and
cannabidiol (CBD).
 Table 1. Predominant cannabinoids with clinical relevance

Molecule Clinical Relavance Molecule Clinical Relavance

Δ9-THCA Antiemetic (Hernandez et al. 2015) CBDA Antipsychotic (Leweke et al. 2012)
C21H30O2 Treatment of PTSD (Roitman et al. 2014) C21H30O2 Palliative Care of Parkinson's (Chagas et al. 2014)
314.47 g/mol Treatment of Sleep Disorders (Gorelick et al. 2013) 314.46 g/mol Anxiolytic (Bergamaschi et al. 2011)
Acidic Form Palliative Treatment of Dementia (Woodward et al. 2014) Acidic Form Treatment of PTSD (Das et al. 2013)
C22H30O4 Treatment of IBS (Wong et al. 2011) C22H30O4 Treatment of Epilepsy (Pelliccia et al. 2005)
358.47 g/mol Appetite Stimulant (Costiniuk et al. 2008) 358.46 g/mol Anti-Inflammatory/Anti-nociceptive (Gallily et al. 2015)
Δ9-THCVA Treatment of Obesity (Tudge et al. 2014) CBDVA Antiemetic (Rock et al. 2013)
C19H26O2 Anti-Inflammatory/Anti-nociceptive (Bolognini et al. 2010) C19H26O2 Anticonvulsant in Mice (Hill et al. 2012)
286.41 g/mol Treatment of Epilepsy (Hill et al. 2010) 286.40 g/mol Treatment of Epilepsy (Amada et al. 2013)
Acidic Form Treatment of Insulin Sensitivity (Wargent et al. 2013) Acidic Form Anti-Acne (Olah et al. 2016)
C20H26O4 C20H28O4 Treatment of Bladder Dysfunctions (Pagano et al. 2015)
330.41 g/mol 330.40 g/mol
Δ8-THCA Improvement of Appetite (Avraham et al. 2004) CBCA Anti-Acne (Olah et al. 2016)
C21H30O2 Antineoplastic Activity (Munson et al. 1975) C21H30O2 Anti-Inflammatory (Wirth et al. 1980)
314.47 g/mol Antiemetic (Abrahamov et al. 1995) 314.46 g/mol Treatment of Colitis (Romano et al. 2013)
Acidic Form Acidic Form Treatment of Hypertension (O'Neil et al. 1979)
C22H30O4 C22H30O4 Treatment of Hypermotility (Izzo et al. 2012)
358.47 g/mol 358.46 g/mol Reduction of Intraocular Pressure (Colasanti et al. 1984)
CBGA Appetite Stimulant (Brierley et al. 2016) CBCVA No Clinical Research Preformed
C21H32O2 Treatment of Huntington's Disease (Diaz-Alonso et al. 2016) C19H26O2
316.48 g/mol Reduction of Intraocular Pressure (Szczesniak et al. 2011) 286.40 g/mol
Acidic Form Treatment of Dry-Skin Syndrome (Olah et al. 2016) Acidic Form
C22H32O4 Anti-Cancer (Scott et al. 2013) C20H30O4
360.48 g/mol 330.40 g/mol
CBGVA Treatment of Dry-Skin Syndrome (Olah et al. 2016) CBNA Analgesia (Sofia et al. 1975)
C19H28O2 Anti-Cancer (Scott et al. 2013) C21H26O2 Reduction of Intraocular Pressure (Colasanti et al. 1984)
288.42 g/mol 310.43 g/mol Appetite Stimulant (Farrimond et al. 2012)
Acidic Form Acidic Form
C21H28O4 C21H26O2
332.42 g/mol 354.43 g/mol
74 Istok Nahtigal, Alexia Blake, Andrew Hand et al.

Figure 1. The human endocannabinoid system.

The primary cannabinoid that is responsible for the psychotropic effects of Cannabis sativa
is Δ9-THC (19) (see figure 1). Similar to endogenous post-synaptic released endocannabinoids,
anandamide and 2-arachidonoylglycerol, Δ9-THC interacts with and activates G protein-
coupled CB1 and CB2 cannabinoid receptors (20-22). CB1 receptors are found in a high
concentration in many tissue types throughout the body, including most brain regions and the
peripheral nervous system (23), as well as some non-neuronal tissues such as the liver, stomach,
heart, testes, and fat tissue (24-28). Presynaptic activation of CB1 receptors in neuronal tissue
inhibits release of neurotransmitters such as gamma-Aminobutyric acid and glutamate by
releasing βγ-subunits from the G protein complex, leading to inhibition of voltage-gated
calcium channels and vesicle release (29-30). However, while activation of CB1 receptors
typically inhibits release of neuronal transmitters, in vivo activation of CB1 with Δ9-THC has
been observed to occasionally increase release of acetylcholine, dopamine and glutamate in
various regions of the brain in rats (31-34). It is likely that this is due to selective antagonism
by Δ9-THC of endocannabinoids, as reported by Patel and Hillard (35) when observing anti-
anxiolytic effects of Δ9-THC administration in mice. It is this inhibitory-stimulation modulation
of neurotransmitter release mediated by Δ9-THC that is thought to be responsible for the
psychotropic effects of Cannabis, both depressant and excitatory in nature. Cannabidiol,
however, does not share psychotropic activity with Δ9-THC, instead acting as a CB1 inverse
agonist or even antagonist, thereby attenuating in vivo response to Δ9-THC in multiple model
species (36). Cannabinoid CB2 receptors on the other hand, are more typically located on organs
related to the immune system, and when activated attenuate pro-inflammatory responses such
 The pharmacological properties of cannabis 75

as cytokine release and immune cell response (37-38) (see Figure 1). There is evidence that
CBD interacts with CB2 receptors as an inverse agonist, leading to the well-documented
reduction of clinical pro-inflammatory markers such as TNF-α, iNOS and COX-2 expression
(39). In addition to the effects on CB2, CBD has also been reported to interact with additional
immune system related receptors. For example, CBD has been found to potently inhibit uptake
of adenosine at A2A receptors, the mechanism by which adenosine signaling terminates,
thereby enhancing the anti-inflammatory effects of adenosine agonists (40). CB2 receptors are
also found in both brain and peripheral neuronal tissue in a lower concentration relative to CB1
receptors, however their role has yet to be elucidated (41).

INHALATION VERSUS ORAL CONSUMPTION AND BIOAVAILABILITY

As with all drugs, the pharmacokinetics (PK) of cannabis are dependent on the route of
administration.. To date, most human clinical trials have evaluated the PK activity of cannabis
after inhalation or ingestion. While different studies report a wide range of PK parameters due
to differences in dosing, it is still clear that the onset, rate of absorption, and bioavailability of
THC and CBD are significantly higher after inhalation than after ingestion or oral
administration (42, 43) (see Table 2).

Table 2. Pharmacokinectics of cannabis based on route of administration

Route of
Inhalation Oral
Administration
% Dose Consumed ~ 50% (loss due to pyrolysis) 100%
Trajectory to Lungs – Bronchi-Bronchiole - Stomach – Small Intestines – Portal
Circulation Alveoli Vein - Liver
Absorption (stomach contents,
Intake upon inhalation (puff
Other Factors metabolic rate, genetic variants in
duration, intake volume,
Affecting Uptake CYP 450 enzyme activity, enzyme
holding time)
regulation by other drugs)
First-Pass Hepatic First-Pass Hepatic Metabolism by
Bypassed
Metabolism CYP450 enzymes
Bioavailability 2 – 56% < 20%
Onset Immediate 30 – 90 minutes
Time of Peak
5 – 10 minutes 1 – 6 hours
Plasma
Duration 2 - 4 hours 4 – 8 hours

THC is detectable in blood almost immediately after smoking, with peak plasma
concentrations measurable after 5 – 10 minutes (42, 44-46). Reported peak values vary with
administered dose. For instance, one study reported that inhalation of cigarettes containing
1.75% THC (equivalent to 16 mg THC) and 3.55% THC (34 mg THC) resulted in mean peak
plasma concentrations of 84.3 ng/ml and 162.2 ng/ml, respectively (42). However, the range of
measured peak plasma concentrations for the low dose cigarette was 50-129 ng/ml and 76-267
ng/ml for the high dose cigarette.
76 Istok Nahtigal, Alexia Blake, Andrew Hand et al.

Such wide ranges are also found when comparing reported bioavailability values. Some
studies have reported the bioavailability of inhaled THC as 30% (46), 10 – 35%(43), and
18%(47). One study comparing the pharmacokinetics of THC between frequent and occasional
users concluded that the bioavailability was 23 – 27% for frequent users, and 10 – 14% for
occasional users (45). These differences arise from variances in smoking technique, with
factors such as puff duration, intake volume, and holding time determining drug intake (42, 43,
48). Furthermore, up to 30% of THC has been shown to be lost during the pyrolysis process,
with additional loss occurring in the side stream smoke and incomplete absorption in the lungs
(43, 45, 49). As a conservative calculation, the bioavailability of THC after smoking is reported
as 2-56% (42, 48).
Fewer studies have focused exclusively on the PK activity of CBD. One study reported
that the bioavailability of CBD after inhalation was 31%, while others remark on the similarity
in PK activity between THC and CBD (43, 50). However, it has been reported that CBD may
alter the PK activity of THC, and can mediate some of its adverse effects, such as paranoia and
anxiety (42, 50-53). The exact reason for this modulatory effect is unknown, but current
scientific opinion is that CBD inhibits the activity of cytochrome P450 enzymes, which in turn
effects THC metabolism, particularly after oral administration (42, 48, 51).
The PK activity of cannabis after oral administration is rather different. Absorption is much
slower and irreproducible, with the onset of action ranging between 30 – 90 minutes. Peak THC
plasma concentrations may be reached as early as 1-2 hours after ingestion or as late as 4 – 6
hours (42, 45). Also, the duration of effects is noticeably longer after oral administration than
after inhalation (48).
Oral administration is known to diminish the bioavailability of both THC and CBD
compared to inhalation. Several studies have reported that the bioavailability of THC after
ingestion is 4-20% (42), 4-12% (43), 3-14% (50), and 6% (52). Similarly, the oral
bioavailability of CBD has been reported as 13 – 19% (54) and 6% (55).
The major explanation for this reduction in oral bioavailability is that cannabinoids
undergo extensive first pass hepatic metabolism by CYP 450 genes prior to reaching systemic
circulation (42, 43, 50). Oxidation into 11-OH-THC and other metabolites diminishes the
amount of THC that reaches systemic circulation, thereby reducing oral bioavailability. For the
same reason, plasma levels of 11-OH-THC are significantly higher after oral administration
compared to inhalation (43). With inhalation, first pass hepatic metabolism is avoided since the
cannabinoids enter system circulation via the lungs. Overall, these differences in PK activity
allow patients to customize their treatment based on their therapeutic needs. For example, a
patient in need of instant pain relief may prefer to smoke or vape cannabis. Conversely, a patient
with insomnia may be less interested in instant effects, and instead may prefer to ingest
cannabis and experience its effects throughout the night.

THE COCKTAIL VERSUS THE INDIVIDUAL COMPOUNDS

The use and efficacy of herbal drugs in traditional medicine has been documented for centuries
among many cultures. Recently published data has presented evidence for the therapeutic
bennefits of whole botanical extracts over single isolated constituents, as well as their
bioequivalence with synthetic chemotherapeutics (56, 57).
 The pharmacological properties of cannabis 77

Different molecules and metabolic pathway components such as enzymes, substrates,

receptors, ion channels, transport proteins, DNA/RNA, ribosomes, monoclonal antibodies and
physicochemical mechanisms are the possible targets for different bio-chemical molecules that
are present in a plant extract (59). Synergistic effects of plant extracts result in the following
ways: (i) constituents of a plant extract affect different targets (ii) constituents interact with one
another to improve their solubility, thereby enhancing the bioavailability of one or several
substances of an extract and (iii) compounds may also have their efficacy enhanced with agents
that antagonize mechanisms of resistance (58).
A given synergistic effect can be tested by comparing the pharmacological effects of the
mono-substances versus the combination of substances by analyzing isobole curves based on
data from several dose combinations (60). This analysis enables one to discriminate effects
between simple additive, antagonistic interactions or real synergism with potentiated or over-
additive effects (56).
However, other compounds in plant extracts could enhance the overall efficacy if negative
symptoms or ‘‘lateral damages’’ have developed during a disease. Many plant extracts are rich
in other secondary metabolites, such as polyphenols and terpenoids. These have an important
role in this way, specifically when their bioavailability is high. Polyphenols possess a strong
ability to bind with proteins or glycoproteins and terpenoids have great affinities for cell
membrane because of their lipophilicity and therefore a high potential to permeate through cell
wall of the body or bacteria (56).
For example, a study clearly illustrated that cannabis plant extracts are superior to pure
cannabidiol for the treatment of inflammatory disease. This higher efficiency might be
explained by additive or synergistic interactions between CBD and minor phytocannabinoids
or non-cannabinoids presented in the extracts (61). A study of efficacy of the whole plant
Artemisia annua and pure artemisinin (the active compound) in the treatment of malaria showed
the whole plant to be clinically efficacious, well-tolerated, and can be more effective than
purified compounds used to reduce malaria morbidity and mortality (62). While the synergism
between compounds in the whole plant extract increases the extracts’s efficacy, there are also
conerns about adverse reactions (ADRs). Adverse reactions tend to be more apparent with
combinations of prescribed synthetic medicines, but clinical manifestations of ADRs do not
seem to be common for botanical extracts. This may be due, in part, to a lack of reporting of
adverse reactions for herbal medicines (63).

TERPENE BIOCHEMISTRY AND FREE RADICAL SCAVENGING

Terpenes comprise a diverse class of organic compounds which are produced by a variety of
plants. Their functions range from plant protection by deterring herbivores to attracting
predators and pollinating insects. In addition to their roles as end-products or secondary
metabolites, terpenes are biosynthetic building blocks within nearly every living creature.
Steroids, as an example, are derived from the terpene squalene.
When terpenes are modified chemically, through oxidation or structural rearrangement, the
resulting compounds are generally referred to as terpenoids. More often than not, the term
terpene is used to include all terpenoids. The difference between terpenes and terpenoids is that
terpenes are hydrocarbons, whereas terpenoids contain additional functional groups such as
78 Istok Nahtigal, Alexia Blake, Andrew Hand et al.

oxygen moieties or branching methyl groups. Terpenes and terpenoids are the primary
constituents of the essential oils of plants and flowers (64). They are a chief constituent of the
Cannabis sativa plant; as of 2011, over 200 terpenoids have been identified in cannabis, with
little being known of how they affect the pharmacological properties (65). The synergistic
relationship between terpenes and cannabinoids can occur through four different mechanisms;
i) multi-target physiological effects, ii) pharmacokinetics, iii) bacterial resistance and iv) side
effect modulation. The synergistic potential of terpenes adds weight to the idea that plants can
be better drugs than singular compound derived from them (65).
Terpenoids are pharmacologically versatile due to their lipophilic nature, enabling
interaction with cell membranes, neuronal and muscle ion channels, neurotransmitter receptors,
G-protein coupled receptors, second messenger systems and enzymes (66). These substances
have immensely broad biochemical effects, influencing some of the most critical enzyme
systems, while affecting neurotransmitter levels and other fundamental processes. These effects
are exactly what pharmaceutical drugs are designed to do. One of the most important and
captivating aspects of these novel compounds is that they are pharmacologically active in
extremely minute quantities well below toxic levels. Terpenoids are bioavailable in high
percentages due to their lipophilic properties, permitting passive migration across biological
membranes and enter the blood stream moving onto influencing activities of the brain, heart or
other organs. Some of the most commonly found terpenes in Cannabis sativa are:

 D-limonene: studies using citrus oils in mice and humans showed profound anxiolytic
and antidepressant effects (67, 68).
 β-Myrcene: anti-inflammatory, analgesic and sedative properties (69).
 α-Pinene: anti-inflammatory, antibacterial and a bronchodilator, as well as being able
to counteract short-term memory deficits induced by THC intoxication (65, 68).
 D-Linalool: anxiolytic activity (68, 70).
 β-Caryophyllene: is the most common sesquiterpenoid encountered in cannabis.

While these compounds are the major representatives by mass, it is important to note that
there are significantly more chemical species present in small quantities each with its own and
compounded effects.
Plant antioxidants are composed of a broad variety of compounds, such as ascorbic acid,
polyphenolic compounds, and terpenoids. Terpenes are the main components of essential oils,
their anti-oxidative capacity contributes to the beneficial properties of fruits and vegetables.
Three main modes of antioxidant action have been detected to date: (i) quenching of singlet
oxygen, (i) hydrogen transfer, and (iii) electron transfer. Several investigations have studied
reactive oxygen species and the antioxidant activity of monoterpenes and diterpenes or essential
oils in vitro (71). Reactive oxygen species (ROS) are created from free radicals generated
during energy metabolism and by environmental deterioration, inadequate nutrition and
exposure to irradiation and stress involved in the pathological development of many human
diseases such as neurodegeneration, cardiovascular deterioration, diabetes and others. The most
promising strategy to avert oxidative damage caused by these reactive species is the use of
antioxidant molecules. Antioxidants play an important role in defending the body against free
radical attack by delaying or inhibiting the oxidation of lipids or other biomolecules,
preventing, or facilitating the repairing, of the damage to cells (72). These compounds can act
 The pharmacological properties of cannabis 79

as direct antioxidants through free radical scavenging mechanisms and/or as indirect

antioxidants by enhancing the antioxidant status (enzymatic and non-enzymatic). Terpenes, one
of the most extensive and varied structural compounds occurring in nature, display a wide range
of biological and pharmacological activities. Due to their antioxidant behaviour terpenes have
been shown to provide relevant protection under oxidative stress conditions in different
diseases including liver, renal, neurodegenerative and cardiovascular diseases, cancer, diabetes
as well as in aging processes (73).

CONCLUSION
Cannabis is plant rich with diverse compounds that exhibits a range of effects on human
physiology. These effects are primarily attributed to cannabinoids and terpenes, large families
of metabolites that can interact with many cellular and physiological systems in the body.
Although much research still needs to be done, the effects of these metabolites provides an
important tool in managing a range of clinical symptoms. Among cultivars of the plant, varying
levels of these compounds create different physiological effects and depending on how the
plant is administered to patients, can alter the clinical utility.

ACKNOWLEDGMENTS
We thank Dean Pelkonen for assistance with graphic design for Figure 1.

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SECTION THREE: CLINICAL APPLICATIONS
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 6

MEDICAL CANNABIS USE IN AN OUTPATIENT

PALLIATIVE CARE CLINIC

Noah Spencer, BASc(C), Erynn Shaw, MD

and Marissa Slaven*, MD
Bachelor of Arts and Science Program, Faculty of Science and Faculty of Health
Sciences, McMaster University, Hamilton, Ontario, Canada

Despite medical cannabis’ capacity for symptom relief and its legality in many
regions, it still remains a controversial treatment. Our outpatient palliative care oncology
clinic has experienced an increase in interest from patients to incorporate medical cannabis
into their symptom management. The aim of this chapter is to better understand the
demographics, diagnosis, and symptom profile of patients with advanced cancer accessing
medical cannabis. Methods: A retrospective chart review was undertaken of patients
accessing medical cannabis at an academic tertiary Symptom Management Clinic for a
seven month study period in 2014. Results: Of approximately 340 patients seen in clinic,
43 patients (12.5%) were identified as having obtained authorization for medical cannabis.
Patients were predominantly older with 74.4% of patients aged 51-75 years, and 4.7% of
patients were over 75 years of age. They had a wide variety of cancer diagnosis, of which
GI maligancies (30%) and lung cancer (20.9%) were the most common. Patients
experienced a multitude of symptoms with pain being the most common (88.4%), followed
by fatigue, nausea and lack of appetite. Of note, a significant number (39.5%) reported
already using medical cannabsi at the time of lisencing. Conclusions: The field of medical
cannabis use is young and much work still needs to be done to understand its place amongst
symptom management in general and in palliative patients specifically. This small
retrospective study describes a cohort of pallaitive cancer patients who accessed medical
cannabis to manage a variety of symptoms.

*
Correspondence: Marissa Slaven, MD, Faculty of Health Sciences, McMaster University, 699 Concession St,
Hamilton, Ontario L9H 1Z8, Canada. E-mail: slavenm@hhsc.ca.
86 Noah Spencer, Erynn Shaw and Marissa Slaven

INTRODUCTION
Medical cannabis has been in use for thousands of years. In 2737 BCE, Chinese emperor
Shen-Nung wrote that cannabis could be used to treat constipation, gout, rheumatism, and
absent-mindedness (1). The Ancient Egyptians used cannabis to relieve the pain of hemorrhoids
(2), the Ancient Indians for insomnia (3) and the Ancient Greeks for tapeworms (4).
Despite medical cannabis’ capacity for symptom relief and its legality in many regions
(including Canada), it still remains a controversial treatment due in part to its psychoactive
components. Consequently, there has been a relatively small amount of research on medical
cannabis users. The limited literature available suggests that modern users are primarily middle-
aged (5-7), male (5-12), and Caucasian (5-9, 13). The most commonly studied modern uses for
medical cannabis are to: treat chronic pain (8, 10, 13-15), improve sleep (10, 13), relieve muscle
spasms, headaches, anxiety, and nausea (10, 13, 15), to relieve depression (7, 10, 13), and to
increase appetite (7, 10, 13, 15).
In 2001, Canada developed a legal system to regulate the use and distribution of medical
cannabis, and in 2014, shifted away from a homegrown-system to licensed commercial
producers. There are currently 31 licensed producers throughout Canada, which has facilitated
prompt access to safe and reliable sources or medical cannabis (16). Despite the improved
access, there remains a paucity of literature to guide its medical use. The literature available on
medical cannabis use is sparse and limited in its applicability. The majority of studies are small
in sample size, geographically specific, and do not focus on oncology or palliative patients.
As a tertiary outpatient palliative care oncology clinic, we have experienced an increase in
interest from our patients to incorporate medical cannabis into their symptom management
regime. The aim of this chapter is to better understand the demographics, diagnosis, and
symptom profile of patients with advanced cancer accessing medical cannabis in an out-patient
clinic setting.

OUR STUDY
This study was a retrospective chart review of patients accessing medical cannabis at a Pain
and Symptom Management Clinic, an academic tertiary center practice in Ontario. The clinic’s
caseload fluctuates between 110 and 130, with a total of 233 new consults seen during the study
period (January 1, 2015 – July 31, 2015). Patients attending the clinic must be 18 or older, have
a cancer diagnosis, and a prognosis of <12 months. Patient records are kept as a combination
of electronic records and paper charts.
Charts were reviewed for patients having obtained medical cannabis authorization during
their attendance at clinic during the study period. A data extraction tool was created and utilized
to ensure consistency when extracting data from charts. Patient information was de-identified
at completion of collection using numerical identifiers. Data was kept on secure computer with
password protected files. This project was approved by local Research Ethics Board and was a
non-funded study.
 Medical cannabis use in an outpatient palliative care clinic 87

Table 1. Demographic characteristics of included patients

Patient characteristics n = 43 %
Age
31-50 9 20.9
51-75 32 74.4
>75 2 4.7
Gender
Male 27 62.8
Female 16 37.2
Relationship Status
Married* 25 58.1
Single 8 18.6
Relationship, not married 3 7.0
Not specified 7 16.3
Living Situation
With spouse/partner 24 55.8
Alone 3 7.0
Other** 5 11.6
Not specified 11 25.6
Children at home 6 14.0
*Common-law marriages included.
**Other included: with friends and with extended family.

FINDINGS
Of approximately 340 patients seen in clinic, 43 patients (12.5%) were identified as having
obtained authorization for medical cannabis over the timeline of the review. 20.9% of patients
were aged 31-50 years, 74.4% of patients were aged 51-75 years, and 4.7% of patients were
over 75 years of age. 62.8% of patients were male and 37.2% of patients were female. 58.1%
of patients were married, 18.6% were single, 7.0% were in an unmarried relationship, and
16.3% of patients’ relationship statuses were unspecified. 55.8% of patients were living with a
spouse or partner, 7.0% were living alone, 11.6% were living either with friends or with
extended family, and 25.6% of patients’ living situations were unspecified. 6 patients were
living with children at home (14.0%) (see Table 1).
Of the cancer diagnoses represented in this sample, the majority were primary
gastrointestinal malignancies (30.2%), and in particular, colorectal, cholangiocarcinoma,
hepatocellular, and pancreatic malignancies. Many other patients were being treated for a
variety of primary cancers, including lung cancer (20.9%), gynecological cancer (14.0%),
breast cancer (4.7%), and prostate cancer (2.3%). Additional diagnoses represented in this study
and classified together as ‘other’ included melanoma, hematological cancer, genitourinary
cancer, connective tissue cancer, bone cancer, or “unknown origin” (25.6%). 2.3% of patients’
diagnosis were unspecified (see Table 2).
88 Noah Spencer, Erynn Shaw and Marissa Slaven

Table 2. Cancer diagnosis of included patients

Patient cancer diagnosis n = 43 %

GI malignancy* 13 30.2
Breast cancer 2 4.7
Prostate cancer 1 2.3
Lung cancer 9 20.9
Gynecological 6 14.0
Other** 11 25.6
Not specified 1 2.3
*Colon, rectal, biliary duct, liver, and pancreas malignancies represented.
**Other included: melanoma, hematological, GU, connective tissue, bone, unknown origin.

With regards to physical symptoms, the majority of patients (88.4%) reported experiencing
pain. Amongst these, 48.8% reported moderate to severe pain, and 39.5% reported mild pain.
Tiredness was present amongst 46.5% of patients assessed for this symptom; however, nearly
half (48.8%) of charts had not reviewed this symptom specifically. While nausea was also a
prevalent symptom, with 30.2% of patients experiencing this, it is interesting to note that a large
portion (51.5%) reported absence of this symptom. Amongst other physical symptoms present
at the time of authorization were reduction in appetite (37.2%), dyspnea (25.6%), reflux
(16.3%), bowel dysfunction (7.0%), and early satiety (4.7%).
From a mental health standpoint, 11.6% of patients reported depression and 34.9% reported
anxiety. For both symptoms, a significant number of charts did not report specifically on
presence/absence of symptoms (see Table 3).
Roughly a quarter of patients were tobacco smokers at the time of their licensing (23.3%),
while 27.9% had smoked in the past and quit, and 23.3% were lifelong non-smokers. 25.6% of
patients’ smoking histories were unspecified. 39.5% of patients were current alcohol consumers
at the time of their licensing, 18.6% had a history of consumption, but were not presently
drinking, 14.0% did not have a history of consumption, and 27.9% of patients’ alcohol
consumption histories were unspecified. 11.6% of patients reported they consumed alcohol
heavily or abused alcohol. No patients were current recreational drug users at the time of their
licensing, 2.3% of patients had used recreational drugs in the past and stopped, and 53.5% of
patients reported no recreational drug use at any time. A large portion (44.2%) of patients’
recreational drug use histories were unspecified (see Table 4).
A significant number of patients were using cannabis already at the time of their licensing
(39.5%). One patient had used cannabis in the past but had since stopped (2.3%), one patient
had never used cannabis (2.3%), and 55.8% of charts did not specify the patients’ cannabis use
histories (see Table 4).
 Medical cannabis use in an outpatient palliative care clinic 89

Table 3. Symptom profiles of included patients

Patient symptoms n = 43 %
Pain (presence)
Present 38 88.4
Absent 3 7.0
Not specified 2 4.7
Pain (severity)
None 3 7.0
Mild 17 39.5
Moderate to severe 21 48.8
Not specified 2 4.7
Tiredness
Present 20 46.5
Absent 2 4.7
Not specified 21 48.8
Drowsiness
Present 0 0.0
Absent 1 2.3
Not specified 42 97.7
Nausea
Present 13 30.2
Absent 22 51.2
Not specified 8 18.6
Lack of appetite
Present 16 37.2
Absent 16 37.2
Not specified 11 25.6
SOB/dyspnea
Present 11 25.6
Absent 16 37.2
Not specified 16 37.2
Depression
Present 5 11.6
Absent 14 32.6
Not specified 24 55.8
Anxiety
Present 15 34.9
Absent 8 18.6
Not specified 20 46.5
Other symptoms
Reflux 7 16.3
Bowel deregulation* 3 7.0
Early satiety 2 4.7
Other** 6 14.0
Not specified 27 62.8
*Constipation or diarrhea.
**Cough, hiccups, trouble concentrating, edema, thrush.
90 Noah Spencer, Erynn Shaw and Marissa Slaven

Table 4. Substance use among included patients

Substance n = 43 %
Smoking
Current smoker 10 23.3
Past smoker* 12 27.9
Non-smoker 10 23.3
Not specified 11 25.6
Alcohol consumption
Current consumption 17 39.5
Past consumption* 8 18.6
None 6 14.0
Not specified 12 27.9
Heavy use/abuse 5 11.6
Substance/recreational drug use
Current user 0 0.0
Past user* 1 2.3
None 23 53.5
Not specified 19 44.2
Cannabis use
Current user 17 39.5
Past user* 1 2.3
None 1 2.3
Not specified 24 55.8
*Have used in the past, but do not currently use substance.

DISCUSSION
Following the introduction of the "Marihuana for medicinal purposes regulations" in 2014,
medical cannabis treatment became readily accessible to palliative patients. In the busiest
outpatient palliative cancer clinic in Ontario, within a few months of change in policy, the rate
of prescribing was found to increase from less than 1% to 12.5%. We undertook this study to
demographics and symptom profile of palliative oncology patients accessing medical cannabis
at our clinic.
When reviewing the age of our patients, we found our median age of 58 to be older than
the median age of patients in studies involving non-palliative patient population accessing
cannabis, but younger that the age of palliative patients in general. O’Connell et al. (9) had a
median age of 32 years for long term cannabis users seeking medical cannabis in California,
while Swift et al. (12) found a median age of 45 years. Our patient population, however, was
slightly younger when compared to Kirkova et al. (19), who found a median age of 65 years.
Our study was similar to existing literature regarding a gender differential amongst medical
cannabis users. Our data found 62.8% of users were male; this is in line with Swift et al. (12)
on the characteristics of 128 Australian medical cannabis patients (63% male) and Ogborne et
al. (11) of 49 Ontario medical cannabis users (63.2%). In large scale studies of general palliative
patient populations, the gender differential is less noticeable. For example, Teunissen et al. (17)
in their systematic review of patients with incurable cancer found that of 2,219 patients
 Medical cannabis use in an outpatient palliative care clinic 91

reviewed, 53% were male. In Riechelmann et al. (18) study of 255 adult cancer patients
attending Ontario palliative care clinics 54% were male. Finally, Kirkova et al. (19) in their
study of 997 American palliative cancer patients found that 55% were male. It is unclear why
for both palliative patients in our study and non-palliative patients using medical cannabis in
the literature the male cohort is larger than the female cohort.
From a symptom standpoint, pain was the symptom most prevalent amongst our patients,
with 88.4% reporting at least mild pain and 55.3% rating moderate-severe scores. This
symptom is consistent with much of the existing literature looking at medical cannabis use in
the chronic pain population (9, 11, 14, 15). When compared to the literature specific to
palliative care, pain was prevalent in 84% of in the study population of Kirkova et al. (19), 75%
of Riechelmann et al. (18) and 71% of Teunissen et al. (17).
Although 46.5% of patients in our study presented with tiredness, fatigue was not common
among participants in studies about the general medical cannabis using population. However,
fatigue was the most common symptom among the palliative cancer patients in studies
conducted by Riechelmann et al. (77%) (18) and Teunissen et al. (74%) (17).
Both nausea and lack of appetite were reported frequently (30.2% and 37.2% respectively)
amongst our patients. The prevalence of these symptoms are consistent with that previously
found in non-palliative patient populations accessing medical cannabis. Bonn-Miller et al. (13)
in a study of medical cannabis users found 38% used cannabis for appetite stimulation and 25%
for nausea. This is also comparable to the study of Harris et al. (7) of a medical cannabis club
members, in which 33% of participants used cannabis primarily to improve appetite. Amongst
the general palliative patient population nausea and lack of appetite were even more prevalent
with 66% of Riechelmann et al. (18) participants reported lack of appetite and 46% reported
nausea.
Our patients reported anxiety more frequently (34.9%) compared to depression (11.6%). It
is, however, difficult to draw any meaningful conclusions in this area as the non-response rate
amongst our chart review was high (55.8% and 46.5%, respectively).
When reviewing the prevalence of alcohol and substance use amongst our patients, the
majority of charts had not recorded specifics around this, leading to high non-response rate for
these variables. Therefore, it is difficult to draw meaningful comparisons in this regard, and
more research would be warranted to better understand the backgrounds of medical cannabis
users receiving palliative care.
Despite this issue of non-response, one interesting finding was that 39.5% of subjects (and
89.5% of reporting subjects) were already using cannabis at the time of their prescription. This
is a positive sign in that it represents a sizable number of patients who sought to begin using
cannabis grown from sanctioned producers. These producers abide by much stricter health and
safety regulations than their non-approved counterparts.
In addition to the usual limitations resulting from using data from a retrospective chart
review, the small sample size (n = 43) limits the generalizability and applicability of results.
Furthermore, many of the charts reviewed contained incomplete data, further limiting the
quality of the results. We did not review charts on non-cannabis users; as such, it is difficult to
know how our subjects compared to the general patient population of our clinic. Finally, we
only reviewed charts of oncology patients in the palliative phase of illness, so it is unclear how
generalizable our findings are to non-oncology patients and those in earlier phases of their
illness.
92 Noah Spencer, Erynn Shaw and Marissa Slaven

CONCLUSION
In seeking to better understand the demographics and symptom profile of palliative
oncology patients accessing medical cannabis, we found that the large majority of our patient
population were over fifty years old with a predominance of married male patients with GI and
lung malignancies. Additionally, although most had a variety of symptoms almost all (88.4%)
were experiencing pain. A significant portion (39.5%) were already using cannabis at time of
authorization.
The field of medical cannabis use is young and much work still needs to be done to
understand its place amongst symptom management in general and in palliative patients
specifically. Future studies involving larger sample sizes, direct symptom effect, and more in-
depth sociodemographic information would be helpful to further understand the profile of
patients who derive benefit from this substance.

REFERENCES
[1] Mack A, Joy J. Can marijuana help? In: Mack A, Joy J. Marijuana as medicine? The science beyond
the controversy. Washington, DC: Nat Acad Press, 2001:14.
[2] Pain S. The pharoah’s pharmacists. New Scientist. URL: https://www. newscientist.com/
article/mg19626341.600-the-pharaohs-pharmacists/
[3] Touw M. The religious and medicinal uses of cannabis in China, India, and Tibet. J Psychoactive Drugs
1981;13(1):23-34.
[4] Butrica JL. The medical use of cannabis among the Greeks and Romans. J Cannabis Therapeutics
2002;2(2):51-70.
[5] Reiman A. Medical cannabis patients: patient profiles and health care utilization patterns. J Evidence-
Based Complem Altern Med 2007;12(1):31-50.
[6] Reiman A. Cannabis as a substitute for alcohol and other drugs. Harm Reduct J 2009;6:35.
[7] Harris D, Jones RT, Shank R, Nath R, Fernandez E, Goldstein K, et al. Self-reported marijuana effects
and characteristics of 100 San Francisco medical marijuana club members. J Addict Dis 2000;19(3):89-
103.
[8] Zaller N, Topletz A, Frater S, Yates G, Lally M. Profiles of medicinal cannabis patients attending
compassion centers in Rhode Island. J Psychoactive Drugs 2015;47(1):18-23.
[9] O’Connell TJ, Bou-Matar CB. Long term marijuana users seeking medical cannabis in California
(2001-2007): demographics, social characteristics, patterns of cannabis and other drug use of 4117
applicants. Harm Reduct J 2007;4:16.
[10] Nunberg H, Kilmer B, Pacula RL, Burgdorf J. An analysis of applicants presenting to a medical
marijuana specialty practice in California. J Drug Policy Anal 2011;4(1):1.
[11] Ogborne AC, Smart RG, Adlaf EM. Self-reported medical use of marijuana: a survey of the general
population. CMAJ 2000;162:1685-6.
[12] Swift W, Gates P, Dillon P. Survey of Australians using cannabis for medical purposes. Harm Reduct
J 2005;2:18.
[13] Bonn-Miller MO, Boden MT, Bucossi MM, Babson KA. Self-reported cannabis use characteristics,
patterns and helpfulness among medical cannabis users. Am J Drug Alcohol Abuse 2014;40(1):23-30.
[14] Ashrafioun L, Bohnert KM, Jannausch M, Ilgen MA. Characteristics of substance use disorder
treatment patients using medical cannabis for pain. Addict Behav 2015;42:185-8.
[15] Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for
medical use. A systematic review and meta-analysis. JAMA 2015;313(24):2456-2473.
[16] Health Canada. Medical use of marijuana. URL: http://www.hc-sc.gc.ca/dhp-mps/marihuana/info/
index-eng.php
 Medical cannabis use in an outpatient palliative care clinic 93

[17] Teunissen SCCM, Wesker W, Kruitwagen C, de Haes HCJM, Voest EE, de Graeff A. Symptom
prevalence in patients with incurable cancer: a systematic review. J Pain Sympt Manage 2007;34(1):94-
104.
[18] Riechelmann RP, Krzyzanowska MK, O’Carroll A, Zimmermann C. Symptom and medication profiles
among cancer patients attending a palliative care clinic. Support Care Cancer 2007;15(12):1407-12.
[19] Kirkova J, Rybicki L, Walsh D, Aktas A. Symptom prevalence in advanced cancer: age, gender, and
performance status interactions. Am J Hosp Palliat Care 2012;29(2):139-145.
[20] Barclay JS, Owens JE, Blackhall LJ. Screening for substance abuse risk in cancer patients using the
opioid risk tool and urine drug screen. Support Care Cancer 2014;22:1883-8.
[21] Hye Kwon J, Hui D, Chisholm G, Bruera E. Predictors of long-term opioid treatment among patients
who receive chemoradiation for head and neck cancer. Oncologist 2013;18(6):768-74.
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 7

FOUR PATIENT PERSPECTIVES

ON MEDICAL CANNABIS

Jeremy Friedberg, PhD

MedReleaf Corp, Markham Industrial Park, Markham,
Ontario, Canada

The use medical cannabis has been increasing in recent years. This paper provides the
perspectives of four patients with very different clinical backgrounds and their reported
experiences using medical cannabis. Not all patients respond the same way to cannabis and
effective use requires a degree of experimentation as these patients’ perspectives illustrate.
In these perspectives it is important to note the reported effective management of specific
symptoms, but also of importance is the reported improvement in general well-being and
vast improvement in reported quality of life.

INTRODUCTION
As the research into the clinical utility of medical cannabis continues, the significant benefits
of using cannabis in patient care is becoming clear. There are varying degrees of effectiveness
that have been reported on specific symptoms and symptom management as it relates to
particular active components in the plant. But, it has become clear that there is more to the use
of the plant as a whole than just its constituting components. Similarly, many patients are
reporting significant benefits on specific symptoms such as pain or nausea while also reporting
improvements is their ability to cope with their symptoms, translating to improvements in their
general wellbeing. Not intended as detailed case reports, this paper provides the perspectives
of four patients with very different clinical backgrounds and their reported experiences using
medical cannabis. The names and details for each of the patients has been altered to protect
their privacy and maintain confidentiality. Consent was obtained from each patient to report on
the information presented in this article.


Correspondence: Jeremy Friedberg, PhD, MedReleaf Corp, Markham Industrial Park, POBox 3040, Markham,
Ontario, L3R 6C4, Canada. E-mail: jfriedberg@medreleaf.com.
96 Jeremy Friedberg

CASE STORY 1
Jon is a 32-year-old male, actively working as an independent business owner, and has been
diagnosed with post-traumatic stress syndrome (PTSD). He is currently managing both
symptoms of pain and typical symptoms related to his PTSD diagnosis. Prior to his introduction
to cannabis, Jon’s symptoms were being managed by 8 pharmaceutical medications. Since his
introduction to cannabis Jon reports that all of his symptoms are effectively controlled with
self-regulated doses of up to 7-8 g of cannabis per day. He consumes his cannabis primarily
through vaporizing, but also uses extracted oil – adding it to butter to consume with his meals
– tincture, and occasionally he smokes. As a result of this shift to cannabis, he is no longer
using any pharmaceutical medications. Jon has experimented with several cultivars (strains) of
cannabis but reports that four specific cultivars have been most effective. These varieties
include Luminarium (26-29% THC; 0-0.2% CDB), Elevare (21-24%; 0-0.2% CDB), Sedamen
(20-23% THC; 0% CBD), and Eran Almog (28% THC; 0% CBD). Jon reports that his cannabis
regime has helped with both symptom management and general wellbeing. “… it works very
well, helps take the edge off, and helps regulate symptoms of my PTSD.”

CASE STORY 2
Michael is a retired 73-year-old male diagnosed with a lower lumbar spine injury. As a result
of this injury he is coping with symptoms of burning sensations, intense pain in his feet and
legs, and extreme fatigue. In managing these symptoms, his physician has prescribed him
oxycontin, however, varying dosage regimes have had a marginal effect on pain and produced
a side effect that makes him very drowsy. Under physician guidance, Michael began to
supplement his oxycontin regime with cannabis, specifically the cultivars Avidekel (0-1.3%
THC; 15-18% CBD) and Midnight (7-10% THC, 10-13% CBD), at a dosage of 1g per day.
Michael’s preference is for inhalation, specifically smoking and occasional vaporization.
As a result of his cannabis use, Michael reported that his pain symptoms are significantly
reduced and when inhaled, the burning sensations are immediately soothed. This effect allowed
him to reduce his Oxycontin intake by 60%. Michael indicated that the oxycontin was the
source of his fatigue and this reduction translated into having more energy. “I’m not sleeping
as much during the day… I fall asleep faster at night. More active, able to dance again.”
Most notably for Michael was his general improvement in his perceived quality of life.
“We (my wife and I) have our lives back! I am able to go out with my wife, I can dance, I can
spend quality time with her and do the things I have always loved to do. It has changed my
whole life. I no longer have to sleep 16 hours a day anymore.”

CASE STORY 3
Rose is a retired 67-year-old female that has been diagnosed with diffused systemic
scleroderma and pulmonary fibrosis. The primary symptoms of her condition are muscle
and nerve pain, and sleep deprivation. To manage these symptoms she is currently on a
prescribed drug regime that includes myfortic, dexilant, motilium, pentoxifylline, oxycontin,
dimenhydrinate (gravol), and hydroxychloroquine. Under the guidance of her family doctor,
Rose is orally consuming cannabis oil extracts that she adds to her food and drinks. She
 Four patient perspectives on medical cannabis 97

primarily prepares her cannabis oil doses from cultivars including Avidekel (0-1.3% THC; 15-
18% CBD) for daytime, Eran Almog (28% THC; 0% CBD), Stellio (22-25% THC; 0% CBD),
Sedamen (20-23% THC; 0% CBD), and Luminarium (26-29% THC; 0% CBD) for nighttime.
For her symptoms, Rose has reported that cannabis is providing exceptional pain management
to the extent that she no longer requires the oxycontin. Her cannabis regime is also effectively
managing her nausea and she no longer needs dimenhydrinate. In terms of her quality of life
and wellbeing, Rose is reporting a significant improvement and attributing it to the cannabis.
“It’s given me a bit of my life back. The pain relief is amazing. I had been on so many different
kinds of medications that were not touching on the pain. Avidekel has really helped with my
daytime wellbeing.”

CASE STORY 4
Cole is 25-year-old male, currently employed. In January 2014 while on vacation, Cole dove
into water from a height of 30 feet and hit his head. He was carried out of the water and couldn’t
walk for several weeks. He has been diagnosed with post-concussion syndrome, spinal
concussion, injury to upper cervical atlas bone, shifted his C1 vertebra, and inflammation in
the brain. As a result of these injuries he is coping with several symptoms including migraine
headaches, severe neck pain, back pain, all of which are causing depression. In coping with
these symptoms his physician had prescribed several pain medications that Cole reported as
having little effect, and actually made him feel worse. When low on traditional options, his
physician suggested trying medical cannabis. Cole began experimenting with CBD cultivars,
specifically Avidekel (0-1.3% THC; 15-18% CBD), but eventually switched to cultivars
containing THC as well. He found that the presence of the THC had a more immediate and
effective reduction of his pain. Cole also reported a general loss of appetite and subsequent
weight loss on traditional pain medications, and that the cannabis use provided the pain
management without affecting his appetite. In his own words, “Normal every day activities that
are extremely easy for everyone, like talking or walking, making a bowel movement, or sexual
intercourse, used to be extremely painful.” In addition to his reported success with pain
management from cannabis, his improvement general wellbeing is also of note. “As soon as I
use it I feel immediate relief… Cannabis has affected my general well-being by helping me live
almost completely normally, which at one point I thought would never be possible.”

CONCLUSION
Medical cannabis is now an established option in a physician’s medical toolkit. Its utility is
derived from the whole-plant mixture of active components and it is the relative proportion of
these components that differentiates cannabis cultivars from one other, their subsequent effects
on symptom management, and how the active components are processed by the patient’s
physiology. However, like all medications, not all patients will respond the same way. Thus,
cannabis requires a degree of experimentation as these patients’ perspectives have illustrated.
It is important to note the reported effective management of specific symptoms, but also of
great importance is the patient’s reported improvement in general well-being and vast
improvement in quality of life.
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 8

SAFETY CONCERNING MEDICAL CANNABIS

Bonnie Cheung, MD(C) and Hance Clarke, MD, PhD

Pain Research Unit, Toronto General Hospital, Univerity Health Network, Toronto,
Ontario, Canada; Department of Anesthesia, University of Toronto,
Toronto, Ontario, Canada

Medical cannabis refers to cannabis or cannabinoids used as medical therapy in order to

treat disease or alleviate symptoms. Currently, two pharmaceutical cannabinoids are
available legally and have been approved for use in Canada. There is a need for
standardizing the naming, dosing, and monitoring of medical cannabis, which can
drastically improve the safety of medical cannabis administration and the stigma
surrounding its use. Currently the public is at the mercy of an industry that lacks stringent
regulation. With the coming legalization of cannabis in Canada, it is imperative that
research be conducted with the patients’ best interests in mind.

INTRODUCTION
Cannabis, more commonly known as marijuana, consists of a group of drugs produced from
plants under the genus Cannabis (1). Cannabis plants contain at least 489 distinct compounds
from 18 different chemical classes and more than 70 different phytocannabinoids (2). The
principal cannabinoids include Δ9-tetrahydrocannbinol (Δ9-THC), cannabinol (CBN), and
cannabidiol (CBD) (3).
The endocannabinoid system is a ubiquitous lipid signalling system found in all vertebrates
(4). It includes the two main cannabinoid receptors, CB1 and CB2 (4). CB1 receptors are densely
distributed in the brain, whereas CB2 receptors are primarily found in the cells of the immune
and hematopoietic systems (4). The endocannabinoid system is involved in a wide range of
physiological processes in the human body, including immune function, appetite regulation,
pain and inflammation, cardiovascular function, bone development and bone density, synaptic

 Correspondence: Hance Clarke, MD, Staff Anesthesiologist, Director of Clinical Pain Services and Medical Director
of Pain Research Unit, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON Canada. E-mail:
Hance.Clarke@uhn.ca.
100 Bonnie Cheung and Hance Clarke

plasticity and learning, psychiatric disease, psychomotor behaviour, memory, and the
regulation of stress and emotional states (5,6).
Δ9-THC is a partial agonist at both CB1 and CB2 receptors, while CBN is a product of of
Δ9-THC oxidation and only has 10% of the activity of Δ9-THC (3). CBD lacks any detectable
psychoactivity and does not bind to either CB1 or CB2 receptors at physiologically meaningful
concentrations (7). It has been shown to have antioxidative, anti-inflammatory, and
neuroprotective effects independent of the CB1 and CB2 receptors (3). As a result, it has
therapeutic potential with fewer adverse effects than Δ9-THC.

MEDICAL CANNABIS AND ITS USES

“Medical cannabis” refers to cannabis or cannabinoids used as medical therapy in order to treat
disease or alleviate symptoms (8). Currently, two pharmaceutical cannabinoids are available
legally and have been approved for use in Canada: Cesamet (nabilone), a synthetic Δ9-THC
analogue indicated for treating severe chemotherapy-induced nausea and vomiting; and Sativex
(nabiximols), an oromucosal spray containing a whole-plant extract of two standardized strains
of Cannabis sativa with approximately equal concentrations of Δ9-THC and CBD, indicated
for adjunctive treatment of neuropathic pain in patients with multiple sclerosis and pain in
patients with advanced cancer (9). Dronabinol is a synthetic Δ9-THC that was approved in
Canada for Acquired Immune Deficiency Syndrome (AIDS)-related anorexia and severe
chemotherapy-induced nausea and vomiting, but was discontinued by the manufacturer in 2012
for unstated reasons (9).
The number of clinical trials on the uses of medical cannabis have increased in recent years
and have shown therapeutic potential for a number of debilitating medical conditions.
Systematic reviews suggest that cannabinoids may be useful in reducing pain in patients with
chronic pain (10), rheumatoid arthritis (11), and refractory neuropathic pain when used in
conjunction with traditional analgesics (12). Furthermore, two systematic reviews involving
patients with multiple sclerosis have shown that cannabinoids may lead to a reduction in
spasticity, painful spasms, and urinary dysfunction (13, 14).

CANADA’S FORTHCOMING LEGALIZATION OF CANNABIS

The currently elected Liberal Party of Canada has stated its plans to introduce legislation for
cannabis in Spring 2017 (15). In the interim, medical cannabis is currently regulated under the
Marihuana for Medical Purposes Regulations (MMPR) (16). Under the MMPR, a doctor must
formally assess and authorize a patient to purchase cannabis from one of 34 authorized licensed
producers. Only producers authorized to produce and sell cannabis may legally do so.
With legalization of marijuana scheduled to take place in less than a year, determining
evidence-based and regulated methods for distribution, administration, and monitoring is a top
priority. The following three recommendations aim to improve safe access to medical cannabis
for patients:
 Safety concerning medical cannabis 101

1) Formalize naming and removal of recreational terms

Many patients when assessed in clinic will refer to the dired bud being consumed by the
lisenced producer’s or dispensary’s listed name (e.g., Alaska or Treasure Island). Unfortunately
when pressed further, patients often have no idea the concentartions of THC or CBD within the
plant product. If we are to truly medicalize this industry, these names should be removed and
the percentage of the medicinal ingerdient should be the primary inforamtion used to identify
the products. Patients would then be able to understand the medicinal value of titrating up or
down the medicinal contents. A standard naming system for different types of cannabis strains
should be established. Further complicating the industry, more than 80% of 75 edible cannabis
products purchased within two large medical cannabis markets in the U.S. were inaccurately
labelled with respect to THC content, which may lead to overdosing or underdosing (17), a
significant public safety issue. Moving away from street names would destigmatize both
patients’ and health care providers’ attitudes towards medical cannabis. Although Canada
legalized cannabis for medical use in 2001, many users still report experiencing stigma from
family, friends, health care providers, and law enforcement, as well as experiencing guilt or
discomfort in using something “illicit” (18). The stigma of medical cannabis acts as a
significant barrier to its acceptability and use. In a qualitative study looking at barriers of access
for Canadian cannabis users, approximately half of the respondents wanted to discuss medical
cannabis with a physician but did not, with the most frequent reason being that they did not feel
comfortable enough to do so (19). Ensuring that the naming and labelling clearly reflects the
contents and indications of the different strains of medical cannabis would likely also improve
communication between the patient and prescriber, such that patients would better understand
the reasons for being prescribed a specific strain of medical cannabis.

2) Standardize dosing

More research regarding the pharmacokinetics as well as into the safe and effective dosing of
medical cannabis should be conducted in an effort to create standard dosing guidelines. Unlike
the majority of prescription medications that consist of single active compounds, cannabis
contains more than 100 cannabinoids, terpenoids, and flavonoids (2). According to Health
Canada, precise dosages for medical cannabis have not yet been established and only rough
dosing guidelines for smoked or vapourized cannabis have been published (9). Dosages for
orally administered products in humans are yet to be established (9). This calls for further
research into how cannabis is metabolized in patients and the factors that determine individual
differences in metabolism.

3) Establish monitoring guidelines

Currently, there are no clinical guidelines that exist to monitor patients who are taking cannabis
for therapeutic purposes (9). Cannabis continues to be one of the most used illicit drugs;
however, it can lead to physical and psychological dependence (20). Careful consideration must
be taken in certain patient populations, including patients under the age of 25 (21), patients
with severe cardiopulmonary disease (22), smoked cannabis in patients with respiratory
102 Bonnie Cheung and Hance Clarke

insufficiency (23), patients with history of psychiatric disorders (24), patients with severe liver
disease (25), and pregnant women (26). While the majority of adverse events from cannabis
are not serious, serious adverse effects of cannabis include impairment in brain connectivity
associated with cannabis in adolescence (27), earlier onset of psychosis (28), and the more
recently discovered cannabinoid hyperemesis syndrome (29). Moreover, there is much less
information on the adverse effects of the medical use of cannabis as compared to the adverse
effects of recreational use (9). This research gap must be addressed if we are to create proper
clinical guidelines for monitoring patients on medical cannabis.

CONCLUSION
In conclusion, standardizing the naming, dosing, and monitoring of medical cannabis will
drastically improve the safety of medical cannabis administration and the stigma surrounding
its use. Currently the public is at the mercy of an industry that lacks stringent regulation. With
the coming legalization of cannabis in Canada, it is imperative that research be conducted with
the patients’ best interests in mind.

ACKNOWLEDGMENTS
Dr. Clarke is supported by a Merit Award from the Department of Anesthesia at the University
of Toronto.

REFERENCES
[1] Small E, Cronquist A. A practical and natural taxonomy for cannabis. Taxon 1976;25(4):405.
[2] Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids.
Life Sci 2005;78(5):539–48.
[3] Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new
therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009;30(10):515–27.
[4] Rodríguez de Fonseca F, Del Arco I, Bermudez-Silva FJ, Bilbao A, Cippitelli A, Navarro M. The
endocannabinoid system: physiology and pharmacology. Alcohol Alcohol Oxf Oxfs 2005;40(1):2–14.
[5] Serrano A, Parsons LH. Endocannabinoid influence in drug reinforcement, dependence and addiction-
related behaviors. Pharmacol Ther 2011;132(3):215–41.
[6] Aggarwal SK. Cannabinergic pain medicine: a concise clinical primer and survey of randomized-
controlled trial results. Clin J Pain 2013;29(2):162–71.
[7] Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9‐
tetrahydrocannabinol, cannabidiol and Δ9‐tetrahydrocannabivarin. Br J Pharmacol 2008;153(2):199–
215.
[8] Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for
medical use: a systematic review and meta-analysis. JAMA 2015;313(24):2456.
[9] Health Canada. Information for health care professionals: cannabis (marihuana, marijuana) and the
cannabinoids. Health Canada. Accessed 2016 Jul 26. URL: http://www.hc-sc.gc.ca/dhp-mps/alt_
formats/pdf/marihuana/med/infoprof-eng.pdf.
[10] Martín-Sánchez E, Furukawa TA, Taylor J, Martin JLR. Systematic review and meta-analysis of
cannabis treatment for chronic pain. Pain Med 2009;10(8):1353–68.
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[11] Richards BL, Whittle SL, Buchbinder R. Neuromodulators for pain management in rheumatoid arthritis.
Cochrane Database Syst Rev 2012;1:CD008921.
[12] Deshpande A, Mailis-Gagnon A, Zoheiry N, Lakha SF. Efficacy and adverse effects of medical
marijuana for chronic noncancer pain: Systematic review of randomized controlled trials. Can Fam
Physician Médecin Fam Can 2015;61(8):e372–81.
[13] Lakhan SE, Rowland M. Whole plant cannabis extracts in the treatment of spasticity in multiple
sclerosis: a systematic review. BMC Neurol 2009;9:59.
[14] Koppel BS, Brust JCM, Fife T, Bronstein J, Youssof S, Gronseth G, et al. Systematic review: efficacy
and safety of medical marijuana in selected neurologic disorders: Report of the Guideline Development
Subcommittee of the American Academy of Neurology. Neurology 2014;82(17):1556–63.
[15] Honourable Jane Philpott. Plenary statement for the Honourable Jane Philpott Minister of Health -
UNGASS on the World Drug Problem. United Nations General Assembly Special Spession on the
World Drug Problem. Accessed 2016 Aug 02. URL: http://news.gc.ca/web/article-en.do?nid=1054489.
[16] Government of Canada. Marihuana for medical purposes regulations Government of
Canada Department of Justice. Accessed 2016 Aug 02. URL: http://www.laws-lois.justice.gc.ca/eng/
regulations/SOR-2013-119/FullText.html.
[17] Vandrey R, Raber JC, Raber ME, Douglass B, Miller C, Bonn-Miller MO. Cannabinoid dose and label
accuracy in edible medical cannabis products. JAMA 2015;313(24):2491.
[18] Bottorff JL, Bissell LJ, Balneaves LG, Oliffe JL, Capler NR, Buxton J. Perceptions of cannabis as a
stigmatized medicine: a qualitative descriptive study. Harm Reduct J 2013;10(1):2.
[19] Belle-Isle L, Walsh Z, Callaway R, Lucas P, Capler R, Kay R, et al. Barriers to access for Canadians
who use cannabis for therapeutic purposes. Int J Drug Policy 2014;25(4):691–9.
[20] Lichtman AH, Martin BR. Cannabinoid tolerance and dependence. Handb Exp Pharmacol
2005;(168):691–717.
[21] Health Canada. Consumer information - cannabis (marihuana, marijuana). Government of Canada.
Accessed 2016 Aug 02. URL: http://www.hc-sc.gc.ca/dhp-mps/alt_formats/pdf/marihuana/info/cons-
eng.pdf.
[22] Mathew RJ, Wilson WH, Davis R. Postural syncope after marijuana: a transcranial Doppler study of the
hemodynamics. Pharmacol Biochem Behav 2003;75(2):309–18.
[23] Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on
pulmonary function and respiratory complications: a systematic review. Arch Intern Med 2007;167
(3):221–8.
[24] Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M, et al. Cannabis use and risk
of psychotic or affective mental health outcomes: a systematic review. Lancet 2007;370(9584):319–28.
[25] Tarantino G, Citro V, Finelli C. Recreational drugs: a new health hazard for patients with concomitant
chronic liver diseases. J Gastrointest Liver Dis 2014;23(1):79–84.
[26] Richardson GA, Ryan C, Willford J, Day NL, Goldschmidt L. Prenatal alcohol and marijuana exposure:
effects on neuropsychological outcomes at 10 years. Neurotoxicol Teratol 2002;24(3):309–20.
[27] Zalesky A, Solowij N, Yücel M, Lubman DI, Takagi M, Harding IH, et al. Effect of long-term cannabis
use on axonal fibre connectivity. Brain J Neurol 2012;135(7):2245–55.
[28] Large M, Sharma S, Compton MT, Slade T, Nielssen O. Cannabis use and earlier onset of psychosis: a
systematic meta-analysis. Arch Gen Psychiatry 2011;68(6):555–61.
[29] Wallace EA, Andrews SE, Garmany CL, Jelley MJ. Cannabinoid hyperemesis syndrome: literature
review and proposed diagnosis and treatment algorithm. South Med J 2011;104(9):659–64.
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 9

MEDICAL CANNABIS IN THE TREATMENT OF

CHEMOTHERAPY-INDUCED NAUSEA AND VOMITING

Jordan Stinson, BSc and Carlo DeAngelis*, PharmD

Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada
Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

In recent years cannabis has been used for various medical purposes. The most interesting
benefit may be related to chemotherapy-induced nausea and vomiting, with cannabis being
used as an antiemetic in combination with other agents to combat a troublesome side-effect
of cancer treatment. Medical oncologists are split between whether cannabis should be
used medicinally because of the quality of evidence. Although patients advocate the benefit
of cannabis and studies conducted before the 2000s show its efficacy, there have been no
phase III RCT’s conducted in the last five years that compare cannabis to modern day
antiemetic regimens. It is critical that phase III trials are conducted to create guidelines for
future users who will be interested in trying medical cannabis.

INTRODUCTION
Legalization of cannabis has been a hot topic over the past year in Canada with push for
legislation to move forward in the upcoming year. Already in the United States 23 states have
legalized cannabis for medicinal use and four others have completely legalized for recreational
use. Cannabis has been shown to be beneficial in mitigating chronic pain in HIV/AIDS and
cancer patients, and those with fibromyalgia and arthritis. There is evidence that cannabis can
be used to prevent weight loss and increase appetite, minimize seizures for those with epilepsy,
and it can be used to relieve stress and anxiety, especially those with post-traumatic stress
disorder (PTSD). The most interesting benefit may be related to chemotherapy-induced nausea
and vomiting, with cannabis being used as an antiemetic in combination with other agents to
combat a troublesome side-effect of cancer treatment. Medical oncologists are split between

*
Correspondence: Carlo DeAngelis, PharmD, RPh, Department of Pharmacy, Sunnybrook Health Sciences Centre,
2075 Bayview Avenue, Toronto, ON, Canada. E-mail: carlo.deangelis@sunnybrook.ca.
106 Jordan Stinson and Carlo DeAngelis

whether cannabis should be used medicinally because of the quality of evidence mainly
conducted in the 1980s and 1990s, however patients time and again support having access to
medical cannabis and find it very beneficial to manage their disease or condition.
The issue of legalizing dried cannabis for medicinal use in Canada was kick-started in 2000
and by 2001 the Government of Canada adopted the Marijuana Medical Access Regulations
(MMAR), which recognized medical cannabis as a treatment option for various medical
conditions, including chemotherapy-induced nausea and vomiting (CINV) (1). Applicants
applied directly to Health Canada for authorization to possess, and had the option to grow their
own cannabis or purchase directly from Health Canada (1, 2). As of March 31st, 2014 the
Government of Canada repealed the MMAR and replaced these regulations with the Marijuana
for Medical Purposes Regulations (MMPR), which removed Health Canada from the patient
approval process and eliminated authorization for patients to grow their own cannabis. Patients
now receive their medical cannabis from commercial producers licensed by Health Canada (1,
2). Along with the availability of dried cannabis, two other oral synthetic agents have been
developed and approved for the indication of chemotherapy-induced nausea and vomiting
(CINV); dronabinol (Marinol®), a stereoisomer of delta-9 –THC, and nabilone (Cesamet®), a
synthetic analogue of delta-9-THC. However, in 2012 dronabinol was withdrawn from the
Canadian market for unknown reasons which left nabilone as the only oral agent currently
available. This commentary will explore the currently published data on synthetic and
naturally-derived cannabis to answer the question, is there a role for medical cannabis in the
treatment of chemotherapy-induced nausea and vomiting? We will also shed light on the
opinions of healthcare providers including medical oncologists, pharmacists, and most
importantly the patient.

THE ENDOCANNABINOID SYSTEM

Cannabinoid receptors are G-protein-coupled receptors that are expressed throughout the body.
The CB1 receptors are mainly concentrated in the brain and central nervous system, specifically
the basal ganglia (movement), cerebellum (movement), cerebral cortex (higher cognitive
functioning), hippocampus (learning, memory, stress), hypothalamus (appetite), medulla
(nausea and vomiting, chemoreceptor trigger zone), and spinal cord (peripheral sensation,
pain). The CB2 receptors are associated with the immune system, especially B and T
lymphocytes, monocytes, and natural killer cells, which suppress and modulate pain and
inflammatory responses (3-7). CB2 receptors may also contribute to sympathetic inhibition.
Δ9-THC and cannabidiol (CBD) are the most abundant phytocannabinoids in cannabis that
interact with the CB1 and CB2 receptors in humans. Δ9-THC is the psychoactive component
and an agonist of the CB1 and CB2 receptors, whereas CBD is non-psychoactive and has little
affinity for these receptors. CBD appears to modulate the pharmacological effects of Δ9-THC,
increasing therapeutic effects while decreasing psychotropic effects (3-7). Since emesis is
mediated by multiple neurotransmitters including serotonin, dopamine, substance P, GABA
and others, cannabinoids act as agonists of the CB1 receptors and directly inhibit or modulate
neurotransmitter release (3-7). It is the agonism of both these receptors (CB1/CB2 non-
selective) that leads to a decrease in emesis.
 Medical cannabis in the treatment of chemotherapy-induced nausea… 107

SYNTHETIC CANNABINOIDS VERSUS MEDICAL CANNABIS

From the time Δ9-THC was successfully isolated in 1964 to when dronabinol, the first synthetic
THC drug, was approved for marketing in 1986, there was a period of great experimentation
with smoked cannabis. Several state sponsored clinical trials (see Table 1) were conducted
between 1981 and 1990 and their results were reported in the Journal of Cannabis Therapeutics
in 2001 (8). The report concluded that patients who smoked cannabis experienced great relief
from nausea and vomiting, while those who used THC capsules experienced moderate relief.
Patients were only placed on a clinical trial after treatment with a standard antiemetic regimen
failed. Common side-effects from the use of cannabis included sedation, feeling high, dizziness,
dry mouth, and smoke intolerance.

Table 1. State trials on the effect of smoked cannabis on chemotherapy-induced nausea

and vomiting

State & Year Population Method Results

of Trial
Tennessee 28 patients Single-arm/crossover 40% - Very effective
(1981) THC capsules 40% - Moderately effective
Smoked cannabis (cigarettes) 15% - Slightly effective
Michigan 165 patients RCT/crossover 15% - No nausea (smoked)
(1982) Smoked cannabis (cigarettes) 33% - Mild nausea (smoked)
Thiethylperazine 18% - No CINV (smoked)
Georgia 119 patients RCT 76% - Capsule success
(1983) THC capsules
Smoked cannabis (cigarettes) 65% - Smoked success
New Mexico 142 patients RCT 75% - Improvement (capsule)
(1983) THC capsules 90% - Improvement (smoked)

Smoked cannabis (cigarettes)

New Mexico 174 patients RCT/crossover or BOTH 55% - Success (capsule)
(1984) THC capsules 95% - Success (smoked)
Smoked cannabis (cigarettes)
California 355 patients Single-arm choice 9% - No nausea (smoked)
(1989) THC capsules (n = 257) 15% - No nausea (capsule)
Smoked cannabis (cigarettes) 17% - Severe nausea (smoked)
(n = 98) 22% - Severe nausea (capsule)
19% - No vomiting (smoked)
35% - No vomiting (capsule)
New York 199 patients Single-arm 93% - Effective
(1990) Smoked cannabis (cigarettes)
*RCT – randomized controlled trial.

Before the year 2000 it appeared that dried cannabis was an effective treatment option for
CINV with manageable side-effects, but what about synthetic oral agents? A systematic review
by Tramer and colleagues published in the BMJ in 2001 looked at 30 randomized trials of
nabilone (16), dronabinol (13), and levonantradol (1) compared to other antiemetics such as
prochlorperazine, metoclopramide, domperidone, and placebo (9). Data from over 1300
108 Jordan Stinson and Carlo DeAngelis

patients was collected and analyzed. In trials where cannabinoids were compared to placebo,
complete control of nausea was 70% versus 57%, respectively. Complete control of vomiting
was 66% versus 36%, respectively. In trials where cannabinoids were compared to active
controls, complete control of nausea was 59% versus 43%, respectively. Complete control of
vomiting was 57% versus 45%, respectively. Patients preferred cannabinoids over placebo 76%
of the time and against active controls patients still preferred using cannabinoids 61% of the
time. Side-effect profiles occurring in greater than 50% of patients included drowsiness,
sedation and dizziness.
In 2007 Meiri and colleagues conducted the first study to compare synthetic cannabinoids
with a 5HT3 receptor antagonist for patients receiving moderately to highly emetogenic
chemotherapy (10). In this double-blinded, randomized placebo trial 64 patients received either
ondansetron, dronabinol, or a combination of both drugs. Total response was defined as no
vomiting and less than 5mm on a 0-100mm on the visual analog scale (VAS). Total response
was achieved in 54% of patients that received dronabinol, 58% in patients that received
ondansetron, and 47% in patients that received dronabinol and ondansetron combined. No
statistically or clinically significant difference was observed between both drugs, and total
response for cannabinoid use was less than Tramer and colleagues’ systematic review.
The conclusion from studies conducted before the new millennium suggested that smoked
cannabis and oral THC capsules were at least comparable and equally effective to antiemetics
such as prochlorperazine and ondansetron, although validity of these studies are questionable
compared to todays’ standards. In 2015 Smith and colleagues conducted a detailed Cochrane
review on the use of cannabinoids for management of chemotherapy-induced nausea and
vomiting (11). In their findings they concluded that cannabis-based medications may be useful
in treating refractory CINV, however the quality of evidence was graded as low and did not
reflect current chemotherapy and antiemetic treatment regimens.

ONCOLOGIST PERSPECTIVE
In 1990 an anonymous, random-sample survey was sent out to the members of the American
Society of Clinical Oncology (ASCO) concerning antiemetic use of dried cannabis in cancer
patients. In that survey over 1000 responses were received and a slight majority (54%) thought
cannabis should be available by prescription. As a group, respondents also considered smoked
cannabis to be somewhat more effective than oral synthetic THC drug dronabinol (12). This
survey was the first to demonstrate that oncologists’ experience with medical cannabis was
more favourable then the opinion of the Food and Drug Administration (FDA) at the time.
In 1997 another survey was mailed to members of ASCO with a similar response rate of
over 1000 medical oncologists (13). This time however recipients were asked whether the DEA
should reschedule dried cannabis to allow it to be prescribed as medicinal cigarettes. Only 28%
of respondents favoured the rescheduling of cannabis as prescription medicine compared to the
54% in 1990 survey. A survey of physicians from multiple disciplines in 2005 found that only
36% were in favour of legalization of medical cannabis (14).
 Medical cannabis in the treatment of chemotherapy-induced nausea… 109

PHARMACIST PERSPECTIVE
Although a pharmacist is not currently involved in the prescribing of medical cannabis in
Canada, new legislation in the upcoming year may change the way patients can access the drug
and more training to educate pharmacists on the use and side-effects will be necessary. Over
the past two decades the amount of research conducted on the use of medical cannabis for
nausea and vomiting, pain, and appetite has resulted in the discovery of multiple routes of
administration including edibles, vaporization, and oils (15). All these routes involve different
pharmacodynamics and pharmacokinetics, but further research on safety and standardization
of strengths is required.
In the United States the American Society of Health-System Pharmacists (ASHP) is
opposed to the preparation and distribution of medical cannabis but with more states legalizing,
pharmacists are more likely to be asked by patients about drug interactions or disease impact
with regards to their medical cannabis (16). A study conducted by Moeller at al. measured 311
pharmacy students’ knowledge of medical cannabis and their attitude towards it. A moderate
59% of students felt that cannabis should be legalized in all states for medicinal use, and almost
all students did not feel comfortable answering patients’ questions about efficacy, safety, and
drug interactions. 91% of students were aware that medical cannabis was permitted for treating
chemotherapy-related side-effects. The results from this study show that pharmacy students
would benefit from courses on medical cannabis with focus on screening patients, prescribing,
and counseling.

PATIENT PERSPECTIVE
Regardless of whether medical cannabis is beneficial for patients suffering from nausea and
vomiting, pain, or lack of appetite the negative stigma of using cannabis still remains. This
stigma comes from the fact that the majority of cannabis use is recreational and not for
medicinal use. A 2004 national survey showed that only 28% of users in Canada reported using
cannabis for medical reasons (17). The negative image of smoking a joint has been reinforced
by film and television labeling users as “potheads”, and public opinion is that cannabis is an
illegal substance (18). However, when ill patients are asked why they use cannabis it paints a
different picture.
A study by Bottorff and colleagues interviewed 23 individuals with various medical
conditions including HIV/AIDS, fibromyalgia, arthritis, anxiety/mood disorders, cancer,
epilepsy, and chronic pain. To these individuals cannabis was seen as life preserving, an
adjuvant therapy to their disease, and a means of self-management (19). Significant gender
differences were observed with men focusing more on the physical health benefits of smoking
cannabis, while women found improvements in mental health to be the most beneficial. Both
genders shared the idea that cannabis enabled them to take control of their health by choosing
a drug they perceived to be safer and more effective than their prescription medication (19).
When looking at the patient perspective not only is the psychological aspect of
consuming cannabis important, but also how the patient consumes the product. While the
majority of patients take prescription medication in pill form and ingest orally, there are many
routes of administration for cannabis that make it personalized and completely dependent on
110 Jordan Stinson and Carlo DeAngelis

the patient to choose. While clinical trials in the 1980s and 1990s involved smoking cannabis
or ingesting THC capsules, patients now have the option to vaporize their cannabis or consume
them in an edible form. With the invention of the vaporizer it is now possible to heat cannabis
to a temperature that vaporizes the cannabinoids while avoiding combustion, which reduces
carbon monoxide and tar generation (15). Peak plasma concentrations of THC are similar for
those that use a vaporizer versus those that smoke cannabis (15). The International Association
for Cannabinoid Medicines (IACM) performed a survey completed by 953 participants world-
wide in over 30 countries on the preference for route of administration. Not surprisingly 92%
of participants tried smoking cannabis with only 72% preferring it as their route of choice.
Vaporizers were the preferred method for 50% of the 450 users who tried it at least once (20).
The participants in this survey who vaporized or smoked cannabis were heavy users consuming
up to 3 grams daily. Top three indications of use were chronic pain (30%), anxiety (18%), and
appetite/weight loss (11%). The most interesting aspect from this survey was that less than 10%
of participants had ever tried dronabinol or nabilone, and for those that did only 23% and 7%
preferred dronabinol and nabilone, respectively (20).

FUTURE DIRECTIONS
Earlier this year a systematic review of current cannabinoid use for chemotherapy-induced
nausea and vomiting concluded that cannabinoids cannot be recommended as first-line
antiemetics. The authors also stated that due to the lack of randomized controlled trials (RCT)
and safety concerns, medicinal cannabis cannot be recommended for management of CINV
(21). There lies the current problem with medical cannabis. Although patients advocate the
benefit of cannabis and studies conducted before the 2000s show its efficacy, there have been
no phase III RCT’s conducted in the last five years that compare cannabis to modern day
antiemetic regimens. Instead of the Canadian Medical Association (CMA) joining others in
discouraging the prescribing of cannabis, attributing their decision to a lack of clinical evidence
on efficacy, mechanism of action, and potential harm (22, 23) they should be actively
conducting the necessary trials to show the therapeutic benefits of medical cannabis. Physicians
have a responsibility to make clinical decisions in accordance with the best available scientific
evidence and cannot ignore the fact that many drugs used in place of cannabis also have harmful
side-effects that patients must tolerate, with mechanisms of actions that are not fully understood
(24). It is critical that phase III trials are conducted to create guidelines for future users who
will be interested in trying medical cannabis if legislation is passed next year. Future research
should look at the therapeutic benefits of different strains and strengths of dried cannabis to
meet the needs of the user. Ultimately, if cannabis provides physiological or psychological
relief from a medical condition who are we to deny these people access.

REFERENCES
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 Medical cannabis in the treatment of chemotherapy-induced nausea… 111

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marijuana. J Addict Dis 2005;44(2):311-7.
[15] Abrams DI, Vizoso HP, Shade SB, Jay C, Kelly ME, Benowitz NL. Vaporization as a smokeless
cannabis delivery system: a pilot study. Clin Pharmacol Ther 2007;82(5):572-8.
[16] Moeller K, Woods B. Pharmacy students’ knowledge and attitudes regarding medical marijuana. Am J
Pharm Educ 2015;79(6):1-8.
[17] Tjepkema M. Use of cannabis and other illicit drugs. Health Rep 2004;15(4):41-7.
[18] Bottorff J, Bissell L, Balneaves L, Oliffe J, Capler N, Buxton J. Perceptions of cannabis as a stigmatized
medicine: a qualitative descriptive study. Harm Reduct J 2013;10(2):1-10.
[19] Bottorff J, Bissell L, Balneaves L, Oliffe J, Kang H, Capler N, et al. Health effects of using cannabis
for therapeutic purposes: a gender analysis of users’ perspectives. Subst Use Misuse 2011;46:769-80.
[20] Hazekamp A, Ware M, Muller-Vahl K, Abrams D, Grotenhermen F. The medicinal use of cannabis
and cannabinoids – an international cross-sectional survery on administration forms. J Psychoactive
Drugs 2013;45(3):199-210.
[21] Ablin J, Ste-Marie PA, Schafer M, Hauser W, Fitzcharles M. Medicinal use of cannabis products:
lessons to be learned from Israel and Canada. Schmerz 2016;30:3-13.
[22] Canadian Medical Association. Medical marijuana. Canadian Medical Associaton 2011. URL:
https://www.cma.ca/Assets/assets-library/document/en/advocacy/PD11- 02-e.pdf.
[23] Canadian Medical Association. CMA statement authorizing marijuana for medical purposes (update
2015). Canadian Medical Association 2015. URL: http://policybase.cma.ca/dbtw-wpd/Policypdf/
PD15-04.pdf.
[24] Lake S, Kerr T, Montaner J. Prescribing medical cannabis in Canada: are we being too cautious?. Can
J Public Health 2015;106(5):328-30.
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 10

MEDICAL MARIJUANA, CANCER ANOREXIA

AND CACHEXIA

Meiko Peng, PharmD(C), Minhaz Khaiser, PharmD(C),

Michael Lam, BMSc(C), Soha Ahrari, MScPhm(C),
Mark Pasetka, PharmD and Carlo DeAngelis*, PharmD
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada;
School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada;
Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

Many patients with advanced cancer experience decreased appetite and involuntary weight
loss. Weight loss in these patients is rarely recognized, assessed, or actively managed, and
thus represents an important unmet need in the clinical management of cancer-associated
anorexia and cachexia. Cannabis has been used as an appetite stimulant since 300 AD and
presents as a viable therapeutic option for these cachectic patients. A scoping review was
conducted to: 1) explore the therapeutic use of cannabis to improve appetite in cancer
patients, 2) investigate potential reasons for inconsistency amongst available studies, and
3) identify implications on current practice. Methods: A comprehensive search strategy of
four electronic databases (MEDLINE, EMBASE, PsycINFO, and Cochrane Central) was
completed and included the literature published between May 1990 to July 2016. Key
articles were also hand-searched for further citations, and references from reviews were
checked to identify additional studies. Results: A total of 315 articles were identified for
screening, and application of inclusion/exclusion criteria resulted in eight studies being
included in qualitative synthesis. Small studies (n=6) suggest positive effect between
tetrohydrocannabinol (THC) use and increased appetite whereas large clinical trials (n=2)
suggest otherwise. Conclusions: Despite anecdotal observations suggesting the potential
for cannabis to stimulate appetite, existing studies use various methods of administration
and dosing, making it difficult to draw meaningful conclusions. Weak methodological
choices in smaller studies have resulted in a high degree of variability in results. Further
clinical trials that are well designed and carefully executed are essential to clearly define
the role of these agents as appetite stimulants.

*
Correspondence: Carlo DeAngelis, PharmD, RPh, Department of Pharmacy, Sunnybrook Health Sciences Centre,
2075 Bayview Avenue, Toronto, ON, Canada. E-mail: carlo.deangelis@sunnybrook.ca.
114 Meiko Peng, Minhaz Khaiser, Michael Lam et al.

INTRODUCTION
The usage of marijuana, also known as cannabis, for medical and recreational purposes has
been documented over thousands of years across different cultures. Asian and Indian historical
literature has described the therapeutic potential of cannabis. Medicinal uses of this agent have
been numerous throughout history and include seizure control, analgesia, anxiolysis, cough
suppression, and appetite stimulation (1, 2).
Cannabis interacts with the endocannabinoid system (ECS), a ubiquitous lipid signaling
organization found in all vertebrates. Of the two cannabinoid receptors, CB1 (widely
distributed in the central nervous system) is thought to be responsible for behavioral effects,
such as reward, pain perception, and euphoria, while CB2 (found predominantly on B
lymphocytes and natural killer cells) plays a role in immune suppressive actions (3–5). The
purported therapeutic effects of cannabis are due to the activation of CB1 by the main
psychoactive cannabinoid, tetrahydrocannabinol (THC). The isolation of THC from cannabis,
in conjunction with a greater understanding of cannabinoid pharmacology through the
discovery of the ECS, has opened doors to new areas of research, including plausible drug
targets and therapeutic potential in the management of various medical entities such as
chemotherapy-induced nausea and vomiting (6), refractory spasticity in multiple sclerosis (7),
and AIDS-related anorexia (8).
Many patients with advanced cancer experience decreased appetite and involuntary weight
loss characterized by ongoing loss of skeletal mass that cannot be reversed using conventional
nutritional support, also known as the "cancer anorexia cachexia syndrome" (CACS) (9, 10).
Anorexia (loss of desire to eat) differs from cachexia (progressive wasting of skeletal muscle
mass), but synergistically works with cachexia to reduce food intake and promote weight loss,
thus significantly increasing patient mortality and accounting for up to 20% of cancer deaths
(11). Although the pathophysiology of this syndrome is not yet well defined, the underlying
mechanism is postulated to be secondary to the metabolic changes induced by tumor presence
and growth. These changes are triggered by alterations in the hormonal environment, release
of different tumor factors, and a systemic inflammatory reaction characterized by the
production of pro-inflammatory cytokines, such as interleukins and tumor necrosis factor (12).
CACS continues to be a challenging syndrome to manage, and while optimal therapy involves
treating the underlying cancer, this is not always possible. CACS management requires
integration of both nutritional counseling and pharmacologic agents; however, there are no
established treatment regimens for CACS and options are often limited (13). Megestrol acetate
is currently used as first-line treatment for CACS, and while it can improve the patient’s
appetite and overall weight, it works by increasing fat accumulation with no effect on lean body
mass and quality of life (11, 14). Progestogens such as megestrol are also associated with
significant side effects such as adrenal insufficiency and thrombosis; therefore, given the
possible side effect profile, it is important to explore other possible agents that can optimize
nutritional state and increase quality of life (15, 16).
Historically, cannabis has been noted to have a significant effect on appetite, which has led
to further exploration into use of the ECS to provide supportive care in patients with CACS
(17–19). It is hypothesized that activation of CB1 receptors regulate appetite at the level of the
hypothalamus, where food intake is controlled, and in the mesolimbic reward system for the
motivational or reward aspects of eating (20, 21). Additionally, stimulation of these receptors
 Medical marijuana, cancer anorexia and cachexia 115

on adipocytes and in the liver increases lipogenesis, thus promoting anabolic processes (22).
Nonetheless, the exact mechanism by which cannabinoids exert their effects has yet to be fully
clarified.
Dronabinol, a synthetic THC analogue, is one of the most commonly studied CB1 agonists.
It was developed initially for the treatment of nausea and vomiting in cancer patients in 1986;
its indication then expanded to also cover treatment of weight loss in HIV-wasting syndrome
(23). At present, there is mixed evidence regarding the use of cannabis as an appetite stimulant
in palliating cancer-associated anorexia. Cannabis is the only antiemetic that may also have
orexigenic properties; however, no clinical trials have been conducted to date that evaluate the
effects of the whole plant on CACS. Furthermore, hindered by political and societal barriers
regarding its legalization status and reputation as an illicit drug, research has been inconsistent
and limited. However, as there are now significant changes in legalization of cannabis, both in
the USA and Canada, this is an opportune time to better understand the effect of this substance
on CACS.
This scoping review will aim to (1) explore the therapeutic use of cannabis in improving
appetite and related metabolic processes in cancer patients, (2) investigate potential reasons for
inconsistency amongst available studies, and (3) examine implications of available evidence on
current practice.

OUR REVIEW
The current study used a scoping review methodology (24). Key search terms included
neoplasms, cannabis, anorexia and cachexia. Four non-overlapping databases were searched
from May 1990 up to July 2016: Ovid MEDLINE, Ovid Embase Classic, Cochrane Central
Register of Controlled Trials, and PsycINFO. All searches were limited to humans and the
English language (see Table 1). Abstracts that only focused on cachexia or cannabis alone were
excluded, as the purpose of this scoping review is to better understand the effect of cannabis in
CACS. Full text articles were excluded if they were review articles and only focused on
pharmacology to the exclusion of human trials. Key articles were also hand-searched for further
citations for additional relevant studies. Authors then conducted data extraction and appraised
the quality of the included studies.

Table 1. Search strategy

Database Date Search Strategy

Embase 1947 to June 1. exp neoplasm
2016 2. cannabis
3. exp cannabinoid
4. exp cachexia
5. exp appetite
6. exp appetite stimulant
7. exp decreased appetite
8. exp weight reduction
9. exp anorexia
10. exp anorexia nervosa
11. 1 and (2 or 3) and (4 or 5 or 6 or 7 or 8 or 9 or 10)
12. limit 11 to (human and English language)
116 Meiko Peng, Minhaz Khaiser, Michael Lam et al.

Table 1. (Continued)

Database Date Search Strategy

Medline 1946 to June 1. exp neoplasms
2016 2. exp cannabis
3. exp cannabinoids
4. exp cachexia
5. exp appetite
6. exp appetite stimulants
7. exp weight loss
8. exp anorexia
9. exp anorexia nervosa
10. 1 and (2 or 3) and (4 or 5 or 6 or 7 or 8 or 9)
11. limit 10 to (English language and humans)
Cochrane May 2016 1. exp neoplasms/ or (neoplasm* or cancer or tumor or
Central tumour).mp.
Register of 2. exp Cannabis/ or marijuana.mp.
Controlled 3. exap cannabinoids/ or cannabinoid*.mp.
Trials 4. exp Cachexia/ or cachexia.mp.
5. exp Appetite/ or appetite.mp.
6. exp Appetite/ or (appetite stimulant* or decreased appetite).mp.
7. exp weight loss/ or weight loss.mp.
8. exp Anorexia/ or anorexia.mp.
9. exp Anorexia nervosa/
10. 1 and (2 or 3) and (4 or 5 or 6 or 7 or 8 or 9)
11. limit 10 to English language
PsycINFO 1806 to June 1. exp neoplasms
2016 2. exp marijuana
3. exp marijuana usage
4. exp cannabis
5. exp cannabinoids
6. exp cachexia
7. exp appetite
8. (appetite stimulant* or decreased appetite).mp.
9. exp Weight Loss
10. exp anorexia nervosa
11. 1 and (2 or 3 or 4 or 5) and (6 or 7 or 8 or 9 or 10)

FINDINGS
The search strategy resulted in 315 unique articles (see Figure 1), with 72 full text articles
examined for inclusion/exclusion. After assessing the papers based on the screening criteria,
eight studies that investigated the use of cannabis for appetite stimulation in anorexic/cachectic
cancer patients were identified and all eight were included in the final analysis (see Table 2).
These studies were conducted in the USA (n=4) (21, 25–27), Canada (n=1) (28), Switzerland
(n=1) (29), and Israel (n=1) (30) and published between 1990 and 2015.
 Medical marijuana, cancer anorexia and cachexia 117

*focused on cannabis- or cachexia-only, indications other than cachexia, legal processes †review articles,
pharmacology focused.

Figure 1. Study selection flow diagram.

Study findings

Historical observations of cannabis to stimulate hunger and increase appetite are

well documented, and many findings from small-scale studies are in agreement with these
anecdotal reports. Cannabis’ reputation as an appetite stimulant has been borne out by studies
demonstrating that healthy subjects who use the agent have higher food consumption, calorie
intake, and body weight (32–35). In 1971, Hollister et al. conducted the first study on the acute
effect of oral cannabis extracts on appetite in healthy volunteers and demonstrated an increase
calorie intake in about half of the subjects when compared to placebo (32). In 1976, Greenberg
et al. found similar findings in the first systematic study using smoked cannabis containing 20%
THC (34). Subsequently, in 1986, Foltin et al. studied the effect of smoked cannabis on feeding
in a group of healthy subjects living in a residential laboratory for up to 4 weeks and found a
positive correlation compared to placebo (33). These studies suggest that cannabis may act as
an appetite stimulant in healthy subjects. This has prompted the assessment of cannabis in
clinical syndromes featured by appetite or weight loss, such as cancer or AIDS-associated
anorexia and cachexia.
 Table 2. Characteristics and findings of appetite stimulation studies

Author, Year Study Design Study Population Intervention Appetite Body Weight
Duration
Sacks et al. Case report 2 weeks Patient (n=1) with Hodgkin’s Intervention: Dronabinol 5 mg Maintained Maintained
1990 (31) disease three times daily
Age: 60 Control: N/A
Active treatment
Plasse et al. Dose-ranging 3-6 weeks Adult cancer patients (n=42); Intervention arm 1: Dronabinol 2.5 mg twice daily Maintained at all
1991 (25) pilot study most common tumor types were 2.5 mg daily group (Increased dose levels
lung, prostate, colon Intervention arm 2: 2.5 mg 47%)
Mean age: not reported twice daily
Active treatment: one course of Intervention arm 3: 5 mg daily
chemo permitted during study Intervention arm 4: 5 mg twice
period daily
Control: N/A
Nelson et al. Phase II, 4 weeks Adult patients (n=19) with Intervention: Dronabinol 2.5 Increased Not measured
1994 (26) prospective, cancer-associated anorexia Life mg three times daily one hour
open label expectancy >4 weeks after meals
study Mean age: not reported Control: N/A
Active treatment: N/A
Jatoi et al. 2002 Phase III Megestrol Adult advanced cancer patients Intervention arm 1: Megestrol Megesterol Megestrol
(27) clinical trial (80 days), (n=469) with CACS (≥5 pounds acetate 800 mg/d liquid (Increased 75%) (Increased 11%)
dronabinol weight loss during preceding 2 suspension plus placebo Dronabinol Dronabinol
(57 days), months and/or a daily intake of Intervention arm 2: Dronabinol (Increased 49%) (Increased 3%)
combo (74 ≤20 calories/kg of body weight) 2.5 mg twice daily plus Combo Combo
days) Life expectancy ≥ 3 months placebo (Increased 66%) (8%)
Mean age: 66 Intervention arm 3: both
Active treatment: chemo or agents above
radiation permitted
Walsh et al. Case series 2-30 Adult cancer patients (n=6) Intervention: Dronabinol 2.5 Increased (50%) Increased (67%)
2005 (21) weeks Mean age: N/A mg three times daily for 4
Active treatment: N/A weeks (26). Patients then given
opportunity to escalate dose if
tolerated without toxicity. Max
15 mg daily.
Control: N/A
 119

Author, Year Study Design Study Population Intervention Appetite Body Weight
Duration
Strasser et al. Phase III 6 weeks Adult advanced cancer patients Intervention arm 1: Cannabis Cannabis extract Maintained
2006 (29) clinical trial (n=243) with CACS (weight extract capsule (2.5 mg THC (Increased 73%)
loss ≥5% over 6 months) and 1 mg cannabidiol) twice Dronabinol
Life expectancy of 3 months daily (Increased 58%)
and ECOG ≤2 Intervention arm 2: Dronabinol Placebo (Increased
Mean age: 61 2.5 mg twice daily 69%)
Active treatment Control: placebo orally twice
daily
Brisbois et al. Phase II 22 days Adult advanced cancer patients Intervention: Dronabinol 2.5 Increased (64%) Not measured
2011 (28) pilot trial (n=21) with poor appetite and mg twice daily
chemosensory alterations Control: Placebo oral capsules
(decreased food intake ≥2 twice daily
weeks)
Life expectancy >2 months
Mean age: 67
Active treatment: chemo
permitted
Waissengrin et Observational 1 year Adult patients (n=279), treated None; measured perceptions of Increased (60%) Not measured
al. 2015 (30) study and received permit for medical patients regarding efficacy of
cannabis cannabis
Mean age: 60
Active treatment
120 Meiko Peng, Minhaz Khaiser, Michael Lam et al.

Anorexia and cachexia are common in palliative care populations and are independent risk
factors for morbidity and mortality (36). The first investigation of using cannabis as an appetite
stimulant in cancer patients was conducted by Regelson et al. in 1975 (37). In this Phase II,
placebo-controlled, cross-over study of 54 patients with advanced cancer, significant weight
gain was observed with three oral doses of 0.1 mg/kg/day of dronabinol. However, almost 40%
of patients discontinued treatment due to side effects (drowsiness, mood changes, and memory
problems), perhaps indicating that the majority of patients would not be able to tolerate higher
doses in order to realize the beneficial effects on appetite (37). A case report suggested benefit
of 5 mg dronabinol taken orally three times daily in a patient with Hodgkin’s lymphoma by
maintaining adequate food intake during chemotherapy (31). Other Phase II studies in the 1990s
also suggest cannabinoids’ potential at fixed doses of 2.5 mg THC two to three times daily in
advanced cancer patients (25, 26). Both studies noted that THC was effective and well-tolerated
at low doses. Despite these positive results, the studies are limited by high dropout rates,
variable patient inclusion criteria, placebo effect, and small sample sizes. For example, in the
case report (31), the use of a placebo was not possible and the results were obtained via a self-
recorded food diary. Moreover, Nelson et al.’s Phase II clinical trial was also not blinded or
controlled, and enrolled only 19 patients over 4 weeks (26). Although they found a reduction
in anorexia in 68% of patients, only 53% were able to complete the 28-day trial, and 16% had
to suspend the treatment due to intervention-associated toxicity. Taken together, these trials
suggest a modest benefit, associated with significant toxicity, from dronabinol. It is important
to note that most orally-dosed studies use dronabinol, THC formulated in sesame oil and
supplied as soft gelatin capsules. In comparison, inhalation studies use the dried plant that
contains other potentially active cannabinoids other than THC alone.
Fortunately, trial robustness and scientific rigor improved moving into the 21st century.
Prompted by the positive findings of previous Phase II trials, further investigations were made
into the cannabinoids. A Phase III trial of 469 advanced cancer patients assessed the efficacy
of low-dose dronabinol (2.5 mg twice daily) against high-dose megestrol (800 mg daily) in
palliating cancer-associated anorexia (27). Despite the previously positive results, the study
showed that dronabinol was inferior to megestrol, with only 49% versus 75% of patients noting
an improved appetite. A combination of both treatments did not appear to confer additional
benefit, suggesting that the capacity for appetite stimulation is easily saturated. Further
investigation was undertaken by a Swiss group who performed a Phase III trial that compared
the weight-inducing effects of cannabis extract (1:1 ratio of THC:CBD) or dronabinol to
placebo in 243 patients with CACS. Results showed no improvement in appetite or quality of
life in the treatment group (29). These two large multicenter clinical trials presented very
different results as what one would expect based on the smaller studies previously conducted.
Recently, in a twelve-month study period of non-cancer patients who failed to respond to
treatment for anorexia and weight loss, dronabinol use was associated with a trend toward
weight gain (38). Minor weight gain was also observed in an older population with Alzheimer’s
disease (39). Furthermore, a randomized, double-blinded, placebo-controlled pilot study
suggested that cancer patients with altered chemosensory had increased appetite and improved
taste with dronabinol (2.5 mg twice daily) compared to placebo (40). Though this was a small
and short trial, with only 21 patients completing the study over 18 days, the goal of the study
was for proof-of-concept and to provide a starting point for future trials to build upon. There is
increasing interest in other forms of medical marijuana, such as by inhalation or ingestion of
oils from natural legal sources; however, no clinical trials have tested the efficacy of these
 Medical marijuana, cancer anorexia and cachexia 121

formulations in cancer patients to date. An Israeli study analyzed the indication of cannabis in
cancer patients who are actively being treated with the agent (>90% via smoking) (30). Of the
multiple indications for which cannabis was prescribed, anorexia followed pain as the second
most cited (56%), and was reported to improve appetite in 60% of patients (30).

DISCUSSION
With cannabis quickly gaining prominence in the medical world for its therapeutic potential,
several trials have focused on supportive care issues in cancer; however, clinical trials for
CACS are difficult to conduct and become even more challenging to interpret when trying to
establish clinical practice guidelines.

Route of administration

The two main routes of administration studied are oral extracts of THC analogues (tablets)
and inhalation of marijuana (cigarettes). It is interesting to note that while all smoking
studies, which were conducted in non-cancer populations, reported a positive effect of cannabis
on appetite (33–35), oral studies seem to be inconsistent, with the two largest clinical trials
demonstrating negative findings (27, 29). Despite the multiple smoking studies that
demonstrated positive correlations between cannabis and appetite before the 21st century (33,
34), adverse effects of smoking have since then gained prominence in the medical community.
Consequently, modern clinical trials are wary of utilizing this method due to the many
documented toxic effects associated with smoking. This presents a dilemma; while smoking is
the predominate method used in anecdotal reports of cannabis-induced appetite, use of smoking
is associated with clear harm and as such has not been used in CACS studies. However, recent
studies show promise for vaporization (heating to a point where cannabinoids are emitted
without combustion) due to not only faster onset without negative effects of smoking but also
ability for self-regulation of dosage (41). Smoking is the most common method of cannabis
ingestion, as the dried plant is often conveniently rolled into a cigarette-type vehicle. Though
the pharmacologic and psychoactive cannabinoids are found in all parts of the plant, they are
traditionally accessed from the dried leaves and flowers of the hemp plant (42). The THC
content varies considerably depending on the strain of cannabis, but typically ranges from 5-
25% of the dry plant weight (41). Since the dried plant contains many other potentially active
cannabinoids that can account for activities not observed with THC alone, these constituents
may also interact with specific cannabinoid receptors to modulate the hyperphagic system. The
intervention used in oral studies contained only THC, thus it is inappropriate to extrapolate and
compare the results of THC-only versus dried plant studies.
Inhalation achieves rapid drug delivery from the lungs to the brain and studies have shown
that more than 2000 diverse compounds are produced by pyrolysis during smoking of cannabis
(43). Multiple animal studies suggest that exposure to cannabis smoke alone has
pharmacological consequences (44). In comparison, the bioavailability of oral intake is low and
variable primarily due to the extensive first pass metabolism. Furthermore, oral intake can be
inconsistent for different people due to inter-dependent patient factors. When THC passes
122 Meiko Peng, Minhaz Khaiser, Michael Lam et al.

through the liver, it is metabolized into an equipotent hydroxylated product, which may be more
psychoactive for some people depending on individual cytochrome P450 enzyme activity. Thus
while most patients have a slower effect from oral intake, some patients report a more
significant psychoactive effect compared with those who inhale it. There are many options for
oral intake aside from the capsule form, such as edibles (in form of baked goods) and THC-
infused oils. Studies have shown that baked products yield low and irregular plasma
concentrations and thus are not practical to use in research studies (45). On the other hand, the
oil formulation presents as a viable avenue for research because administration of the oil
without the gelatin capsule may increase bioavailability and provide patients with similar
benefits as smoking without the pulmonary risks. Regardless, the myriad of discrepancies
between routes of administration, such as patient dependent factors and pyrolysis byproducts,
may help explain the inconsistencies observed in inhalation versus oral studies.

Patient inclusion criteria

Although the inclusion criteria for patients in recent studies are more explicitly defined, they
remain inconsistent between studies, making them difficult to compare. Inclusion of patients
with metastatic and incurable cancer versus those of potentially curable malignancies may
yield significantly different results. Studies have shown that nutritional counselling leads to
improvement in cancer symptoms and quality of life, but not in chemotherapy-treated patients
with advanced disease (46). Thus since nutritional counselling is often standard of care when
treating CACS, depending on the disease progression, the patient may respond differently.
Most studies also did not specify the degree and intensity of nutritional counseling, potentially
having a significant impact on results. It is unknown whether cannabis’ effectiveness as an
appetite stimulant is dependent on the severity of the disease, and a greater focus on better
defined patient populations is required to tease out these discrepancies.
Concurrent chemotherapy or radiation therapy are also important factors for consideration.
Some patients may do better on concurrent treatment, and derive these benefits in the form of
increased appetite and weight gain (47). Therefore, studies should balance treatment groups on
the basis of whether the patients were receiving concomitant cancer therapy. For example, in
the phase III trial that compared dronabinol against megestrol in patients with advanced cancer,
chemotherapy or radiation was permitted throughout the study period (27). Thus it is unclear
whether any observed weight gain was due to the intervention or as a result of concurrent anti-
cancer therapy that reduced tumor burden and thus CACS.
Finally, the criteria for cancer-associated weight loss remain questionable as each study set
their own defined measures, whether noting a numerical target of weight loss in pounds, or as
a percentage weight loss. To date, it remains unclear as to the optimal point at which anti-
cachectic treatment should be introduced. As CACS is a continuum, it is difficult to both assess
the stage of CACS the patient falls into, and decide when treatment should start. Consequently,
efforts have been made to develop a framework for the definition and classification of cancer
cachexia. An international consensus publication was published in 2011 that defines the
diagnostic criteria for various stages of cancer cachexia. Cachexia is predominantly defined as
weight loss >5% over the past 6 months (in absence of simple starvation); or BMI <20 and any
degree of weight loss >2% (9). Only one study recruited patients based on these consensus
criteria (29). At present, further studies are required to standardize the patient inclusion process
 Medical marijuana, cancer anorexia and cachexia 123

and assess patients at the same point of the CACS spectrum in order to draw meaningful
conclusions on the therapeutic potential of cannabis.

Dosing inconsistencies

The effects of dronabinol are dose-dependent as studies have shown only specific doses are
associated with appetite stimulation (25). Jatoi and colleagues’ study presented a negative
correlation between dronabinol (2.5 mg twice daily) and appetite, but this result was criticized
for its use of low dose THC, potentially impacting its ability to demonstrate superiority over
megestrol (48). However, the authors justified their dosing choice based on results from a
previous study which showed higher toxicity rate with higher doses of dronabinol (26).
Nevertheless, it is difficult to interpret Jatoi et al.’s phase III trial findings because they
evaluated dronabinol at a dose of 2.5 mg twice daily, while Nelson et al.’s phase II trial assessed
a dose of 2.5 mg three times daily. Similarly, Strasser et al.’s negative findings in the large
Phase III trial were also criticized on their low dosing selections. The incidence of adverse
events was similar for the treatment group versus placebo; this either confirms dronabinol’s
safety profile, or suggests that the chosen dose was too low to demonstrate efficacy.
Unfortunately, there are few dose titration trials of dronabinol in cancer patients that can
establish an optimal dose; further research is required in this area (37, 49).

Cancer cachexia versus HIV-wasting

Anorexia and cachexia are common symptoms in palliative care populations, and the use of
cannabis as an appetite stimulant in other chronic disease have also been explored. Cannabis
has been advocated in patients with HIV/AIDS in order to increase appetite, promote weight
gain, and improve mood (50). In placebo-controlled studies of HIV-positive chronic cannabis
smokers, smoking cannabis led to an increase in food intake (51–53). Dronabinol has been
studied in treatment of HIV wasting, and has been approved for the treatment of this syndrome
(41, 49). Akin to CACS, proinflammatory cytokines are likely the major factor responsible for
HIV wasting (54). Although dronabinol has had positive effects in studies for HIV cachexia,
these effects have not been replicated in the cancer population.
The evidence for cannabis’ positive effects for HIV-wasting syndrome are limited, and was
largely based upon a single placebo-controlled trial that demonstrated dronabinol significantly
increased appetite in 139 AIDS patients, even with long-term use (55, 56). Even though
monotherapy with dronabinol was associated with appetite stimulation, when compared head-
to-head with megestrol in a small randomized trial of 39 patients with HIV-wasting syndrome,
dronabinol was again found to be inferior and combination therapy did not confer additional
benefits (57). These results mirror those found in the dronabinol versus megestrol study
amongst cancer patients (27). Criticisms of early positive observations in HIV patients include
small number of participants and inadequate length of study that focused only on short-term
effects. After expanding its indication to include treatment of AIDS-related cachexia in 1992,
dronabinol was discontinued in 2012 in Canada by the manufacturer (41). Overall, similar to
the cancer literature, there is currently insufficient research into the use of dronabinol for
124 Meiko Peng, Minhaz Khaiser, Michael Lam et al.

appetite stimulation in HIV wasting, and long-term data showing a sustained effect in this
population has yet to be presented (58).

Weight gain significance

Observations of increased appetite from acute cannabis use has set the stage for studies in
patients with HIV and cancer, and in both clinical venues, marijuana has been purported to
stimulate appetite with varying strengths of evidence. However, recent studies indicate that
while appetite may be stimulated, the weight gain may not be clinically meaningful. This was
first alluded to when Strasser et al. failed to find a difference in weight gain in the treatment
group (29). According to several large epidemiological studies, they found that cannabis use in
healthy populations is associated with a lower rather than a higher body mass index, despite
consuming increased calories (59–61). For example, in a 15-year longitudinal study with 3,617
participants, the researchers found that cannabis users had higher daily calorie intake but no
increase in body mass index (59). These puzzling results challenge the traditional notion that
cannabis causes weight gain, and suggest that the effects of cannabis is a function of initial
weight status (62). This may contribute to the inconsistent results noted from both the HIV and
cancer literature, as no standardization was made based on initial patient weight. Furthermore,
there could be differences between short-term and chronic cannabis use as the longest study to
date only looked at 7 months of treatment. The type of weight gain is also an important
assessment because to date, no treatment options have assessed and distinguished weight gain
in terms of fat accumulation or increases in lean body mass. Future studies should consider
incorporating bioelectrical impedance analysis that can measure body composition to assess
whether weight gain with dronabinol is caused by fat, lean body mass, or water (63).

Current use in practice

Cancer anorexia and cachexia continues to be responsible for up to one out of five deaths in
cancer patients, and is considered an important comorbidity of cancer. Current guidelines
classify the syndrome into three stages of clinical relevance: pre-cachexia, cachexia, and
refractory cachexia. Considered as a dynamic process, it is likely that the progression of CACS
may be modulated by timely and effective interventions with nutrition and/or pharmacological
therapy. Indeed, studies have shown that in head/neck, lung and colorectal cancer patients, early
intervention may maintain nutritional status and improve clinical outcome (64–66).
Appetite stimulants such as anti-inflammatory agents and anabolic steroids are some of the
current and emerging treatment options for CACS. However, no single pharmacological agent
has shown clear efficacy in counteracting depletion of muscle mass and in attenuating CACS
symptoms (67). There continues to be a lack of consensus in clinical application of cannabinoid
in cancer anorexia and cachexia. Currently, the only international guideline available has been
published by the French National Federation of Cancer Centers working group on the use of
appetite stimulants in oncology patients (68). The current first and second line treatments,
megestrol and corticosteroids, respectively, are recommended with level B evidence (good
quality evidence from randomized trials and results are consistent when considered together).
In agreement with our findings, dronabinol was found to have level C evidence, indicating that
 Medical marijuana, cancer anorexia and cachexia 125

the methodology of available studies is weak and that the results when taken together are not
consistent. Despite the lack of convincing evidence, the Marijuana for Medical Purposes
Regulation (MMPR) currently permits the use of cannabis for cancer-related cachexia where
other agents have failed, and select patients continue to find benefits for appetite stimulation
with the medication.

Study limitations

Though studies were assessed for quality and the results helped identify parameters and gaps
in the available literature, a detailed data extraction and quantitative synthesis was not
performed. Also, there is no guarantee that all cannabis interventions in CACS were retrieved
as a result of the limitation using MeSH terms. This may have contributed to the low number
of results obtained, and perhaps a more comprehensive search strategy could have generated
further insight. Moreover, this review identified studies that used synthetic THC (dronabinol)
instead of cannabis as the intervention; there may be differences in outcomes between herbal
cannabis and synthetic THC which could not be assessed in this study. Finally, as there is a
dearth of studies in humans, future syntheses may consider including animal studies in order to
increase the scope of the review and to better understand how cannabis could affect CACS.

CONCLUSION
The progress achieved over the past decade in understanding the ECS has revived the
therapeutic interest in cannabis. It is clear that this system plays a role in diverse biological
pathways, including modulation of appetite. Historical and anecdotal observations suggest the
potential of cannabis as an appetite stimulant, but existing studies are littered with
inconsistencies in terms of standardization of patient inclusion criteria, route of administration,
and dosing, making it difficult to draw meaningful conclusions across trials. Specifically, in the
setting of CACS, future well-designed clinical trials that are carefully executed are essential to
clearly define the role of these agents as appetite stimulants. Although cannabis’ anti-emetic
and orexigenic effects suggest potential benefit in the palliative care setting for patients with
cancer, there are currently no data from controlled studies to indicate a significant benefit from
ingested marijuana extract or smoked marijuana for cancer-related anorexia and/or cachexia.

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In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 11

MEDICAL CANNABIS DOSING STRATEGIES

IN PAIN RELATED CONDITIONS

Minhaz Khaiser, PharmD(C), Meiko Peng, PharmD(C),

Michael Lam, BMSc(C), Soha Ahrari, MScPhm(C),
Mark Pasetka, PharmD and Carlo DeAngelis*, PharmD
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada;
School of Pharmacy, University of Waterloo, Waterloo, Ontario, Canada; Odette Cancer
Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada

In Canada, patients may access dried/fresh cannabis or cannabis oil from licensed
producers when prescribed for medical use. Pain management is the most common reason
for medical cannabis use and strategies for dosing, potency, and selection of modes of
delivery need to be further explored. This scoping review aimed to determine therapeutic
dosing strategies for different forms of cannabis in acute or chronic pain conditions. A
literature search was performed in four databases – MEDLINE, Embase, Cochrane Central
and PsycInfo. Additional publications were identified by hand searching key articles,
reviews and Health Canada documents. In total, 11 articles were selected for inclusion.
Seven randomized controlled trials assessed smoked cannabis use in different pain
conditions: three studies used vaporized cannabis; and one retrospective, observational
study reviewed different cannabis formulations. Current literature supporting
smoked/vaporized cannabis is limited by small sample sizes, short intervention periods,
and large variability in dosing. Evidence for oral forms of cannabis (oils, brownies) is even
more limited. Vaporizing should be recommended over smoking cannabis and the best
dosing strategy is to start at a low delta-9-tetrahydrocannabinol (THC) potency (e.g., 1%
THC) and slowly titrate to tolerance at 3-4 inhalations daily with ~45 seconds between
inhalations. The same strategy can be used with oils while maintaining at least two hours
between individual doses to assess pain relief versus side effect profile.

*
Correspondence: Carlo DeAngelis, PharmD, RPh, Department of Pharmacy, Sunnybrook Health Sciences Centre,
2075 Bayview Avenue, Toronto, ON, Canada. E-mail: carlo.deangelis@sunnybrook.ca.
130 Minhaz Khaiser, Meiko Peng, Michael Lam et al.

INTRODUCTION
Cannabis, also called marijuana (derived from the plant Cannabis sativa or indica), is one of
the most popular recreational drugs used worldwide and has a long history of medicinal use
dating as far back as 2737 B.C. (1, 2). The plant material contains many different classes of
compounds and more than 70 phytocannabinoids that interact with receptors of the
endocannabinoid system (ECS). The ECS is a ubiquitous lipid signaling system containing the
cannabinoid 1 and 2 receptors (CB1 and CB2) that regulate various immune and nervous
system processes in the body. These include inflammation, neural development and pain (1, 3,
4). The most well studied cannabinoid, THC, is associated most with the physical and
psychotropic effects of cannabis (5). The second most abundant cannabinoid, cannabidiol
(CBD), is minimally psychoactive and present in lesser amounts (4). Thus, medical cannabis is
available as different strains primarily classified by potency or percentage of THC available.
Medical use of “cannabis” in its dried plant or oil form will be the focus of this review.
This term should not be confused with “cannabinoids”, which refers to the synthetic forms of
cannabis where one or two active molecules have been extracted from the plant material to
create medications commercially available for oral use: nabilone (synthetic analogue of THC,
Cesamet®), dronabinol (synthetic THC, Marinol®), or nabiximols (oromucosal spray,
Sativex®; containing THC:CBD in approximately equal amounts) (4, 6).
Cannabis is commonly available as dried herb, oil, or butter (4, 6). There are also synthetic
formulations available in the form of capsules (containing sesame oil) and plant extracts as
oromucosal sprays (nabiximols/Sativex®) (4). It can be administered orally by mixing with
foods, infused in tea, inhaled by smoking or vaporizing, or rarely administered topically or
rectally (4, 6). Of the available modes of delivery, smoking is the most common and preferred
form as it results in a more rapid onset of action and delivery of THC to the brain compared to
oral consumption (7, 8). Smoking cannabis is the act of inhaling smoke produced by burning
the plant material in hand-rolled cigarettes or pipes with temperatures for combustion reaching
200° Celsius (C) or higher (7, 9). Vaporizing is an increasingly popular alternative to smoking
where the herb is heated below the combustion point so that the vapors produced lack hazardous
compounds such as tar, carbon monoxide and carbon dioxide present in cannabis smoke (7).
Vaporizing and smoking have comparable onsets of action (10).
With growing evidence to prove that targeting the ECS can have therapeutic benefits,
cannabis is being used to treat a wide variety of conditions such as nausea and vomiting,
cachexia and appetite stimulation, and pain. Cannabinoid receptors of the ECS have been found
in many areas of the central and peripheral pain pathways and several mechanisms have been
associated with analgesic effects of cannabis (11, 12). These include antinociceptive effects in
descending pain pathways, inhibition of prostaglandin synthesis reducing inflammation, and
modulation of neural activity centrally (1, 13). Some studies have shown that concomitant use
of THC can enhance analgesic effects of morphine by increasing activation of kappa and delta
opioid receptors (14). Cannabis has been prescribed commonly for pain related conditions such
as neuropathic pain, musculoskeletal pain, chemotherapy-induced pain and Multiple Sclerosis
(MS) related refractory pain (15). Systematic reviews of randomized trials have shown
supporting evidence of cannabis and cannabinoid use in various pain conditions, but have not
provided clear dosing recommendations (15–17). With the increase in chronic pain related
 Medical cannabis dosing strategies in pain related conditions 131

conditions and failure of standard therapies (non-steroidal anti-inflammatory drugs, opioids,

antidepressants and anticonvulsants) cannabis may be an alternative treatment option.
Currently, cannabis has not been approved in Canada for therapeutic use but the Federal
government has required reasonable access to a legal source for medical use. As of June 2013,
under The Marihuana for Medical Purposes Regulations (MMPR), patients who have been
prescribed medical cannabis by physicians can access a supply through ‘licensed producers’
who follow strict compliance and quality control measures (18). These producers may provide
dried cannabis, fresh cannabis or cannabis oil of various strains and potencies to patients (19).
When prescribing; physicians are required to specify the dispensing quantity and the strain of
cannabis on the prescription (20). Thus, the primary objective of this review is to scope current
and existing evidence on the indications and dosing strategies in treating pain related conditions
with medical cannabis.

OUR REVIEW
A scoping review methodology was used to quickly explore existing literature on the topic.(21)
Eligible studies were identified using four non-overlapping databases including MEDLINE,
Embase, Cochrane Central and PsycInfo. The search strategy included the following broad
terms: cannabis, cannabinoid, pain, and dose-response relationship (see Table 1). Additional
papers were identified through hand searching of key articles, reviews and government (Health
Canada) documents.
Initially, the titles and abstracts were subject to the following inclusion criteria: cannabis
use was evaluated in a pain management setting; formulation of cannabis used included
smoking, vaporizing, topicals, edibles (cookies, brownies, teas, infusions, butters or oils);
studies were conducted in humans; studies were published in English; and the full article was
retrievable. Studies were excluded if they: solely used synthetic cannabinoids (dronabinol,
nabilone and other novel cannabinoids) or oromucosal sprays of cannabis extracts; did not
assess effect of cannabis on pain; used animal models; reviewed the pharmacology of cannabis;
and full text was inaccessible. The first author conducted initial data extraction (see Table 2).
Extracted data included study design, participant characteristics (age, type of pain), sample size,
intervention (type, dose, duration), and clinical outcomes.

FINDINGS
The search strategy resulted in 900 potentially eligible articles and 5 other articles were found
through review of references, including the Information for Health Care Professionals
document published by Health Canada (see Figure 1) (4). After applying eligibility criteria and
excluding duplicates, a full-text review of 44 articles was performed. Eleven publications in
total were selected for inclusion in this scoping review (see Table 2). Studies were conducted
in America (n = 9 studies) (22–30) and Canada (n = 2 studies) (31, 32) and were published
between 2007 and 2016. All studies that solely used smoked or vaporized cannabis had a
randomized, double-blind and placebo controlled design. The intervention potencies used in all
studies were represented as percentage of THC by weight of cannabis material. As smoked and
132 Minhaz Khaiser, Meiko Peng, Michael Lam et al.

vaporized forms of cannabis were the two most common interventions, the relevant studies
have been discussed in detail below.

Table 1. Literature search strategy breakdown based on database

Database Search Strategy

1. exp Cannabis/ (7320)
2. exp Cannabinoids/ (11372)
3. exp Pain Management/ (23966)
Ovid MEDLINE(R)
4. exp Pain/ (333950)
<1946 to June Week 4
5. (dose or dosing or dosage).mp. (1266559)
2016>
6. exp Dose-Response Relationship, Drug/ (377511)
7. (1 or 2) and (3 or 4) and (5 or 6) (187)
8. limit 7 to (english language and humans) (87)
1. exp cannabis/ (27764)
2. exp cannabinoid/ (52325)
3. exp analgesia/ (130610)
4. exp pain/dt (141609)
Embase Classic+Embase 5. exp drug dose/ (512995)
<1947 to 2016 Week 6. exp dose response/ (386731)
27> 7. (dose or dosing or dosage).mp. (1935136)
8. exp cannabis/do [Drug Dose] (185)
9. exp cannabinoid/do [Drug Dose] (1356)
10. (1 or 2) and (3 or 4) and (5 or 6 or 7 or 8 or 9) (1113)
11. limit 10 to (human and english language) (653)
1. exp Cannabis/ or (marijuana or cannabis).mp. (1656)
2. exp Cannabinoids/ or cannabinoid.mp. (724)
3. exp Pain Management/ or (pain adj3 (management or
EBM Reviews -
control)).mp. (9688)
Cochrane Central
4. exp Pain/ or (pain or analgesia).mp. (93063)
Register of Controlled
5. (dose or dosing or dosage).mp. (171294)
Trials
6. exp Dose-Response Relationship, Drug/ or dose response.mp.
<May 2016>
(36561)
7. (1 or 2) and (3 or 4) and (5 or 6) (92)
8. limit 7 to english language (84)
1. exp Cannabis/ (5976)
2. exp Cannabinoids/ (4236)
PsycINFO 3. exp Pain Management/ (8099)
<1806 to June Week 5 4. exp Pain/ (48175)
2016> 5. (dose or dosing or dosage).mp. (69668)
6. exp Dose-Response Relationship, Drug/ (0)
7. (1 or 2) and (3 or 4) and (5 or 6) (76)
 Medical cannabis dosing strategies in pain related conditions 133

Figure 1. Literature review flow diagram.

Vaporizing and smoking

In order to standardize dosing of inhaled forms of cannabis, a common, modified smoking and
vaporizing inhalation protocol was implemented called the “Foltin Puff Procedure” (33). The
standardized protocol requires participants to inhale for 5 seconds, hold inhalation for 10
seconds, and then exhale fully. Participants were also required to have 40-45 seconds resting
periods between inhalations. Subjects were mostly given verbal cues by investigators or clinical
trial nurses (23, 24, 29), or were taught to self-administer at home using a titanium pipe in one
case (32).
 Table 2. Study characteristics – use of different forms of cannabis in pain conditions

PRIMARY
AUTHOR CLINICAL INTERVENTION
STUDY POPULATION DOSING OUTCOME
AND PAIN DURATION (THC POTENCY PAIN RELIEF
DESIGN (N) FREQUENCY MEASURE (PAIN
DATE CONDITION %)
ASSESSMENT)
SMOKED CANNABIS
Randomized, Decrease in capsaicin-
Healthy double-blind, 4 sessions; 1 N = 19 (M = 11, Smoked cannabis: induced pain by medium
Wallace et
volunteers placebo- week interval F = 7); 15 low dose (2%), 4 inhalations dose and increase in
al. (2007) VASPI
(Capsaicin- controlled, between completed trial medium dose (4%), per session capsaicin-induced pain by
(23)
induced pain) crossover sessions Age: Mean 28.9 y high dose (8%) high dose; no change by low
study dose
Randomized, 3, 6-hour
Decrease in neuropathic
Wilsey et NP (central double-blind, sessions; 3-21 N = 38 (M = 20, Smoked cannabis: 100-mm VAS; 7-
9 puffs per 6- pain; equivalent results for
al. (2008) and placebo- day interval F = 18); high dose (7%), point PGIC scale;
hour session high (7%) and low (3.5%)
(24) peripheral) controlled, between Age: Mean 46 y low dose (3.5%) 11-point NP scale
doses
crossover sessions
Decrease in neuropathic pain
with high dose (9.4%);
Randomized, Four 14-day
3 inhalations Average daily pain intensity
double-blind, treatment
Neuropathic N = 23 (M = 11, Smoked cannabis daily for first 5 less for 9.4% (score 5.4)
placebo- periods (5
Ware et al. pain (post- F = 12); 21 cigarettes weighing days of cycle versus 0% THC (score 6.1) 11-Point Numeric
controlled, days
(2010) (32) traumatic or completed trial 25 mg of four followed by 9 control (difference = 0.7, Rating Scale
four-period treatment
post-surgical) Age: Mean 45.4 y potencies (0%, day washout 95% CI 0.02 to 1.4)
crossover followed by 9
2.5%, 6%, 9.4%) period
study day washout)
Other potencies had modest
but nonsignificant decreases
Decrease in neuropathic pain
4 inhalations
Phase II, at maximum tolerable dose
daily for 5
randomized, 7 weeks; 5 Smoked cannabis (1-8% THC) of smoked
days after
Ellis et al. HIV double-blind, days N = 28, all male cigarettes ranging cannabis
titrating THC DDS; 10 cm VAS
(2009) (27) neuropathy placebo- treatment Age: 48.8 y between 1 and 8% Pain relief (DDS score) and
potency to
controlled, periods THC >30% reduction in pain from
tolerance on
crossover trial baseline: greater with
Day 1
cannabis versus placebo
 PRIMARY
AUTHOR CLINICAL INTERVENTION
STUDY POPULATION DOSING OUTCOME
AND PAIN DURATION (THC POTENCY PAIN RELIEF
DESIGN (N) FREQUENCY MEASURE (PAIN
DATE CONDITION %)
ASSESSMENT)
Decrease in daily pain with
N = 55: 28 smoked cannabis
Prospective, control, 27 >30% reduction in pain from
Abrams et randomized, 21 day trial; 5 intervention - 25 3 inhalations baseline: 52% of
HIV Smoked cannabis 100 mm VAS;
al. (2007) double-blind, day treatment completed trial daily for 5 intervention group; 24% in
neuropathy cigarettes weighing daily diary
(22) placebo- periods for each category days control group
0.9g (3.56%)
controlled (M = 48, F = 7); Median reduction on daily
Age: Mean 50 y VAS: 34% in intervention
group; 17% in placebo group
Decrease in pain and
spasticity with smoked
cannabis
Randomized, Ashworth Scale
Corey- 17 day trial; Ashworth scale - smoked
Multiple double-blind, N = 30 (M = 11, Smoked cannabis 1 inhalation (spasticity
Bloom et intervention cannabis modified score by
sclerosis and placebo- F = 19); cigarette weighing daily for 3 assessment); VAS
al. (2012) for 3 days 2.74 points more than
spasticity controlled, Age: Mean 21 y 0.8g (4%) days (Secondary
(31) total placebo
crossover trial Outcome)
Pain relief (VAS score) -
5.28 points more than
placebo
SMOKED CANNABIS - Dronabinol vs Cannabis
Randomized, Decrease in experimentally-
Healthy Dronabinol (0mg,
placebo- 5, 6-hour N = 30 (M = 15, 3-7 puffs (70% induced pain with McGill Pain
Cooper et individuals 10mg, 20mg) OR
controlled, outpatient F = 15) of cigarette dronabinol and cannabis Questionnaire (post
al. (2013) (experimental cannabis cigarettes
double- sessions; 2-4 Age: 21-45 y pyrolyzed) per cigarettes; dronabinol CPT); 100-mm
(26) ly-induced (0.00, 1.98, 3.56%
dummy, weeks trial (Mean 27 y) session produced longer-lasting VAS
pain) THC; ca. 800mg)
double-blind decreases
VAPORIZED CANNABIS
Randomized, 3, 6-hour
N = 39 (M = 28, Vaporized
double-blind, sessions; 3 to
F = 11); current cannabis: placebo Decrease in neuropathic
Wilsey et al. placebo- 14 day 8-12 puffs per 100-mm VAS &
NP or past cannabis (0%) medium dose pain; equivalent results for
(2013) (28) controlled, intervals 6-hour session PGIC
users (3.53%); low dose low and medium doses
crossover between
Age: Mean 50 y (1.29%)
study sessions
 Table 2. (Continued)

PRIMARY
AUTHOR CLINICAL INTERVENTION
STUDY POPULATION DOSING OUTCOME
AND PAIN DURATION (THC POTENCY PAIN RELIEF
DESIGN (N) FREQUENCY MEASURE (PAIN
DATE CONDITION %)
ASSESSMENT)
Vaporized Decrease in spontaneous
Randomized,
(aerosolized) Single dosing pain scores most with high
Wallace et placebo- N = 16 (M = 9, F
Diabetic 4 sessions; 2 cannabis: low dose session; 4 dose (7% THC); no 10-cm VAS; foam
al. (2015) controlled, = 7);
neuropathy week intervals (1%); medium dose inhalations per statistical difference between brush; von Frey
(29) crossover Age: Mean 56.9 y
(4%); high dose session medium and low dose (4 and
study
(7%); placebo (0%) 1%)
Chronic pain N = 21 (M = 11, Inhaled on
Vaporized
(on twice- F = 10); evening of
cannabis: from
Abrams et daily doses Not placebo- Age: Mean 42.9 y Day 1, three Drug Effects
cigarette 0.9g on Decrease in pain ratings on
al. (2011) of sustained controlled, not 5 days total (morphine cohort) times daily on Questionnaire
average containing Day 5 compared to Day 1
(25) release randomized and 47.1 y days 2-4, (subjective)
3.56% THC (~96
morphine or (oxycodone morning of
mg THC/day)
oxycodone) cohort) day 5
SMOKED, VAPORIZED, EDIBLE, TOPICAL
Primary: monthly
frequency of
migraine HA
Forms of cannabis
Secondary: Type
used: vaporized (n
Rhyne et Retrospective, N = 121 (M = 51, Decrease in monthly and dose of
Migraine = 42), edible (n =
al. (2016) observational -- F = 63); -- frequency of migraine medical cannabis
headache 66), topical (n =
(30) chart review Age = 18-89 y headache used, previous and
15), smoked (n =
adjunctive
55)
migraine therapies,
patient reported
effects
Abbreviations: CPT = cold pressor test; DDS = descriptor differential scale; F = female; M = male; NP = neuropathic pain; PGIC = patient global impression of
change; THC = delta-9-tetrahydrocannabinol; VAS = visual analog scale; VASPI = visual analog scale of pain intensity; y = years.
 Medical cannabis dosing strategies in pain related conditions 137

Smoked cannabis

In total, seven studies used smoked cannabis to manage pain associated with various conditions.
Two trials were performed in healthy individuals with no pain history who received a painful
stimulus (23, 26); four studies assessed neuropathic pain (NP) (24, 32), two of which explored
HIV-related neuropathy (22, 27); and one trial assessed MS-associated pain and spasticity (31).
All seven trials demonstrated a significant effect on pain relief compared to controls. The
control in all studies was a placebo cigarette containing 0% THC content, while in one study
smoked cannabis was also compared to an active control (dronabinol, a synthetic cannabinoid).
The dosing frequency and THC content of the intervention drug varied between the studies (see
Table 2).
Relief of acute pain using smoked cannabis was studied in two trials. The first trial, by
Wallace et al., used 15 healthy volunteers who received intradermal capsaicin-induced
cutaneous pain after four standardized inhalations of smoked cannabis (23). When capsaicin
was used 20 minutes after smoking cannabis (early time course), none of the cannabis potencies
(low [2% THC], medium [4% THC], high [8% THC]), or placebo showed any difference in
pain perception. However, at 55 minutes after smoking cannabis (late time course), capsaicin-
induced pain was decreased by the medium dose (4% THC), but increased by the high dose
(8% THC). Plasma levels of THC and metabolites showed a correlation to the decrease in pain
at the medium dose but this correlation did not exist with the high dose. The authors
hypothesized that there may be another compound not accounted for in the high dose cannabis
that may have contributed to the hyperalgesia. The high dose cannabis was also associated with
increased mild to moderate side effects such as dizziness and somnolence compared to other
doses.
In another study of cannabis users (≥ 3 cannabis cigarettes at least 4 times per week),
dronabinol was compared to smoked cannabis (26). Pain was experimentally induced using the
Cold Pressor Test, where participants inserted their hands in a warm water bath (37°C) followed
by a cold water bath (4°C) (26). Pain sensitivity (time taken to first report pain sensation), pain
tolerance (time taken to withdraw hand from the cold water) and subjective pain ratings (Pain
Intensity and Bothersomeness Scales) were assessed. As expected, peak effects of the drugs
were seen 15 minutes after cannabis use and 180 minutes after dronabinol use. Compared to
placebo, both smoked cannabis and dronabinol showed decreased pain sensitivity by increasing
the time taken to report the pain sensation (p ≤ 0.01): 3.56% THC (13.1 ± 3.9s from baseline),
20 mg dronabinol (12.1 ± 5.6s from baseline) compared to placebo (0.3 ± 1.0s from baseline).
Pain tolerance was improved (p ≤ 0.05) with low dose cannabis, 1.98% THC and both
dronabinol doses (10mg and 20mg). Although the high dose cannabis (3.56%) increased pain
tolerance in the first hour of administration (9.0 ± 3.0s from baseline), this decreased below
baseline after the first hour and no significant change in tolerance was seen compared to
placebo. In terms of subjective pain ratings of ‘pain intensity’ and ‘bothersomeness’, both
cannabis doses (1.98%, 3.56% THC; p ≤ 0.001) produced a greater decrease compared to high
dose dronabinol (20 mg; p ≤ 0.05). Thus, while smoked cannabis produced more subjective
pain relief than dronabinol, the latter peaked later and produced longer lasting pain relief by
increasing tolerance. Both drugs did not produce any negative subjective effects and cognitive
effects were not assessed.
There were four studies that looked at relief of neuropathic pain using smoked cannabis.
In all four studies, patients had a mean age range of 45-50 years. They were randomized to
138 Minhaz Khaiser, Meiko Peng, Michael Lam et al.

smoked cannabis of varying potencies versus placebo (0% THC). Three of the studies had a
crossover design with participant numbers ranging from 23-38 (24, 27, 32) while one had 25
participants in each arm of the study (22). To reduce risk of adverse psychoactive effects in
cannabis naïve patients, two trials limited enrolment to previous cannabis users (22, 24), while
others had no limitations. All studies excluded patients with any psychoactive issues or drug
dependence. Even though neuropathic pain relief was the common outcome, each of the studies
varied in the interventions and pain assessments used.

Pain relief outcomes

A 2008 study conducted in central and peripheral neuropathic pain patients by Wilsey et al.
reported an equianalgesic effect between high (7% THC) and low (3.5% THC) potencies of
cannabis cigarettes compared to placebo (24). Pain relief was assessed using the Visual Analog
Scale (VAS) and a 0.0035 reduction per minute in pain intensity was recorded for both doses
(p = 0.016). Another study assessed neuropathic pain caused by trauma or surgery using
three active cannabis potencies (2.5%, 6% and 9.4% THC) smoked for five days (32). An
approximate 11% decrease in daily pain intensity was achieved with the high dose (9.4% THC)
cannabis compared to placebo (p = 0.023). The other potencies (2.5%, 6%) resulted in
nonsignificant, moderate decreases in pain. The higher dose was also associated with more
drowsiness, better sleep with less periods of wakefulness (p < 0.05) there were no reports of
confusion or disorientation which are serious cognitive effects. In the studies assessing HIV
neuropathy, a decrease of > 30% in pain intensity measuring numeral rating scales (clinically
significant decrease) (34) relative to placebo was reported with smoked cannabis use (22, 27).
In both studies, a larger proportion of participants reported reduction in pain intensity when
smoking cannabis (46%-52%) compared to the placebo groups (18%-24%) (22, 27).

Dosing frequency

Three of the studies (HIV and post-traumatic neuropathy) had a range of 3-4 inhalations daily
for five treatment days after which pain relief measures were taken (22, 27, 32). In one study
of mixed neuropathic pain, the intervention had a significantly higher dose, with nine
inhalations over a single 6-hour session (24).
Some evidence exists for cannabis use in MS-related pain and spasticity. Corey-Bloom et
al. reported reductions in patient reported scores with single inhalation of 4% THC cannabis
for three treatment days (31). There was a decrease in the modified Ashworth scale of 2.74
points representing better spasticity compared to placebo (p < 0.0001). Pain measured using
the VAS decreased by an average of 5.28 points compared to placebo (p = 0.008) (31). Five
participants withdrew from the study due to treatment-related adverse effects in the intervention
arm (feeling euphoria, dizziness, fatigue).
 Medical cannabis dosing strategies in pain related conditions 139

Vaporized cannabis

Of the three studies using vaporized cannabis, two were conducted to assess neuropathic pain
relief (28, 29). Both were follow-up studies of previous work that had been conducted using
smoked cannabis. In the 2013 follow-up study by Wilsey et al., lower THC concentrations were
used compared to the 2008 study done with smoked cannabis (24, 28). Vaporized cannabis at
a medium (3.53% THC) and low dose (1.29% THC) was inhaled through 8-12 inhalations in a
6-hour session. Even though both doses improved pain tolerance the effect was equianalgesic
when compared to each other. Wallace et al. assessed vaporized cannabis use at three THC
doses (1%, 4%, 7%) in diabetic neuropathy (29). This was a follow up study of one published
in 2007, where similar doses of smoked cannabis were assessed in healthy individuals with
experimentally-induced pain (23). Spontaneous pain scores were significantly decreased by the
high dose (7% THC) compared to other interventions. No statistical difference was reported
between low and medium doses (p = 0.92).
Vaporized cannabis has also been studied in chronic pain patients currently using opioids.
In one 2011 study, 21 participants with chronic pain on sustained-release morphine (average
dose: 62 mg twice daily) or oxycodone (average dose: 53 mg twice daily) therapy were given
vaporized cannabis (3.56% THC) to augment pain relief (25). Participants in both opioid groups
reported a 27% average decrease in pain measures on Day 5 of treatment compared to Day 1
when they had no exposure to cannabis. Cannabis inhalation was associated to a subjective
“high” that was not seen in opioid use alone.

Other dosage forms

A recent study in migraine headache (HA) showed a decrease in frequency from 10.4 to 4.6
headaches per month (p < 0.0001) with chronic use of medical cannabis (30). The study was a
retrospective, observational chart review of patients with a follow-up appointment post
migraine diagnosis. In the study, 121 patients used different forms of cannabis, most of whom
used edible (n = 66, 77.4 g monthly), smoked (n = 55, 45.1 monthly), vaporized (n = 42, 74.8
g monthly), and some used topical cannabis (n = 15, 73.4 g monthly). Most patients used
cannabis for both prophylaxis and treatment (90%), though differences in doses have not been
reported. Edible cannabis users were more likely to report negative outcomes including
somnolence, increase headache and difficulty determining dosing and onset of action. While
approximately 85% patients reported reduced frequency of migraine HAs monthly, about 10%
patients who used inhaled forms of cannabis reported complete control of migraine HAs. This
study concluded that cannabis has positive effects in migraine prophylaxis and treatment, and
warrants further prospective studies to assess dose-response relationships in a controlled
environment.

Other edible forms

Though the following studies were not included in the final screened trials due to unmet
inclusion criteria (case study; pain relief not assessed), it is worthwhile to explore the evidence
that exists for edible forms of cannabis.
140 Minhaz Khaiser, Meiko Peng, Michael Lam et al.

Brownie

No randomized trials have been conducted in any pain related indication using cannabis
brownies. A 1988 study by Cone et al. used a double-blind crossover design to assess behavioral
measures for five healthy, male subjects after consumption of cannabis-laced brownies (35).
The participants had a history of cannabis use and the brownies contained 2.8% THC either at
a dose of two 800mg cannabis cigarettes, one 800 mg cigarette or placebo (0% THC) (4, 35).
The intervention group scored higher on behavioral measures assessed using subjective scales
including the Single Dose Questionnaire, Addiction Research Center Inventory (ARCI), and
VAS compared to placebo. However, the peak effects were slow to appear and variable at 2.5-
3.5 hours after brownie consumption unlike smoking cannabis where effects are seen in minutes
(35). Subjects were not restricted in terms of diet that may have contributed to differences in
absorption and inter-subject variability. In another study by Watchel et al., peak plasma THC
levels were analyzed upon consumption of brownies versus smoked cannabis (36). Brownies
containing low dose of THC (9 mg THC/brownie) resulted in a mean peak plasma levels of 5
ng/mL and high dose brownies (13 mg THC/brownie) resulted in mean peak plasma levels of
6-9 ng/mL (whole plant material versus THC) (36). It is interesting to note that the level
associated with euphoria ranges from 50 to 100 mcg/L (37). However, smoking equivalent
THC amounts produced at least five times higher peak plasma THC levels. The dose-dependent
plasma THC levels increased one hour after brownie ingestion, while smoking resulted in a
rapid increase in THC plasma levels (36).

Cannabis oil

No clinical trials were identified for cannabis oil use in pain management. A 1997 case study
of a young male patient with chronic relapsing pain, gastric inflammation and familial
Mediterranean fever symptoms, used cannabis oil as an intervention (38). A peripheral
cannabinoid receptor (unnamed) was identified and localized to the immune system in the
gastrointestinal tract. This investigation hoped to assess the role of cannabinoids in gastric
inflammatory conditions. The patient was randomly assigned to olive or cannabis oil weekly
over six weeks (1 washout week, 1 active week, 2 placebo weeks, 2 active weeks, 1 placebo
week). The dose used was 50 g THC per day as 10 g THC in 5 doses in an effort to minimize
psychotropic effects.(38) The patient continued oral sustained-release morphine (30 g twice
daily) throughout the study and used 10 mg morphine for breakthrough pain management.
During two consecutive placebo weeks, the patient experienced mood disorders due to possible
withdrawal from previous THC use and during the final two weeks he was unable to
differentiate between placebo and drug suggesting possible development of tolerance to the
active medication with two weeks of continuous (38). The most interesting finding in this case
is that the total amount of breakthrough pain medication requirement decreased with use of
cannabis. The patient used 17 tablets of breakthrough morphine during the active weeks versus
41 tablets during placebo weeks. Cannabis oil did not show any anti-inflammatory effects but
this case showed a significant reduction in additional analgesic requirements.
 Medical cannabis dosing strategies in pain related conditions 141

DISCUSSION
With implementation of new regulations in Canada, eligible individuals with an authorized
prescription can access medical cannabis through licensed producers. A number of Canadians
associate cannabis use with low risk of harm, and it is gaining popularity as a potential treatment
option for unmanageable conditions (39, 40). However, the act of prescribing cannabis is
complicated by the lack of strong evidence on dosing (41). Various professional governing
bodies and researchers have published standards of practice and guidelines to help physicians
navigate through this issue, but further research is warranted to solidify recommendations (20,
42, 43). The College of Family Physicians of Canada recommends physicians follow the
strategy, “Start low, go slow” when prescribing cannabis (37). The recommendation is to
prescribe an inhaled dose of 100-700 mg of no more than 9% THC cannabis daily, titrating to
a maximum 3 g dried cannabis per day. No specific inhalation instructions have been provided
except that patients should start with a single inhalation and appreciate the effects over 4 hours
before increasing (37). One review article made preliminary recommendations to prescribe,
“12g cannabis (9% THC) for 30 days, start with 1 inhalation/day to a maximum of 4
inhalations/day” after conducting a literature review in a chronic non-cancer pain setting (43).
There is a growing body of evidence in support of synthetic THC capsules (dronabinol or
nabilone) and plant extract oromucosal sprays (nabiximols), but less is known about herbal
cannabis (17, 44). The current scoping review aimed to assess existing evidence on dosing and
potency specifically for herbal cannabis in pain related conditions.

Limitations of clinical trials

Even though nine out of 11 studies included in this review had a randomized, double-blind and
placebo controlled design, common limitations across the studies reduced the quality of
evidence. One issue that was recognized by most studies is the small participant size ranging
from 16-27 participants in the intervention groups. With the exception of one study, where HIV
neuropathy patients were all male, there is a fairly good representation of both genders in other
trials (27). Thus, the generalizability of the data is limited. The crossover design of most studies
makes blinding of cannabis versus placebo challenging. The psychoactive effect of THC
(especially at high potencies) contributes in patients correctly guessing the intervention they
receive. Ellis et al. tried to correct for this factor by asking participants to report what they think
they received at several points during the study (27). In the first treatment week, guessing was
no better than chance and cannabis was still shown to be better than the control group in
providing pain relief. In other studies, treatment effects could have been enhanced due to
unmasking of interventions. However, using more than one intervention group, for example
2.5% versus 6% versus 9.4% THC would increase the likelihood of blinding among
intervention groups as participant may not be able to determine the exact potency (32).
142 Minhaz Khaiser, Meiko Peng, Michael Lam et al.

Oral administration versus inhalation

This review mainly assessed herbal cannabis delivered through inhalation (smoking or
vaporizing) and commentary has been included on cannabis brownies and oil. Evidence shows
that oral administration has a slower onset, longer duration of action, and lower peak levels of
medication in the blood when compared to inhalation (8). Peak plasma THC levels can be at
least 5 times higher through smoking compared to oral routes (36). Even though some
behavioral changes were noticed using 2.8% THC cannabis-laced brownies, these appeared
2.5-3.5 h after consumption (35). Thus, the typical side effect of THC, euphoria, and other
positive reinforcement effects such as relaxation and enhanced sensory experiences occurs
rapidly through inhaled forms (~15 minutes) compared to oral administration (45). Individual
physiological differences such as rate of gastrointestinal absorption, degree of first-pass
metabolism and genetic makeup of the participant may also contribute to inter-subject
variability with oral cannabis. Since inhalation provides a direct and fast onset of pain relief, it
is the more preferred route of administration. However, there is a proven relationship for THC
dose-related adverse neurologic or psychoactive effects (e.g., dysphoria, sedation and poor
concentration) with inhaled cannabis (16). In one study, the ratings for “feeling high” (p <
0.003) and “feeling stoned” (p < 0.004) were highest with the higher dose (3.53% THC) versus
the lower dose (1.29% THC) (28). Since oral cannabis results in lower plasma levels of THC
these may cause less psychoactive effects and may be designed to reduce the euphoric “high”
that is experienced by inhaled cannabis. This is relevant for certain patient populations (e.g.,
older, work requiring high cognitive performance) who may opt for oral cannabis to avoid the
“high” even if it means a delayed pain relief effect. Low THC potencies used in low doses have
also shown to cause cognitive impairment in some patients that lasts up to 24 hours (4). Thus,
even if oral cannabis or low THC potencies of inhaled cannabis are selected to prevent
psychoactive effects, there is no guarantee of how a patient may respond.

Smoking versus vaporizing

Smoking is the act of burning the plant material and inhaling the smoke while vaporizing is
heating the herb below point of combustion (7). Taking into account the hazards of smoking,
investigators of two follow-up studies chose to repeat their initial smoking studies using
vaporized cannabis as this would reduce exposure to carcinogens (23, 24, 28, 29). Smoking is
not an optimal delivery system as similar carcinogenic materials usually found in tobacco
smoke are also present in cannabis smoke (9). Vaporizing cannabis can produce carbon
monoxide as a by-product but it is comparably in much smaller amounts compared to smoking
(7). Thus, in agreement with the recommendations by governing bodies, vaporizing should be
the chosen mode of delivery (20, 43).

Standard inhalation protocol versus reality

In most studies, the “Foltin Puff Procedure” was used which standardized the inhalation
protocol. Participants mostly self-administered cannabis while being given verbal cues, but in
one study were taught the inhalation method to be used at home (32). Participants in this study
 Medical cannabis dosing strategies in pain related conditions 143

collected daily urine samples and returned all capsules (containing herbal cannabis to be used
in a titanium pipe) at the end of each intervention period. Investigators concluded compliance
was excellent as all dispensed capsules were returned, and urine and plasma THC assays were
consistent with results (32). Participants in a clinical trial are under supervision and have regular
follow-ups in a controlled environment, but this is not the case in clinical practice. Practitioners
who choose to prescribe cannabis need to consider various methods to prevent or control
substance abuse, such as prescribing small amounts at a time, or ordering regular urine testing
to reduce risk of diversion or abuse.

Dose-response relationship

Trials studying smoked cannabis for neuropathic and MS pain conditions had the shortest
intervention periods, lasting 1-5 days. The dosing frequency ranged from one inhalation daily
to nine inhalations in a 6-hour session, with majority of the studies ranging from 3-4 inhalations
per day. A number of the studies defined low, medium, or high dose using THC percentage by
weight.
The wide variation in the design of the trials makes it challenging to compare them head-
to-head but some important conclusions can be highlighted. Overall, use of cannabis reduced
participant reported pain measures compared to placebo. This was observed in studies using a
single potency of THC (~4%) in HIV related neuropathy and MS related pain settings (22, 31)
Similar studies of smoked and vaporized cannabis in neuropathic pain settings found
equianalgesic effects between low, medium, and high THC potencies (24, 28). In other studies,
decrease in spontaneous pain scores was most with the highest dose studied (25, 28). These
results highlight the challenge that exists in selecting the best initial cannabis potency for
treatment. One study avoided this dilemma by first titrating participants to a maximum
tolerance ranging 1-8%, and then performed the intervention phase of the trial, which resulted
in successful pain reduction from baseline (27). Therefore, titration by “starting low, going
slow” is the best dosing strategy as 1) lower potencies have shown equivalent efficacy to higher
doses; 2) all patients may not equally tolerate higher potencies of cannabis.

Dosing recommendation

In neuropathic pain settings, controlled trials have shown efficacy of THC doses from 1% to
9%. The best dosing strategy in this group is to start at the lower THC doses based on patient
history of cannabis use (e.g., 1-2% THC) up to 3-4 vaporized inhalations daily (separated by
45 seconds based on Foltin procedure) (33). For cannabis-naïve patients, it should be required
for patients to start at the lowest THC dose (i.e., 1% THC) to avoid undesirable side effects and
titrate up to pain relief (19). Cannabis-naïve patients should be counseled to separate inhalations
by at least 30 minutes to assess side effect and prevent overdosing. For non-neuropathic pain
the same recommendations may be followed as above. Cannabis oil may be dosed using
dronabinol/Marinol® (oral capsules of synthetic THC in sesame oil) as a reference as no
clinical trials exist (19). Average dose of Marinol® used is 20 mg THC per day and doses range
from 2.5 mg to maximum 210 mg THC per day. Just as with the inhaled cannabis, oils should
be prescribed at the lowest dose (e.g., 2.5 mg THC) and then titrated to effect (19). Patients
144 Minhaz Khaiser, Meiko Peng, Michael Lam et al.

should wait at least two hours between administrations of single oral doses as acute effects may
last up to 4 hours (4). To start, dried cannabis should be prescribed at 1 g per day (30 g/month)
to a maximum of 3 g per day (90 g/month) (4). The amount prescribed should follow the MMPR
regulation: “30 times the daily quantity of dried marijuana indicated by your healthcare
practitioner on your medical document, or 150 grams of dried marijuana, whichever is less”
(18).

Limitations of the scoping review

Due to the nature of this scoping review where MeSH terms were used in databases deemed
most appropriate, it is not possible to ensure all relevant studies were gathered for inclusion.
Cannabis dosing in pain settings has very limited evidence and clinical studies of cannabis-
based edible products (e.g., oils, teas, brownies etc.) are non-existent. Case studies and animal
studies were excluded and should be considered for inclusion moving forward as they may
provide some perspective on novel dosing strategies that may be of clinical importance.

CONCLUSION
Even though medical cannabis is not approved as a therapeutic agent in Canada, it is available
for medical use by patients with an authorized prescription. Current literature on herbal
cannabis mostly involves smoked and vaporized mode of delivery, and very little evidence
exists regarding oral forms such as brownies and oils. Smoking is not an optimal delivery
system due to toxic by-products and thus, vaporizing cannabis is preferred. The studies
identified in this review are limited by large variability in dosing strategies, small sample sizes
and short intervention periods. Standardized studies regarding orally consumed cannabis (oils,
brownies etc.) are essentially non-existent and limit our ability to make substantial conclusions.
It is best to choose a low potency to start treatment with and titrate to an optimal dose that
provides pain relief, improves function with minimal adverse effects.

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Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 12

HOW TO ADMINISTRATE CANNABIS AND EFFICACY

Stephanie Stockburger*, MD
Division of Adolescent Medicine, UK Healthcare, Department of Pediatrics, Lexington,
Kentucky, US

The legalization of marijuana for medical use is increasingly common in the United States.
The marijuana plant contains a number of cannabinoids along with chemical delta-9-
tetrahydrocannabinol (THC) which is known to be psychoactive. In states where medical
marijuana is legal, physicians may be trained to certify patients for medical marijuana use.
Patients then take their certification and obtain medical marijuana from a dispensary. The
dispensary provides advice on which marijuana species or strain to purchase as well as
dosing and administration. Forms of medical marijuana are the same as recreational
marijuana. Forms include dried leaves or buds for smoking or ingestion and hashish which
may also be smoked or ingested. Marijuana concentrates are becoming more popular as
they are easier to conceal and require a smaller amount to produce the desired effect. Types
of concentrates include butane honey oil, CO2 honey oil, wax or budder, and shatter.
Dabbing is a technique used for consuming concentrates that involves placing a “dab” of
the concentrate on a heated surface and inhaling the vapors. As products are not regulated
by the United States Food and Drug Administration, there is concern that potency and
product-labeling of THC content varies widely among dispensaries and patients are at risk
for under- and over-dosing. Overall, more research is needed about the effects of specific
cannabinoids on individual body systems and health conditions in order to standardize
forms of administration and their efficacy as well as dosing.

INTRODUCTION
The legalization of marijuana for medical use is increasing in the United States. Marijuana is
the dried leaves, flowers, stems, and seeds from the hemp plant, Cannabis sativa (1, 2).
Marijuana contains numerous cannabinoids. The chemical delta-9-tetrahydrocannabinol (THC)
is a known mind-altering chemical that is found within the plant. Currently, there are two

*
Correspondence: Stephanie J Stockburger, MD, Division of Adolescent Medicine, UK Healthcare, Department of
Pediatrics, KY Clinic Room J413, Lexington, KY 40536-0284, United States. E-mail: sjstoc2@uky.edu.
148 Stephanie Stockburger

United States Food and Drug Administration (FDA) approved cannabinoids: dronabinol and
nabilone. The FDA-approved indications for these drugs are nausea and vomiting associated
with chemotherapy and appetite stimulation in acquired immunodeficiency syndrome (AIDS)
(1).
Marijuana (as opposed to the isolated cannabinoids mentioned above) is classified as a
schedule I drug which means it has no currently accepted medical use and has a high potential
for abuse (1). However, our current law permits individual states to allow physicians to certify
marijuana use for certain medical conditions (3). Many states agree that Alzheimer’s disease,
amyotrophic lateral sclerosis, cachexia/wasting syndrome, cancer, Crohn’s disease, epilepsy
and seizures, glaucoma, hepatitis C virus, human immunodeficiency virus/acquired
immunodeficiency syndrome, multiple sclerosis and muscle spasticity, severe and chronic pain,
and severe nausea are conditions that physicians can certify patients for medical marijuana use
(3). Typically, it is recommended that the FDA-approved cannabinoids dronabinol and
nabilone are tried initially. Then if patient has minimal or no improvement, therapy may be
escalated to medical marijuana use that is certified by the physician. The patient then goes to a
dispensary and receives advice on which marijuana species or strain to purchase as well as
dosing and administration (1). The forms and administration of medical marijuana are identical
to the use of recreational marijuana.

FDA-APPROVED CANNABINOIDS
Currently, there are two isolated cannabinoids that are approved by the FDA. These are
dronabinol and nabilone. They are approved for the treatment of chemotherapy-induced nausea
and vomiting as well as appetite stimulation in patients with acquired immunodeficiency
syndrome (AIDS) (4). Both drugs are available in capsule form. Dosing of dronabinol is 2.5
mg to 10 mg three or four times daily. Dronabinol is available in a 2.5 mg capsule, 5 mg capsule,
and a 10 mg capsule (4). It is considered a controlled substance, category C-III. For appetite
stimulation, the initial recommended dose is 2.5 mg twice daily (before lunch and dinner) or
once daily if dose is not tolerated (4). Dose can be titrated up based on response and tolerability
to a maximum of 20 mg per day (4). For chemotherapy-induced nausea and vomiting the
recommended dose is 5 mg/m2 administered 1 to 3 hours before chemotherapy, then give
5mg/m2/dose every 2 to 4 hours after chemotherapy for a total of 4 to 6 doses/day (4). Dose
can be increased in increments of 2.5 mg/m2 based on response and tolerability with a
maximum dose of 15 mg/m2/dose. Off-label dosing of chemotherapy-induced nausea and
vomiting that is refractory is 2.5 to 10 mg 3 or 4 times daily (4).
Nabilone is FDA approved for treatment of nausea and vomiting associated with cancer
chemotherapy (5). It also comes in a capsule form (5). Capsules are 1 mg. Dosing instructions
are 1-2 mg twice daily with a maximum of 6 mg in 3 doses daily (5). It is recommended to
begin with the lower dose and increase if needed. Nabilone is also considered a controlled
substance and is category C-II (5). It is approved for treatment for adults but use in pediatric
patients is considered off-label (5).
 How to administrate cannabis and efficacy 149

MEDICAL MARIJUANA
As mentioned previously, the use of medical marijuana can be certified by a physician for
certain conditions within state laws. States that allow physicians to certify medical marijuana
have their own list of approved conditions that may be managed with medical marijuana (1).
Each state that has legalized medical marijuana also has a legal limit which may be something
like “1-2 ounces every 30 days”. The legal limit varies widely by state (1). It is important to
note that physicians are not prescribing marijuana but instead are certifying that the patient has
a medical condition that may benefit from medical marijuana use and that the physician has
discussed the risks and benefits (1). Certification must state the medical condition that the
physician believes would be treated effectively with the medical marijuana (1). In some states,
the recommended amount of marijuana needed to treat the condition must also be stated on the
certification (1). Marijuana cannot be prescribed due to its status at the federal level of being a
schedule I drug which makes it illegal (1). It is not regulated by the FDA or dispensed by
pharmacies (1). Physicians must have training in prescribing medical marijuana which usually
consists of continuing medical education (CME) activities prior to certifying patients for
medical marijuana use (1).
When physicians are treating patients for conditions that would otherwise be treated by
marijuana itself, it is reasonable to start therapy with dronabinol or nabilone (1). If these
medications are not successful, treatment may be escalated to marijuana itself (1). Marijuana
contains a number of cannabinoids and it is currently not known how individual cannabinoids
affect the various diseases that are currently managed with medical marijuana (1). Conditions
which are permissible for treatment with medical marijuana vary by state. However, there are
a number of conditions that states agree upon in which management with medical marijuana is
permissible (3). These conditions include Alzheimer’s disease, amyotrophic lateral sclerosis
(ALS), cachexia/wasting syndrome, cancer, Crohn’s disease, epilepsy and seizures, glaucoma,
hepatitis C virus, HIV/AIDS, multiple sclerosis and muscle spasticity, severe and chronic pain,
and severe nausea (3). Once a patient begins medical marijuana treatment, close physician
follow-up is very important as it is with any medication that could have significant adverse
effects and abuse potential (1). It is recommended that the patient be seen for follow-up within
30 days with additional telephone contact as necessary (1). After this, the patient may be
followed monthly for three months and then in intervals depending on the clinical situation (1).
Medical marijuana is administered in the same way as recreational users use the drug.
When a patient receives certification from a physician for treatment with medical marijuana,
they take the certification to a dispensary (1). The dispensary provides advice on which
marijuana species or strain to purchase as well as dosing and administration (1). Forms of
marijuana include dried leaves and buds, resin from the flowers, and extracts. Only the leaves
and buds of the female Cannabis Sativa and Cannabis indica plants contain psychoactive
properties (6). The male plants do not contain THC and therefore do not have psychoactive
properties (6).

SMOKING
Smoking leaves and buds of the marijuana plant is a common way to use marijuana
recreationally or medically. Joints (also called “spliffs or doobies” are hand-rolled cigarettes
150 Stephanie Stockburger

that contain marijuana leaves and buds (2). A blunt is an emptied cigar that is partly or
completely refilled with marijuana (6). The lumpy texture of marijuana as well as the distinct
odor of marijuana distinguishes it from tobacco (6). The marijuana may be sprayed with
contaminants such as other psychoactive drugs to enhance effects of poor quality, stale, or male
(not psychoactive) marijuana plants (6). Pipes and water pipes may also be used to smoke
marijuana.
Hashish (hash, for short) is made by shaking the buds of marijuana and dropping the resin
glands onto silk screens (6, 7). The resin glands are then sieved through the silk screens to
create kief. Kief has a loose powdery consistency. Kief is normally compressed to form a block
of hash. Kief and hash may be smoked in pipes, water pipes, bongs or mixed with tobacco and
smoked (6). The different names for hashish include black, goldseal black, redseal black, and
Morrocan (Rocky for short) (6). Hashish is an oily, solid substance (6).

EDIBLES
Marijuana can be mixed in food such as brownies, cookies or candy (2). It can also be brewed
as a tea (2). It can also be used like a kitchen herb and added to many types of food (6). Hashish
and hashish oil can also be dissolved into milk and consumed in drinks (6). Cannabis is an oil-
based substance and the emulsive properties of milk allow it to be dissolved. When marijuana
is ingested, compared to inhaling the smoke or vapors of marijuana, it has a delayed-onset of
effect, and tends to last for a longer period of time (8). It is estimated that 16% to 26% of
patients using medical cannabis consume edible products (9). Oral consumption does not have
the harmful effects of smoking but users may have a more difficult time titrating their dose to
desired effect (10).

CONCENTRATES
Concentrates contain a higher percentage of THC than marijuana leaves or hash products (7).
All concentrates must be made by using some type of solvent to extract the THC (7). Toward
the end of the concentrate-making process, the solvents and plant matter are removed (7).
Solvents used are either butane or carbon dioxide (CO2) (7). There is concern that it is difficult
to completely remove the solvent from the concentrate. Health concerns exist about consuming
concentrate that still contains butane (7). However, professional concentrate manufacturers
have supposedly become extremely efficient at removing butane (7). In addition, because the
process usually involves butane, which is lighter fluid, individuals who have attempted to create
extracts at home have caused fires and explosions and have been seriously burned and injured
(2).
Concentrates may be in the form of oil, wax, or shatter. Hash oil or honey oil is a gooey
liquid that is usually used in vape pens (7). As above, the extraction process either involves the
use of butane (butane honey oil or BHO) or CO2 (CO2 honey oil). Wax or budder is a soft solid
that has a texture like lip balm (2). It is created by whipping hash oil during the purging process
and has a consistency that is comparable to earwax (7). The percentage of THC between oil
and wax are similar (7). Shatter is a hard, amber-colored solid that is a refined version of butane
 How to administrate cannabis and efficacy 151

honey oil (2, 7). It takes multiple steps to make in order to extract all the plant matter and
solvents and is usually made in a pressure vacuum (7). It is usually a thin cake, is yellow or
amber in color, and “shatters” when you break a piece off (7). Shatter is the most potent
concentrate and can contain 90% THC (7).

DABBING
Dabbing is a technique that is used for consuming concentrates (7). It involves placing a “dab”
of concentrate onto a heated surface which vaporizes the concentrate. The concentrate is then
inhaled (7). There is a recent increase in “dabbing” among recreational marijuana users as well
as medical marijuana users (11). Users are recommended to start with a single inhalation of
marijuana vapor and monitor for effect (1). If twenty minutes pass without effect, the patient
may take two inhalations and monitor for another twenty minutes (1).

CANNABINOID (CBD) OIL

Cannabinoid oil is not FDA-approved in the United States but is a product worth mentioning
due to its likelihood of beneficial effects for several medical conditions. Cannabidiol (CBD) is
a compound found in marijuana that is not psychoactive like THC (12, 13). Cannabidiol and
THC levels vary among different plants and breeders have created strains of the marijuana plant
that have high levels of CBD and very low, next to zero, levels of THC (12). CBD oil is thought
to have antipsychotic, antihyperalgesic, anticonvulsant, neuroprotective, and antiemetic
properties (13). The American Academy of Neurology published guidelines in 2014 that
recommended an oral cannabis extract containing both THC and CBD as having the highest
level of evidence-based support as treatment for spasticity as well as pain associated with
multiple sclerosis (14). This product is not currently FDA-approved for use in the United States
(14).

POTENCY AND LABELING CONCERNS

The potency of THC and other cannabinoids is not regulated and varies widely among products
with the exception of the FDA-approved and regulated cannabinoids dronabinol and nabilone.
The mean potency of marijuana preparations appears to be increasing over the last two decades.
A study by Mehmedic, et al. evaluated confiscated cannabis preparations from 1993 to 2008
(13). A total of 46,211 samples were seized and analyzed by gas chromatography-flame
ionization detection. It was found that the mean Δ9-THC content increased from 3.4% in 1993
to 8.8% in 2008 (13). Hashish potencies were not noted to increase consistently during this
period but were noted to vary widely from 2.5% to 9.2% (1993-2003) to 12.0-29.3% (2004-
2008) (13). The study concluded that the increase in cannabis preparation potency was mainly
due to an increase in the potency of nondomestic versus domestic samples (13).
There is also a large concern about the consistency of cannabinoid dose and label accuracy.
A study by Vandrey et al. (10) evaluated the package contents of edible medical cannabis
152 Stephanie Stockburger

products from three major metropolitan areas (10). Dispensaries were located by an internet
directory and three dispensaries from each of the three major metropolitan areas were randomly
identified (10). Individuals with physician certification for medical cannabis use purchased
products from the dispensaries. The samples were tested with high-performance liquid
chromatography. Researchers noted that the products failed to meet basic label accuracy
standards for pharmaceuticals (10). They found that greater than 50% of products evaluated
had significantly less cannabinoid content than labeled, with some products containing
negligible amounts of THC (10). They noted that other products contained significantly more
THC than labeled. If products are over-labeled, the medical benefits may be negligible (10). If
products are under-labeled, the higher THC content puts patients at risk of experiencing
increased adverse effects (10).

DOSING
Dosing for the FDA-approved products dronabinol and nabilone is well-established. However,
the dosing for medical marijuana is not standardized. According to the World Health
Organization, a standard marijuana cigarette contains as little as 0.5 g of marijuana (1). As an
example, in Massachusetts, state law allows a 60-day supply of 10 oz of medical marijuana (1).
A 60-day supply of 10 oz is up to 560 marijuana cigarettes or about 10 per day (1). If a patient
smokes 1 to 2 marijuana cigarettes a day, they would need about 0.5 to 1 oz of marijuana per
month (1).
It is estimated that ingesting marijuana requires about three to five times the smoked dosage
(8). When cannabis is ingested, the effects are spread out over a longer period of time (8). This
may be useful for patients who are having trouble with sleep or situations where smoking is
impractical or impossible (8). However, ingested cannabis can be harder to titrate due to its
delayed onset and an individual’s metabolic activity (8).
It is recommended that medical marijuana users have an accurate scale to weight, measure,
track and titrate their dosage and supply of cannabis (8). Patients tend to “stockpile” their
marijuana as they cannot purchase it at the pharmacy (8). One author recommends a personal
supply of three to six pounds (8). There is concern that potency diminishes a little with time
but cannabis can be reportedly stored in a cool, dark, dry place for years without significant
loss of effect (8).

CONCLUSION
In conclusion, there are a number of different forms of administration of medical marijuana. At
this time, medical marijuana is not regulated by the FDA and therefore dispensaries often have
under- or over-labeled THC content of their products. Marijuana contains a number of different
cannabinoids which may have different effects on different medical conditions. There may be
a role for the non-psychoactive CBD oil in treatment for a number of medical conditions. More
research is needed to safely recommend marijuana forms and route of administration as well as
specific strains and species of the plant.
 How to administrate cannabis and efficacy 153

REFERENCES
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publications/drugfacts/marijuana.
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for the treatment of commonly state-approved medical and psychiatric disorders. Addict Sci Clin Pract
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https://www.verywell.com/types-of-marijuana-22323.
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https://www.coloradopotguide.com/colorado-marijuana-blog/2014/february/06/different-types-of-
marijuana-concentrates-available-in-colorado/
[8] Conrad C. Cannabis yields and dosage. URL: http://www.safeaccessnow.net/yieldsdosage.htm.
[9] Grella CE, Rodriguez L, Kim T. Patterns of medical marijuana use among individuals sampled from
medical marijuana dispensaries in Los Angeles. J Psychoactive Drugs 2014;46(4):267-75.
[10] Vandrey R, Raber JC, Raber ME, Douglass B, Miller C, Bonn-Miller MO. Cannabinoid dose and label
accuracy in edible medical cannabis products. JAMA 2015;313(24):2491-3.
[11] Stogner JM, Miller BL. Assessing the dangers of “dabbing”: mere marijuana or harmful new trend?
Pediatrics 2015;136(1):1-3.
[12] Leaf science. 5 must-know facts about cannabidiol (CBD). URL: http://www. leafscience.com/
2014/02/23/5-must-know-facts-cannabidiol-cbd/
[13] Mehmedic Z, Chandra S, Slade D, Denham H, Foster S, Patel A, et al. Potency trends of Δ9-THC and
other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci 2010;55
(5):1209-17.
[14] Wright S, Yadav V, Bever C Jr, Bowen J, Bowling A, Weinstock-Guttman B, et al. Summary of
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In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 13

CANNABIS AND PAIN

Jonathan K Hwang, BSc(C) and Hance Clarke, MD, PhD*

Pain Research Unit, Department of Anesthesia and Pain Medicine,
Toronto General Hospital, University Health Network, Toronto, Ontario, Canada;
Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada

Cannabis and cannabis derivatives are sometimes used to relieve pain. Objective: To
conduct a scoping review to explore the extent of the literature on the efficacy, safety, and
side effects of cannabis and cannabis derivatives as a treatment for pain. Methods: The
English-language literature was searched using electronic databases for studies published
from 1960 to August 15, 2016. All randomized controlled trials that compared cannabis to
a control and that examined pain as an outcome were included. Data on demographic and
clinical characteristics, study duration, intervention duration, and outcomes were
abstracted. Results: Of 4,472 articles identified through the literature search, only 28
studies satisfied eligibility criteria. An additional five were identified through hand search
Most studies had very small sample sizes. The primary methods of administration were
oromucosal spray of nabiximol, oral ingestion of cannabis extract capsules, and inhalation
of smoked cannabis. Overall, nabiximol oromucosal sprays resulted in reductions in pain
that were statistically significant but of variable clinical relevance. Studies of oral cannabis
extracts nabilone and dronabinol yielded mixed results, with some studies demonstrating
effectiveness and others being negative. Studies of smoked cannabis consistently
demonstrated statistically significant and clinically relevant reductions in neuropathic pain.
Conclusions: Published research on the efficacy of cannabis as a treatment for pain is
extremely limited. Evidence of effectiveness was strongest for smoked cannabis for
neuropathic pain.

INTRODUCTION
Cannabis and cannabis derivatives have been used since ancient times as an analgesic to relieve
pain from a variety of conditions. Although long considered a natural remedy for

* Corresponding author: Hance Clarke, MD, PhD, Staff Anesthesiologist, Director of Clinical Pain Services and Medical Director of
Pain Research Unit, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON Canada. E-mail: Hance.Clarke@uhn.ca.
156 Jonathan K Hwang and Hance Clarke

various conditions, the evidence for its use has not been systematically reviewed until relatively
recently. This scoping review will explore the extent of the literature on the efficacy, safety,
and side effects of cannabis and cannabis derivatives as a treatment for pain.

OUR REVIEW
We searched the English-language literature for studies published from 1960 to August 15,
2016 using electronic databases such as MEDLINE, EMBASE, CINAHL, EBM Reviews and
Cochrane Databases. Our search strategy includes the MESH terms: marijuana, cannabis,
cannabinoids, and pain. We also searched the bibliographies of systematic reviews and all
included studies by hand for additional relevant studies.

Eligibility criteria

We included all randomized controlled trials that compared cannabis to a control and examined
pain as an outcome; the control could be placebo or another analgesic. We excluded cross-
sectional studies, prospective and retrospective observational studies, case-control studies, case
reports, case series and review articles. We also excluded studies that were published in abstract
form only.

Selection process and data abstraction

We reviewed titles and abstracts from the literature search to select articles that met our
eligibility criteria. Then, one of the authors abstracted data from the selected articles, including
demographic and clinical characteristics of the study, study duration, intervention duration, and
outcomes. During our review, we further excluded studies that were not blinded and studies
with sample size less than 10 when considering efficacy data. When considering long-term
safety data, we did include open label studies as there was not much long-term safety data.

FINDINGS
A total of 4,472 articles were identified through the literature search. Of these, there were only
28 studies that satisfied our eligibility criteria (see Figure 1). An additional 5 studies (1-5) were
identified through hand search of bibliographies of review articles and included studies. After
excluding 5 studies that were not blinded (6-10) and 1 with small sample size (11), we included
a total of 27 articles (see Table 1).
The majority of evidence on cannabis and pain comes from randomized controlled trials
that use either a placebo or known analgesics as controls. As there is no standard dose for
cannabinoids, the studies vary greatly in the amount of the cannabinoid administered. Specific
studies covered conditions that caused pain such as cancer, multiple sclerosis (MS), HIV-
induced neuropathy, fibromyalgia, or trauma-induced neuropathy. Other studies were more
 Cannabis and pain 157

general and did not specify the primary cause of pain. Of particular interest is the use of
cannabis for cancer pain and multiple sclerosis as cannabis is thought to have other positive
anti-emetic and anti-spastic effects. The primary methods of administering the treatments
included use of a nabiximol oromucosal spray, ingestion of cannabis extract capsules, and
inhalation of smoked cannabis.

Figure 1. Scoping review flow diagram.

 Table 1. Characteristics of included RCTs (n = 27)

Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
Abrams et al. 55 87 48.5 HIV Neuropathy 3 weeks Smoked Ratings of Pain Reduction -Anxiety, Sedation,
(2007), USA (6.6) Cannabis (3.56% pain (VAS) by 34% using Disorientation,
THC) x 3/ day Cannabis vs. Paranoia,
for 5 days vs 17% by placebo Confusion,
placebo (p= 0.03) Dizziness, and
Nausea (all mild)
-No dropouts due to
adverse events
Berman et al. 48 96 39 (10) Brachial Neuropathy 6 weeks Sativex Oro- Pain on an Pain Scores Dizziness (n=9),
(2004), United Plexus mucosal Spray 11 point -Baseline: 7.5, - Somnolescence (n
Kingdom Avulsion (2.7 mg THC + box scale, After Placebo: =7), Dysgeusia (n
2.5 mg CBD/ Short-Form 6.9, -After 1:1 =10), Nausea (n =
spray) vs placebo McGill THC:CBD: 6.1 1), Feeling Drunk
and THC Oro- Pain (p = 0.005), (n = 4) (all mild to
mucosal Spray Question- -After THC moderate)
(2.7 mg THC/ naire, only: 6.3 (p =
spray) x 1-48 Pain 0.02)
sprays vs Disability
placebo Index
Cooper et al. 30 50 27 (6) Cold Pressor Nociceptive 5 x 6-7 Smoked Pain on an Unable to Subjective Drug
(2013), USA Test hour Cannabis (1.98% 11 item abstract due to Effects: Smoked
sessions and 3.56% numeric method of Cannabis (1.98%
THC), scale recording and 3.56% THC)
Dronabinol 10 and 20 mg
mg, 20 mg, Dronabinol
placebo produced increased
“High” and “Good”
Drug Effects
relative to placebo
Corey-Bloom et 30 37 51 (8) Multiple Spasticity 17 days Smoked Pain (using Effect (95% CI) Acute Cognitive
al. (2012), USA Sclerosis (nociceptive) Cannabis (4% VAS) = 5.28 (2.48 – Effects (Dizziness,
THC) x 1/ day vs 10.01) Headache, Fatigue,
placebo reduction in feeling too “high”)
VAS scores in
cannabis vs
placebo group
 Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
Ellis et al. 34 97 49.1 HIV Neuropathy 7 weeks Smoked Pain Median -Concentration
(2012), USA (6.9) Cannabis (1-8% intensity on difference in Difficulties,
THC) x 4/day vs a DDS points for Fatigue, Sleepiness,
placebo Descriptor pain reduction Sedation, Increased
Differen- of cannabis vs. sleep duration,
tial Scale placebo: 3.3 (p Reduced salivation
(DDS) = 0.016) and thirst; moderate
to severe adverse
events more
common in
treatment group -1
drop out due to
Psychosis, 1 due to
Intractable Cough
Frank et al. 96 52 50.2 Various Neuropathy 6 weeks 250ug-2 mg Pain (using VAS Scores Tiredness (n = 79),
(2008), United (13.6) Nabilone or 30- VAS) (mm): Sleeplessness (n =
Kingdom 240 mg -Baseline: 69.6 46), Sickness
dihydrocodeine (range 29.4- (n=46), Tingling (n
per day 95.2), - = 25), Strangeness
Nabilone: 59. (n = 27),
93 (SD = Nightmares (n = 7),
24.42), - Shortness of Breath
Dihydrocodeine (n=18), Headaches
: 58. 58 (SD = (n = 20), Other (n =
24.08) 66)
-3/64 in
Nabilone group
had a clinically
significant drop
in VAS (by 10
mm or more)
Johnson et al. 177 54 60.2 Cancer Mixed 2 weeks Oromucosal Pain on an Numeric Pain -THC:CBD:
(2010), United (12.3) THC Extract 11 item Scale Scores: Somnolescence (n =
Kingdom Spray (2.7 mg numeric -Baseline 8), Dizziness (n =
THC per spray), scale THC:CBD 7), Confusion
Oromucosal Group(SD): (n=4), Nausea
THC:CBD 5.68 (1. 24), (n=6), Vomiting
Extract Spray, -Baseline THC (n = 3), Raised
 Table 1. (Continued)

Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
(2.7 mg THC Group (SD): Gamma GT (n =2),
+ 2.5 mg CBD 5.77 (1.33), Hypercalcemia (n =
per spray) x 8-12 -Baseline 0), Hypotension (n
sprays according Placebo(SD): =3) -THC:
to individual 6.05(1.32), Somnolescence (n =
response, -Median 8), Dizziness (n =
placebo Reduction 7), Confusion
THC:CBD (n=1), Nausea (n =
Group: - 4), Vomiting (n =
1.37(p=0.024), 4), Raised Gamma
-Median GT (n = 5), -Mostly
Reduction THC mild or moderate.
Group: -
1.01(p=0.204),
-Median
Reduction
Placebo Group:
-0.69
-Statistically
significant
reduction for
THC:CBD
group only,
clinically
significant
(>30% pain
Reduction)
reduction
observed in
43% of
treatment
patients vs.
21% of placebo
patients
 Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
Kalliomaki et al. 30 100 29.3 Healthy Nociceptive 3 treatment Nabilone Pain (using No significant -Dizziness (n = 21),
(2013), Sweden (6.25) volunteers using a heat- sessions Capsules (1 mg, a VAS) difference Postural Dizziness
pain model or 2 mg, and 3 mg), between (n = 11), Fatigue (n
intradermal placebo. Single nabilone doses = 10), Dry Mouth
capsaicin dose. and placebo for (n=10),
electronic VAS Tachycardia (n =
(maximal pain) 9). Mostly mild to
or VAS (area moderate.
under curve) - 14 severe adverse
events led to the
withdrawal of four
patients
Killestein et al. 16 N/A 46 (7.9) Multiple Spasticity 12 weeks Dronabinol Pain (using No abstractable -Adverse events
(2002), Nether- Sclerosis (nociceptive) (THC) 2.5 mg, VAS) pain data were more common
lands C. sativa extract with the C. sativa
(2.5 mg THC, extract than the
CBD, other Dronabinol
cannabinoids) treatment. All were
mild to moderate.
-1 severe adverse
effect (acute
psychosis) with C.
sativa extract.
Kraft et al. 18 0 23.5 Healthy Nocioceptive-- 8 hour Oral Cannabis Pain (using No significant Drowsiness,
(2008), (2.6) volunteers Sunburn sessions Extract Capsules VAS) difference Sedation, Dry
Germany Hyperalgesia, (2:1 THC:CBD between Mouth, and Vertigo
Electrical Pain, Content) (20 mg cannabis extract had significantly
and THC) per session capsules and different self-report
Intradermal placebo was and observer
Capsaicin found for any reported VAS
pain models scores for the
cannabis treatment
compared to
placebo
 Table 1. (Continued)

Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
Langford 339 32 49.0 Multiple Neuropathy (Phase A) 4 Oral muscosa Validated Responders at 15 (9%) in the
(2013), 33 study (10.5) sclerosis weeks spray (2.7 mg of self- the 30 % THC/CBD spray
sites globally THC + 2.5 mg of reported 0– improvement group and 12 (7 %)
CBD), x max 12 10 point level in mean in the placebo
sprays/ day, numerical pain NRS score group, stopped
placebo rating scale totaled 50 % in study medication
(NRS) the THC/CBD due to AEs.
assessing spray group vs Majority of AEs
mean daily 45 % in leading to
neuro- the placebo permanent cessation
pathy group of study medication
(p = 0.234) were within the
nervous system
disorders and
gastrointestinal
disorders system
organ classes
Lynch et al. 18 17/83 56 Chemothera Neuropathy 6 months Oromucosal Pain on an No significant Fatigue (n = 7), Dry
(2014), United (10.8) py induced THC Extract 11 item difference was Mouth (n = 5),
Kingdom pain Spray (2.7 mg numeric found between Dizziness (n = 6),
THC/spray), scale placebo and the Nausea (n = 6),
Oromucosal nabiximol Increased Appetite
THC:CBD spray, however (n = 2), Diarrhea (n
Extract Spray, 5/16 = 2), Decreased
(2.7 mg THC + participants Appetite (n = 1),
2.5 mg CBD/ experienced a Feeling “stoned” (n
spray) x 1-12 clinically = 1), Anxiety (n =
sprays according significant 1), Panic Attack (n
to individual reduction in = 1), Headache (n =
response, pain at the end 2), Confusion (n =
placebo of 6 months. 1), “Fuzzy
Thinking” or
“Foggy Brain” (n =
1)
 Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
Narang (2008), 30 47 Median Non-cancer Chronic pain Phase 1 ~4 10 mg or 20 mg Total Pain -Patients on 2 adverse events
USA (range): pain (taking weeks of dronabinol Relief at 8 Dronabinol had during the study,
43.5 opiods) (single dose), hours decreased pain both related to
(21-67) placebo (TOTPAR) intensity and anxiety (tremors,
increased dizziness, inability
satisfaction to concentrate).
compared with Both occurred in
placebo. subjects who
-No difference received
in benefit were 20 mg of
found between dronabinol.
the 20 mg and
10 mg
Nurmikko et al. 125 41 53.3 Allodynia Neuropathy 5 weeks Sativex Pain on an -Difference -Dizziness (n = 18),
(2007), United (15.5) Oromucosal 11 item between Nausea (n = 14),
Kingdom Spray (2.7 mg numeric Sativex and Fatigue (n = 13),
THC + 2.5 mg scale, Placebo Dry Mouth (n =
CBD/ spray) x 1- Neuropathi Decrease: -0.96 11), Vomiting (n =
48 sprays c Pain (p=0.004) 8), Feeling Drunk
according to Scale -Statistically (n = 6), Headache
individual significant (n = 6), Diarrhea (n
response, decrease in pain = 4),
placebo -26% of Nasopharyngitis (n
Sativex vs 15% = 4), Anorexia (n =
placebo patients 4), Somnolescence
achieved a (n = 4), Abdominal
clinically Pain Upper (n=3),
significant Disturbance in
decrease in pain Attention (n=3),
(>30% pain Memory
reduction) Impairmnet (n = 3)
-91% of patients
experienced at
least1 AE; most
were mild
 Table 1. (Continued)

Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
-11% on Sativex
experienced a
severe AE vs. 8%
on placebo
Portenoy et al. 360 52 58 Various Various 24 months Sativex Pain on an No statistical or Neoplasm
(2012), US (12.2) Oromucosal 11 item clinical Progression (n =
Spray (2.7 mg numeric significant 47), Nausea (n =
THC + 2.5 mg scale difference in 59), Dizziness (n
CBD/ spray) x 1- pain relief =51), Vomiting (n
4,6-10,11-16 between =42),
sprays according Sativex spray Somnolescence
to individual and placebo (n=39),
response Disorientation (n =
18), Anorexia (n =
22), Constipation
(n=20), Dry Mouth
(n=22), Anemia
(n=19), Diarrhea
(n=17), Dysgeusia
(n = 11), Headache
(n =15), Asthenia (n
=18),
Hallucination (n =
8), Decreased
Appetite (n = 11),
Fatigue (n = 13),
Pain (n = 11),
Insomnia (n = 8),
Stomatitis (n =11),
Weight Decreased
(n = 8)
-29.5% of patients
receiving Sativex
had a severe
adverse event
 Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
Rog et al. 66 21 49.2 Multiple central pain 4 weeks Sativex Pain on an Numeric Pain -Dizziness (n = 18),
(2005), United (8.3) Sclerosis Oromucosal 11 item Scale Scores Somnolescence (n =
Kingdom Spray (2.7 mg numeric (SD) -Baseline 3), Disturbance in
THC + 2.5 mg scale Sativex: 6.5 Attention (n = 2),
CBD/ spray) x 1- (1.6), -Baseline Headache (n = 1),
48 sprays Placebo: 6.4 Dissociation (n =
according to (1.7),-Decrease 3), Euphoria (n =
individual in Pain Scale 2), Dry Mouth (n =
response, Score Sativex, 4), Nausea (n = 3),
placebo Placebo: -2.7, - Diarrhea (n = 2),
1.4 (between Glossodynia (n =
groups 1), Mouth
difference((p = Ulceration
0.005) (n = 1), Vomiting (n
= 1), Falls (n = 3),
Weakness (n = 3),
Fatigue (n = 2),
Feeling
Abnormal (n = 1),
Feeling Drunk (n
=1), Pharyngitis (n
= 2), Hoarseness (n
= 1), Throat
Irritation (n = 1)
- 88.2% of patients
on Sativex
developed one or
more AE,
-2 patients
withdrew due to
severe AEs
Skrabek et al. 40 7 48.9 Fibromyalgi Nociceptive 8 weeks Nabilone (THC) Pain (using -Decrease in After 4 weeks:
(2008), Canada (7.6) a Capsules (0.5-1 VAS) Pain for 1 mg -Drowsiness (n =
mg)/day for one Nabilone BID 7), Dry Mouth (n =
week?, placebo from Baseline 5), Vertigo (n = 4),
after 4 weeks: Ataxia (n = 3),
-2.04 (p < Confusion (n = 2),
0.02). Decreased
 Table 1. (Continued)

Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
-No significant Concentration (n =
differences 2), Dissociation (n
observed for = 2), Orthostatic
0.5 mg Hypertension (n=2),
Nabilone PO at Anorexia (n = 2),
2 or 4 weeks Headache (n = 1),
and no Dysphoria (n = 1),
significant Euphoria (n = 1),
differences Sensory
observed for 1 Disturbance (n = 1).
mg Nabilone Mostly mild.
BID at 2 weeks. -No serious adverse
events occurred
-Adverse events
were significantly
more common in
the treatment group
at 2 and 4 weeks
Svendson et al. 24 42 50 (8) Multiple Spasticity 6 weeks Dronabinol Pain on an -Median -Dizziness or
(2004), Sclerosis (nociceptive) (THC) 10 11 item spontaneous Lightheadedness (n
Denmark mg/day for 3 numeric pain = 14), Tiredness or
weeks, placebo scale significantly Drowsiness (n =
lower for 10), Fatigue (n = 1),
Dronabinol Balance Difficulty
than for (n = 2), Headache
placebo (n = 6), Migraine (n
(p=0.02) with = 1), Speech
13 (54%) Disorders (n = 1),
patients Feeling of
achieving Drunkenness (n =
clinically 2), Sleep Difficulty
significant (n = 1), Multiple
(>30% pain Sclerosis
reduction) pain Aggravated (n = 1),
reduction on Myalgia (n = 6),
active treatment Muscle Weakness
 Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
versus 5 (21%) (n = 3), Limb
on placebo Heaviness (n = 1),
Distortion of Wrist
(n = 1), Mouth
Dryness (n = 3),
Nausea (n = 3),
Palpitations (n = 4),
Euphoria (n = 3),
Hyperactivity (n =
1), Hot Flushes (n =
1), Anorexia (n =
1), Chills (n = 1),
Upper Airway
Infection (n = 1),
Tenderness in Nose
(n = 1)
-Number of adverse
events was high for
the active treatment
group than for the
placebo group
-No severe adverse
events were
reported; no
withdrawals due to
adverse events
Toth (2012), 26 54 61.2 Refractory Neuropathy 5 weeks nabilone 1-4 Pain diaries Improvement in Treatment-emergent
Canada (14.7) human mg/day, taken as the change in adverse
diabetic 2/day, 12 hours mean end-point events were
peripheral apart neuropathic reported by 6/13
neuropathic pain in nabilone (46%) subjects
pain vs receiving placebo
placebo (mean and by 7/13 (54%)
treatment subjects receiving
reduction of nabilone (most
1.27; 95% were mild or
confidence moderate)
interval 2.29-
0.25)
 Table 1. (Continued)

Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
Turcotte (2015), 15 13 45.5 Relapsingre MS-induced 9 weeks Nabilone Pain (using After Nabilone
Canada (10.8) mitting neuropathic 5-week VAS): pain adjustment, a was well tolerated,
multiple pain maintenance of intensity significant with dizziness/
sclerosis 1mg oral (VASpain), group x time2 drowsiness
(MS) nabilone and interaction term most frequently
patients (on (placebo) twice impact of was reported reported.
gabapentin) daily pain on for both the
daily VASpain and
activities VASimpact
(VAS score,
impact) demonstrating
the adjusted
rate of decrease
for both
outcomes was
statistically
greater in
nabilone vs
placebo group.
Wade et al. 24 50% N/A Various Various 8 weeks Sativex Pain (using - Statistically -THC:CBD only:
(2003), United Oromucosal VAS) significant “Drug Toxicity” (n
Kingdom Spray (2.7 mg decrease in pain = 1), Headache (n =
THC + 2.5 mg for THC and 1), Nausea (n = 1),
CBD/ spray), CBD Vomiting (n = 1),
THC treatments, but Diarrhea (n = 1),
Oromucosal not THC:CBD Sleepiness (n = 2),
Spray (2.7 mg treatment Fall (n = 1), Cough
THC), CBD (n = 1), Impaired
Oromucosal Balance (n = 1),
Spray (2.5 mg Fatigue (n = 1),
CBD) x 1-44 Influenza-like
(120 mg Symptoms (n = 1),
THC/120 mg Thirst (n = 1)
CBD) sprays -Feeling Intoxicated
according to led to 3 withdrawals
individual
 Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
response,
placebo
Wallace et al. 19 58 28.9 Healthy Nociceptive – 1 day Smoked Pain (using Five minutes -Low Dose:
(2007), USA (10.9) volunteers pain induced Cannabis (2%, VAS; after cannabis Dizziness/Faintness
by Capsaicin 4%, 8% THC) Visual exposure, there (n = 1), Injection
Analogue was no Side Effects (n = 2).
Spon- effect on -No Medium Dose
taneous capsaicin- Adverse
Pain induced pain at Events reported.
Intensity - any dose. By 45 - High Dose:
VASPI) min after Dizziness/Faintness
cannabis (n = 3),
exposure, Somnolescence (n =
however, there 1), Feeling Cold (n
was a = 1), Cognitive
significant Impairment (n = 1),
decrease Dyspnea (n = 1),
in capsaicin- Dry Mouth (n = 1),
induced pain Injection Side
with the Effects (n = 1),
medium dose Nausea and
and a Vomiting (n = 1)
significant
increase in
capsaicin-
induced pain
with the high
dose.
There was no
effect seen with
the low dose,
nor was there
an effect on the
area of
hyperalgesia at
any dose.
Significant
negative
correlations
 Table 1. (Continued)

Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
between pain
perception and
plasma _-9-
tetrahydrocanna
binol levels
were found
after adjusting
for the
overall dose
effects.
Ware et al. 23 48 45.4 Post- Neuropathy 8 weeks Smoked Pain on an Difference -9.4% THC:
(2010), Canada (12.3) Trauma/Surg Cannabis 11 item between Asthenia (n = 2),
ery (2.5%,6%, and numeric placebo and Decreased Motor
9.4% THC) x 3/ scale 9.4% THC: 0.7 Skill (n = 1),
day, placebo (p=0.023) Dizziness (n = 4),
-Statistically Headache (n = 4),
significant pain Heavy-headed (n =
relief for 9.4% 1), Lightheaded (n
THC cigarettes, = 1), Numbness (n
but non- = 2), Sleepiness (n
significant pain = 2), Unbalanced (n
relief at other = 1), Burning
THC Sensation (n = 3),
concentrations Fatigue (n = 1),
Heaviness (n = 1),
Hematoma (n = 1),
Irritation of Oral
Cavities (n = 1),
Itchiness (n = 1),
Itchiness in Face (n
= 1), Itchiness of
Nose (n = 1), Pain
(n = 2), Tingling
Nose (n = 1),
Craving for Sweets
(n = 1), Disinterest
 Mean
First author, No. of Male age* Clinical Duration
Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) (SD) condition of study

in Surroundings (n
= 1), Dysphoria (n
= 2), Euphoria (n =
1), Fidgety Fingers
(n = 1), Foggy
Mental State (n =
1), Lack of
Concentration (n =
2), Less Alert (n =
1), Paranoia (n = 1),
Racing Thoughts (n
= 1), Cough (n = 3),
Short of Breathe (n
= 1), Throat
Irritation (n = 3),
Dry Mouth (n = 1),
Increased Appetite
(n = 2), Nausea (n =
1), Dry Eyes (n =
1), Itchiness of Eyes
(n = 1), Edema (n =
1), Injury to Right
Knee (n = 1); all
were mild to
moderate.
-No severe adverse
events
Wilsey et al. 38 53 Median Unspecified Neuropathy 3 x 6 hour Smoked Pain (using -Mean Adverse events
(2008), USA (range): sessions Cannabis (3.5% VAS) and Difference were not mentioned
46 (21– and 7% THC) x Neuro- VAS Pain individually,
71) 9 puffs per pathic Pain Intensity per however a
session Scale minute (7% significant “good
THC vs. drug effect” was
Placebo): - reported for both
0.0035 (p = treatments when
0.04), compared to the
-Mean placebo and a
 Table 1. (Continued)

Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
Difference significant “bad
VAS Pain drug effect” was
Intensity per reported only for
minute (3.5% the 7% THC dose
THC vs. nearer to the end of
Placebo): the trial
-0.0036
(p=0.03)
-No significant
difference
between the
two THC doses
Wilsey et al. 39 72 50 (11) Unspecified Neuropathy 3 x 6 hour Smoked Pain (using -Difference Adverse events
(2013), USA sessions Cannabis (1.29% VAS) and between both were not mentioned
and 3.5% THC) Neuropathi treatment individually,
x 8-12 puffs per c Pain groups and however a
session Scale placebo significant “good
observed at 120 drug effect” was
mins (p = noted with both
0.0002), and treatments when
evident at 240 compared to
mins (p = placebo and a
0.0004), and significant “bad
300 mins (p = drug effect” was
0.018). noted with the
-10/38 patients medium dose THC
had a clinically at 240 mins
significant
(>30% pain
reduction)
reduction in
pain on placebo
vs. 21/37 on the
low dose THC
and 22/ 36 on
 Mean
First author, No. of Male Clinical Duration
age* Type of pain Treatment Outcome Results Adverse events
year, country subjects (%) condition of study
(SD)
the medium
dose THC.
Wissel et al. 17 24 44.8 Multiple Spasticity 9 weeks Nabilone Pain on an Nabilone 1 patient dropped
(2006), Austria (14.4) Sclerosis (Nociceptive) Capsules (1 mg 11 item treatment out due to weakness
per day) numeric decreased by a of the lower limbs,
scale, median 2 points other adverse events
Ashworth when compared not mentioned
Score to placebo (p <
(Spasticity) 0.05)
Zajicek et al. 277 37 51.9 Multiple Spasticity 12 weeks Dronabinol Pain on an -Mean Change -Dizziness (n = 89),
(2012), United (7.8) Sclerosis (nociceptive) (THC) 2.5 mg 11 item in Body Pain Urinary Tract
Kingdom taken up to 25 numeric from Baseline Infection(n = 34),
mg daily Likert Dronabinol Dry Mouth (n =
scale, (SD): -1.2 (2.6) 34), Headache (n =
Ashworth -Mean Change 22), Asthenia (n =
Score in Body Pain 25), Fatigue (n =
(Spasticity) from Baseline 25).
Pain is a Placebo(SD): -Mostly mild to
secondary -0.3 (2.4) moderate.
outcome. -Statistically -233/277
significant experienced at least
decrease in pain one adverse event
between THC -More adverse
and placebo (p events present in
<0.025) the treatment group
(93.0% vs. 74.6%)-
30 patients
withdrew from
active treatment due
to AE.
-7 serious adverse
events
VAS = Visual Analog Scale.
* When means and SDs are given for men and women separately, we combined the means and SDs using methods described in
http://handbook.cochrane.org/chapter_7/table_7_7_a_formulae_for_combining_groups.htm.
174 Jonathan K Hwang and Hance Clarke

Nabiximol oromucosal spray

Nabiximols are a cannabis extract that contain tetrahydrocannabinol (THC) and cannabinidiol
(CBD) in an approximate 1:1 ratio and are administered as a sublingual spray. This mix of
cannabinoids is marketed under the name Sativex in Europe and Canada, and contains 2.7 mg
THC and 2.5 mg CBD per spray. Studies that administered this spray almost exclusively left
dosing up to the patient, providing them with a range of allowed sprays per day, but not giving
them an exact dose that they should take in a period of time (2, 3, 5, 6, 12-16). As such, the
amount of THC and CBD consumed between individuals varied greatly.
Nabiximols have been studied for their efficacy on pain as a result of chemotherapy-
induced neuropathy (13), cancer (12), multiple sclerosis (5, 15, 16), neuropathy characterized
by allodynia (2), various cancers (14), and neuropathy as a result of a brachial plexus avulsion
(3). Of the eight studies, five of the eight reported a statistically significant decrease in pain (2,
3, 12, 14, 15). Of the five studies that reported a decrease in pain, one showed quantitative
clinical relevance (12), another two did not show clinical relevance (3, 14) and two did not
mention clinical relevance in a quantitative form, if at all (2, 15). Side effects such as dry mouth,
dizziness, nausea, vomiting and fatigue were generally well tolerated, with relatively few severe
adverse events (3, 5, 12, 13, 15); however in two other studies, severe adverse events were
relatively common (29.5% of patients in one study (14) and 10% of patients in another study
(16)).
The literature is sparse in terms of the long term effects of using nabiximol sprays. Two
open label studies, one documenting nabiximol use over 38 weeks for neuropathic pain (6) and
the other documenting nabiximol use over 2 years for terminal cancer pain (7), both concluded
that there were no significant adverse effects for long term usage, however more research needs
to be done to verify this finding. One study found that nabiximols were associated with a larger
incidence of severe adverse affects (29.5% of nabiximol treated patients vs. 24.2% of placebo
treated patients) and a larger incidence of death (20.9% of nabiximol treated patients vs. 17.6%
of placebo treated patients) over a period of 24 months (14). The study acknowledged that the
lack of correlation between severe adverse events, death, and number of Nabiximol sprays
administered means that the association likely came about purely by chance (14). Nevertheless,
more research is needed to examine this association.
Overall, nabiximol sprays seem to have a statistically significant effect on pain, with
variable clinical relevance. A consideration with respect to studies of nabiximols is that the
majority of these studies were funded by the pharmaceutical company that manufactures this
product (2, 3, 5-7, 12, 15, 16).

Cannabis extract capsules

Orally ingested capsules of cannabinoid extracts dronabinol and nabilone have been tested for
their analgesic effects. Dronabinol is a THC extract, while nabilone is a synthetic cannabinoid
that mimics the action of THC. Studies testing dronabinol varied in their dosing considerably,
giving dosages ranging from 2.5 mg to 25 mg per day (1, 4, 17-19), while studies testing
nabilone prescribed between 0.5 mg to 4 mg per day (20-25).
Dronabinol was studied for its efficacy on pain as the result of multiple sclerosis (1, 4, 18),
unspecified chronic pain (19), and sunburn induced hyperalgesia (17). Three of the five studies
 Cannabis and pain 175

reported a statistically significant decrease in pain (4, 18, 19). Of these three studies, one study
claimed a 54% clinically significant decrease in pain with the active agent compared to a 21%
clinically significant decrease in pain with the placebo (4), while the other two studies did not
talk about clinical significance (18, 19). Of the two studies that did not find a decrease in pain,
one argued that dronabinol had no analgesic effects on acute inflammatory pain whatsoever
(17), while the other stated that although dronabinol use was found to be tolerable in patients,
its efficacy was questionable (1).
Nabilone was studied for its efficacy on pain as a result of fibromyalgia (24), multiple
sclerosis (22, 25), chronic neuropathic pain (20), diabetic peripheral neuropathic pain (21), and
capsaicin induced pain (23). Five of the six studies for nabilone and pain reported a statistically
significant decrease in pain (20-22, 24, 25). Of the five studies, two discussed clinical
significance in quantitative terms. One of the studies reported that 3 of 64 patients experienced
a clinically significant decrease in pain (20) and the other study reported that 11 of 13 patients
experienced a clinically significant decrease in pain with nabilone compared to 5 of 13 on
placebo (21). All of the five studies concluded that nabilone was a tolerable and possibly
effective treatment (20-22, 24, 25). When nabilone was compared to a dihydrocodeine, it was
found to have less of an analgesic effect (20). The one study that did not find a significant
decrease in pain tested for the effects of a single dose of nabilone and acknowledged that this
finding could not rule out efficacy over a longer treatment period (23).
In terms of adverse effects, studies identified certain short-term adverse effects (1, 4, 17-
25). The most common adverse events were tiredness, dizziness, lightheadedness, and
headaches, (1, 4, 17, 18, 20, 23-25) and some participants withdrew from studies due to these
events (18, 23, 24, 26). A study on the psychoactive effects of dronabinol found that its adverse
effects were similar to those of smoking cannabis (26). There were no studies that documented
the effects of using nabilone or dronabinol on a long-term basis.
Overall, nabilone and dronabinol seem to have some analgesic effect on chronic pain. As
the extent to which the analgesic effect is clinically significant is highly debatable, more
research needs to be done to verify their effects. Despite their effect on chronic pain, cannabis
extract capsules may not have much of an effect on acute inflammatory pain. The current
literature on orally consumed cannabis extract capsules is sparse and more research is required
to draw conclusions on their effect on pain.

Smoked cannabis

Smoking cannabis is the simplest way of ingesting cannabis and is commonly done on a
recreational basis. Studies examining the effects of smoking cannabis for its analgesic effects
vary in the duration the cannabis was smoked for, the frequency cigarettes were smoked, and
the THC content of the cannabis cigarettes. The range of THC content between studies varied
significantly from 1.29% THC content to 9.4% THC content (27-34). While studies measured
THC content contained in the cigarettes, the content other cannabinoids such as cannabinidiol
were not recorded.
Smoked cannabis was studied for its efficacy on pain as a result of unspecified neuropathy
(33, 34), HIV induced neuropathy (27, 30), post-traumatic neuropathy (32), multiple sclerosis
(29), and capsaicin injection (31). Of the eight studies on smoked cannabis and pain, all eight
reported a significant decrease in pain (27-34). Among the studies that reported on the clinical
176 Jonathan K Hwang and Hance Clarke

relevance of pain reductions, there was considerable variation in findings. Wilsey and
colleagues found that 26% of its population on the active agent achieved a clinically relevant
decrease in pain (33), while Abrams and colleagues found that 52% of its population on the
active agent achieved a clinically relevant decrease in pain (27). In addition, one of the studies
found that cannabis’ analgesic effects were dose dependent, reducing pain with 4% THC, but
inducing increased pain at 8% THC (31). Studies generally reported that the side effects of
smoking cannabis were well tolerated, with relatively few serious adverse events (27-29, 31-
34).
There were no studies that documented the long-term effects of using smoked cannabis as
an analgesic. Long term use of smoked cannabis may result in adverse respiratory effects
similar to those of smoking tobacco (35). More research needs to be done in terms of examining
the long-term tolerability of smoking cannabis and its psychoactive effects at higher cumulative
doses (34).
As such, smoking cannabis was consistently found to have a statistically significant and
clinically relevant effect in reducing neuropathic pain. As its effects on other types of pain have
yet to be studied, more research is needed to determine its effects. The vast majority of adverse
events experienced were only mild to moderate in severity and generally people tolerated
smoking cannabis quite well. A major limitation of studies examining the effect of smoking
cannabis is that the blinding is often compromised, as patients are often able to differentiate
between smoking the active agent versus placebo (27, 29-31). The potential loss of blinding
should be taken into account when examining the positive effects of smoking cannabis on pain.

CONCLUSION
More research is needed in order to better determine the efficacy of cannabis as an analgesic
treatment. Although the results generally show that cannabis does have a statistically significant
positive effect on pain, the quality of the literature needs improvement. Despite the large
proportion of RCTs in the cannabis and pain literature, many studies have small sample sizes
and possible conflicts of interest that could potentially bias results. Of the three methods of
administration, smoking cannabis had the fewest severe adverse effects and had the largest
number of studies favouring its effects on pain. Nabiximol sprays also had a large number of
studies that favoured its effects on pain, however the clinical significance of the effect varied
between studies. Although adverse events were generally mild to moderate for nabiximols, a
relatively large number of severe adverse events did occur in a single study. The data on
dronabinol capsules was far more mixed, with some studies showing benefits for chronic pain
and other studies showing no analgesic effects. Nabilone had a reasonably large body of
evidence favouring its effect on pain, however it’s clear that more research is needed on
cannabis extract capsules to verify their efficacy. The body of literature on cannabis and pain
as a whole is small and of variable quality. In addition, the majority of studies are very small
RCTs. Larger RCTs would help further confirm the findings presented in the existing data and
would lend credibility to the existing treatments.
 Cannabis and pain 177

ACKNOWLEDGMENTS
Dr. Clarke is supported by a Merit Award from the Department of Anesthesia at the University
of Toronto.

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marijuana in daily marijuana smokers. Neuropsychopharmacology 2013; 38(10): 1984-92.
[29] Corey-Bloom J, Wolfson T, Gamst A, Jin S, Marcotte TD, Bentley H, et al. Smoked cannabis for
spasticity in multiple sclerosis: a randomized, placebo-controlled trial. CMAJ Canadian Medical
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[30] Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, et al. Smoked medicinal
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[31] Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, et al. Dose-dependent
effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers.
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[32] Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, et al. Smoked cannabis for chronic
neuropathic pain: a randomized controlled trial. CMAJ 2010; 182(14): e694-701.
[33] Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis
significantly improves neuropathic pain. J Pain 2013; 14(2): 136-48.
[34] Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, et al. A randomized, placebo-
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Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 14

MEDICAL CANNABIS FOR PAIN IN ADOLESCENCE

Barry Knishkowy*, MD, MPH

Meuhedet Health Services, Jerusalem District, Jerusalem, Israel

The use of medical cannabis for pain in adolescence is controversial. The purpose of this
chapter is to summarize the literature regarding efficacy, adverse bio-psychosocial and
neurodevelopmental effects, as well as legislation and utilization patterns of adolescents.
Clinical trials demonstrating efficacy of cannabis for adolescent pain are essentially
nonexistent. Adolescent marijuana use may result in a number of physical symptoms, has
a strong association with schizophrenia, may affect neurocognitive development in the not
fully mature adolescent brain, and may lead to school, relationship and work problems as
well as motor vehicle accidents. The proportion of legal medical cannabis patients under
the age of 18 years ranges from 0.04% to 0.36% in different US states with medical
marijuana laws. Leading reasons for its being given are pain and epilepsy. Adolescents
who use medical cannabis have an increased likelihood of displaying high-risk drug related
behavior. Diversion of medical cannabis to other teenagers is not uncommon. There is a
need for clinical trials of cannabis for pain control in different adolescent health conditions.
Clinical guidelines should be prepared to aid physicians and legislators in determining
when medical marijuana is justified in this age group, and in identifying adolescents likely
to misuse the drug.

INTRODUCTION
The use of cannabis, referring to drugs derived from the genus cannabis, or its synthetic
cannabinoid derivatives, for treating disease or alleviating symptoms has increased
dramatically in recent years. Chronic or severe pain is one of the most common, if not the
leading, indication for its use.
Medical cannabis for adolescent pain is controversial. This is because of the scant
knowledge base regarding efficacy, and because of marijuana’s untoward effects – making
decisions for this age group more difficult than for the adult population. The purpose of this

*
Correspondence: Barry Knishkowy, MD, MPH, POBox 80716, Mevasseret Zion, 90805, Israel. E-mail:
knishkowyb@gmail.com.
180 Barry Knishkowy

review is to summarize the literature regarding clinical trials, adverse bio-psychosocial and
neurodevelopmental effects, as well as legislation and utilization patterns of adolescents.
Suggestions for future research and policy development are offered.

CHRONIC PAIN IN ADOLESCENCE

Chronic pain is extremely common in children and adolescents, with headache being the most
prevalent complaint. Median prevalence rates for different kinds of chronic pain, including
headache, abdominal pain, back pain and others, range from 11% to 38% (1). Ideally,
management will often involve a multidisciplinary approach that does not necessarily
emphasize prescription medication (2).
There are, however, specific medical conditions that frequently cause unusually severe pain
requiring potent pharmacological treatment. For example, significant disease-related and
treatment-related pain is commonly reported among adolescents with lymphoma, leukemia,
and solid malignant tumors. In one study of adolescents and young adults in a
hematology/oncology institution, 94 of 398 patients were prescribed opioid therapy (3). They
constitute a subset of adolescent pain patients for whom medical cannabis would potentially be
considered as an option.

DATA SUPPORTING EFFICACY OF CANNABIS IN TREATING PAIN

In a 2015 review of medical marijuana for chronic pain and other medical and psychiatric
problems, the author cites 3 systematic reviews of cannabinoids as pharmacotherapy, one set
of guidelines, and over 40 clinical trials. The strongest evidence for the use of marijuana and
cannabinoids exists for chronic pain, neuropathic pain, and spasticity associated with multiple
sclerosis (4). The evidence for efficacy in other conditions is equivocal or weak (4, 5).
A subsequent systematic review and meta-analysis of the benefits and adverse effects
of cannabinoids reviewed a total of 79 trials with 6,462 participants through April 2015.
Chronic pain was assessed in 28 studies that included 2,454 participants. These trials were
performed in adult populations and used a variety of cannabinoid types and delivery methods.
The conditions causing the chronic pain varied between studies and included neuropathic
pain [12 studies], cancer pain [3], diabetic peripheral neuropathy [3], fibromyalgia [2],
HIV-associated sensory neuropathy [2] and one study for each of the following: refractory
pain due to MS or other neurological conditions, rheumatoid arthritis, noncancer pain
(nociceptive and neuropathic), central pain (not further specified), musculoskeletal problems,
and chemotherapy-induced pain. The average number of patients who reported a reduction of
pain of at least 30% was statistically significantly greater with cannabinoids than with placebo
in eight studies, and there was a greater average reduction in numerical rating scale pain
assessment in six trials. The authors concluded that there was moderate-quality evidence to
support the use of cannabinoids for the treatment of chronic pain (6).
There are no published studies demonstrating the efficacy of medical marijuana or
pharmaceutical cannabinoids for pain control or any other indications in children or adolescents
(5-7).
 Medical cannabis for pain in adolescence 181

ADVERSE HEALTH EFFECTS

The short-term and long-term health effects of marijuana use have been well documented, and
continue to be elucidated. Many of these are unique to or have greater consequences for
adolescents than for older individuals, and therefore impact upon recommendations for the use
of cannabis among youth for pain control or other medical conditions.
Common physical side effects of cannabis include dry mouth, red eyes, tachycardia,
nausea, weakness, and delayed motor skills (5). Regular or chronic marijuana use, often defined
for adolescents as near-daily use over several years, is associated with numerous physical
problems, including increased incidence of symptoms of chronic bronchitis and increased rates
of various respiratory infections including pneumonia. Increased rates of dental and periodontal
disease, as well as dysplastic and premalignant lesions of the oral mucosa have been reported.
The cannabis hyperemesis syndrome has recently been described, with symptoms of nausea,
vomiting, abdominal pain and occasionally diarrhea. Chronic use may lead to a dose-related
decrease in testosterone levels, with erectile dysfunction and oligospermia. Some studies
suggest an association between marijuana use and congestive heart failure, arrhythmias, stroke,
peripheral vascular disease, and acute coronary syndrome, with elevated mortality among those
with a previous myocardial infarction. There have been reports linking chronic use to
respiratory malignancies (4, 8, 9).
Frequent marijuana use is strongly associated with schizophrenia, while data implicating
marijuana use in the development of depressive and anxiety disorders are conflicting (8, 9).
The adolescent brain continues to develop into the mid-20s (10), and therefore it is possible
that chronic cannabis use may result in irreversible neurocognitive effects. Indeed, studies have
shown an association with deficits in prospective memory and executive functioning, mental
slowness and reduced reaction times (4, 8, 9). In one study of adolescents with ADHD who
were regular marijuana users, there was an association between marijuana use and impaired
executive function and possibly impaired cognitive function when smoking marijuana began
before 16 years of age, but not afterwards (11). Neuroimaging studies in young adult marijuana
users have shown differences in grey matter density, volume and shape compared with controls
(5, 10).
Risk of developing marijuana dependence ranges between 9% and 50% among recreational
users, and appears to be higher when use begins in adolescence and occurs on a daily basis.
Cessation of chronic cannabis use is commonly associated with withdrawal symptoms
including headaches, sleep disruption, irritability, dysphoria and anxiety (4, 5).
The impact on psychosocial and behavioral parameters for adolescents is very significant.
Cross-sectional studies have demonstrated an association between marijuana use and poor
school performance, negative attitudes towards school and decreased high school completion,
as well as unemployment, criminal behavior and decreased satisfaction with life. Significant
problems in school, work and relationships have been shown in about 17% of adolescent
users. In the acute intoxication period, probably related to marijuana’s effect upon motor
coordination, reaction times and judgment, there is a near-doubling of the odds of motor vehicle
accidents (4, 8, 9, 12).
182 Barry Knishkowy

MEDICAL MARIJUANA LEGISLATION

The use of cannabis is illegal in most countries. For medical purposes, in the United States,
marijuana is classified by the US Drug Enforcement Administration (DEA) as an illegal
Schedule 1 Drug – defined as having “no currently accepted medical use and a high potential
for abuse”. Despite this and in contrast to federal law, as of May 2016, medical marijuana was
legal under state law in 24 states and the District of Columbia. The medical marijuana laws
require a physician recommendation, and list the conditions for which cannabis may be
recommended. These vary by state, but the majority list “chronic and/or severe pain” as one of
the conditions, and individuals 18 years and older are usually eligible. Minors are able to obtain
medical marijuana with parental or their legal guardian’s consent (13).
In Canada, limited access to medical marijuana was sanctioned in 2001. Due to numerous
barriers to authorization, however, only a fraction of users actually received it legally.
Revisions to the legislation intended to increase access were enacted in 2013 (4, 14).
In Europe, medical cannabis and/or synthetic cannabinoids are used legally in several
countries, including Croatia, the Czech Republic, Finland, France, Germany, Italy, the
Netherlands, Romania, Slovenia and the United Kingdom. The legal status, types of
cannabis/cannabinoids allowed, and limitations on use vary considerably among these
countries. The Netherlands permits use in authorized “coffeeshops”, and in Spain marijuana
may be used in private areas only. Other nations where medical cannabis may be used legally
or de facto include Argentina, Australia, Colombia, the Dominican Republic, India (in certain
states), Israel, Jamaica, Northern Mariana Islands, Puerto Rico and Uruguay (15).
Two synthetic cannabinoids in capsular form are approved by the United States Food and
Drug Administration: dronabinol (Marinol) and nabilone (Cesamet). A third synthetic
cannabinoid, nabiximols (Sativex), is a fast-acting oral-mucosal spray which is approved for
use in Canada and the United Kingdom, and recently in several other countries. Marinol is
indicated for anorexia associated with weight loss in AIDS and for nausea and vomiting
associated with cancer chemotherapy, Cesamet for the latter indication, and Sativex for
spasticity in multiple sclerosis. In children and adolescents, Marinol may be used with caution
for chemotherapy-associated nausea and vomiting only, while the manufacturers of Cesamet
and Sativex state that the safety and effectiveness of these medications have not been
established in patients under the age of 18 years, and therefore should not be used (16-18).

UTILIZATION OF MEDICAL CANNABIS

Data regarding the use of medical cannabis are available from three types of sources: state or
national health department medical cannabis program statistical reports, surveys of medical
cannabis users, and youth risk behavior surveys.
 Medical cannabis for pain in adolescence 183

Health department statistical reports

In the United States, there were 1,246,170 legal medical cannabis patients in states with medical
marijuana laws, or an average of 8.06 patients per 1,000 residents in March 2016 (19). Only a
few states provide the age distribution of medical marijuana registered patients. There are data
regarding the number and percentage of patients under the age of 18 years available for Arizona
(42 patients, 0.15%), Colorado (343 patients, 0.32%; 215 under the age of 11), Montana (6
patients, 0.04%), Nevada (41 patients, 0.26%) and Oregon (278 patients, 0.36%; 95 under the
age of 11) (20-24).
In most states, severe or chronic pain is by far the most common condition for receiving
medical marijuana (13). Data from Colorado show that for children and adolescents in the 0-
10 and 11-17 year age groups, the leading reason is ‘seizures’, whereas it is ‘severe pain’ for
older age groups (21). In Oregon, for children and adolescents under the age of 18, the leading
reasons for receiving medical cannabis are: severe pain (48.6%), seizures (36.0%), spasms
(21.6%), and nausea (17.6%) (24).
Differences in the rates of use and the diagnoses of registered patients among the states
may result not only from different population characteristics, but from different regulations in
the various medical marijuana programs. There is considerable variability in features of the
various policies, with regard to the number (ranging from 6 to 40) and types of conditions for
which medical marijuana may be given (25). Thus, adolescents with chronic pain from a
specific illness may have legal access to marijuana in one state but not in another.

Medical cannabis surveys

Several surveys of medical cannabis users have been conducted in different countries/US states,
with the greatest number in the state of California. Various sample selection methods were
used, and the study groups were generally not shown to be representative of the entire medical
cannabis-using population.
One survey in California, which examined data on 1,746 consecutive admissions to nine
medical marijuana clinics in 2006, included data on adolescents. Of the population surveyed,
0.2% were 12-18 years old, and 17.8% were 18-24 years old. For the entire study population,
82.6% used the marijuana for pain relief, 70.6% for sleep, 55.6% for relaxation, 41.3% for
spasms, and 40.8% for headache. The most common physician diagnoses were low back pain
(26.2%), anxiety disorders (18.7%) and arthritis (18.0%). Of note, 50.8% used the marijuana
as a substitute for prescription medication, often opioids (26).

Youth risk behavior surveys

In the United States, three periodic surveys of the adolescent population track substance use,
including marijuana: Monitoring the Future (MTF), the Centers for Disease Control and
Prevention’s Youth Risk Behavior Survey (YRBS), and the National Survey on Drug Use and
Health (NSDUH) (10).
Monitoring the Future provided the first nationally representative sample of 12th graders’
medical marijuana use. Data from the 2012 and 2013 MTF study were analyzed to determine
184 Barry Knishkowy

the percentage of teens who were illicit users (source of marijuana was illegal or nonmedical),
medical users, or diverted medical marijuana users (received their marijuana from someone
else’s marijuana prescription) during the past year. In this sample of 4,394 adolescents, 28.8%
were illicit users, 1.1% were medical users, and 6.1% were diverted medical marijuana users.
Compared with illicit users, medical users had a higher odds of engaging in other high-risk
behaviors (such as using illegal prescription drugs or illicit drugs other than marijuana), while
those using diverted marijuana had a higher odds of engaging in all of the other behaviors
studied (27).

CONSIDERATIONS IN THE USE OF CANNABIS

FOR PAIN IN ADOLESCENTS

First and foremost, the use of medical cannabis by adolescents is currently limited because of
a lack of data demonstrating efficacy and the high potential for current and future untoward
health effects in this age group. These are among the reasons for policy statements by several
professional organizations opposing medical marijuana use in this population. The American
Academy of Pediatrics, for example, is against cannabinoid administration to children and
adolescents except for FDA-approved indications, and possibly for patients with life-limiting
or severely debilitating illnesses for whom current therapies are inadequate (7).
Additional considerations may play into decisions regarding adolescent use of medical
cannabis in general, and for pain in particular. Data from the MTF survey show that high-risk
drug-related behavior was more prevalent among medical marijuana users than among illicit
marijuana users (27). Similar findings were reported in the study of adolescent and young adult
cancer patients cited previously, where 11.7% of 94 patients given opioid therapy displayed
aberrant opioid-associated behavior (AOB). In that study, psychosocial risk factors were
identified in 90.9% of those with AOB, with a past or current mental health diagnosis probably
being the most significant risk factor for opioid abuse (3). Data comparing adolescent and
young adult non-cancer patients with older adults have shown that the younger patients are
more likely to abuse opioids and illicit substances (28). These studies raise the question of
which adolescent medical cannabis users might be at relatively high risk for aberrant drug-
related behavior.
In contrast, some studies (mainly involving adults) have shown that medical cannabis use
is associated with a decrease or cessation in the use of opioids and other medications for pain
control (26, 29). And so, if one views cannabis use as a less problematic option than opioids, it
may constitute a positive alternative in some cases.
There are also public health issues related to the legalization and use of medical cannabis.
Several studies have looked at the effect of such legislation upon recreational marijuana use
among youth, with conflicting results (30, 31). Although there is no solid evidence that
adolescent marijuana use increases when medical marijuana is legalized, the phenomenon of
large-scale medical cannabis diversion (27), including to high-risk populations (32), cannot be
ignored.
 Medical cannabis for pain in adolescence 185

SUMMARY
1. Data regarding the efficacy of cannabis in the treatment of adolescent pain are
essentially nonexistent.
2. There are significant health risks entailed in the use of cannabis, many of which are
unique to children and adolescents.
3. Adolescents using medical cannabis display high-risk drug related behavior more
frequently than recreational users.
4. The utilization rates of legally prescribed medical cannabis among children and
adolescents are proportionately very low, ranging from 0.04% to 0.36% of all patients
in published state statistical reports.
5. Common reasons for using medical marijuana in children and adolescents, based on
very limited data, are pain control and seizures.
6. Public health problems, including medical cannabis diversion to other teenagers, may
result from its legal, medical utilization.

CONCLUSION
The approach to adolescent use of medical cannabis is inherently different than that for adults.
Two major challenges follow from this review of the topic.
The first is to conduct research regarding which conditions causing significant pain in this
age group respond to treatment with cannabinoids, and when that treatment would be preferred
to other therapeutic options. Further research is also needed to determine risk factors for
potential medical cannabis misuse.
The second challenge is to develop, with limited current knowledge, clinical guidelines to
help clinicians and legislators decide on the indications and contraindications for medical
marijuana use among youth, and to determine exclusion criteria and risk reduction measures
based upon risk factor assessment.

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pain in children and adolescents: a clinical review. PM R 2015;11(Suppl):S295-315.
[3] Ehrentraut JH, Kern KD, Long SA, An AQ, Faughnan LG, Anghelescu DL. Opioid misuse behaviors
in adolescents and young adults in a hematology/oncology setting. J Pediatr Psychol 2014;39(10):1149-
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[4] Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems:
A clinical review. JAMA 2015;313(24):2474-83.
[5] Rieder MJ; Canadian Paediatric Society Drug Therapy and Hazardous Substances Committee. Is the
medical use of cannabis a therapeutic option for children? Paediatr Child Health 2016;21(1):31-4.
[6] Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for
medical use: A systematic review and meta-analysis. JAMA 2015;313(24):2456-73.
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[7] Committee on Substance Abuse, Committee on Adolescence. The impact of marijuana policies on
youth: clinical, research and legal update. Pediatrics 2015;135(3):584-7.
[8] Greydanus DE, Hawver EK, Greydanus MM, Merrick J. Marijuana: Current concepts. Front Public
Health 2013;1:42.
[9] Hadland SE, Harris SK. Youth marijuana use: state of the science for the practicing clinician. Curr Opin
Pediatr 2014;26(4):420-7.
[10] Ammerman S, Ryan S, Adelman W; Committee on Substance Abuse, Committee on Adolescence. The
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[12] Hartman RL, Huestis MA. Cannabis effects on driving skills. Clin Chem 2013;59(3):478-92.
[13] 24 Legal medical marijuana states and DC: laws, fees and possession limits. URL:
http://medicalmarijuana.procon.org/view.resource.php?resourceID=000881.
[14] Lucas P. It can’t hurt to ask; a patient-centered quality of service assessment of health canada’s medical
cannabis policy and program. Harm Reduct J 2012;9:2.
[15] Legality of cannabis by country. URL: http://en.wikipedia.org/wiki/Legality_of_cannabis_ by_country.
[16] Marinol capsules. URL: http://www.rxabbvie.com/pdf/marinol_PI.pdf.
[17] Full prescribing information – Cesamet. URL: https://www.cesamet.com/pdf/Cesamet_PI_50_
count.pdf.
[18] GWPharma – Sativex. URL: http://www.gwpharm.com/Sativex.aspx.
[19] Number of legal medical marijuana patients. URL: http://medicalmarijuana.procon.org/
view.resource.php?resourceID=005 889.
[20] Arizona Department Health Services: Medical Marijuana. URL: azdhs.gov/licensing/medical-
marijuana/index.php.
[21] Colorado Department of Public Health and Environment: Medical Marijuana Registry. URL:
https://www.colorado.gov/pacific/cdphe/medicalmarijuana.
[22] Montana Marijuana Program. URL: https://dphhs.mot.gov/marijuana.
[23] Nevada Division of Public and Behavioral Health: Medical marijuana. URL: dpbh.nv.gov/Reg/
Medical_Marijuana/.
[24] Oregon Medical Marijuana Program (OMMP). URL: public.health.oregon.gov/Diseases Conditions/
ChronicDisease/MedicalM arijuanaProgram/Pages/index/aspx.
[25] Bestrashniy J, Winters KC. Variability in medical marijuana laws in the United States. Psychol Addict
Behav 2015;29(3):639-42.
[26] Nunberg H, Kilmer B, Pacula RL, Burgdorf J. An analysis of applicants presenting to a medical
marijuana specialty practice in California. J Drug Policy Anal 2011;4(1):1-16.
[27] Boyd CJ, Veliz PT, McCabe SE. Adolescents’ use of medical marijuana: a secondary analysis of
Monitoring the Future data. J Adolesc Health 2015;57(2):241-4.
[28] Pergolizzi JV Jr, Gharibo C, Passik S, Labhsetwar S, Taylor R Jr, Pergolizzi JS, et al. Dynamic risk
factors in the misuse of opioid analgesics. J Psychosom Res 2012;72(6);443-51.
[29] Swift W, Gates P, Dillon P. Survey of Australians using cannabis for medical purposes. Harm Reduct
J 2005;2:18.
[30] Choo EK, Benz M, Zaller N, Warren O, Rising KL, McConnell KJ. The impact of state medical
marijuana legislation on adolescent marijuana use. J Adolesc Health 2014;55(2):160-6.
[31] Wall MM, Poh E, Cerda M, Keyes KM, Galea S, Hasin DS. Commentary on Harper S, Strumph EC,
Kaufman JS. Do medical marijuana laws increase marijuana use? Replication study and extension. Ann
Epidemiol 2012;22(7):536-7.
[32] Salomonsen-Sautel S, Sakai JT, Thurstone C, Corley R, Hopfer C. Medical marijuana use among
adolescents in substance abuse treatment. J Am Acad Child Adolesc Psychiatry 2012;51(7):694-702.
SECTION FOUR: POLICY, ETHICS AND SOCIAL
COMMENTARY
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 15

MEDICAL CANNABIS FROM THE PAIN

PHYSICIAN’S PERSPECTIVE

Ainsley M Sutherland, MD, PhD, Judith Nicholls, MD

and Hance Clarke*, MD, PhD
Pain Research Unit, Department of Anesthesia and Pain Medicine,
Toronto General Hospital, University Health Network, Toronto, Ontario, Canada;
Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada

In 2013 the Canadian Government enacted the Marihuana for Medical Purposes
Regulations, allowing licensed marihuana producers to grow and sell medical marihuana
to patients for a variety of medical conditions, including pain. Patients require a medical
document from a health professional in order to register with a licensed producer, so
physicians are now being asked to provide a prescription for a drug that has not undergone
standardized Health Canada regulations and without clear dosing guidelines. The focus of
this chapter is to review the legislation, the Health Canada document on Medical
Marihuana and the Canadian Pain Society consensus statement on the management of
neuropathic pain in order to highlight the role of marihuana in the management of
neuropathic pain and propose a prescribing strategy for medical marihuana.

INTRODUCTION
In 2001 the Canadian government permitted possession and use of marihuana for medical
purposes via the Marihuana Medical Access Regulation (MMAR) (1). Patients were required
to obtain authorization from Health Canada, subsequent to validation from a physician that they
suffered from a condition for which medical marihuana use was approved. In 2013, in order to
address concerns about the lack of standards in the production of marihuana by small producers
and the cumbersome authorization process, the government replaced the MMAR with the
Marihuana for Medical Purposes Regulations (MMPR) (2, 3).

*
Corresponding author: Hance Clarke, MD, Staff Anesthesiologist, Director of Clinical Pain Services and Medical
Director of Pain Research Unit, Toronto General Hospital, 200 Elizabeth Street, Toronto, ON Canada. E-mail:
Hance.Clarke@uhn.ca.
190 Ainsley M Sutherland, Judith Nicholls and Hance Clarke

Under the MMPR producers were granted licenses to grow and distribute dried marihuana
for medical purposes. Production practices, packaging and labelling, security measures and
transportation are all now closely regulated under the MMPR. Licensed producers must report
to provincial licensing authorities (2, 3). Patients no longer have to apply to Health Canada for
authorization to possess marihuana. They can now ask their physician for a medical document
for medical marihuana, to be filled by one of the licensed producers (2, 3). Licensed producers
can provide dried marihuana to another licensed producer, a licensed dealer, the Health
Minister, or a person (patient) who is registered with the licensed producer after submitting a
medical document confirming their eligibility for medical marihuana. The medical document
must specify how many grams of marihuana per day the patient is permitted, which is akin to
a prescription.
This poses the question then: how do we as physicians prescribe marihuana? In our practice
there has been an exponential increase in the number of patients requesting prescriptions for
medical marihuana for chronic pain. There are, however, no large randomized controlled trials
examining the efficacy of medical marihuana in various pain syndromes. A number of small
trials in patients suffering from painful diabetic neuropathy, HIV neuropathy and post-
traumatic/post-surgical neuropathic pain have shown medical marihuana to be more efficacious
than placebo for pain control (4-9). However, these trials need to be replicated with larger
numbers of patients. There are no dosing guidelines, and it remains unclear what doses patients
receive when they inhale medical marihuana. Furthermore, we remain unclear as to which
component of medical marihuana is responsible for the analgesic effects as Cannabis plants
contain at least 489 distinct compounds from 18 different chemical classes (10).
For these reasons Health Canada clearly states on the front page of its document –
Cannabis: Information for Health Care Professionals that “Cannabis is not an approved
therapeutic product and the provision of this information should not be interpreted as an
endorsement of the use of this product, or cannabis generally, by Health Canada” (11).
However, physicians are expected to provide prescriptions without high quality evidence of
efficacy, or dosing guidelines.
In this chapter, we will summarize Health Canada’s Information for Health Care
Professionals on Cannabis as a starting point for the rational prescription of medical marihuana
in Canada. Many more high-quality randomized controlled trials and dose-finding trials will be
required before we can establish a true evidenced based approach to prescribing marihuana for
pain.

PATIENT CASE
A 62-year-old woman is referred to a tertiary care chronic pain clinic with a two-year history
of debilitating neuropathic pain following a left-sided mastectomy for breast cancer. Her pain
has led to severe functional decline. She reports that she has constant burning pain and
paresthesias on the left lateral chest, and her clothes cause her severe pain when they brush
against the skin. Her mood is low, and she is not sleeping because of the pain. She rarely leaves
her house now except for medical appointments. She is desperate for help with her pain, and
her daughter suggested trying medical marihuana. Her family doctor is not comfortable
 Medical cannabis from the pain physician’s perspective 191

prescribing medical marihuana, and so has referred her to the pain clinic. How should this
patient be counselled and managed?

APPROACH TO THE PATIENT WITH NEUROPATHIC PAIN REQUESTING

MEDICAL MARIHUANA

The Canadian Pain Society released a revised consensus statement in 2014 regarding the
pharmacological management of chronic neuropathic pain (12). The guideline stresses the
importance of assessing all patients with chronic neuropathic pain for comorbidities such as
anxiety and depression, and to focus the goals of treatment on improvement in function and
quality of life (12). It is important to keep these goals in mind when considering the initiation
of therapy with medical marihuana. First and second line agents should be considered before
trialing medical marihuana.
First-line agents for neuropathic pain are the anticonvulsants gabapentin and pregabalin,
tricyclic antidepressants (TCAs) and the serotonin-norepinephrine reuptake inhibitors (SNRIs)
duloxetine and venlafaxine (12). Patients should have an adequate trial of these medications,
preferably in combination, before other modalities such as cannabinoids are considered.
Second-line agents include the weak opioid agonist tramadol and other opioid analgesics
(12). The number needed to treat (NNT) for opioids in neuropathic pain syndromes is 2.6 (13).
With the use of opioids, however, the risk of adverse events increases significantly, including
respiratory depression, drowsiness, and the risk of abuse and addiction. Many older patients
with medical comorbidities do not tolerate treatment with opioids. In patients with several
complex co-morbidities (e.g., renal failure, cardiac compromise, encephalopathy) it may be
justified to consider cannabinoids before opioids, or as adjuncts to reduce opioid requirements,
because initiating opioids in these patients may lead to sudden decline.
The major change in the Canadian Pain Society Consensus Statement in 2014 from the
previous statement in 2007 was to list cannabinoids as third-line agents in the management of
neuropathic pain. In the 2007 statement, they were listed in as fourth-line agents (12). This
change was based on a systematic review of trials of cannabinoids in chronic pain that found
there had been six positive studies out of seven high quality studies investigating cannabinoids
in chronic neuropathic pain (14). These studies, however, were all small and examined the
efficacy of different cannabinoids in different pain syndromes. Although the results of these
studies are intriguing, they are inadequate for evidence-based practice.
Fourth line agents now include selective serotonin reuptake inhibitors (SSRIs), other
anticonvulsants such as lamotrigine, lacosamide, topiramate and valproic acid, methadone and
topical lidocaine (12).

PHYTOCANNABINOIDS AND PAIN MODULATION

The endocannabinoid system is comprised of two G-protein coupled receptors, cannabinoid
1 and 2 receptors (CB1 and CB2). They are bound and activated primarily by the
endocannabinoid ligands N-arachidonoylethanolamine (anandamide or AEA) and 2-
arachidonoylglycerol (2-AG), and by the phytocannabinoids delta-9 tetrahydrocannabinol (Δ9-
192 Ainsley M Sutherland, Judith Nicholls and Hance Clarke

THC), Δ8-THC, and cannabinol (CBN) from cannabis sitava, or marihuana. Δ9-THC is
responsible for the psychoactive effects of cannabis (15). Cannabidiol (CBD) is a component
of cannabis that is thought to possess anti-inflammatory and analgesic properties, but it does
not act through the CB1/2 receptors at physiological concentrations (16) and has minimal
psychotropic effects. Data does not exist regarding the ideal ratio of THC to CBD for treating
pain.
Activation of the CB1 or CB2 receptors by endo- or phytocannabinoids results in
inhibition of adenylyl cyclase activity, and decreased formation of cyclic AMP (17) leading
to among other things, inhibition of neurotransmitter release in the CNS (17,18). This
includes neurotransmitters with important roles in pain transmission and modulation (5-
hydroxytryptamine (5-HT), glutamate, acetylcholine, γ-Aminobutyric acid (GABA), and
noradrenaline) (18). CB1 and CB2 receptors are expressed throughout the body and brain (19),
this presents a challenge in using phytocannabinoids for pain without adverse effects such as
cognitive dysfunction.

APPROACH TO PRESCRIBING PHYTOCANNABINOIDS FOR PAIN

Phytocannabinoids approved for medical use in Canada include synthetic cannabinoids such as
nabilone (Cesamet®), dronabinol (Marinol®, no longer manufactured), nabiximols (Sativex®)
and dried marihuana for inhalation. Three licensed producers have been granted approval to
sell cannabis oils. In order for an oil product to be biologically active, the oil has to be heated
in order to transform tetrahydrocannabinolic acid into Δ9-THC (the psychoactive compound).
The heating process decarboxylates tetrahydrocannabinolic acid into Δ9-THC. Unbeknownst
to many consumers, the oils often found in dispensaries are may not be decarboxylated, and
therefore inactive. Edible products are not currently approved for sale or distribution by any
licensed producers (2). Any physician can provide a patient with the medical document for
dried medical marihuana provided the professional consults with the applicant and confirms
that the information in the medical document is correct and complete. The professional must
be licensed to practice their profession in the province in which they consulted with the
applicant and “must not be named in a notice issued under section 59 of the Narcotic Control
Regulations that has not been retracted under section 60 of those Regulations” (2).
The approach accepted by many pain clinicians when dealing with a cannabinoid naïve
patient is to first trial a synthetic cannabinoid such as nabilone. The onset of synthetic oral
cannabinoids is slower than inhaled cannabis, and the resultant serum concentrations of Δ9-
THC are lower (see Table 1) (20-22). Nabilone is a synthetic cannabinoid available in 1mg
capsules. The usual dosing is 0.5-2mg BID, up to a maximum of 6mg per day in 3 divided
doses (22). Nabiximols is an oro-mucosal spray that delivers 10.8mg of Δ9-THC and 10mg of
CBD per dose (4 sprays) (23). Patients may titrate their dose from one spray (2.7 mg Δ9-THC
and 2.5 mg CBD) to 16 sprays (43.2 mg Δ9-THC to 40 mg CBD) per day (23). Dronabinol is
no longer available in Canada, but was dosed from 2.5mg to 40mg total daily dose (24). In
cannabinoid naïve patients, synthetic cannabinoids may provide sufficient analgesia without
intolerable side effects. Regular cannabis users are less likely to notice a benefit based on our
clinical experience. For patients who do not derive benefit from oral synthetic cannabinoids, it
has been suggested that the next step in the treatment algorithm be medical cannabis.
 Medical cannabis from the pain physician’s perspective 193

The regular/recreational cannabis user is a very unique clinical situation. The surge in
registered patents to date is likely linked to many recreational users seeking their licenses for
various therapeutic causes such as insomnia, anxiety, nausea, insomnia, or pain. The question
becomes how to rationally and safely prescribe medical marihuana given many long time users
consume strains with very high THC content (e.g., >25%) and the ethics behind this practice.
Several patients in our clinic have been victims of assault and there is a harm reduction
component for individuals that will continue to consume recreational cannabis sought outside
of the regulated licensed producers. According to the MMPR the health care professional must
indicate the daily quantity of dried marihuana to be used by the person, expressed in grams (2).
But what is an appropriate daily amount for a patient with pain? And what dose of
phytocannabinoids with analgesic properties will the patient actually receive by inhaling dried
marihuana?

Table 1. Dosing and resultant serum concentrations of synthetic cannabinoids versus

inhaled dried marihuana (20-24, 41)

Serum [Δ9-THC]
Cannabinoid Components Dose Onset Duration
(range)
Nabilone Δ9-THC 2mg BID 60- 8-12h 2ng/mL
90min
Dronabinol Δ9-THC 2.5mg BID 30- 4-6h 1.3ng/mL (0.7 -
5mg BID 60min 1.9ng/mL)
10mg BID 2.9ng/mL (1.2 –
4.7ng/mL)
7.9ng/mL (3.3 –
12.4ng/mL)
Nabiximols Δ9-THC + 4 sprays 15- 2-4h 5.5ng/mL
CBD (10.8mg Δ9- 40min CBD: 3ng/mL
THC and
10mg CBD)
Dried 1.75% (16mg 5min 2-4h 7.0 ± 8.1ng/mL
Marihuana Δ9-THC)
3.55% (34mg 18.1 ± 12.0ng/mL
Δ9-THC)

Table 2. Dose calculations and conversions (11)

Smoked dose (mg) = %THC x mg dried cannabis

Oral dose (mg) = smoked dose (mg) x 2.5

As physicians we are trained to prescribe medications at a specific dose in order to achieve

a predictable response, and titrate to effect. In prescribing medical marihuana we must
understand how many milligrams of Δ9-THC are in a “dose”. The World Health Organization
describes a typical marihuana cigarette as being around 750mg of cannabis (25). The available
Δ9-THC, or “smoked dose” can thus be calculated based on the percentage of Δ9-THC by
weight in a standard 750mg joint (smoked dose = %THC x mg dried cannabis) (see Table 2)
(11). In a 750mg joint with 1% THC, the THC dose would be 7.5mg (0.01 x 750mg). In a
750mg joint with 30% THC the THC dose would be 225mg (0.3 x 750mg) (11). It is important
194 Ainsley M Sutherland, Judith Nicholls and Hance Clarke

to remember that the smoked dose is the amount of Δ9-THC in milligrams that is available in
the entire marihuana cigarette. The actual amount of Δ9-THC delivered to the patient is highly
variable as it is dependent on smoking technique, effort, number of puffs, etc.
Keeping in mind the variability in the dose actually received by the patient due to
variability in inhalation, a reasonable smoked dose for analgesia may be around 30-150mg per
day of THC. A study of smoked cannabis in neuropathic pain found patient’s visual analogue
scores (VAS) decreased after inhalation of the equivalent of either 28mg or 56mg per day of
THC compared to placebo, but there was no difference between the lower and higher doses (5).
Another study in chronic post-surgical or post-traumatic pain found that patients receiving only
the equivalent of 7mg per day of THC reduced pain and improved sleep (7). A smoked dose of
7mg a day appears to be very low however, in light of a titration study in HIV neuropathy that
found most patients self-titrated to a smoked dose between 64-128mg THC per day (6). Only
one patient out of 28 in this trial titrated to a lower smoked dose of 32mg per day of THC (6).
Another study in HIV neuropathy found patients had decreased pain with a smoked dose of
96mg per day of THC versus placebo (4). This is in line with the finding that in patients on
chronic opioids for a variety of pain conditions, a smoked dose of 96mg/day of THC decreased
their pain scores by 27% with no change in the pharmacokinetics of the opioids (26). Based on
these studies it would be reasonable to recommend a patient with a neuropathic pain condition
begin with a smoked dose of 30mg of THC per day and titrate up or down according to the
degree of analgesia they achieve while avoiding side effects and cognitive dysfunction.
Surveys of medical marihuana patients show that the average consumption is 1-3g of dried
marihuana per day (27-29). A reasonable starting prescription would be around 1-2g per day
recognizing that content of Δ9-THC, and thus the smoked dose, in any given gram of dried
marihuana is highly variable. According to Health Canada the average THC content in illicit
marihuana is 10% (11). The dried marihuana provided by Health Canada has a THC content of
12.5  2% and less than 0.5% CBD (11). Licensed producers have a wide range of products
with varying THC content (0.5-27% in one case), and CBD (0-18% in one case) (30). Cannabis
naïve patients being initiated on medical marihuana therapy should be advised to start
with low THC (i.e., less than 10-15%) content to avoid adverse psychotropic effects.
Several cannabis naïve patents in our clinic have presented to emergency departments having
acquired marihuana from dispensaries and licensed producers with THC content greater than
20% THC experiencing intolerable hallucinogenic effects of the strain. Patients without any
prior experience need to be warned of this potential. Licensed producers list the THC and CBD
percentages on their websites, so the patient can select a product with a low THC content.
Patients in consultation with their medical practitioners can then titrate the amount of
marihuana smoked, the THC and CBD content, to achieve a therapeutic effect with minimal
adverse effects.
Currently medical marihuana is not legal for oral consumption in edible form under the
MMRP. There exists no solid evidence for converting a smoked dose to an oral dose of
marihuana, however, Health Canada suggests using a conversion factor of 2.5 to account for
differences in bioavailability between smoking (25% bioavailability) and orally ingesting (10%
bioavailability) marihuana (11,31). Thus, if a patient has good therapeutic effect from smoking
1g of medical marihuana with 10% THC (0.1 x 1g = 100mg THC), they may need to ingest
2.5g of the same strain with 10% THC (250mg THC) to achieve the same therapeutic effect
(smoked dose (mg) x 2.5 = oral dose (mg)) (see Table 2) (11). Health Canada provides a table
for quick conversion from smoke to oral dose of marihuana (see Table 3) (11). As stated above,
 Medical cannabis from the pain physician’s perspective 195

patients should be advised that marihuana in any form must be heated above 120°C in order to
decarboxylate inactive THCA to the active form (THC) (32).

POPULATIONS THAT MAY BENEFIT FROM MEDICAL CANNABIS

Cannabinoids administered in combination with opioids have been shown to result in superior
analgesia in both rats and humans (26, 33, 34). As discussed previously, patients with complex
co-morbidities may benefit from cannabinoids as adjuncts to reduce opioid requirements and
avoid opioid-related adverse events. Other populations of patients that may benefit from
cannabinoids are patients with diseases that cause intermittent flares of pain, such as
rheumatoid arthritis, sickle cell disease, inflammatory bowel disease (IBD) or other abdominal
visceral pains such as chronic pancreatitis. These patients often increase their opioid
consumption acutely with a flare, which then becomes their new baseline dose. With multiple
flares they may end up on opioid doses far beyond what is suggested as a watchful dose (200mg
morphine equivalent/day) by the Canadian Guideline for Safe and Effective Use of Opioids for
Chronic Non-Cancer Pain (35). Inhaled or oral cannabinoids may be useful during these
intermittent flares of pain so as to avoid ramping up patients’ daily opioid dose. One small
study in patients with IBD and healthy volunteers did not find that 5 or 10mg of oral Δ9-THC
improved symptoms of rectal sensitivity compared to placebo (36). Five to ten milligrams of
oral Δ9-THC, however, is a low dose (<1% THC in a 750mg marihuana cigarette, see Tables
2 and 3), and there were design problems with the study. In a survey of 291 patients with IBD
18.5% reported lifetime use of marihuana for abdominal pain (37), while another observational
study of 30 patients with IBD found that cannabis use was associated with decreased Crohn’s
disease activity scores (38).

Table 3. Conversion of a “smoked dose” of THC in a standard 750mg marihuana

cigarette to oral dose (replicated from Information for Health Care Professionals:
Cannabis (marihuana, marijuana) and the cannabinoids, 2013) (11)

“Smoked dose”
% THC in a 750 mg cannabis cigarette Estimated oral dose (mg Δ9-THC)
(Total available mg Δ9-THC)
1% THC (7.5 mg) 18.8 mg
2% THC (15 mg) 37.5 mg
2.5% THC (18.8 mg) 46.8 mg
3% THC (22.5 mg) 56.3 mg
5% THC (37.5 mg) 93.8 mg
7.5% THC (56.3 mg) 140.6 mg
10% THC (75 mg) 187.5 mg
12.5% THC (93.8 mg) 234.4 mg
15% THC (112.5 mg) 281.3 mg
20% THC (150 mg) 375 mg

Medical marihuana may also be used as an adjunct to wean opioids. In one such case a
patient with chronic abdominal pain was weaned from an equivalent of hydromorphone 30mg
196 Ainsley M Sutherland, Judith Nicholls and Hance Clarke

per day following a liver transplant to a total daily dose of 6mg per day with the addition of
medical marihuana (39). This patient used 1g of high CBD:low THC cannabis strain per day
for analgesia (THC 0.79%, CBD 17.08%) (39). Another study found that the use of the
cannabinoid dronabinol in patients undergoing detoxification from opioids was associated with
a decrease in the severity of withdrawal symptoms and that patients who smoked marihuana
were more likely to complete detoxification (40).

CONCLUSION
Neuropathic pain is one of the most difficult conditions to treat effectively, and the evidence
for any of the therapies currently recommended is weak. A step-wise approach to treatment
based on the 2014 Canadian Pain Society consensus statement should be used for all patients.
Cannabinoids are considered third-line treatment and should only be considered when other
treatment modalities have failed, or to supplement these modalities in cannabinoid naïve
patients. For the cannabinoid naïve patient, we suggest trying oral synthetic cannabinoids such
as nabilone first. If this therapy is not successful, or if the patient is already using medical
marihuana, start patients on a low smoked dose of around 30mg of THC and titrate to analgesia
and side effects.
Early clinical trials are promising, but they are small with varying study designs and pain
disorders. With the legalization of medical marihuana in Canada and the trend towards
legalization in the United States there is hope for better data and clearer, evidence-based
prescribing guidelines in the future. The most helpful evidence will come from companies
invested in generating pharmacokinetic data in humans with the aim to generate an oral tablet
that could be reliably absorbed and prescribed.

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In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 16

ETHICAL AND POLICY IMPLICATIONS CONCERNING

MEDICAL CANNABIS

Sally Bean*, JD, MA and Maxwell J Smith, PhD, MSc

Ethics Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada;
Joint Centre for Bioethics, Toronto, Ontario, Canada

In 2014, the Canadian federal Marihuana for Medical Purposes Regulations (MMPR)
shifted the role of authorizing medical cannabis (MC) from Health Canada to physicians.
Accordingly, provincial and territorial bodies are issuing physician practice standards to
provide guidance; however, this does not address how healthcare organizations (HCOs),
like hospitals, handle the use of MC. Therefore, unless provinces and territories pass MC
legislation, HCOs must develop institutional policy to control the use of MC. Objective:
We argue that HCOs should consider five policy issues when considering organizational
MC policy: 1) locus of administration, 2) permissible modes of administration, 3) clinical
management, 4) security, and 5) the therapeutic relationship. Additionally, associated
ethical issues should be taken into consideration; namely, harm reduction and principles
such as respect for autonomy, non-malificence, reciprocity, justice and the harm principle.
Discussion: The possible modes of MC administration could include smoking,
vapourizing, ingesting, and oral synthetic preparations, and each raises unique issues for
HCOs. Clinical management may include authorizing and monitoring for side-effects and
overseeing a change in route of administration such as from smoking to ingesting. The
security element addresses avoiding the abuse, misuse and diversion of MC through
appropriate storage and establishing guidelines for healthcare provider involvement. The
therapeutic relationship entails recognition that MC is a permitted medical treatment and
patients should not be unreasonably and unfairly disadvantaged by institutional policy.
Conclusions: With an evolving Canadian legal and policy landscape, HCOs managing MC
use in acute care settings are complex but can be informed by key ethical and policy
considerations outlined herein.

*
Corresponding author: Ms Sally Bean, Ethics Centre, Sunnybrook Health Sciences Centre, H263-2075 Bayview
Avenue, Toronto, Ontario, M4N 3M5, Canada. E-mail: sally.bean@sunnybrook.ca.
200 Sally Bean and Maxwell J Smith

INTRODUCTION
With an evolving Canadian legal and policy landscape surrounding medical cannabis (MC),
the role of healthcare organizations (HCOs) in managing MC use in acute care settings is unique
and complex. Due to the use of ‘medical cannabis’ in the most recent Canadian federal
legislation, we prefer the nomenclature of medical ‘cannabis’ as opposed to ‘marijuana’ or
‘marihuana’, which is variably used in the Canadian legal context.
Consider the following illustrative case: an end-stage cancer patient has found successful
symptom relief by smoking MC authorized by his family physician in the community. The
patient is admitted to hospital due to an exacerbation of cancer related symptoms and wishes to
continue use of MC, while in hospital. The hospital has a smoke-free policy for tobacco
products that prohibts smoking or vaping on hospital property. The hospital is currently
developing its MC policy and intends to treat MC like tobacco. The patient does not wish to
switch to a different route of administration, such as a synthetic cannabinoid or edibles given
his familiarity and prior success with inhaled MC. If applicable law has not clarified if MC
should be treated like tobacco in acute care settings, HCOs must decide whether or how they
might accommodate the patient’s use of MC both in the case at hand and more broadly through
HCO policy.
Canada legalized MC in 2001 and implemented a major regulatory overhaul in 2013 by
enacting the “Marihuana for medical purposes regulations” (MMPR) (1, 2). The purpose of
the regulatory shift in 2013, which came into effect in 2014 via the MMPR, was to treat MC
similar to a narcotic (2, 3). Notably, the MMPR shifted the role of authorizing MC from Health
Canada to physicians (4). Since installing the MMPR, provincial bodies have begun to issue
physician practice standards to guide physician practice; however, such practice standards do
not address how healthcare organizations, like hospitals, should handle the use of MC (5, 6).
Therefore, unless provinces and territories pass MC legislation, HCOs must develop
institutional policy to address the use of MC.
In August 2016, the MMPR was replaced by the “Access to cannabis for medical purposes
regulations” (ACMPR) (7). The main reason for the passage of ACMPR in 2016 was to
faciliate better access to MC by permitting individuals to register with Health Canada to grow
their own limited supply or to designate someone to produce it on their behalf (8). Additionally,
the regulations now also include fresh cannabis and cannabis oil, whereas the MMPR only
addressed dried cannabis (8). The new regulations also adopted the terminology of MC (9).
As practicing healthcare ethicists in large academic and community acute care settings, we
have been consulted both for individual patient MC cases such as the illustrative one above as
well as on institutional policy development. Based on our experience to date, for Canadian
healthcare institutions that are developing a MC policy, we suggest that there are five broad
policy considerations that should be contemplated, which include the following: 1) clinical
management; 2) locus of administration; 3) route(s) of administration; 4) supply security; and
5) the therapeutic relationship. Additionally, in the context where applicable legislation is
evolving or provides incomplete direction, we have identified several associaed ethical issues
that warrant consideration; namely, harm reduction and key principles such as respect for
autonomy, non-malificence, reciprocity, justice and the harm principle (10). In the following
we will explore each of the five policy considerations and associated ethical issues in the
Canadian MC context.
 Ethical and policy implications concerning medical cannabis 201

INDICATIONS FOR MEDICAL MARIHUANA

Under the ACMPR, individuals must receive authorization and a signed “medical document”
from a healthcare practitioner (any physician or nurse practitioner whose scope of practice
inlcudes this type of approval) in order to access cannabis for medical purposes (7). The College
of Physicians and Surgeons of Ontario (CPSO), for instance, has interpreted this medical
document as being equivalent to a prescription (5). The medical document must adhere to the
legal requirments in oder to authorize the individual to legally access MC, and must include
information such as the patient’s name, physician’s name and provincial regulatory college
number, the daily quantity of dried cannabis prescribed, the period of use, and the percentage
of THC that the cannabis must contain (3, 5)
There is no set list of approved or specific qualifying conditions for MC. Therefore, it is
up to each physcian to assess whether MC is appropriate for their patient (5). However,
according to the litaerature, the conditions for which MC is most commonly prescribed include:
neuropathic pain (4); antiemetics (treating nausea) in cancer patients (11); appetite stimulation
in HIV/AIDS patients (11); pain and spasticity in Multiple Sclerosis (11); epilepsy (11);
glaucoma (12); agitation in Alzheimer's (12); and post-traumatic stress disorder (12).

DISCUSSION
The CPSO marihuana for medical purposes policy directs physicians when considering whether
they want to prescribe MC for a patient to prudently weigh whether MC is the most appropriate
treatment for their patient, and weigh the available evidence in support of dried cannabis against
other available treatment options (5). Additionally, because current evidence suggests that
children, adolescents and young adults have an increased risk of negative effects, physicians
are directed not to prescribe dried cannabis to patients under the age of 25 years unless all other
conventional therapeutic options have been attempted and have failed to alleviate the patient’s
symptoms (5). Physicians are also directed to advise patients about the material risks and
benefits of dried cannabis, such as operating a motor vehicle (5). The CPSO also recommends
that physicians require patients for whom they are prescribing MC to sign a written treatment
agreement (5). This type of written agreements are common for patients who are prescribed
opiods.
In the acute care context, clinical management of MC may include either initiating or
authorizing continued use of MC and monitoring for side-effects. Authorization for continued
use is necessary since continuting therapy in the acute care context (typically) requires a
physician order. In our experience, it is rare that MC use is initiated in the acute care context;
rather, it is more common for physicians to be asked by patients to authorize the continued use
for MC prescribed previously in the community. In the event of the latter, the Most Responsible
Physician is charged with deciding whether they wish to authorize the continued use of MC
while the patient is in hospital.
Additionally, clinical managment may involve overseeing a change in administration
modes. For example, if we reconsider our illustrative case, if the hospital has a policy
prohibiting smoking or vaping (either tobacco or MC, or both) within the hospital, a switch to
another mode of administration, such as ingesting MC, may be required.
202 Sally Bean and Maxwell J Smith

Locus of administration

Institutional and community settings pose unique practice concerns. For example, allowing
smoking or vapourizing in a public hospital could contravene provincial smoke-free and
workplace health and safety legislation as well as institutional policy. In the community setting,
e.g., there may be applicable workplace legislation protecting home health workers; however,
there generally has to be greater flexibility since care is being provided in the patient’s home.

Routes of administration

There are four main options for of the route of administration for MC. Administration by
smoking offers the benefit of being rapidly absorbed because the inhaled route allows for real-
time dose titration (12). However, smoking MC produces second-hand smoke and commonly
a pungent odor. There is little evidence regarding the potential harms of second-hand smoke of
MC (13). Administration of MC by vapourizing mirrors the absorption and titration of smoking
MC, and the evidence of the potential harms of second-hand vapour of MC is more scant than
for smoking MC (12). Ingesting MC through edibles or tea produces a delayed onset (from 30-
120 minutes), which can make dose titration more challenging but does not produce second-
hand smoke or vapour (12). Finally, there are oral synthetic preparations (i.e., Cannabinoids)
that can be prescribed. Cannabinoids are pharmaceutically engineered, cannabis alternatives
and contain the active ingredient in marijuana, THC (14).

Security

Within the acute care setting, avoiding the abuse, misuse and diversion of MC supply through
appropriate storage is a key liability and policy concern. This is typically addressed by
establishing a policy or guideline for healthcare provider involvement with the administration
of MC as well as use of patient waiver or consent forms.

The therapeutic relationship

Although stigma around the use of MC may linger, it must be acknowledged that MC is a
permitted medical treatment and that individuals using it should not be stigmatized or
unreasonably disadvantaged by institutional policy. Integrating the ethical principles outlined
below may militate against these negative outcomes in HCO policy development. Additionally,
given the positive benefits of a healthy trust-based relationship, such as treatment adherence,
enduring relationships and perceived effectiveness of care, it is important that physicians and
patients maintain a healthy trust-based relationship that is not undermined by stigma or a
burdensome or unfair HCO policy (15).
 Ethical and policy implications concerning medical cannabis 203

ETHICAL ISSUES
With a limited evidence-base on negative effects of second hand smoke from MC, HCOs ought
to consider relevant ethical considerations and principles to help inform policy decision-making
for MC. We first consider potential contributions from the harm principle and the harm
reduction paradigm.

Harm principle

Anti-smoking interventions are (largely) justified by the harm principle, which affirms that
individuals are free to self-abuse unless harms accrue to others (16). The harm principle itself
generally posits that ‘. . . the only purpose for which power can be rightfully exercised over any
member of a civilized community, against his will, is to prevent harm to others’ (17). When
applied in the smoking context, this means that the negative effects of second-hand smoke
override the right of the smoker to smoke around others (16, 10) As such, HCOs may choose
to prohibit the use of MC on similar grounds. However, smoking is just one route of
administration for MC. Additionally, there is very little evidence regarding MC and potential
harm to others. One study, for instance, demonstrated that second hand smoke can produce
levels of THC in blood and urine and induce physiological effects (13). However, there is very
limited evidence and further research is required to make an evidence-based policy decision
stricly on these grounds.

Harm reduction

Harm reduction is to implement a measure, action or policy that has less harmful consequences
than a more harmful behaviour (16). The goal within a harm reduction paradigm is to introduce
a measure, action or policy that satisfies the need or behaviour associted with the harmful action
but that produces less harmful side effects or direct harm (16, 10). It is noteworthy that MC is
not associated with mortality, unlike opioids, which may be prescribed for similar conditions
(4). For example, a JAMA article noted a 25% reduction in opioid-related overdose fatalities
in states within the United States that enacted MC laws (4, 18). While it is unclear if this is a
correlative or causal relationship, the potential for harm reduction over opioids cannot be
overlooked.
In addition to the insights generated from considering to the harm principle and harm
reduction paradigm, we can also draw upon complementary ethical principles of respect for
autonomy, non-maleficence, reciprocity and justice to further guide policy development in this
arena.
The principle of respect for autonomy reflects the importance of patient self-determination.
HCOs that place significant restrictions on MC use may impair patients’ abilities to implement
a treatment regimen that best aligns with their preferred therapeutic goals. Additionally, overly
burdensome restrictions on legally available therapeutic options may undermine patient’s
abilities to implement potential harm reduction measures (relative to opioids).
204 Sally Bean and Maxwell J Smith

The principle of non-maleficence or doing no harm contributes the idea that if a patient has
received authorization to use MC then changing their route of administration (i.e., from inhaling
to ingesting) may unnecessarily harm the patient (i.e., produce less desirable health outcomes).
The principle of reciprocity suggests that if we restrict or take away something away that
an individual is otherwise entitled (e.g., the use of MC in a form of administration as previously
authorized), we have an obligation to limit or mitigate the burden generated by that action.
Since there are other routes of administration of MC, some may argue that alternatives to
smoking or vaping, such as edibles or synthetic cannabinoids, meet this requirement. However,
that application is in tension with the principle of non-maleficence and autonomy if an
alternative route of administration is perceived to be less efficacious or if the patient does not
wish to switch routes of administration.
Consideration of justice supports the idea that like cases should be treated alike and
dissimilar cases should be treated in a way that reflects relevant dissimilarities. Inconsistent
policy approaches across a patient population, or across HCOs, may foster injustice if a patient
using MC is treated different based on arbitrary reasons. Additionally, MC being held to more
stringent standards than other pain-relieving drugs with potential harmful effects broaches
notions of injustice if the different treatment cannot be justified by dissimilarities relative to
comparators.

POLICY OPTIONS
For HCOs considering a policy approach to MC, we believe there are three broad policy options
for routes of administration:

 Prohibit smoke or vapour-producing routes of MC administration everywhere and

allow only ingestible or synthetic forms;
 Allow all forms of legal administration anywhere;
 Prohibit smoke or vapour-producing routes of administration only indoors (allow
outdoors, as long as any legislated permiter from exits and entrances is satisfied).

Option 1—to prohibit smoke or vapour-producing routes of MC administration—

eliminates the potential second hand smoke or vapour harm concerns and treats MC similar to
other smoke or vapour-producing products like tobacco. Tobacco, however, is not a medically
prescribed treatment, so prohibiting tobacco use on HCO property does not necessarily risk
jeopardizing the therapeutic relationship as may prohibiting smoking or vapourising MC. With
that said, in jurisdictions that have implemented legislation treating MC like tobacco, this would
likely be the only legally viable option.
Option 2—to allow all forms of legal administration anywhere—is the most
accommodating option but would have to be balanced against the unique obligations that arise
from being a HCO, i.e., promoting health and avoiding potential harm to other patients, staff,
visitors, and so forth, and especially, those with a compromised state of health that may be
more negatively affected by exposure to smoke or vapour from MC. In most jurisdictions with
tobacco or smoke-free legislation, this may not be feasible or it may be practically difficult to
 Ethical and policy implications concerning medical cannabis 205

handle MC smoke or vapour differently than tobacco smoke or vapour and enforce a policy
banning the latter but allowing the former.
Option 3—to prohibit smoke or vapour producing routes of MC administration indoors
only—has the benefit of allowing patients that are able to ambulate individually or with
assistance to still continue their preferred route of administration without potentially harming
others. Similar to option 2, if in a jurisdiction with tobacco or smoke-free legislation, this also
may not be feasible or it may be practically difficult to enforce a different standard to MC
versus tobacco.
In addition to the overarching route of administration questions, some common questions
warrant further consideration in HCO MC policy development given the brief discussion above:

 Should healthcare institutions prohibit or restrict the initiation of MC therapy? In other

words, physicians practicing in the HCO would not have the option to initiate MC
therapy, but rather only authorize the continuation of MC therapy. This may be too
restrictive for HCOs with palliative or other patient populations that are more likely to
be on MC therapy.
 Should healthcare institutions prohibit, restrict, or otherwise provide guidance with
regards to the continuation of MC therapy for inpatients?
 Should physicians/pharmacists aim to switch patients to approved synthetic
cannabinoid medications?
 Even if applicable legislation allows healthcare providers to handle or administer a
patient’s MC supply, should HCOs discourage or prohibit healthcare providers from
handling or aiding in the administration of MC therapy to their patients/clients in order
to mitigate supply safety or liability concerns?

LIMITATIONS
Although many of the policy and ethical considerations are transferable to other contexts, this
paper has focused on the Canadian context which may differ from other jurisdicitons.

CONCLUSION
In the backdrop of current MC discussions in Canada is the stated intention of Canadian Prime
Minister, Justin Trudeau, to introduce legislation in the Spring of 2017 to legalize recreational
use of cannabis (19). As a result, some may question the need for a HCO to create a MC policy
if such legislation is passed. While the contents of the draft legislation to be introduced are
hitherto unknown, it is safe to assume that there will be some use parameters for recreational
cannabis use that may potentially be differentiated from MC use, and that these parameters will
likely require careful consideration within HCOs.
In this brief review we have highlighted a number of policy and ethical considerations for
HCOs that are now charged with developing MC policy. While additional research on MC
routes of administration and potential harm via MC second hand smoke or vapour is required
in order to make evidence-informed policy, the considerations and options discussed in this
206 Sally Bean and Maxwell J Smith

article provide a starting point for HCOs wishing to develop policy to address MC use until
relevant legislation is passed.

REFERENCES
[1] Minister of Justice. Marihuana for Medical Purposes Regulations, SOR/2013-119. Government of
Canada Department of Justice 2015. URL: http://www.laws-lois.justice.gc.ca/PDF/SOR-2013-119.pdf.
[2] Spithoff S. Emerson B. Spithoff A. Cannabis legalization: adhering to public health best practice. CMAJ
2015; 187(16): 1211-6.
[3] Canadian Medical Protective Association. Medical marijuana: considerations for Canadian doctors.
Canadian Medical Protective Association 2016. URL: https://www.cmpa-acpm.ca/en/duties-and-
responsibilities/-/asset_publisher/bFaUiyQG069N/content/medical-marijuana-new-regulations-new-
college-guidance-for-canadian-doctors.
[4] Lake S, Kerr T, Montaner J. Prescribing medical cannabis in Canada: Are we being too cautious? Can
J Public Health 2015; 106(5): e328–30.
[5] College of Physicians and Surgeons of Ontario. Marijuana for medical purposes – policy statement
#1-15. Toronto, ON: College of Physicians and Surgeons of Ontario, 2015.
[6] College of Physicians and Surgeons of British Columbia. Marijuana for medical purposes - professional
standards and guidelines. Vancouver, BC: College of Physicians and Surgeons of British
Columbia, 2015.
[7] Government of Canada. Access to cannabis for medical purposes regulation, (SOR/2016-230). Canada
Gazette 2016. URL: http://gazette.gc.ca/rp-pr/p2/2016/2016-08-24/html/sor-dors230-eng.php.
[8] Laviolette C. Wakulowsky L. Guidance for health care organizations on the new cannabis regulations.
Borden Ladner Gervais 2016. URL: http://www.blg.com/en/NewsAndPublications/Publication_4636
[9] Vallerihani J. New pot rules a welcome step on the road to legalization. Globe and Mail 2016. URL:
http://www.theglobeandmail.com/opinion/new-pot-rules-a-welcome-ste p-on-the-road-to-legalization/
article31381947/.
[10] Bean S. Smith M. A vaping matter: e-cigarette use in health care organizations. Hastings Cent Rep 2015:
45(6): 11-12.
[11] Hall W. U.S. policy responses to calls for the medical use of cannabis. Yale J Biol Med 2015; 88(3):
257-64.
[12] Wilkinson ST, Yarnell S, Radhakrishnan R. Ball SA, D’Souza DC. Marijuana legalization: impact on
physicians and public health. Annu Rev Med 2016; 67: 453-66.
[13] Herrmann ES, Cone EJ, Mitchell JM, Bigelow GE, LoDico C, Flegel R, et al. Non-smoker exposure to
secondhand cannabis smoke II: Effect of room ventilation on the physiological, subjective, and
behavioral/cognitive effects. Drug Alcohol Depend 2015; 151: 194-202.
[14] Canadian Medical Association. Medical marijuana. Canadian Medical Association 2011. URL:
http://policybase.cma.ca/dbtw-wpd/Policypdf/PD11-02.pdf.
[15] Shea K, Effken J. Enhancing patients’ trust in the virtual home healthcare nurse. Comput Inform Nurs
2008; 26: 135-141.
[16] Holland S. Public health ethics, 2nd ed. Cambridge, UK: Polity Press, 2007.
[17] Mill JS. On liberty and other essays. New York: Kaplan Publishing, 2009.
[18] Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic
overdose mortality in the United States, 1999–2010. JAMA Intern Med 2014; 174(10): 1668–73.
[19] Federal marijuana legislation to be introduced in spring 2017, Philpott says. Canadian Broadcasting
Corporation News 2016. URL: http://www.cbc.ca/news/politics/philpott-un-marijuana-legislation-
legalize-1.3544554.
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 17

ADVERSE EFFECTS OF CANNABIS USE

Amy L Burnett, MSN, APRN

Division of Adolescent Medicine and Young Parent programs, J422 Kentucky Clinic,
Department of Pediatrics, Kentucky Children’s Hospital,
University of Kentucky College of Medicine, Lexington, Kentucky, US

Cannabis is a drug that has been around since ancient times and continues to be one of the
most popular drugs used worldwide today. Even though cannabis is looked at as a low risk
drug with medicinal benefits, there are actually many concerning adverse effects related to
marijuana use. Research shows that there are various psychiatric, neurological, respiratory,
endocrine, and gastrointestinal complications that can be caused by cannabis use. Medical
providers need to be aware of these various adverse effects, especially when caring for the
adolescent population.

INTRODUCTION
Due to the increase in medicinal use and legalization of recreational use in some US states and
many countries around the world, marijuana is a drug that has made its way back into the
spotlight. Marijuana has been around since ancient times and has been mainly used to achieve
euphoria. The medicinal purposes of marijuana are currently being studied and touted by some,
but due to the complex legal atmosphere surrounding the therapy it has not been widely
prescribed. Recreational use of the drug continues at very high rates. The supply of marijuana
is more abundant than ever before, making it much easier for the adolescent population to
obtain.
Adolescents are not only experimenting with marijuana, but some are using it in various
forms on a daily basis. In recent surveys, teens admit that marijuana is easy to obtain (1). In
2014, 21% of high school seniors reported having tried marijuana and almost 6% of high school
seniors reported daily marijuana use (1). One of the most concerning survey findings was that

 Correspondence: Amy L Burnett, MSN, APRN, Adolescent Medicine, University of Kentucky College of Medicine,
740 S Limestone, Lexington, KY 40536, United States. E-mail: amy.burnett1@uky.edu.
208 Amy L Burnett

the perception of risk associated with the use of marijuana in the adolescent population has
consistently declined over the past few years (1). Adolescents not only feel that there is no risk
in marijuana use, but can often endorse benefits from marijuana use (2, 3). The purpose of this
article is to explore the various adverse effects associated with cannabis use in the adolescent
population.

ADVERSE EFFECTS
Most people are aware of the acute adverse effects caused by marijuana, or cannabis, ingestion.
The physical symptoms of conjunctival injection, increased appetite, dry mouth, and
tachycardia are seen in most individuals within two hours of use (1). These physical symptoms
accompany the psychological symptoms of euphoria, which can present differently across
individuals. Some are very relaxed and sedate, while others develop more of an anxious
paranoia. These acute symptoms typically fully resolve within a few hours of cannabis use.
Chronic cannabis use can lead to more significant, and sometimes irreversible, adverse
effects. The most studied adverse effects of chronic cannabis use are the effects that the drug
has on the brain.
Cannabis is known to cause short-term memory impairment, decrease concentration and
attention span, and altered problem solving capabilities (4). Most of those that use marijuana
are under the assumption that the drug decreases anxiety, when in reality 20% to 30% of users
report an increase in generalized anxiety and panic attacks (5). There is conflicting research as
to the effects that cannabis use has on depression and if there is a causal relationship, but it is
thought that marijuana may worsen existing depression (5). Cannabis use has been associated
with increased rates of psychosis in those with a schizophrenia diagnosis and in those that are
genetically predisposed to schizophrenia (6). Due to an immature prefrontal cortex in the
adolescent, marijuana use is particularly concerning during the teenage years. It is uncertain
what impact this drug has on the developing brain, but research has shown that chronic cannabis
use has been associated with lower high school completion rates and lower college degree
attainment (7).
It goes without saying that there are adverse respiratory affects associated with cannabis
use, seeing as the most common form of use is inhalation. Cannabis use has been linked to
increased irritation, swelling, and secretions of the airways, leading to more frequent respiratory
infections, cough, asthma, and chronic bronchitis (8). Chronic cannabis use has been associated
with the development of chronic obstructive pulmonary disease later in life. It has been difficult
to conclusively link long-term marijuana smoking to lung cancer, but it is thought that there
could be a causal relationship (9).
There have been many noted effects on the endocrine system of the body and chronic
cannabis use. Cannabis causes an imbalance in the sex hormone production in both males and
females, leading to a host of reproductive issues (10). Cannabis use lowers testosterone levels
in males, which can result in decreased libido and sperm count and gynecomastia in the male
(11). Chronic use has been shown to increase prolactin levels in females, resulting in
galactorrhea in some chronic users (10). Cannabis use has also been found to inhibit growth
hormone secretion, thyroid function, and glucose levels (10).
 Adverse effects of cannabis use 209

Another adverse effect of chronic cannabis use that has come to light in recent years is
cannabinoid hyperemesis syndrome (CHS). This syndrome is characterized by cyclic nausea,
vomiting, and epigastric pain (12). These side effects resolve with taking hot showers and the
cessation of marijuana use, but do not typically respond to anti-emetics (13). With chronic
cannabis use, disequilibrium within the hypothalamus occurs, causing issues with
thermoregulation. It is thought that being in hot water helps to correct this imbalance (13). With
CHS, patients will typically have a decrease in symptoms when they stop cannabis use and
should fully resolve after about a week of complete cessation (14). The symptoms of CHS can
recur if the individual starts using cannabis again in the future (14).
Not only does cannabis use cause unintended adverse effects, the cessation of use can also
create a host of unwanted symptoms. Cannabis withdrawal has been well studied and many
physical and psychological withdrawal symptoms have been identified. Individuals will
commonly present with the psychological symptoms of anger, aggression, anxiety, restlessness,
insomnia, irritability, and depressed mood (15). Physical symptoms of cannabis withdrawal of
decreased appetite, weight loss, chills, abdominal pain, shakiness, and sweating have also been
noted with cannabis withdrawal (15). It is thought that around 67% of adolescents who are
cannabis dependent will develop withdrawal symptoms with cessation of the drug (16). The
onset of these symptoms can occurs within the first 1-3 days and can last up to 14 days after all
cannabis use has stopped (17).

CONCLUSION
Cannabis is a drug that continues to grow in popularity and use. It is now being marketed as a
treatment for many illnesses and is being legalized for recreational use in some states and
countries around the globe. While the medicinal benefits sound appealing, medical providers
must be aware of the various adverse effects caused by cannabis use, especially in the
adolescent population. With more legal marijuana in circulation, adolescents will have much
more exposure to, and use of, this drug. Those providing care to this patient demographic need
to be aware of all potential dangers of cannabis use in order to properly care for the adolescent
population.

REFERENCES
[1] High school and youth trends. Drugabuse.gov. 2016. URL: https://www.drugabuse.gov/
publications/drugfacts/high-school-youth-trends.
[2] Roditis ML, Halpern-Felsher B. Adolescents’ perceptions of risks and benefits of conventional
cigarettes, e-cigarettes, and marijuana: A qualitative analysis. J Adolesc Health 2015;57:179-85.
[3] Krader CG. Why AAP opposes marijuana use. Contemp Pediatr 2016 Febr 01.
[4] Harvard Medical School. Medical marijuana and the mind. Harv Ment Health Lett 2010;26:1-3.
[5] Volkow ND, Baler RD, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Eng J
Med 2014;370:2219-27.
[6] American Academy of Pediatrics. The impact of marijuana policies on youth: Clinical, research, and
legal update. Pediatrics 2015;135:584-7.
[7] Tashkin DP, Baldwin GC, Sarafian T, Dubinett S, Roth MD. Respiratory and immunologic
consequences of marijuana smoking. J Clin Pharmacol 2002;42:71S-81S.
210 Amy L Burnett

[8] Joshi M, Joshi A, Bartter T. Marijuana and lung diseases. Curr Opin Pulm Med 2014;20:173-9.
[9] Brown TT, Dobs AS. Endocrine effects of marijuana. J Clin Pharmacol 2002;42:90S-6.
[10] Kolodny RC, Masters WH, Kolodner RM, Toro G. Depression of plasma testosterone levels after
chronic intensive marihuana use. N Engl J Med 1974;290(16):872.
[11] Beech RA, Sterrett DR, Babaiuk J, Fung H. Cannabinoid hyperemesis syndrome: A case report and
literature review. J Oral Maxillofac Surg 2015;73:1907-19.
[12] Heise L. Cannabinoid hyperemesis syndrome. Adv Emerg Nurs J 2015;37:95-101.
[13] Wilson O, Lutton S, Doherty K. Diagnosing and treating cannabinoid hyperemesis. Emerg Nurs
2015;23:22-5.
[14] Budney AJ, Hughes JR, Moore BA, Vandrey R. Review of the validity and significance of cannabis
withdrawal syndrome. Psychiatry 2004;161:1967-77.
[15] Kouri EM, Pope HG, Lukas SE. Changes in aggressive behavior during withdrawal from long-term
marijuana use. Psychopharmacol 1999;143:302-8.
[16] Haughey HM, Marshall E, Schacht JP, Louis A, Hutchinson KE. Marijuana withdrawal and craving:
influence of the cannabinoid receptor I (CNRI) and fatty acid amide hydrolase (FAAH) gene. Addict
2008;103:1678-86.
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 18

CANNABIS AND THE ROLE OF OUR SCHOOLS

Venus Wong and Alissa Briggs, PhD, NCSP*

Division of Adolescent Medicine and Young Parents Program,
Pediatrics Behavioral Health Clinic and Division of Pediatric Genetics and Metabolism,
Kentucky Children’s Hospital, Lexington, Kentucky, US

Despite all the efforts to prevent and remediate adolescent drug use, the use of
marijuana among adolescents remains both high and stable. Of equal concern, more and
more adolescents think that occasionally smoking marijuana is not harmful. In this chapter
we aim to discuss the role of schools in combating adolescent use of marijuana and possible
interventions through the Multi-Tier Systems of Support (MTSS).

INTRODUCTION
Marijuana is the most popularly used illicit drug among adolescents (1, 2). According to the
Monitoring the Future study (national survey of 8th, 10th, and 12th grade students), about 24%
of adolescents reported that they used marijuana in the past year (1). Nationwide, 14% of
students reported they used marijuana one or more times within 30 days before the survey (1).
The use of marijuana among adolescents remains stable, while the use of alcohol, cigarettes,
and prescription pain relievers is declining (1). Of equal concern is that more and more
adolescents think that occasionally smoking marijuana is not harmful (1).
During adolescence, young individuals go through many physical, cognitive,
psychological, and social changes. As discussed below, the use of marijuana puts the
transforming body and mind at risk. Adolescent use of marijuana has been linked to a variety
of short- and long-term problems.

*
Corresponding author: Alissa Briggs, PhD, NCSP, Assistant Professor and Licensed Psychologist, UK Healthcare,
Department of Pediatrics, Division of Adolescent Medicine and Young Parents Program, KY Clinic, Room
L443, Lexington, KY 40536-0284, United States. E-mail: alissa.briggs@uky.edu.
212 Venus Wong and Alissa Briggs

MEMORY, ATTENTION, LEARNING CAPABILITY

AND SCHOOL PERFORMANCE

Research found that persistent use of marijuana during adolescence impairs cognitive
functioning (3-5). A study found that persistent adolescent-onset marijuana users have
significantly weaker working memory, processing speed, perceptual reasoning, and verbal
comprehension, when compared to non-marijuana users, after controlling for years of education
and childhood cognitive ability (4). Such a global cognitive impairment is more prevalent
among adolescent-onset marijuana users than adult-onset users (4).
Not surprisingly, use of marijuana is associated with low school performance, which may
be a result of declining cognitive ability. Research found that use of marijuana predicted years
of education (6), high school dropout (7), perceived academic failure (8), low grades (9), and
academic achievement (10). However, the relationship between the use of marijuana and low
school performance appears to be complex (9). Some studies treated low school performance
as a predictor of the use of marijuana. A number of studies found that negative educational
outcomes precede marijuana use (11-13). Some other evidence supports the idea that a third
variable accounts for the use of marijuana and negative education outcomes (9, 14).

BEHAVIORAL AND PHYSICAL HEALTH

Marijuana use also appears to relate to a wide range of behavioral and physical health outcomes.
Adolescent use of marijuana is associated with a range of risky behaviors, such as inconsistent
safe-sex practices (15, 16), risky driving (17, 18), and criminal behavior (19, 20). The use of
marijuana is also associated with a variety of mental health concerns (21), such as depression
(22, 23), anxiety (11, 24), and psychosis (25). Such associations are stronger during
adolescence than during developmental periods later in life (11). Also, use of marijuana is
associated with common physical problems, such as respiratory issues and general illness (10).

THE ROLE OF SCHOOL

Schools can play a critical role in addressing adolescent use of marijuana. However, typical
schools are not prepared to provide services for all students with substance abuse of differing
severity (26). Substance abuse education and treatments can be categorized into prevention,
direct intervention, indirect intervention, and maintenance/relapse prevention (27). Substance
abuse education and treatments for adolescents are delivered at multiple levels of care in many
different settings (26). Usually, adolescents with substance use problems are referred to and
receive services from outpatient services (i.e., one or two times a week), intensive outpatient
services (i.e., more twice a week for at least three hours per day), partial hospitalization (i.e.,
four to six hours a day at least five days a week while living at home), or inpatient treatment
(26).
Outpatient and intensive outpatient services are commonly recommended for adolescents
with lower level of addiction, whereas adolescents with more severe addiction problems and
 Cannabis and the role of our schools 213

associated behavioral and mental health issues usually partake in partial hospitalization or
inpatient treatment (26). That is, many direct interventions for adolescents with problems
associated with marijuana use are handled by non-school professionals from outside agencies.
At times, students who exhibit more severe marijuana use and associated behavioral and mental
health issues are placed in a more structured environment (e.g., hospital) and do not attend
regular schools until their problems are relieved.
Even though typical schools may not possess sufficient resources to support students with
current and severe addiction problems, they have unique advantages in two areas across the
spectrum of care. First, schools play an important role in the early identification of marijuana
use (28). Teachers are in a good position to observe marijuana-use related symptoms, such as
changes in mood, academic performance, behaviors, and physical appearance (29). Early
detection benefits students because it usually leads to early interventions that prevent further
damage as a result of the drug use (30, 31). Second, since the majority of adolescents attend
school on a regular basis, schools have the advantage of delivering prevention education for
the general student population, supplementary services, and relapse prevention services.

TYPES OF PROGRAMS AND DELIVERY SYSTEM IN SCHOOL

Prevention and early intervention are critical components to enhance protective factors and
diminish risk factors for marijuana use. In the current literature, more research exists in the area
of school-based prevention programs, yet the role of schools in supporting students with mild-
to moderate marijuana use and their families, providing supplementary services, and delivering
relapse support is less clearly defined.

DRUG ABUSE PREVENTION AND EARLY INTERVENTION

PROGRAMS CLASSIFICATION

Adolescent drug abuse prevention and early intervention programs can be categorized into three
levels: universal, selective, and indicated programs to (32). Universal programs target the
general adolescent population, with the aim of preventing or delaying the use of drugs. This
type of program addresses common risk and protective factors (e.g., peer pressure, learning
difficulties) (32). Selective programs are more restricted and target high-risk adolescent groups
(e.g., students who display a variety of risk-taking behavior, students whose parents abuse
drugs, students who are diagnosed with anxiety or depression). The aim of selective programs
is to provide students with more intensive, specific support to make responsible, healthy
decisions (32). Indicated programs are designed for adolescents who have used drugs. The aims
of indicated programs are to motive adolescents to reduce the use of drugs and diminish the
negative outcomes associated with drug use (32). Indicated programs should cover all forms of
drug abuse (e.g., use of illegal drugs, inappropriate use of legally obtained drugs, underage
alcohol consumption), even though these programs should also be tailored to address specific
drug use problems and risk factors (1, 33, 34).
214 Venus Wong and Alissa Briggs

Schools also use a a three-tiered model of service delivery. Within schools, a three-tiered
model of service delivery is referred to as Multi-Tier System of Supports (MTSS). Multi-Tier
System of Supports is used as a vehicle to coordinate prevention and intervention efforts for a
wide variety of concerns (e.g., academic, behavioral, and social-emotional) (35) and can target
drug use. Moreover, MTSS is a data-based decision making model (36) that involves parents.
Within MTSS, universal screening and ongoing data collection are implemented periodically
in order to provide information about intra-and inter-student needs and progress (37). Parents
should be involved in the planning and intervention process (38). Furthermore, involving
parents in interventions can ensure continuing quality support outside the school and prompt
generalization of skills. The nature of the MTSS echoes the needs for parental involvement and
on-going monitoring for students who use marijuana (see (39, 40)).

EFFECTIVE PROGRAMS AND PRACTICES WITHIN MTSS

Marijuana use prevention and early intervention and MTSS are highly compatible. Since the
National Institute on Drug Abuse already provides detailed descriptions of different types of
evidence-based drug prevention programs (universal, selective, and indicated) for different age
groups (elementary, middle, and high school) (26), more attention will be paid to the discussion
of how other effective practices can be implemented effectively within the MTSS model.
Additionally, it is worth noting that the MTSS is not a one-way model; instead, students can
move up and down the tiers based on their progress. For students released from more restricted
programs, the MTSS functions like a maintenance or relapse prevention mechanism to support
students on top of outpatient services (see Figure 1).

Figure 1. A combined model of MTSS and outside services.

 Cannabis and the role of our schools 215

Tier 1

Description. Tier-one interventions target the whole student population, with the aim of
preventing or delaying the use of marijuana and other drugs. The target of this group should be
drug-users and non-drug users (26). Universal programs are generally less expensive per
student, shorter in length, less intensive, include all youths in schools, and do not require trained
professionals for implementation (41). Yet, because of the general nature of the programs, they
usually do not meet individual needs. Also, the intensity of these programs is not sufficient to
eliminate the negative effects of risk factors.
Other common effective practices. Teachers also need to keep a close eye on students
when they are in school. A national report found that around 6% of students admitted using
marijuana on school property at least one time within the 30 days before the survey (2). Close
monitoring of student behaviors (e.g., during transition, recess) is needed in order to ensure
drug-free schools.
Ongoing assessment. As part of MTSS, schools should be regularly (usually monthly)
reviewing data in order to identify students who are at-risk. As aforementioned, marijuana use
is associated with a variety of negative educational outcomes, and thus promptly identifying
students who are at-risk educationally may help interrupt the likely bi-directional relationship
between marijuana use and academic failure. Moreover, some schools regularly screen for signs
of depression in an effort to prevent suicide, and such screening could also help identify
students at-risk for marijuana use.
Parent involvement. Parents are an important factor in the prevention of marijuana use
(39, 42). One of the main aims at tier one is to increase parents’ awareness of drug use issues
in their communities and empower them with the knowledge necessary for them to identify the
use of drugs. All parents should be given information with regard to drug prevention and the
signs of marijuana use and addiction. Parents should also be clearly informed about the steps
they need to take if they suspect their child of using drugs. Since research has found that parent-
child relationships (e.g., closeness, warmth) and parental monitoring (e.g., parental knowledge
of the child’s whereabouts, friendships, activities, and use of money) are two important
predictors of adolescent drug use (39), teachers could support parents in incorporating effective
parenting practices when communicating with parents through newsletters, school-to-home
notebooks, monthly phone calls, and, if appropriate, parent-teacher conferences (42). Schools
could also facilitate positive parental involvement through (1) shared governance on advisory
committees; (2) active, two-way communication; (3) encouraging parents to plan and attend
school events; (4) assisting teaching in the classroom; and (5) providing parent education
activities (43).

Tier 2

Description. Tier-two interventions target high-risk adolescent groups identified through

regular data monitoring at tier one and aims to provide students with more intensive, specific
support in order to make responsible, healthy decisions (32).
216 Venus Wong and Alissa Briggs

Ongoing student assessment. Data monitored at tier one should be monitored on a more
regular basis for students at tier 2 (e.g., bi-monthly). In addition, regular assessment of at-risk
students could be implemented by qualified school professionals (e.g., school nurse, school
psychologist) using tools such as the Universal Screening for Substance Use, Brief
Intervention, and/or Referral to Treatment (SBIRT; (44)) and the CRAFFT screening (45).
Parent involvement. At this stage, home-school collaboration is critical so that parents
and school personel can work together to support high-risk adolescents. The first step in the
process is for school personnel provide parents with data, inform them of their concerns, and
develop a plan of action. At this stage, parents need to be aware of and even consent to
additional supports put in place for their children and should be informed their progress. They
also must have the opportunity to help develop a support plan and reinforce interventions
provided at home.

Tier 3

Description. Tier-three interventions target adolescents who have already begun using, or are
experimenting with marijuana. Services provided at tier three may be provided through
alternative schools or recovery schools. The main goals of this tier are to motivate adolescents
to reduce their use of marijuana and diminish the negative outcomes associated with marijuana
use (32). Services at this level should target students who are also receiving regular outpatient
or intensive outpatient services from outside agencies with regard to their marijuana use and
any other associated problems. Some students at tier three may be students who are released
from partial hospitalization and inpatient services. For this group of students, the services in
school can also aim to prevent relapse.
Compared to tier-one and tier-two programs, programs at tiers three are more specific and
intensive. For instance, the Reconnecting Youth program is a daily curriculum that consists of
75 session and targets students who show low academic performance, have potential for
dropping out of high school, and exhibit other problem behaviors patterns such as substance
abuse. This program should only be conducted by a trained professionals (46).
Other effective practices. Since students at tier three may have recently been released
from more restricted inpatient drug treatment programs, this stage can also be considered a
transition. Before the student is transferred back to the school, school professionals, parents,
and staff from the inpatient unit should develop an individualized transition plan. The
continuity of services is the key to student success (47). Schools need to ensure good
communication with both parents and outpatient units about the goals of the transition and the
steps needed to achieve these goals. Quality transition goals need to be specific, measurable,
achievable, realistic/relevant, and timed (48). The transition plan also needs to specify clearly
the roles of each party and the services needed by the family.
The MTSS system is designed in such a way as to provide the majority of the
aforementioned components early on (e.g., encouraging family involvement; increasing
prosocial leisure habits). However, compared to students without drug use, students at tier three
need extra intense, targeted, and structured opportunities to learn prosocial behaviors. The
aforementioned components can be a guideline for schools to develop tier- three relapse
prevention support.
 Cannabis and the role of our schools 217

Ongoing student assessment. Since students at this stage have already started
experimenting or using drugs regularly, they usually partake in outside services. Despite the
relatively high need for support, students at tier three usually still spend a significant amount
of time in school. Frequent communication between the school and outside professionals will
facilitate data-based decision making, provided that the parents and adolescents concsent to
such collaboration. Assessment that takes place at tier two should continue to take place, but
more frequently (e.g., weekly). In addition, assessment at tier three may also be used for relapse
monitoring. Some simple progress monitoring tools, such as the Routine Outcome-Monitoring
(ROM) questionnaire, can be used regularly after drug abuse treatment (49).
Parent involvement. At this stage, students are usually supported by outside agencies. For
students who are transferred back to school from inpatient programs, the school, outpatient unit,
and parents should collaborate on the transition planning and interventions. It is important to
note that parents at this stage may often seek advice, comfort, or encouragement from school
professionals (50). Teachers and school-based mental health professionals need to be prepared
to provide timely informational and emotional support for parents.

CONCLUSION
Adolescent use of marijuana is a pervasive problem in society. Schools can play a critical in
addressing this problem. Much previous work has developed effective universal, selected, and
indicated marijuana and other drug prevention programs. It is important to note that despite the
established effectiveness, these evidence-based programs suffer from limitations. In face of the
idiosyncratic challenges experienced by different communities, it is important for schools to
select the right drug prevention programs and develop their own anti-drug strategies based on
existing research findings and their particular situations. This paper clearly delineates the utility
of the MTSS model in school as a service delivery framework for students with or without
marijuana use problems, and how MTSS connects with outside service delivery systems.
Schools are encouraged to use the MTSS model to guide their drug prevention implementation,
provide universal screening, make data-based decisions, and involve parents in the prevention
process.

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[45] Kulig JW, American Academy of Pediatrics Committee on Substance Abuse, Tobacco, Alcohol, and
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[48] Bovend'Eerdt TJ, Botell RE, Wade DT. Writing SMART rehabilitation goals and achieving goal
attainment scaling: a practical guide. Clin Rehabil 2009; 23(4): 352-61.
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abuse treatment. Subst Abuse 2013; 7: 155-69.
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In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 19

CANADA AND MEDICAL MARIJUANA

Blair Henry, D. Bioethics, Rachel McDonald, BSc(C),

Stephanie Chan, BSc(C), Edward Chow, MBBS
and Leigha Rowbottom, BSc(C)
Sunnybrook Health Sciences Centre, University of Toronto, Toronto,
Ontario, Canada

Cannabis is not a new drug. In fact, the cannabis or hemp plant grows in most parts of the
world and has a long history of both medical, as well as non-medical use. Little is
documented on the use of cannabis in the first half of the century, however, despite legal
sanctions consumption of cannabis increased notably in the 1960s and 1970s and usage
seems not to have abated since that time. Its resurgence as a medicinal drug of interest
came out of the AIDS pandemic and in 1999 two patients obtained permission by the
Federal Government to smoke marijuana. Subsequently in 2000 the Courts ruled that
Canadians had a right to use cannabis as a medicine, and in 2001 the Liberal government
enacted the Medical Marihuana Access Regulations (MMAR), allowing cannabis for
therapeutic purposes.

INTRODUCTION
In discussing the potential medical uses of cannabis, it is important to remember that cannabis
is not a new drug. In fact, the cannabis or hemp plant grows in most parts of the world and has
a long history of both medical, as well as non-medical use (1-2). However, by the mid 19th
Century stronger and more reliable synthetic drugs, such as opioids and other clinically tested
and approved narcotics, began to form the mainstream pharmacological interventions of choice
in medicine. Scientific interest in cannabis as a medicine waned at the start of the 20th Century,
and among the reasons for this loss of favor were that the plant material was too variable in


Correspondence: Mr Blair Henry, Ethicist, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto,
ON Canada. E-mail: Blair.Henry@sunnybrook.ca.
222 Blair Henry, Rachel McDonald, Stephanie Chan et al.

composition (strength), its shelf-life was too short and unpredictable, uncontrolled sources
meant reduced purity, as well as the changing legal climate (3-4).
The legal framework for drug control in Canada was created in the early 1990s. By 1908,
all medicines, inclusive of tobacco and alcohol, were on the way to regulation and it would be
in the same year that the Opium Act created the first drug prohibition (5). Cannabis was
officially added to the Canadian drug prohibition law in 1923, making its production,
possession, and consumption illegal activities (6). Little is documented on the use of cannabis
in the first half of the century, however, despite legal sanctions consumption of cannabis
increased notably in the 1960 and 1970, and usage seems not to have abated since that time (5).
Its resurgence as a medicinal drug of interest came out of the AIDS pandemic. In 1999 two
patients obtained permission by the Federal Government to smoke marijuana and in 2000 the
Courts ruled that Canadians had a right to use cannabis as a medicine (7).
In 2001, the Liberal government enacted the Medical Marihuana Access Regulations
(MMAR), allowing cannabis for therapeutic purposes (8). Under this framework, physicians
were allowed to authorize cannabis use to patients suffering from an authorized list of severe
or chronic illness. Cannabis has been used to treat a variety of conditions: as an analgesic to
treat neuropathic pain, as antinauseant and antiemetic action in treatment of patients receiving
radiation therapy or chemotherapy for AIDS or cancer an antiemetic, as an appetite stimulant
in patients with anorexia and wasting syndromes, the reduction of intraocular pressure in the
treatment of glaucoma, anticonvulsant action as an adjuvant therapy for epilepsy, and as an aid
in the relief muscle spasticity in patient with muscular sclerosis (9).

ACCESSIBLE FOR CERTAIN MEDICAL CONDITIONS

The 2001 regulations were intended to make cannabis more accessible for certain medical
conditions, however, the number of patients who utilized it was limited due to the complicated
and lengthy bureaucratic process physicians were required to follow to prescribe it (8). In an
effort to reduce such barriers, the federal government introduced the Marihuana for Medicinal
Purposes Regulations (MMPR) in 2014 (8, 10). This new regulation removed the requirement
that an illness must be authorized by the government for the authorization (note not
“prescription”) of cannabis; now, any adult citizen of Canada who has a physician’s
authorization for the use of cannabis is permitted to do so (8).
One of the major concerns for clinicians dealing with patients who request cannabis for
medicinal purposes typically involves a lack of good data to determine the strain, its efficacy
and appropriate dosage rates based on a paucity of clinical trials comparing cannabis with
conventional medicines- in short many clinicians feel inexperienced and uncomfortable in
dealing with cannabis. Adding to the uncertainty, is the fact that cannabis can also be taken in
a variety of methods: smoking, vaping, edibles, sublingual sprays, transdermal patches,
suppositories, beverages (tea), topical applicants, etc.
 Canada and medical marijuana 223

LEGALIZING CANNABIS RECREATIONALLY

Although the new MMPR framework shields a much wider range of Canadians from the
punitive consequences of possession and consumption of cannabis, it does not extend to
individuals who utilize it on a recreational basis. Requests to decriminalize cannabis for this
purpose date back to 1972 and have recently received more support (6, 11). In fact, the majority
of Canadians are now in favour of this reform (12). Certainly this push for change urged parties
during the 2015 federal election to incorporate cannabis for recreational use into their
platforms. In particular, the Liberal party garnered attention during their campaign by pledging
to legalize, regulate, and restrict access to cannabis (13). Now that the Liberal party holds a
majority government, Canadians are calling for action on their promises regarding cannabis
use. However, legalizing cannabis for recreational use is a multifaceted issue that has
significant implications on both the healthcare system and society at large.
One important aspect to consider is the impact of legalizing cannabis recreationally might
have on current therapeutic users. Often, individuals who utilize medicinal cannabis face
stigmatization and discrimination, which can add to psychological and emotional distress.
Legalization of cannabis may help de-stigmatize its use, thereby improving the experience of
medical cannabis users. Additionally, legalization is likely to further reduce barriers to cannabis
procurement, thus making it more accessible to those who require it for therapeutic purposes.
The hope is that with a higher degree of regulation and more controlled access, better
quality and more pure sources can be available, reducing risk of toxicity or addiction to other
chemicals, such as nicotine (14). Proponents of such a plan argue that resources currently used
to deal with minor cannabis-related incidents can be reallocated to larger threats to public
safety, such as violent crimes, human trafficking, and so-called ‘hard drugs’ (13).
With such policy change it is projected there will be an increase in new young adult users,
which could lead to long-term health effects (15). One study conducted by Meier et al. (16)
followed a birth cohort to midlife (38 years) and determined that persistent cannabis use was
associated with global reduction in neuropsychological functioning across various domains of
functioning (16). Data on the long term effects of cannabis use is concerning- several studies
have shown that there is an increased prevalence of mental health disorders, such as depression,
anxiety, and schizophrenia among habitual cannabis users (17-19). While on the other hand,
marijuana may assist individuals struggling with life stresses. For example, one study
hypothesized that marijuana may actually be beneficial in stressful life circumstances, as the
suicide rate in males 20-29 years and 30-39 years of age decreased by 10.8% and 9.4%,
respectively, in states that had legalized marijuana (20). In Colorado, after legalization of both
medical and recreational uses of marijuana, no effect was found on rate of completed suicides
after legalization (21).
An unexpected positive outcome of cannabis use in general has been the drop in mortality
rates related to prescription drug abuse in North America- positing cannabis as a potential first
line or adjuvant harm reduction drug of choice in dealing with a variety of chronic pain issues
(22).
Medical associations have continued to raise concerns over the lack of good data to support
physicians in authorizing its use (5). Perhaps a future de-regulated environment that opens
cannabis use both for medicinal and recreational purposes will facilitate much needed testing
of its import to medicine: The world is watching.
224 Blair Henry, Rachel McDonald, Stephanie Chan et al.

ACKNOWLEDGMENTS
We thank the generous support of Bratty Family Fund, Michael and Karyn Goldstein Cancer
Research Fund, Joey and Mary Furfari Cancer Research Fund, Pulenzas Cancer Research Fund,
Joseph and Silvana Melara Cancer Research Fund, and Ofelia Cancer Research Fund.

REFERENCES
[1] Mikuriya TH. Marijuana in medicine: past, present and future. California Med 1969;110:34-40.
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The botany and chemistry of cannabis. London: J & A Churchill, 1970:11-38.
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Information Canada, 1972:11-25,125-126.
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Pharm Pharmacol 1976;28:1-7.
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[7] A timeline of some significant events in the history of marijuana in Canada. Canadian Press 2014 URL:
http://cponline.thecanadianpress.com/graphics/2014/medical-marijuana-timeline/
[8] Belle-Isle L, Walsh Z, Callaway R, Lucas P, Capler R, Kay R, et al. Barriers to access for Canadians
who use cannabis for therapeutic purposes. Int J Drug Policy 2014;25(4):691-9.
[9] Kalant H. Medicinal use of cannabis: history and current status. Pain Res Manag 2001;6(2):80-91.
[10] Health Canada. Harper government announces new medical marihuana regulations. Canada Gazette
2013 URL: http://www.hc-sc.gc.ca/ahc-asc/media/nr-cp/_2013/2013-79-eng.php.
[11] Le Dain Commission. Cannabis: A report of the commission in the inquiry into the non-medical use of
drugs. Ottawa, ON: Information Canada, 1972.
[12] Fischer B, Kuganesan S, Room R. Medical marijuana programs: Implications for cannabis control
policy – observations from Canada. Int J Drug Policy 2015;26(1):15-9.
[13] Liberal Party of Canada. Real change: A new plan for a strong middle class 2015 URL:
https://www.liberal.ca/files/2015/10/New-plan-for-a-strong-middle-class.pdf.
[14] Kilmer B. Policy designs for cannabis legalization: starting with the eight Ps. Am J Drug Alcohol Abuse
2014;40(4):259-61.
[15] Van Gerpen S, Vik T, Soundy TJ. Medicinal and recreational marijuana: what are the risks? S D Med
2015;58-62.
[16] Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS, et al. Persistent cannabis users show
neuropsychological decline from childhood to midlife. Proc Natl Acad Sci USA 2012;109(40):E2657-
64.
[17] Health Canada. Information for health care professionals: cannabis (marihuana, marijuana) and the
cannabinoids. URL http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/infoprof-eng.php.
[18] Adda J, McConnell B, Rasul I. Crime and the decriminalization of cannabis: evidence from a localized
policing experiment 2010 URL: http://www.iza.org/conference_files/riskonomics2011/mcconnell_
b6110.pdf.
[19] Hall W, Weier M. Assessing the public health impacts of legalizing recreational cannabis use in the
USA. Clin Pharmacol Ther 2015;97(6):607-15.
[20] Anderson DM, Rees DI, Sabia JJ. Medical marijuana laws and suicides by gender and age. Am J Public
Health 2014;104(12):2369-76.
 Canada and medical marijuana 225

[21] Rylander M, Valdez C, Nussbaum AM. Does the legalization of medical marijuana increase completed
suicide? Am J Drug Alcohol Abuse 2014;40(4):269-73.
[22] Collen M. Prescribing cannabis for harm reduction. Harm Reduct J 2012;9:1.
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 20

MEDICAL CANNABIS AND PALLIATIVE CARE

Noah Spencer, BASc(C), Erynn Shaw, MD

and Marissa Slaven, MD
Bachelor of Arts and Science Program,
Faculty of Science and Faculty of Health Sciences McMaster University,
Hamilton, Ontario, Canada

Palliative medicine focuses on relieving the symptoms and supporting the needs of patients
and families faced with terminal illness. It embraces a biopsychosocial model of care for
patients and their loved ones. Attitudes towards use of medical cannabis are becoming
more liberal among those in the palliative care community as well, and for good reason.
Marijuana is relatively safe in comparison with prescription narcotics, both in terms of the
individual patient’s health and public health as there is less damage done by diversion.
Consequently, treatment with medical cannabis presents an opportunity for patient
autonomy, for controlling an aspect of their medication. However, additional research is
required into the substance’s safety and efficacy.

INTRODUCTION
We are called upon as physicians to provide comfort always, but perhaps at no other time in a
person's’ life is managing their comfort as critical, and their vulnerability more evident, than
when they are living with a debilitating illness.

 To cure sometimes, to treat often, to comfort always

 Hippocrates (460-370 BCE)

Palliative medicine focuses on relieving the symptoms and supporting the needs of patients
and families faced with terminal illness. It embraces a biopsychosocial model of care for


Correspondence: Marissa Slaven, MD, Faculty of Health Sciences, McMaster University, Hamilton, Ontario,
Canada. E-mail: slavenm@hhsc.ca.
228 Noah Spencer, Erynn Shaw and Marissa Slaven

patients and their loved ones. In this short communication, we consider the impacts of medical
cannabis on the physical, psychological and social aspects of patient care.

MANAGING PHYSICAL SYMPTOMS: EFFICACY AND SAFETY

Cures and treatments are concepts readily embraced by modern medicine because results such
as tumor markers or hemoglobin A1C levels, fit well in a paradigm where evidence can be
measured objectively. Comfort, however, is by nature a largely subjective result. Efforts to
make it conform to an objective model can often be frustrating and misleading. For example, a
rating of eight out of ten on a pain scale can mean entirely different things to different patients
based on a myriad of factors, including personal history and cultural norms.
Medical cannabis may be used for the management of many symptoms common to
palliative patients. These may include pain, nausea, muscle spasms, depression, anxiety,
insomnia, and anorexia/cachexia. Despite the widely-noted lack of research into medical
cannabis’ efficacy, there have been some randomized controlled trials that support cannabis’
use in treating these symptoms (1-3). Some patients, having acclimatized to the ‘medical
model’, may have concerns about the lack of experimental evidence supporting the use of
medical cannabis, and doctors should be transparent about this. However, palliative care
doctors have long valued experiential evidence in addition to experimental evidence, so it
would also be appropriate to inform patients that cannabis has been used by medical
professionals to alleviate symptoms with a favourable side-effect profile for many years.
There is a paucity of research surrounding medical cannabis in general and about
appropriate dosages specifically. Palliative care doctors typically recommend a somewhat
arbitrary “start low, go slow” schedule, advising patients to start on low doses and increase
their dosages gradually to obtain adequate symptom relief. It is reasonable to consider cannabis
for patient controlled analgesia given that it has been found to have a favorable side-effect
profile and has generally been found to be tolerated well by patients. However, knowing the
most effective dosages to start different patients on would undoubtedly help doctors help their
patients achieve prompt effective symptom relief.
An additional benefit of cannabis in palliative patients is that although cannabis may or
may not be the single best agent to treat any one symptom, it is common for these patients to
have multiple symptoms. The ability of cannabis to address multiple symptoms with one single
agent as opposed to multiple medications, each with its own side effect profile, is beneficial.
While cannabis has been found to lead to increased heart rate, vasodilation, and dizziness
(4), the majority of the concern regarding the substance relates to long-term effects (e.g., lung
cancer, psychiatric conditions, or dependency). These long-term issues are not of as great
concern to palliative patients, and the short-term side effects are not grave compared to those
of most painkilling narcotics. One side effect that is frequently a concern to palliative patients
is the potential for cannabis to impact mental clarity. This side effect can be moderated by
choosing strains with lower THC to CBD ratios.
 Medical cannabis and palliative care 229

PSYCHOLOGICAL ASPECTS OF CARE: EMPOWERMENT AND HOPE

When a patient presents to a palliative care doctor with any of the symptoms detailed above,
the doctor should consider the possibility of using medical cannabis as part of a treatment plan.
However, in our clinical experience, it is more often the case that the patient will start the
dialogue about using medical cannabis. This order may feel somewhat foreign or even
uncomfortable to doctors used to the structure of patriarchal medicine, but they should be
reassured that cannabis is a relatively safe drug. It is nearly impossible to overdose on cannabis,
so patients may be given more liberty to self-titrate as they see fit without fostering great
concern in doctors. In this, we can realize an opportunity for the patient to regain a sense of
empowerment when it comes to their health. This often comes at a critical juncture for palliative
patients who have lost the ability to control many aspects of their care and their lives.
It is not uncommon for palliative patients and their families to struggle with issues around
acceptance and hope. In this age of information, patients may be exposed to media which falsely
represent cannabis’ anti-tumor activities in vitro and in some small scale animal studies as a
new cure for cancer. While the evidence clearly does not support cannabis as a cure for cancer,
and medical professionals should not provide or endorse false hope, we must also understand
that patients and families are on their own personal journeys. We see the need to balance the
role of providing accurate scientific information with maintaining a supportive and therapeutic
relationship which can only come from open and honest communication. In this way, we can
meet our patients and families where they are at and gently help guide them toward making
informed, safe decisions.

SOCIAL ASPECTS: STIGMA AND BEYOND

Especially since the counterculture movement of the 1960s, cannabis has been seen as a drug
taken recreationally to generate a “high” and some degree of an out-of-mind experience. It has
been associated largely with youthful naivete, with laziness, and sometimes even with
immorality. Furthermore, cannabis has been seen as a “gateway drug,” suggesting its users are
also prone to using other recreational drugs. Unsurprisingly, these associations are ones doctors
and patients alike seek to avoid. Doctors may quickly dismiss cannabis as a treatment option
and patients may refrain from requesting medical cannabis out of fear that their doctor will
think of them as a “stoner.” Within palliative care, these issues may be exacerbated because of
the age of most patients. The fact that a 70 year-old grandmother does not fit society’s image
of a cannabis user may prevent such a patient from requesting medical cannabis and/or doctors
from authorizing it for her.
It is important that doctors learn how to appropriately discuss cannabis with patients. There
is a wide variation in comfort levels and knowledge about authorizing medical cannabis
amongst clinicians, even more so than around opioids. In our clinical practice, many patients
have reported negative experiences discussing medical cannabis with other doctors. If a health-
care provider is not comfortable with authorizing cannabis, they should say so in a way that is
non-judgmental and allows them to maintain a therapeutic relationship with their patient. For
example, a clinician could respond to a patient request by saying, “While I am not comfortable
prescribing this substance, I will direct you to a pain and symptom management clinic where
230 Noah Spencer, Erynn Shaw and Marissa Slaven

they can discuss it further with you.” The maintenance of the clinician-patient relationship is
important for many reasons, not least of which is that if patients are not directed to appropriate
resources, then they may still seek cannabis for medical purposes in places other than the state-
sanctioned facilities. Products from local suppliers are far more prone to contaminants and
place patients at unnecessary risk. Further, in this scenario, patients may not disclose to their
physicians that they are using cannabis, which may impact their clinical care.

CONCLUSION
A survey conducted in 2001 on physicians’ views toward prescribing cannabis revealed that
only a third of physicians polled would prescribe cannabis if it were legal (5). In a 2014
WebMD survey of 1,554 physicians in more than 12 specialties, 69% believed it can help with
certain treatments and conditions. Hematologists and oncologists were most likely (82%) to
agree that cannabis delivers health benefits. Attitudes towards use of medical cannabis are
becoming more liberal among those in the palliative care community as well, and for good
reason. Marijuana is relatively safe in comparison with prescription narcotics, both in terms of
the individual patient’s health and public health as there is less damage done by diversion.
Consequently, treatment with medical cannabis presents an opportunity for patient autonomy,
for controlling an aspect of their medication.
However, additional research is required into the substance’s safety and efficacy. Research
into proper dosages and intake methods would be especially beneficial to doctors and patients.
For this research to occur and for other reasons, it is necessary that the stigma against cannabis
use be broken down. Doctors, patients, and the general population must come to understand
that cannabis has a place in healthcare institutions like hospitals and laboratories. If this
research does occur and reflects positively on medical cannabis, it is our hope that this product
will begin to see increased use where appropriate and also that it will be covered by provincial
and/or private insurance plans. Finally, patients must be reminded that the cannabis they buy
from local suppliers is not safe, and that they should seek medical avenues to safely obtain a
quality-controlled product.
This modern version of the Hippocratic Oath includes the following statement:

 I will remember that there is art to medicine as well as science, and that warmth,
sympathy, and understanding may outweigh the surgeon's knife or the chemist's drug.
 In using medical cannabis to help bring comfort to palliative patients we call upon
healthcare professionals to embrace both the science and the art of medicine.

REFERENCES
[1] Grant I, Atkinson JH, Gouaux B, Wilsey B. Medical marijuana: clearing away the smoke. Open Neurol
J 2012;6:18-25.
[2] Grotenhermen F, Muller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl
Int 2012;109(29-30):495-501.
[3] National Cancer Institute. Cannabis and cannabinoids - health professional version. National Cancer
Institute. URL: http://www.cancer.gov/about-cancer/treatment/cam/hp/cannabis-pdq.
 Medical cannabis and palliative care 231

[4] Korantzopoulos P, Liu T, Paruvartsapaioannides D, Li G, Goudevenos JA. Atrial fibrillation and

marijuana smoking. Int J Clin Pract 2008;62(2):308-313.
[5] Charuvastra A, Friedmann PD, Stein MD. Physician attitudes regarding the prescription of medical
marijuana. J Addict Dis 2005;24(3):87-93.
SECTION FIVE: ACKNOWLEDGMENTS
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 21

ABOUT THE EDITORS

Blair Henry, DBioethic is an Assistant Professor in the Department of Family and

Community Health at the University of Toronto. He is a Senior Ethicist at Sunnybrook Health
Sciences, a member of the hospital’s Quality Dying Initiatve and Advance Care Planning, and
has a special interest in end-of-life care. E-mail: blair.henry@sunnybrook.ca

Arnav Agarwal, BHSc, MD(C) is a third-year medical student at University of Toronto.

He has a special interest in clinical epidemiology, knowledge translation, guideline
development and health systems research, and has also been actively involved in end-of
-life care and palliative radiotherapy research for several years. E-mail: arnav.agarwal
@mail.utoronto.ca

Edward Chow, MBBS, MSc, PhD, FRCPC is Professor of Radiation Oncology at the
University of Toronto in Canada. He is the chair of the Rapid Response Radiotherapy Program
and Bone Metastases Site Group at the Odette Cancer Centre, Sunnybrook Health Sciences
Centre, Toronto, Canada and also a senior scientist at the Sunnybrook Research Institute. He
has published in the area of palliative radiotherapy and end of life care issues. E-mail:
Edward.Chow@sunnybrook.ca

Hatim A Omar, MD, FAAP, Professor of Pediatrics and Obstetrics and Gynecology;
Professor of Family Studies; and Chief of the Division of Adolescent Medicine, Department of
Pediatrics, University of Kentucky, Lexington. He is the holder of the Children’s Miracle
Network Endowed Chair in Pediatrics. Dr. Omar has completed residency training in obstetrics
and gynecology as well as pediatrics. He has also completed fellowships in vascular physiology
and adolescent medicine. Dr. Omar is the founder and chairman of the Stop Youth Suicide
Cmpaign. He is the recipient of the Commonwealth of Kentucky Governor’s Award for
community service and volunteerism in 2000, Kentucky Teen Pregnancy Coalition Award for
outstanding service 2002, Awards for suicide prevention from the Ohio Valley Society for
Adolescent Medicine and Kentucky Pediatric Society in 2005 and 2007, Sexual Abuse
Awareness Month Award for his work with sexual abuse victims from the Kentucky
Association of Sexual Assault Professionals in 2007, Special Achievement Award from the
American Academy of Pediatrics 2007 and the Founders of Adolescent Medicine Award from
236 Blair Henry, Arnav Agarwal, Edward Chow et al.

the AAP in 2007. He is well known internationally with numerous publications in child health,
public health, pediatrics, adolescent medicine, pediatric and adolescent gynecology. E-mail:
haomar2@uky.edu

Joav Merrick, MD, MMedSci, DMSc, born and educated in Denmark is professor of
pediatrics, child health and human development, Division of Pediatrics, Hadassah Hebrew
University Medical Center, Mt Scopus Campus, Jerusalem, Israel and Kentucky Children’s
Hospital, University of Kentucky, Lexington, Kentucky United States and professor of public
health at the Center for Healthy Development, School of Public Health, Georgia State
University, Atlanta, United States, the medical director of the Health Services, Division for
Intellectual and Developmental Disabilities, Ministry of Social Affairs and Social Services,
Jerusalem, the founder and director of the National Institute of Child Health and Human
Development in Israel. Numerous publications in the field of pediatrics, child health and human
development, rehabilitation, intellectual disability, disability, health, welfare, abuse, advocacy,
quality of life and prevention. Received the Peter Sabroe Child Award for outstanding work on
behalf of Danish Children in 1985 and the International LEGO-Prize (“The Children’s Nobel
Prize”) for an extraordinary contribution towards improvement in child welfare and well-being
in 1987. E-mail: jmerrick@zahav.net.il
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 22

ABOUT THE RAPID RESPONSE RADIOTHERAPY

PROGRAM AT THE ODETTE CANCER CENTRE,
SUNNYBROOK HEALTH SCIENCES CENTRE,
TORONTO, CANADA

The Odette Cancer Centre, the comprehensive cancer program of Sunnybrook Health Sciences
Centre is a leading regional cancer centre in Toronto, Ontario, Canada. It is the sixth largest
cancer centre in North America in terms of number of new cancer patients seen per year. The
Department of Radiation Oncology at Sunnybrook is an academic unit fully affiliated with the
University of Toronto. Palliative radiotherapy is one of the key research foci in the Department
of Radiation Oncology. The Rapid Response Radiotherapy Program (RRRP) is a specialized
clinic designed to provide timely palliative radiotherapy. The RRRP was developed in 1996,
and approximately 500-600 patients are seen in one year. This program aims to improve the
quality of life of palliative cancer patients, while decreasing wait time and allowing for same
day treatment.

Contact

Professor Edward Chow, MBBS, PhD, FRCPC, Department of Radiation Oncology, Odette
Cancer Centre, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario,
Canada M4N 3M5. E-mail: Edward.Chow@sunnybrook.ca
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 23

ABOUT THE NATIONAL INSTITUTE OF CHILD

HEALTH AND HUMAN DEVELOPMENT IN ISRAEL

The National Institute of Child Health and Human Development (NICHD) in Israel was
established in 1998 as a virtual institute under the auspices of the Medical Director, Ministry
of Social Affairs and Social Services in order to function as the research arm for the Office of
the Medical Director. In 1998 the National Council for Child Health and Pediatrics, Ministry
of Health and in 1999 the Director General and Deputy Director General of the Ministry of
Health endorsed the establishment of the NICHD.

Mission

The mission of a National Institute for Child Health and Human Development in Israel is to
provide an academic focal point for the scholarly interdisciplinary study of child life, health,
public health, welfare, disability, rehabilitation, intellectual disability and related aspects of
human development. This mission includes research, teaching, clinical work, information and
public service activities in the field of child health and human development.

Service and academic activities

Over the years many activities became focused in the south of Israel due to collaboration with
various professionals at the Faculty of Health Sciences (FOHS) at the Ben Gurion University
of the Negev (BGU). Since 2000 an affiliation with the Zusman Child Development Center at
the Pediatric Division of Soroka University Medical Center has resulted in collaboration around
the establishment of the Down Syndrome Clinic at that center. In 2002 a full course on
“Disability” was established at the Recanati School for Allied Professions in the Community,
FOHS, BGU and in 2005 collaboration was started with the Primary Care Unit of the faculty
and disability became part of the master of public health course on “Children and society”. In
the academic year 2005-2006 a one semester course on “Aging with disability” was started as
part of the master of science program in gerontology in our collaboration with the Center for
Multidisciplinary Research in Aging. In 2010 collaborations with the Division of Pediatrics,
Hadassah Hebrew University Medical Center, Jerusalem, Israel around the National Down
240 Blair Henry, Arnav Agarwal, Edward Chow et al.

Syndrome Center and teaching students and residents about intellectual and developmental
disabilities as part of their training at this campus.

Research activities

The affiliated staff have over the years published work from projects and research activities in
this national and international collaboration. In the year 2000 the International Journal of
Adolescent Medicine and Health and in 2005 the International Journal on Disability and Human
Development of De Gruyter Publishing House (Berlin and New York) were affiliated with the
National Institute of Child Health and Human Development. From 2008 also the International
Journal of Child Health and Human Development (Nova Science, New York), the International
Journal of Child and Adolescent Health (Nova Science) and the Journal of Pain Management
(Nova Science) affiliated and from 2009 the International Public Health Journal (Nova Science)
and Journal of Alternative Medicine Research (Nova Science). All peer-reviewed international
journals.

National collaborations

Nationally the NICHD works in collaboration with the Faculty of Health Sciences, Ben Gurion
University of the Negev; Department of Physical Therapy, Sackler School of Medicine, Tel
Aviv University; Autism Center, Assaf HaRofeh Medical Center; National Rett and PKU
Centers at Chaim Sheba Medical Center, Tel HaShomer; Department of Physiotherapy, Haifa
University; Department of Education, Bar Ilan University, Ramat Gan, Faculty of Social
Sciences and Health Sciences; College of Judea and Samaria in Ariel and in 2011 affiliation
with Center for Pediatric Chronic Diseases and National Center for Down Syndrome,
Department of Pediatrics, Hadassah Hebrew University Medical Center, Mount Scopus
Campus, Jerusalem.

International collaborations

Internationally with the Department of Disability and Human Development, College of Applied
Health Sciences, University of Illinois at Chicago; Strong Center for Developmental
Disabilities, Golisano Children's Hospital at Strong, University of Rochester School of
Medicine and Dentistry, New York; Centre on Intellectual Disabilities, University of Albany,
New York; Centre for Chronic Disease Prevention and Control, Health Canada, Ottawa;
Chandler Medical Center and Children’s Hospital, Kentucky Children’s Hospital, Section of
Adolescent Medicine, University of Kentucky, Lexington; Chronic Disease Prevention and
Control Research Center, Baylor College of Medicine, Houston, Texas; Division of
Neuroscience, Department of Psychiatry, Columbia University, New York; Institute for the
Study of Disadvantage and Disability, Atlanta; Center for Autism and Related Disorders,
Department Psychiatry, Children’s Hospital Boston, Boston; Department of Pediatric and
Adolescent Medicine, Western Michigan University Homer Stryker MD School of Medicine,
Kalamazoo, Michigan, United States; Department of Paediatrics, Child Health and Adolescent
Medicine, Children's Hospital at Westmead, Westmead, Australia; International Centre for the
 About the National Institute of Child Health and Human Development, Israel 241

Study of Occupational and Mental Health, Düsseldorf, Germany; Centre for Advanced Studies
in Nursing, Department of General Practice and Primary Care, University of Aberdeen,
Aberdeen, United Kingdom; Quality of Life Research Center, Copenhagen, Denmark; Nordic
School of Public Health, Gottenburg, Sweden, Scandinavian Institute of Quality of Working
Life, Oslo, Norway; The Department of Applied Social Sciences (APSS) of The Hong Kong
Polytechnic University Hong Kong.

Targets

Our focus is on research, international collaborations, clinical work, teaching and policy in
health, disability and human development and to establish the NICHD as a permanent institute
in Israel in order to conduct model research and together with the four university schools of
public health/medicine in Israel establish a national master and doctoral program in disability
and human development at the institute to secure the next generation of professionals working
in this often non-prestigious/low-status field of work.

Contact

Joav Merrick, MD, MMedSci, DMSc

Professor of Pediatrics
Medical Director, Health Services, Division for Intellectual and Developmental Disabilities,
Ministry of Social Affairs and Social Services, POB 1260, IL-91012 Jerusalem, Israel.
E-mail: jmerrick@zahav.net.il
In: Cannabis: Medical Aspects ISBN: 978-1-53610-510-0
Editors: B. Henry, A. Agarwal, E. Chow et al. © 2017 Nova Science Publishers, Inc.

Chapter 24

ABOUT THE BOOK SERIES “HEALTH AND

HUMAN DEVELOPMENT”

Health and human development is a book series with publications from a multidisciplinary
group of researchers, practitioners and clinicians for an international professional forum
interested in the broad spectrum of health and human development. Books already published:

 Merrick J, Omar HA, eds. Adolescent behavior research. International perspectives.

New York: Nova Science, 2007.
 Kratky KW. Complementary medicine systems: Comparison and integration. New
York: Nova Science, 2008.
 Schofield P, Merrick J, eds. Pain in children and youth. New York: Nova Science, 2009.
 Greydanus DE, Patel DR, Pratt HD, Calles Jr JL, eds. Behavioral pediatrics, 3 ed. New
York: Nova Science, 2009.
 Ventegodt S, Merrick J, eds. Meaningful work: Research in quality of working life. New
York: Nova Science, 2009.
 Omar HA, Greydanus DE, Patel DR, Merrick J, eds. Obesity and adolescence. A public
health concern. New York: Nova Science, 2009.
 Lieberman A, Merrick J, eds. Poverty and children. A public health concern. New York:
Nova Science, 2009.
 Goodbread J. Living on the edge. The mythical, spiritual and philosophical roots of
social marginality. New York: Nova Science, 2009.
 Bennett DL, Towns S, Elliot E, Merrick J, eds. Challenges in adolescent health: An
Australian perspective. New York: Nova Science, 2009.
 Schofield P, Merrick J, eds. Children and pain. New York: Nova Science, 2009.
 Sher L, Kandel I, Merrick J, eds. Alcohol-related cognitive disorders: Research and
clinical perspectives. New York: Nova Science, 2009.
 Anyanwu EC. Advances in environmental health effects of toxigenic mold and
mycotoxins. New York: Nova Science, 2009.
 Bell E, Merrick J, eds. Rural child health. International aspects. New York: Nova
Science, 2009.
 Dubowitz H, Merrick J, eds. International aspects of child abuse and neglect. New York:
Nova Science, 2010.
 Shahtahmasebi S, Berridge D. Conceptualizing behavior: A practical guide to data
analysis. New York: Nova Science, 2010.
244 Blair Henry, Arnav Agarwal, Edward Chow et al.

 Wernik U. Chance action and therapy. The playful way of changing. New York: Nova
Science, 2010.
 Omar HA, Greydanus DE, Patel DR, Merrick J, eds. Adolescence and chronic illness. A
public health concern. New York: Nova Science, 2010.
 Patel DR, Greydanus DE, Omar HA, Merrick J, eds. Adolescence and sports. New York:
Nova Science, 2010.
 Shek DTL, Ma HK, Merrick J, eds. Positive youth development: Evaluation and future
directions in a Chinese context. New York: Nova Science, 2010.
 Shek DTL, Ma HK, Merrick J, eds. Positive youth development: Implementation of a
youth program in a Chinese context. New York: Nova Science, 2010.
 Omar HA, Greydanus DE, Tsitsika AK, Patel DR, Merrick J, eds. Pediatric and
adolescent sexuality and gynecology: Principles for the primary care clinician. New
York: Nova Science, 2010.
 Chow E, Merrick J, eds. Advanced cancer. Pain and quality of life. New York: Nova
Science, 2010.
 Latzer Y, Merrick, J, Stein D, eds. Understanding eating disorders. Integrating culture,
psychology and biology. New York: Nova Science, 2010.
 Sahgal A, Chow E, Merrick J, eds. Bone and brain metastases: Advances in research and
treatment. New York: Nova Science, 2010.
 Postolache TT, Merrick J, eds. Environment, mood disorders and suicide. New York:
Nova Science, 2010.
 Maharajh HD, Merrick J, eds. Social and cultural psychiatry experience from the
Caribbean Region. New York: Nova Science, 2010.
 Mirsky J. Narratives and meanings of migration. New York: Nova Science, 2010.
 Harvey PW. Self-management and the health care consumer. New York: Nova Science,
2011.
 Ventegodt S, Merrick J. Sexology from a holistic point of view. New York: Nova
Science, 2011.
 Ventegodt S, Merrick J. Principles of holistic psychiatry: A textbook on holistic
medicine for mental disorders. New York: Nova Science, 2011.
 Greydanus DE, Calles Jr JL, Patel DR, Nazeer A, Merrick J, eds. Clinical aspects of
psychopharmacology in childhood and adolescence. New York: Nova Science, 2011.
 Bell E, Seidel BM, Merrick J, eds. Climate change and rural child health. New York:
Nova Science, 2011.
 Bell E, Zimitat C, Merrick J, eds. Rural medical education: Practical strategies. New
York: Nova Science, 2011.
 Latzer Y, Tzischinsky. The dance of sleeping and eating among adolescents: Normal
and pathological perspectives. New York: Nova Science, 2011.
 Deshmukh VD. The astonishing brain and holistic consciousness: Neuroscience and
Vedanta perspectives. New York: Nova Science, 2011.
 Bell E, Westert GP, Merrick J, eds. Translational research for primary healthcare. New
York: Nova Science, 2011.
 Shek DTL, Sun RCF, Merrick J, eds. Drug abuse in Hong Kong: Development and
evaluation of a prevention program. New York: Nova Science, 2011.
 Ventegodt S, Hermansen TD, Merrick J. Human Development: Biology from a holistic
point of view. New York: Nova Science, 2011.
 Ventegodt S, Merrick J. Our search for meaning in life. New York: Nova Science, 2011.
 Caron RM, Merrick J, eds. Building community capacity: Minority and immigrant
populations. New York: Nova Science, 2012.
 About the Book Series “Health and Human Development” 245

 Klein H, Merrick J, eds. Human immunodeficiency virus (HIV) research: Social science
aspects. New York: Nova Science, 2012.
 Lutzker JR, Merrick J, eds. Applied public health: Examining multifaceted Social or
ecological problems and child maltreatment. New York: Nova Science, 2012.
 Chemtob D, Merrick J, eds. AIDS and tuberculosis: Public health aspects. New York:
Nova Science, 2012.
 Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine:
Basic principles of healing in traditional Hippocratic medicine. New York: Nova
Science, 2012.
 Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine:
Holistic practice of traditional Hippocratic medicine. New York: Nova Science, 2012.
 Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine:
Healing the mind in traditional Hippocratic medicine. New York: Nova Science, 2012.
 Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine:
Sexology and traditional Hippocratic medicine. New York: Nova Science, 2012.
 Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine:
Research, philosophy, economy and politics of traditional Hippocratic medicine. New
York: Nova Science, 2012.
 Caron RM, Merrick J, eds. Building community capacity: Skills and principles. New
York: Nova Science, 2012.
 Lemal M, Merrick J, eds. Health risk communication. New York: Nova Science, 2012.
 Ventegodt S, Merrick J. Textbook on evidence-based holistic mind-body medicine:
Basic philosophy and ethics of traditional Hippocratic medicine. New York: Nova
Science, 2013.
 Caron RM, Merrick J, eds. Building community capacity: Case examples from around
the world. New York: Nova Science, 2013.
 Steele RE. Managed care in a public setting. New York: Nova Science, 2013.
 Srabstein JC, Merrick J, eds. Bullying: A public health concern. New York: Nova
Science, 2013.
 Pulenzas N, Lechner B, Thavarajah N, Chow E, Merrick J, eds. Advanced cancer:
Managing symptoms and quality of life. New York: Nova Science, 2013.
 Stein D, Latzer Y, eds. Treatment and recovery of eating disorders. New York: Nova
Science, 2013.
 Sun J, Buys N, Merrick J. Health promotion: Community singing as a vehicle to promote
health. New York: Nova Science, 2013.
 Pulenzas N, Lechner B, Thavarajah N, Chow E, Merrick J, eds. Advanced cancer:
Managing symptoms and quality of life. New York: Nova Science, 2013.
 Sun J, Buys N, Merrick J. Health promotion: Strengthening positive health and
preventing disease. New York: Nova Science, 2013.
 Merrick J, Israeli S, eds. Food, nutrition and eating behavior. New York: Nova Science,
2013.
 Shahtahmasebi S, Merrick J. Suicide from a public health perspective.
New York: Nova Science, 2014.
 Merrick J, Tenenbaum A, eds. Public health concern: Smoking, alcohol and substance
use. New York: Nova Science, 2014.
 Merrick J, Aspler S, Morad M, eds. Mental health from an international perspective.
New York: Nova Science, 2014.
 Merrick J, ed. India: Health and human development aspects. New York: Nova Science,
2014.
246 Blair Henry, Arnav Agarwal, Edward Chow et al.

 Caron R, Merrick J, eds. Public health: Improving health via inter-professional

collaborations. New York: Nova Science, 2014.
 Merrick J, ed. Pain Management Yearbook 2014. New York: Nova Science, 2015.
 Merrick J, ed. Public Health Yearbook 2014. New York: Nova Science, 2015.
 Sher L, Merrick J, eds. Forensic psychiatry: A public health perspective. New York:
Nova Science, 2015.
 Shek DTL, Wu FKY, Merrick J, eds. Leadership and service learning education: Holistic
development for Chinese university students. New York: Nova Science, 2015.
 Calles JL, Greydanus DE, Merrick J, eds. Mental and holistic health: Some international
perspectives. New York: Nova Science, 2015.
 Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J,
eds. Cancer: Treatment, decision making and quality of life. New York: Nova Science,
2016.
 Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J,
eds. Cancer: Pain and symptom management. New York: Nova Science, 2016.
 Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J,
eds. Cancer: Bone metastases, CNS metastases and pathological fractures. New York:
Nova Science, 2016.
 Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J,
eds. Cancer: Spinal cord, lung, breast, cervical, prostate, head and neck cancer. New
York: Nova Science, 2016.
 Lechner B, Chow R, Pulenzas N, Popovic M, Zhang N, Zhang X, Chow E, Merrick J,
eds. Cancer: Survival, quality of life and ethical implications. New York: Nova Science,
2016.
 Davidovitch N, Gross Z, Ribakov Y, Slobodianiuk A, eds. Quality, mobility and
globalization in the higher education system: A comparative look at the challenges of
academic teaching. New York: Nova Science, 2016.

Contact

Professor Joav Merrick, MD, MMedSci, DMSc

Medical Director, Health Services
Division for Intellectual and Developmental Disabilities
Ministry of Social Affairs and Social Services
POBox 1260, IL-91012 Jerusalem, Israel
E-mail: jmerrick@zahav.net.il
SECTION SIX: INDEX
 INDEX

advocacy, xix, 111, 236

A Africa, 18
African Americans, 31, 41, 56, 218
abstraction, 156
agencies, 213, 216, 217
abuse, 10, 12, 25, 32, 33, 35, 37, 41, 43, 46, 50, 51,
aggression, 42, 57, 209
53, 54, 57, 60, 65, 69, 90, 143, 148, 149, 182,
aggressive behavior, 210
184, 191, 199, 202, 203, 212, 213, 219, 236, 244
aging process, 79
academic performance, 213, 216, 218
agonist, 32, 46, 47, 67, 74, 100, 106, 191, 198
access, xviii, 12, 86, 100, 101, 103, 106, 109, 110,
AIDS, xix, 34, 48, 49, 100, 114, 117, 123, 126, 128,
129, 131, 141, 182, 183, 200, 201, 223, 224
148, 182, 221, 222, 245
Access to Cannabis for Medical Purposes
airway inflammation, 38
Regulations (ACMPR), xviii, xix, 200, 201
Alaska, 28, 101
acetaminophen, 145
alcohol abuse, 31
acetylcholine, 74, 81, 192
alcohol consumption, 88, 213
acid, 11, 22, 25, 28, 32, 48, 50, 67, 68, 72, 74, 79,
alcohol use, 31, 218, 219
191, 192, 210
algorithm, 54, 82, 103, 192
acquired immunodeficiency syndrome, 128, 148
alkaloids, 7
active compound, 77, 101
allele, 22
acute lung injury, 38, 54
ALS, 48, 149
acute renal failure, 69
alternative medicine, 153
additives, 30, 35
alveolar macrophage, 38
adenocarcinoma, 8, 9
American Psychiatric Association, 41, 42, 51
adenosine, 38, 54, 75, 81
amino, 33, 67
ADHD, 41, 56, 181, 186
amputation, 58
adipose tissue, 32, 68
amygdala, 32, 42
adolescents, 16, 29, 41, 42, 43, 45, 46, 47, 50, 51, 56,
amyloidosis, 8
57, 58, 59, 60, 65, 146, 179, 180, 181, 182, 183,
amyotrophic lateral sclerosis, 148, 149
184, 185, 186, 201, 209, 211, 212, 213, 216, 217,
anabolic steroids, 124
218, 244
analgesic, 10, 18, 19, 20, 24, 66, 78, 82, 130, 140,
adrenal insufficiency, 114
145, 155, 156, 174, 175, 176, 178, 190, 192, 193,
adulthood, 31, 41, 45, 56, 218
206, 222
adults, 31, 34, 111, 146, 148, 184, 185
anemia, 9
adverse effects, 12, 23, 24, 27, 28, 35, 36, 37, 38, 39,
anesthesiologist, 60, 196
40, 45, 47, 48, 69, 76, 100, 102, 103, 121, 138,
aneurysm, 8
144, 145, 149, 152, 174, 175, 176, 180, 192, 194,
anger, 42, 209
207, 208, 209
angina, 39
adverse event, 102, 123, 158, 159, 161, 163, 164,
angiogenesis, 33
166, 167, 171, 173, 174, 175, 176, 191, 195
250 Index

Angola, 18 authorities, 48, 190

anorexia, xiv, 32, 34, 100, 113, 114, 115, 116, 117, autonomy, 199, 200, 203, 204, 227, 230
118, 120, 124, 125, 126, 127, 128, 182, 222, 228 avoidance behavior, 45
antagonism, 74, 80 awareness, 215
antibiotic, 16, 18
anti-cancer, 122
anticonvulsant, 18, 151, 222
B
antidepressant, 78, 127, 131
back pain, 97, 180, 183
antiemetics, 37, 107, 108, 110, 201
bacteria, 77
antiepileptic drugs, 16
barriers, xviii, 101, 115, 182, 222, 223
anti-inflammatory agents, 124
basal ganglia, 33, 67, 106
antioxidant, 8, 78, 82
base, 179, 203
antipsychotic, 31, 46, 58, 151
behavioral change, 142
antipsychotic effect, 31, 58
behavioral disorders, 60
antisocial personality, 42
behaviors, 60, 102, 184, 185, 197, 212, 213, 215, 218
antisocial personality disorder, 42
Belgium, 30
anti-spasmodic, 66
beneficial effect, 120, 151
anxiety, 10, 18, 23, 26, 31, 32, 34, 35, 37, 40, 42, 52,
benefits, 11, 14, 18, 28, 33, 34, 48, 95, 109, 110,
66, 69, 76, 81, 86, 88, 91, 105, 109, 110, 163,
122, 123, 125, 149, 152, 176, 180, 201, 202, 207,
181, 183, 191, 193, 208, 209, 212, 213, 218, 223,
208, 209, 213, 230
228
benign, 27, 33, 44
APA, 42
bioactive agents, 8
apoptosis, 7, 8
bioavailability, 24, 47, 67, 71, 75, 76, 77, 81, 121,
appetite, 49, 85, 86, 88, 89, 91, 97, 99, 105, 106,
194
109, 110, 113, 114, 115, 116, 117, 118, 119, 120,
biochemistry, 77
121, 122, 123, 124, 125, 126, 127, 128, 130, 148,
biodiversity, 4
201, 208, 209, 222
biological samples, 70
appointments, 190
biomolecules, 78
Argentina, 182
biosynthesis, 72
Armenia, 29, 30
biosynthetic pathways, 4, 22
arousal, 31
bipolar disorder, 8
arrest, 59
blends, 35, 53
arrhythmias, 39
blood pressure, 31, 39, 40, 51
arteries, 33
blood stream, 68, 78
arthritis, 105, 109, 183
body composition, 124
ascorbic acid, 78
body fat, 35, 69
aspergillosis, 38, 54
body mass index (BMI), 122, 124, 128
assault, 193
body weight, 117, 118, 127, 128
assessment, 15, 46, 57, 81, 117, 124, 135, 180, 185,
bone, 7, 9, 87, 88, 97, 99
186, 215, 216, 217
boredom, 44
assets, 111
bowel, 88, 97
assimilation, 68
brachial plexus, 174
asthma, 18, 19, 36, 208
brain, 12, 32, 33, 34, 35, 40, 41, 43, 44, 51, 52, 56,
astrocytoma, 9
57, 58, 66, 67, 68, 74, 78, 81, 97, 99, 102, 106,
ataxia, 42
121, 130, 179, 181, 192, 208, 244
atherosclerosis, 34
branching, 78
athletes, 40
Brazil, 18
atmosphere, 207
breakdown, 132
atrophy, 8
breast cancer, 7, 52, 87, 190
attitudes, 101, 111, 231
breast milk, 68
Austria, 30, 173
breathing, 12
 Index 251

breeding, 17, 20, 23, 24, 66 cardiovascular diseases, 14, 79

bronchitis, 18, 36, 37, 38, 181, 208 cardiovascular function, 55, 99
bronchodilator, 78 cardiovascular risk, 128
bronchospasm, 37 cardiovascular system, 55
Buddhism, 18 Caribbean, 244
building blocks, 77 carpal tunnel syndrome, xix
Bulgaria, 30 case study, 139, 140
Bulimia, xix causal relationship, 203, 208
CBC, 72
CDC, 29
C cell death, 6, 52
cell membranes, 78
cachexia, xiv, 34, 113, 114, 115, 116, 117, 120, 122,
central nervous system (CNS), 20, 31, 33, 43, 106,
123, 124, 125, 126, 127, 128, 130, 148, 149, 228
114, 178
calcium, 66, 74
cerebellum, 33, 43, 67, 106
caloric intake, 127, 128
cerebral cortex, 32, 106
calorie, 117, 124
certification, 147, 149, 152
Canadian Medical Protective Association (CMPA),
challenges, 14, 20, 50, 52, 54, 127, 185, 217, 246
xix, 206
chemical, 8, 9, 12, 15, 20, 25, 28, 34, 35, 70, 77, 78,
cancer, xiv, xix, 7, 8, 12, 15, 33, 34, 38, 39, 48, 49,
80, 99, 147, 190
52, 79, 85, 86, 87, 88, 90, 91, 93, 100, 105, 108,
chemotherapy, xiv, 6, 7, 34, 100, 105, 106, 107, 108,
109, 111, 113, 114, 115, 116, 117, 118, 119, 120,
109, 110, 111, 114, 120, 122, 126, 127, 130, 148,
121, 122, 123, 124, 125, 126, 127, 128, 141, 145,
174, 177, 180, 182, 222
146, 148, 149, 156, 163, 174, 177, 180, 182, 184,
chemotherapy-induced nausea, 100, 105, 106, 107,
197, 198, 200, 201, 222, 229, 230, 237, 244, 245
108, 110, 111, 114, 126, 148
candidates, 4, 5
Chicago, 240
cannabidiol (CBD), 6, 7, 22, 31, 32, 34, 38, 44, 46,
child abuse, 243
47, 51, 52, 53, 54, 58, 65, 66, 70, 72, 75, 76, 77,
child maltreatment, 245
81, 82, 96, 97, 99, 100, 101, 102, 106, 119, 120,
childhood, 31, 42, 51, 57, 212, 218, 224, 244
126, 130, 151, 152, 153, 158, 159, 160, 161, 162,
children, 10, 58, 87, 180, 182, 183, 184, 185, 201,
163, 164, 165, 168, 174, 177, 178, 192, 193, 194,
216, 219, 243
196, 228
China, 10, 17, 25, 92
cannabinoids, 3, 16, 20, 22, 24, 25, 26, 27, 28, 31,
chloral, 11, 19
32, 33, 35, 37, 39, 40, 42, 43, 48, 49, 51, 52, 53,
cholangiocarcinoma, 87
55, 56, 57, 60, 61, 65, 66, 67, 68, 69, 70, 71, 72,
choline, 6
73, 76, 77, 78, 79, 80, 81, 92, 99, 100, 101, 102,
chorea, 49
106, 107, 108, 110, 111, 115, 116, 120, 121, 126,
chromatographic technique, 68
127, 128, 130, 131, 132, 140, 144, 145, 146, 147,
chromatography, 36, 68, 70, 151
148, 149, 151, 152, 153, 156, 161, 174, 175, 177,
chronic illness, 222, 244
180, 182, 185, 191, 192, 193, 195, 196, 197, 202,
chronic lymphocytic leukemia, 9
204, 224, 230
chronic obstructive pulmonary disease, 208
cannabinol (CBN), 31, 32, 53, 66, 70, 99, 100, 192
cigarette smokers, 38, 58
Cannabis sativa, 6, 7, 16, 25, 27, 28, 31, 48, 50, 51,
circulation, 42, 68, 76, 209
53, 65, 66, 72, 74, 78, 79, 80, 82, 100, 126, 130,
citizens, 19
147, 149
Civil War, 10
capsule, 10, 34, 107, 119, 122, 148
civilization, 3
carbon dioxide, 130, 150
clarity, 228
carbon monoxide, 23, 38, 110, 130, 142
classes, 32, 99, 130, 162, 190
carboxylic acid, 72
classification, 122, 126, 213
carcinogen, 31, 38
classroom, 215
carcinogenicity, 55
clients, 205
cardiovascular disease, 8, 9, 14, 15, 39, 79
252 Index

climate, 222 connective tissue, 87, 88

clinical application, 124 connectivity, 41, 56, 102, 103, 218
clinical symptoms, 24, 79 consciousness, 36, 54, 244
clinical syndrome, 117 consensus, 122, 124, 126, 189, 191, 196, 197
clinical trials, xviii, 5, 8, 9, 11, 75, 100, 107, 110, consent, 182, 202, 216
111, 113, 115, 120, 121, 125, 140, 141, 143, 179, constipation, 86
180, 196, 222 constituents, 9, 27, 76, 77, 78, 79, 80, 102, 121, 144,
cloning, 80 197
CNS, 31, 32, 33, 40, 41, 43, 44, 45, 51, 52, 59, 60, consumers, 44, 48, 88, 192
192, 246 consumption, 23, 24, 27, 30, 31, 36, 38, 39, 40, 42,
CO2, 147, 150 44, 45, 48, 54, 55, 71, 72, 75, 81, 88, 90, 117,
cocaine, 28, 30, 31, 39, 41, 43, 51, 54, 55, 57, 60 130, 140, 142, 150, 194, 195, 218, 221, 222, 223
cocaine abuse, 41 contingency, 45, 59
cognition, 8, 37, 40, 56, 66 control group, 135, 141
cognitive ability, 212 controlled studies, 123, 125
cognitive dysfunction, 192, 194 controlled trials, 49, 103, 110, 129, 143, 145, 155,
cognitive function, 40, 106, 181, 212 156, 190, 228
cognitive impairment, 9, 44, 69, 142, 212 controversial, 27, 28, 38, 48, 85, 86, 179
cognitive performance, 142 controversies, 15
cognitive-behavioral therapy, 45 COOH, 36
colitis, 48 cooking, 23
collaboration, 216, 217, 239, 240 coordination, 181
college students, 31 COPD, 38
Colombia, 182 coronary artery disease, 9
colorectal cancer, 8, 124, 128 coronary heart disease, 39, 55
combination therapy, 123, 126, 128 correlation, 69, 123, 137, 174
combustion, xviii, 23, 24, 110, 121, 130, 142 correlations, 169
commercial, 29, 86, 106 cortex, 66
common symptoms, 123 corticosteroids, 12, 124
communication, 101, 216, 217 cough, 10, 19, 36, 37, 38, 54, 114, 208
community, xix, 18, 46, 121, 200, 201, 202, 203, counseling, 45, 109, 114, 122, 127
215, 217, 218, 219, 227, 230, 235, 244, 245 CPT, 135, 136
community service, 235 craving, 43, 46, 210
comorbidity, 50, 124 criminal behavior, 181, 212
compassion, 18, 92 Croatia, 15, 30, 182
complexity, 32 crop, 18
compliance, 24, 131, 143 cues, 133, 142
complications, 20, 30, 103, 207 cultivars, 20, 79, 96, 97
composition, 12, 26, 126, 222 cultivation, 17, 66
compounds, 4, 7, 10, 11, 20, 22, 23, 48, 52, 65, 66, cultural norms, 228
67, 69, 72, 76, 77, 78, 79, 82, 99, 121, 130, 190 cultural practices, 17
comprehension, 212 culture, 10, 244
concussion, 97 cure, xviii, xix, 15, 19, 227, 229
conduct disorder, 42, 45 curriculum, 216
conference, 224 cystic fibrosis, 8
confidentiality, 95 CYT, 56, 220
configuration, 79 cytochrome, 70, 76, 122
congestive heart failure, 39, 181 cytokines, 10, 114, 123
Congress, xii Czech Republic, 29, 30, 182
conjugation, 69
conjunctiva, 36
 Index 253

District of Columbia, 182

D divergent thinking, 58
diversity, 7
damages, xii, 77
dizziness, 23, 107, 108, 137, 138, 163, 168, 174,
dance, 96, 244
175, 228
danger, 35
DNA, 77
data analysis, 56, 218, 243
doctors, xix, 3, 33, 206, 228, 229, 230
data collection, 214
dominant allele, 22
database, xvii, 132
Dominican Republic, 182
DEA, 28, 108
dopamine, 40, 43, 47, 57, 67, 74, 80, 81, 106
deaths, 14, 16, 124
doping, 40, 56
defects, 40, 44
dosage, 81, 96, 121, 132, 139, 152, 153, 222
deficiency, 58
dose-response relationship, 131, 132, 139, 143
deficit, 41, 51
dosing, xiv, 23, 24, 75, 99, 101, 102, 113, 123, 125,
Delta, 6, 26, 50, 51, 57, 60, 81, 127
129, 130, 131, 132, 133, 136, 137, 139, 141, 143,
delta 9-tetrahydrocannabinol (δ-9THC), 57, 65, 66,
144, 146, 147, 148, 149, 152, 174, 189, 190, 192,
67
197
delusional thinking, 44
double blind study, 178
Denmark, 166, 236, 241
draft, 205
dental caries, 37
drug abuse, 32, 33, 45, 47, 51, 213, 217, 219, 220
Department of Education, 219, 240
drug addict, 43, 44, 45, 47, 60
Department of Justice, 103, 111, 145, 196, 206
drug consumption, 59
depersonalization, 42, 56
drug delivery, 121
deposits, 17
drug dependence, 41, 44, 138
depression, 8, 32, 37, 40, 42, 44, 47, 56, 57, 67, 86,
drug discovery, 4, 14
88, 91, 97, 191, 208, 212, 213, 215, 218, 223, 228
Drug Enforcement Administration (DEA), 182
depth, 67, 92
drug interaction, 46, 82, 109
deregulation, 89
drug metabolism, 31
derivatives, 11, 32, 33, 48, 55, 60, 79, 155, 179
drug reactions, 16
desensitization, 198
drug targets, 51, 82, 114
detainees, 218
drug testing, 35
detectable, 23, 75, 100
drug treatment, 68, 216
detection, 35, 68, 69, 151, 213, 219
drugs, 4, 5, 7, 9, 15, 16, 24, 27, 29, 30, 31, 33, 35,
detoxification, 196, 198
36, 39, 40, 42, 43, 45, 46, 47, 48, 51, 52, 53, 59,
developing brain, 40, 52, 208
69, 75, 76, 78, 88, 92, 99, 101, 103, 108, 110,
developmental disorder, 41
111, 130, 137, 148, 179, 184, 204, 207, 213, 215,
diabetes, 9, 78, 197
217, 219, 221, 223, 224, 229
diabetic nephropathy, 8
Diagnostic and Statistical Manual of Mental
diabetic neuropathy, 139, 145, 190, 196
Disorders (DSM-IV-TR), 41, 42, 51
diagnostic criteria, 122
dysphoria, 142, 181
diarrhea, 7, 34, 89, 181
dysplasia, 38
diet, 128, 140
dyspnea, 88, 89
disability, 236, 239, 241
dystonia, 34, 49
discomfort, 101
discrimination, 223
disease activity, 195 E
disease progression, 122
diseases, xviii, 7, 18, 19, 33, 78, 125, 149, 195 eating disorders, 244, 245
disequilibrium, 209 ecstasy, 59
disorder, 34, 41, 42, 45, 49, 51, 56, 57, 59, 60, 92, edema, 7, 18, 89
219 education, 14, 24, 44, 45, 149, 212, 213, 215, 244,
distribution, 80, 86, 100, 109, 183, 192 246
254 Index

educational attainment, 56, 218 evidence-based policy, 203

educational settings, 219 evidence-based program, 217
EEG activity, 36 evolution, xix, 4
Egypt, 10 excitation, 33
election, 223 exclusion, 113, 115, 116, 185
electrocardiogram, 55 excretion, 40, 67, 69
electron, 78 executive functioning, 40, 181, 186
eligibility criteria, 131, 155, 156 exercise, 40
emergency, 194 exocytosis, 80
emotional distress, 223 exposure, 23, 24, 36, 37, 38, 40, 54, 56, 59, 60, 69,
emotional state, 100 78, 103, 121, 127, 139, 142, 169, 204, 206, 209
emphysema, 38 external environment, 4
employment, 68 extraction, 24, 86, 115, 125, 131, 150
empowerment, 229 extracts, 3, 4, 5, 7, 14, 19, 24, 76, 77, 81, 82, 96, 103,
encephalopathy, 191 117, 121, 130, 131, 149, 150, 155, 174, 177
encoding, 22 exudate, 29
encouragement, 45, 217 eye movement, 36
Endocannabinoids, 10, 32, 33, 52, 67, 74, 126, 197
endocrine, 33, 207, 208
endorphins, 10
F
endothelial dysfunction, 9
families, 46, 79, 213, 219, 227, 229
energy, 78, 80, 96, 126
family history, 45
England, 4
family physician, 200
enkephalins, 10
family therapy, 45, 59
environment, 114, 139, 143, 213, 223
farmers, 33
environmental conditions, 31
fat, 42, 74, 114, 124
environmental factors, 32
fear, 34, 37, 42, 53, 229
enzyme, 22, 28, 48, 50, 68, 70, 75, 76, 77, 78, 79,
feces, 35, 68
122
Federal Government, 221, 222
ependymoma, 9
federal law, 28, 182
epidemiologic, 39
feelings, 31, 34
epidemiology, 55, 70, 144, 185, 235
female partner, 218
epilepsy, 16, 18, 25, 33, 34, 48, 49, 52, 105, 109,
fertilization, 31
148, 149, 179, 201, 222
fever, 11, 18, 140
Epstein-Barr virus, 8
fiber, 3, 11, 20, 41
Estonia, 30
fibrillation, 231
ethical implications, 246
fibromyalgia, 8, 12, 105, 109, 156, 175, 178, 180
ethical issues, 199, 200
fibrosis, 80, 96
ethics, xiv, 187, 193, 206, 245
Finland, 30, 182
ethnicity, 51, 69
fires, 150
etiology, 39
fiscal year, 50
euphoria, 14, 28, 29, 44, 114, 138, 140, 142, 207,
flame, 151
208
flavonoids, 101
Europe, 19, 29, 174, 182
flax fiber, 52
European market, 47
flexibility, 202
European Union, 7
flora, 4
evidence, xviii, 10, 12, 17, 19, 38, 39, 46, 53, 55, 57,
flora and fauna, 4
75, 76, 81, 100, 105, 108, 110, 115, 123, 124,
flowers, 28, 66, 78, 121, 147, 149
130, 131, 138, 139, 141, 144, 145, 151, 153, 156,
fluid, 70, 150
176, 180, 184, 190, 191, 194, 196, 197, 201, 202,
food, 3, 15, 18, 29, 96, 114, 117, 119, 120, 123, 127,
203, 205, 212, 214, 217, 219, 224, 228, 229, 245
150
 Index 255

Food and Drug Administration (FDA), 5, 7, 46, 54, guidelines, 101, 105, 110, 121, 124, 141, 151, 179,
108, 147, 148, 149, 151, 152, 182, 184 180, 185, 189, 190, 196, 197, 199, 206
food intake, 114, 119, 120, 123, 127 guilt, 101
formaldehyde, 30 gynecomastia, 208
formation, 81, 192
fractures, 246
France, 4, 30, 182, 218
H
free radicals, 78
hair, 36, 53, 68, 70
freedom, 18
half-life, 67
frontal cortex, 57
hallucinations, 35, 37, 44
functional MRI, 44
happiness, 18
fusion, 80
harmful effects, 150, 204
hazards, 55, 142
G head and neck cancer, 93, 128, 246
headache, 7, 136, 139, 180, 183
GABA, 67, 80, 106, 192 health care, 4, 25, 81, 92, 101, 102, 144, 193, 197,
galactorrhea, 208 206, 224, 244
gastric mucosa, 80 health care professionals, 25, 81, 102, 144, 197, 224
gastroesophageal reflux, 36 health condition, 27, 28, 65, 66, 147, 179
gastrointestinal tract, 24, 32, 33, 37, 140 health effects, 52, 181, 184, 209, 223, 243
gender differences, 109 health problems, 27, 28, 185, 218
gene expression, 23 health risks, 14, 185
gene promoter, 23 heart disease, 9, 12, 39
generalizability, 91, 141 heart failure, 9
genetic factors, 31, 45 heart rate, 39, 40, 228
genus, 72, 99, 179 height, 97
Georgia, xvii, 27, 107, 236 hematology, 180, 185
Germany, 4, 7, 30, 161, 182, 241 hematopoietic system, 99
germination, 35 hemoglobin, 228
gerontology, 239 hemorrhoids, 86
gestational diabetes, 9 hemp, 16, 19, 20, 25, 28, 31, 79, 80, 121, 125, 147,
glaucoma, 34, 148, 149, 201, 222 197, 221
Glioblastoma, 9 hepatitis, 148, 149
global markets, 15 herbal medicine, 15, 77
globalization, 246 heroin, 10, 11, 28, 41, 42, 44, 59
glucose, 208 heterogeneity, 40
glutamate, 47, 67, 74, 80, 192 high school, 29, 181, 207, 208, 212, 214, 216, 218,
glycerol, 28, 32 219
glycol, 23 higher education, 246
glycoproteins, 77 high-risk populations, 184
goal attainment, 220 hippocampus, 32, 33, 41, 42, 47, 57, 66, 106, 197
gonorrhea, 19 historical overview, 14
gout, 7, 18, 86 history, xvii, xix, 3, 14, 15, 17, 24, 39, 40, 42, 45, 72,
governance, 215 88, 102, 114, 130, 137, 140, 143, 190, 221, 224
Greece, 10, 30 HIV, 7, 34, 49, 82, 105, 109, 115, 123, 124, 126,
Greeks, 86, 92 127, 128, 134, 135, 137, 138, 141, 143, 145, 149,
growth, 4, 8, 33, 53, 59, 114, 208 156, 158, 159, 175, 178, 180, 190, 194, 196, 201,
guardian, 18, 182 245
guessing, 141 holistic medicine, 244
guidance, xix, 26, 96, 199, 205, 206, 219 Hong Kong, 241, 244
hormone, 47, 208
256 Index

hospitalization, 39, 212, 213, 216 inflammatory bowel disease, 34, 49, 52, 195, 198
host, 208, 209 inflammatory disease, 77
House, 177, 240 inflammatory responses, 106
human body, 10, 71, 99 influenza, 8
human brain, 58 informed consent, xix
human development, xv, 236, 239, 241, 243, 245 ingestion, 23, 24, 35, 36, 39, 65, 67, 75, 76, 109,
human immunodeficiency virus, 148 120, 121, 140, 146, 147, 155, 157, 194, 208
human subjects, 44 ingredients, 3
Hungary, 15, 30 inheritance, 20, 25
hydrocarbons, 77 inhibition, 5, 8, 9, 31, 33, 51, 66, 74, 80, 106, 130,
hydrogen, 78 192, 197
hyperactivity, 40, 41, 51 inhibitor, 6, 7, 8, 9, 48
hyperemesis, 37, 54, 102, 103, 181, 209, 210 initiation, 31, 44, 51, 59, 60, 191, 198, 205, 218
hyperinflation, 38 injections, 197
hypertension, 8, 9, 33 injuries, 9, 10, 40, 55, 97
hypodermic needles, xvii, 11 injury, xii, 8, 34, 38, 39, 50, 96, 97
hypothalamus, 43, 106, 114, 209 insects, 77
hypothesis, 57 insomnia, 46, 76, 86, 193, 209, 228
institutions, 200, 205, 230
insulin, 9
I insulin resistance, 9
integration, 17, 114, 243
IBD, 49, 195
interference, 40
Iceland, 30
International Olympic Committee, 40
ideals, 50, 192
interneurons, 32
identification, 20, 36, 43, 48, 213, 219
intervention, 50, 52, 59, 120, 121, 122, 124, 125,
idiosyncratic, 36, 217
128, 129, 131, 135, 137, 138, 140, 141, 143, 144,
illicit drug use, 50, 219
145, 155, 156, 212, 213, 214, 219
illicit substances, 184
intoxication, 35, 40, 42, 46, 53, 78, 181
immune function, 15, 99
intraocular pressure, 31, 34, 222
immune system, 33, 67, 74, 81, 106, 140
intravenous fluids, 37
immunity, 14
ion channels, 67, 77, 78
immunodeficiency, 245
ionization, 151
immunosuppression, 81
Iran, 25, 29, 51, 70, 81, 127
improvements, 95, 109
Ireland, 4, 30
impulsivity, 40
iris, 197
impurities, 35
irradiation, 78
in vitro, 4, 69, 78, 81, 229
irritability, 42, 181, 209
in vivo, 58, 70, 74, 80
irritable bowel syndrome, 8, 49
incidence, 31, 123, 174, 181
isolation, 7, 11, 43, 114
India, 10, 15, 18, 19, 25, 92, 182, 245
Israel, xv, xvii, xviii, 27, 33, 111, 116, 179, 182, 236,
individual differences, 101
239, 241, 246
individuality, 4
issues, 11, 15, 121, 138, 184, 199, 200, 203, 208,
individuals, 19, 22, 24, 34, 44, 45, 47, 49, 109, 135,
209, 212, 213, 215, 223, 228, 229, 235
137, 139, 141, 150, 153, 174, 181, 182, 193, 200,
Italy, 30, 182
201, 202, 203, 208, 211, 223
inducer, 6
induction, 8 J
industry, 14, 82, 99, 101, 102
infection, 38, 127, 128 Jamaica, 182
inflammation, 8, 9, 10, 11, 19, 34, 54, 97, 99, 130, Japan, 28
140 joints, 38
 Index 257

Jordan, xiv, 105 lymphoma, 120, 180

jurisdiction, 205 lysergic acid diethylamide, 30

K M

keratosis, 6 machinery, 80
kidney, 8, 10 macrophages, 67
major depression, 56, 57
major depressive disorder, 40
L majority, 42, 68, 86, 87, 88, 91, 92, 101, 102, 108,
109, 120, 143, 156, 174, 176, 182, 213, 216, 223,
labeling, 109, 147, 151
228
landscape, 53, 199, 200
malaria, 18, 77
lateral sclerosis, 48
malignancy, 88
Latvia, 30
malignant tumors, 180
law enforcement, 42, 101
management, xix, 3, 10, 14, 15, 27, 32, 33, 34, 36,
laws, 28, 103, 111, 145, 179, 182, 183, 186, 196,
41, 42, 44, 45, 46, 47, 48, 51, 53, 59, 85, 86, 92,
203, 206, 224
95, 96, 97, 108, 109, 110, 113, 114, 129, 132,
lean body mass, 114, 124
140, 149, 177, 180, 189, 191, 197, 199, 200, 201,
learning, 100, 106, 212, 213, 246
219, 228, 229, 244, 246
learning difficulties, 213
manipulation, 32
legality, 85, 86
manufacturing, 35
legislation, 19, 100, 105, 109, 110, 179, 180, 182,
Marihuana, 25, 29, 49, 81, 90, 92, 100, 102, 103,
184, 186, 189, 199, 200, 202, 204, 205, 206
111, 125, 127, 131, 144, 145, 189, 190, 191, 192,
lesions, 37, 38, 181
193, 194, 195, 196, 197, 199, 200, 201, 206, 210,
leukemia, 9, 54, 180
221, 222, 224
liberty, 206, 229
Marihuana for Medicinal Purposes Regulations
libido, 208
(MMPR), 100, 106, 125, 131, 144, 189, 190, 193,
lifetime, 29, 195
199, 200, 222, 223
light, 8, 12, 106, 194, 209
marijuana, xiii, xiv, xvii, xviii, xix, 16, 25, 27, 28,
Likert scale, 173
29, 30, 31, 33, 37, 38, 39, 40, 41, 42, 43, 44, 46,
limbic system, 32, 33
47, 49, 50, 51, 52, 53, 54, 55, 56, 60, 61, 65, 70,
lipid metabolism, 9
79, 80, 81, 92, 99, 100, 102, 103, 111, 113, 114,
lipids, 78
116, 120, 121, 124, 125, 127, 128, 130, 132, 144,
liquid chromatography, 35, 53, 60, 68, 152
145, 146, 147, 148, 149, 150, 151, 152, 153, 156,
lithium, 48
178, 179, 180, 181, 182, 183, 184, 185, 186, 195,
Lithuania, 30
197, 200, 202, 206, 207, 208, 209, 210, 211, 212,
liver disease, 9, 12, 16, 102, 103
213, 214, 215, 216, 217, 218, 219, 221, 222, 223,
liver transplant, 196, 198
224, 225, 230, 231
local anesthetic, 37
marketing, 107
locus, 22, 199, 200
mass spectrometry, 36, 53, 68, 70
longitudinal study, 124, 218
mastectomy, 190
loss of appetite, 49, 97
materials, 142
low risk, 14, 65, 141, 207
matter, xii, 38, 41, 55, 150, 151, 181, 206
LSD, 30
measurement, 12
lumbar spine, 96
media, 27, 28, 145, 224, 229
lung cancer, 8, 9, 39, 55, 85, 87, 128, 208, 228
median, 90, 173
lung disease, 210
medical, xiii, xiv, xvii, xviii, xix, 3, 10, 11, 12, 14,
lung function, 54
16, 17, 18, 19, 21, 23, 24, 25, 27, 28, 29, 33, 41,
luteinizing hormone, 35
48, 49, 50, 61, 69, 81, 85, 86, 87, 90, 91, 92, 95,
lymphocytes, 114
97, 99, 100, 101, 102, 103, 105, 106, 107, 108,
258 Index

109, 110, 111, 114, 119, 120, 121, 127, 128, 129, metabolizing, 48
130,131, 136, 139, 141, 144, 145, 146, 147, 148, metastasis, 33
149, 150, 151, 152, 153, 179, 180, 181, 182, 183, methadone, 191
184, 185, 186, 189, 190, 191, 192, 193, 194, 195, methamphetamine, 28, 31, 45, 59
196, 198, 199, 200, 201, 202, 206, 209, 221, 222, methodology, 24, 115, 125, 131
223, 224, 225, 227, 228, 229, 230, 231, 235, 236, methyl groups, 78
244 methylation, 58
medical cannabis, xiii, xiv, xvii, xviii, xix, 14, 16, metropolitan areas, 152
17, 23, 28, 33, 48, 49, 60, 81, 85, 86, 87, 90, 91, Mexico, 19, 107
92, 95, 97, 99, 100, 101, 102, 103, 105, 106, 107, mice, 74, 78, 81, 82, 127
108, 109, 110, 111, 119, 127, 129, 130, 131, 136, microdialysis, 80
139, 141, 144, 150, 151, 153, 179, 180, 182, 183, microsomes, 70
184, 185, 186,189, 192, 195, 196, 198, 199, 200, middle class, 224
206, 223, 227, 228, 229, 230 Middle East, 4
Medical Marihuana, 189, 190, 191, 192, 193, 194, migraine headache, 97, 136, 139, 146
196, 201, 221, 222, 224 migraines, 19
Medical marijuana, xiv, xvii, xviii, xix, 16, 49, 50, migration, 67, 78, 244
53, 61, 92, 103, 111, 113, 120, 145, 146, 147, military, 53
148, 149, 151, 152, 153, 179, 180, 182, 183, 184, milligrams, 193, 195
185, 186, 206, 209, 221, 224, 225, 230, 231 mind-body, 245
medication, xvii, 5, 11, 12, 14, 16, 19, 24, 33, 47, 57, minority groups, 19
93, 109, 125, 140, 142, 149, 162, 180, 183, 227, mission, 239
230 misuse, 16, 51, 179, 185, 186, 199, 202
medicine, xvii, 3, 4, 5, 7, 11, 12, 14, 15, 18, 19, 24, mixing, 130
25, 26, 37, 50, 76, 92, 102, 103, 108, 111, 127, MMS, 25, 81, 127
177, 221, 222, 223, 224, 227, 228, 229, 230, 235, models, 52, 56, 131, 161, 219
241, 243, 245 moderators, 59
Mediterranean, xix, 15, 18, 140 mold, 243
medulla, 106 molecular biology, 4
melanoma, 87, 88 molecules, 32, 77, 78, 79, 130
mellitus, 9 Montana, 183, 186
membranes, 78 mood change, 120
memory, 9, 14, 32, 34, 40, 53, 56, 66, 100, 106, 120, mood disorder, 109, 140, 244
181, 217 morbidity, 77, 120, 128, 145
meningitis, 16 morphine, xvii, 10, 12, 130, 136, 139, 140, 195, 197,
mental disorder, 51, 56, 59, 219, 244 198
mental health, 42, 45, 59, 88, 103, 109, 184, 212, mortality, 3, 16, 34, 36, 39, 77, 114, 120, 128, 145,
213, 217, 218, 219, 223 181, 203, 206, 223
mental health professionals, 217 motivation, 44, 218
mental illness, 46 motor skills, 181
Mesopotamia, 4, 10 movement disorders, 49
meta-analysis, 55, 56, 61, 92, 102, 103, 126, 145, mucosa, 37, 181
146, 180, 185, 218 multidimensional, 45, 59
metabolic changes, 114 multiple sclerosis, 7, 33, 34, 48, 49, 52, 100, 103,
metabolic disorders, 197 114, 126, 146, 148, 149, 151, 153, 156, 168, 174,
metabolic syndrome, 9 175, 177, 178, 180, 182, 197
metabolism, 14, 25, 65, 66, 67, 69, 70, 76, 78, 81, muscle mass, 124
101, 121, 127, 142 muscle spasms, 19, 86, 228
metabolites, 4, 22, 35, 60, 68, 69, 71, 72, 76, 77, 79, muscular dystrophy, 8
137 musculoskeletal, 130, 180
metabolized, 68, 69, 101, 122 mutant, 22
 Index 259

mutilation, 43 Nobel Prize, 236

mycotoxins, 243 nonsmokers, 55, 58
myocardial infarction, 39, 55, 69, 181 non-steroidal anti-inflammatory drugs, 131
norepinephrine, 191
North America, 19, 223, 237
N Norway, 30, 241
NRS, 162
naming, 99, 101, 102
nucleus, 45, 47
nanoparticles, 7
null, 22
narcotics, 19, 221, 227, 228, 230
nurses, 133
nasopharyngeal carcinoma, 8
nutrition, 78, 124, 245
National Survey, 183
nutritional state, 114, 124, 127
natural compound, 7, 82
nystagmus, 42
natural killer cell, 106, 114
nausea, xiv, 7, 34, 36, 37, 49, 85, 86, 88, 91, 95, 97,
100, 105, 106, 107, 108, 109, 110, 111, 114, 115, O
126, 130, 148, 149, 174, 181, 182, 183, 193, 201,
209, 228 Obama administration, xviii, xix
negative attitudes, 181 obesity, 8, 9, 47, 128
negative effects, 36, 41, 121, 201, 203, 215 obsessive-compulsive disorder, 34
negative experiences, 229 obstacles, 11
negative outcomes, 139, 202, 213, 216 obstruction, 38
neglect, 243 obstructive lung disease, 38, 55
neoplasm, 115, 116 officials, 42
nervous system, 10, 47, 80, 130, 162 oil, 18, 23, 24, 28, 29, 33, 66, 82, 96, 120, 122, 129,
Netherlands, 30, 182 130, 131, 140, 142, 143, 147, 150, 151, 152, 192,
neural development, 130 200
neuralgia, 5 olanzapine, 60
neurobiology, 57, 58 oligospermia, 181
neurodegeneration, 78 operations, 10
neuroimaging, 40, 56, 57, 58 opiate addiction, 10
neurological disease, 52 opiates, 15, 19
neurons, 66 opioids, xvii, 3, 10, 12, 14, 15, 30, 67, 131, 139, 183,
Neuropathic pain, 6, 7, 8, 33, 34, 49, 100, 126, 130, 184, 191, 194, 195, 198, 203, 221, 229
134, 135, 136, 137, 138, 139, 143, 145, 146, 155, opportunities, 102, 197, 216
163, 167, 168, 172, 174, 175, 176, 177, 178, 180, oral health, 54
189, 190, 191, 194, 196, 197, 201, 222 organic compounds, 4, 77
neuropathy, 8, 12, 134, 135, 136, 137, 138, 141, 143, organism, 4
145, 156, 174, 175, 178, 180, 190, 194, 196 organs, 10, 35, 74, 78, 162
neuropeptides, 43 orthostatic hypotension, 39
neuropharmacology, 80 osteoporosis, 8
neuroprotection, 33 outpatient, xiii, 85, 86, 90, 135, 212, 214, 216, 217
neurotransmission, 47, 80 oxidation, 68, 69, 77, 78, 100
neurotransmitter, 20, 32, 33, 40, 43, 67, 74, 78, 106, oxidative damage, 78
192 oxidative stress, 9, 79
neutral, 39, 72 oxygen, 78
New Zealand, 7
next generation, 241
NHS, 59
P
nicotine, 30, 40, 43, 46, 47, 58, 223
Pacific, 7
nitric oxide, 38
paclitaxel, 7
NMR, 79
260 Index

pain management, 3, 10, 12, 14, 97, 103, 131, 140 pharmacology, xiii, 53, 60, 63, 70, 80, 81, 102, 114,
pain perception, 60, 66, 114, 137, 170 115, 117, 131
pain tolerance, 137, 139 pharmacotherapy, 16, 46, 126, 180
paints, 109 pharyngitis, 36
palliate, 127 phencyclidine, 28, 30, 42
palliative, xiii, xiv, 49, 61, 85, 86, 90, 91, 92, 93, phenotype, 20, 25
120, 123, 125, 205, 227, 228, 229, 230, 235, 237 phenotypes, 22, 25, 80
pancreas, 88 Philadelphia, 15, 25
pancreatitis, 36, 49, 54, 195 physical activity, 36
panic attack, 42, 208 physical health, 109, 212
panic disorder, 34 physicians, xix, 10, 11, 19, 108, 131, 141, 147, 148,
parallel, 126, 177, 178 149, 179, 189, 190, 193, 199, 200, 201, 202, 205,
paranoia, 23, 35, 43, 44, 76, 208 206, 222, 223, 227, 230
parental involvement, 214, 215 physiological factors, 67
parent-child relationship, 215, 218 physiology, 72, 79, 97, 102, 235
parenting, 215 Phyto-cannabinoids, 66
parents, 40, 45, 56, 59, 213, 214, 215, 216, 217, 219 pilot study, 26, 57, 111, 118, 120, 127, 145, 177
paresthesias, 190 PKU, 240
partial seizure, 52 placebo, 52, 81, 107, 108, 117, 118, 119, 120, 123,
participants, 49, 91, 110, 123, 124, 133, 137, 138, 126, 127, 128, 131, 134, 135, 136, 137, 138, 140,
139, 140, 141, 143, 162, 175, 180 141, 143, 145, 146, 156, 158, 159, 160, 161, 162,
password, 86 163, 164, 165, 166, 167, 168, 169, 170, 171, 172,
patents, 193, 194 173, 174, 175, 176, 177, 178, 180, 190, 194, 195,
pathogenesis, 126 196
pathophysiology, 114, 128 placenta, 68
pathways, 8, 22, 47, 57, 69, 72, 77, 125, 130 plants, 3, 4, 5, 7, 12, 14, 15, 17, 18, 20, 25, 53, 72,
patient care, 95, 228 77, 78, 82, 99, 149, 150, 151, 190
PCP, 30, 42 plaque, 8, 9
PCR, 23, 36, 53 plasma levels, 76, 140, 142
pediatrician, 219 plasticity, 40
peer group, 45, 46 playing, 18
peer influence, 219 plexus, 177
peptides, 10, 15 PM, 69, 185, 217, 218
perforation, 36 pneumonia, 181
perinatal, 40 pneumothorax, 38
periodontal, 37, 181 Poland, 30
periodontal disease, 37, 181 policy, xiv, 16, 24, 52, 71, 90, 180, 184, 186, 199,
peripheral nervous system, 10, 20, 66, 74 200, 201, 202, 203, 204, 205, 206, 223, 224, 241
peripheral neuropathy, 16, 177, 180 policy issues, 199
peripheral vascular disease, 181 policy makers, 71
peritonitis, 36 policy options, 204
permeation, 81 politics, 206, 224, 245
permission, xii, 37, 221, 222 pollen, 17
permit, 119 pollination, 20
personal history, 228 polycyclic aromatic hydrocarbon, 23, 38
pharmaceutical, 4, 5, 7, 14, 34, 78, 82, 96, 99, 100, polymorphism, 43
174, 180 polymorphisms, 16
pharmacokinetics, 25, 50, 52, 75, 76, 78, 81, 101, polyphenols, 77
109, 127, 128, 145, 194, 197, 198 polyunsaturated fat, 128
pharmacological treatment, 180, 197 polyunsaturated fatty acids, 128
 Index 261

population, 40, 44, 51, 55, 90, 91, 92, 120, 123, 124, psychological dependence, 101
146, 176, 179, 183, 184, 204, 207, 208, 209, 213, psychological stress, 45
215, 230 psychological withdrawal, 209
Portugal, 30 psychologist, 216
positive correlation, 117, 121 psychology, 244
positive mood, 47 psychopharmacology, 51, 57, 244
positive reinforcement, 142 psychosis, 8, 35, 37, 43, 44, 45, 47, 48, 50, 58, 69,
positron, 56 102, 103, 161, 208, 212, 219
positron emission tomography, 56 psychosomatic, 5
posttraumatic stress, 34, 49, 60 psychotic symptoms, 43, 44
post-traumatic stress disorder (PTSD) , 34, 48, 49, psychotropic drugs, 53
96, 105, 201 public health, 48, 60, 144, 145, 184, 206, 224, 227,
potassium, 66, 67 230, 236, 239, 241, 243, 244, 245, 246
potential benefits, 33 public opinion, 109
precipitation, 37 public safety, 101, 223
predators, 4, 77 public service, 239
prefrontal cortex, 32, 43, 57, 80, 208 Puerto Rico, 182
preparation, xii, 11, 109, 151 purity, 222
prescription drug abuse, 223 pyrolysis, 23, 75, 76, 121
prescription drugs, 11, 31, 46, 184
prevention, 10, 15, 44, 45, 46, 59, 146, 212, 213,
214, 215, 216, 217, 219, 235, 236, 244
Q
principles, 45, 199, 200, 202, 203, 245
quality control, 131
problem behavior, 216
quality of life, 14, 95, 96, 97, 114, 120, 122, 127,
problem solving, 208
128, 191, 236, 237, 244, 245, 246
procurement, 223
quality of service, 186
producers, 49, 86, 91, 100, 106, 129, 131, 141, 189,
query, xviii, 50
190, 192, 193, 194
questionnaire, 217
professionals, 213, 215, 216, 217, 228, 229, 230,
239, 241
prognosis, 86 R
pro-inflammatory, 74, 114
project, 86 radiation, 8, 118, 122, 222
prolactin, 208 Radiation, 235, 237
proliferation, xix, 32 radiation therapy, 8, 122, 222
promoter, 58 radical formation, 5
propagation, 12, 16, 20 radiotherapy, 235, 237
prophylaxis, 139 rating scale, 138, 146, 162, 180
propylene, 23 reaction time, 40, 181
prosocial behavior, 216 reactions, 35, 37, 77
prostaglandins, 67, 130 reactive oxygen, 78
prostate cancer, 8, 9, 87 reality, 142, 208
prostate carcinoma, 34 reasoning, 212
protection, 77, 79 receptors, 6, 10, 15, 20, 28, 32, 33, 35, 41, 48, 65,
protective factors, 213, 219 66, 67, 69, 70, 72, 74, 77, 78, 80, 81, 99, 100,
proteins, 77 106, 114, 121, 130, 191, 192, 198
PSA, 197 reciprocity, 199, 200, 203, 204
psoriasis, 8, 9 recognition, 53, 199, 219
psychiatric disorders, 32, 40, 41, 45, 56, 58, 102, 153 recommendations, xii, xix, 100, 130, 141, 142, 143,
psychiatry, 51, 244, 246 146, 181
psychoactive drug, xviii, 150 recovery, 37, 216, 245
262 Index

recreational, xvii, 10, 19, 20, 25, 33, 53, 65, 66, 88, salicylates, 10
90, 101, 102, 105, 109, 114, 130, 147, 148, 149, saliva, 36, 68
151, 175, 181, 184, 185, 193, 205, 207, 209, 223, sample survey, 108
224, 229 sanctions, 221, 222
recruiting, 8, 9 scaling, 220
redistribution, 68 schizophrenia, 8, 34, 43, 44, 47, 48, 52, 58, 59, 179,
reflexes, 37 181, 208, 223
reform, 33, 70, 223 schizotypy, 58
Registry, 186 school, xiv, 29, 37, 40, 45, 46, 59, 179, 181, 207,
regulations, xviii, xix, 90, 91, 103, 106, 111, 141, 209, 211, 212, 213, 214, 215, 216, 217, 218, 219,
145, 183, 189, 200, 206, 222, 224 241
rehabilitation, 220, 236, 239 school performance, 181, 212
reinforcement, 57, 102, 197 school psychology, 219
relaxation, 142, 183 science, 12, 25, 82, 92, 145, 153, 186, 219, 230, 239,
relevance, 14, 73, 124, 128, 155, 174, 176 245
relief, 7, 14, 23, 24, 49, 76, 85, 86, 97, 107, 110, 126, scleroderma, 96
129, 134, 135, 137, 138, 139, 141, 142, 143, 144, sclerosis, 52, 135, 157, 162, 178, 222
164, 170, 177, 178, 183, 200, 222, 228 scope, 125, 131, 201
REM, 36 second hand smoke, 203, 204, 205
remission, 8 secretion, 208
renal failure, 191 security, 190, 199, 200
repressor, 22 sedative, 19, 20, 30, 66, 78
reproduction, 4 seedlings, 35, 53
reputation, 115, 117 seizure, 114
requirements, 23, 24, 140, 191, 195, 219 selective serotonin reuptake inhibitor, 191
researchers, xviii, 31, 71, 72, 124, 141, 243 self-regulation, 121
resistance, 23, 38, 39, 77, 78 self-report data, 29
resolution, 3 sellers, 35
resources, 4, 213, 223, 230 sensation, 106, 137, 218
respiratory problems, 10 sensation seeking, 218
response, 51, 74, 82, 91, 108, 127, 132, 143, 148, sensations, 96
160, 162, 163, 164, 165, 169, 193, 219 sensitivity, 69, 137, 195, 198, 218
restrictions, 71, 203 sensor, 10
retail, 35 sensory experience, 142
rheumatic fever, 11 serotonin, 67, 70, 106, 191
rheumatoid arthritis, 16, 34, 100, 103, 180, 195 serum, 192, 193
ribosomes, 77 services, xii, 50, 212, 213, 214, 216, 217
risk, 12, 14, 16, 23, 24, 27, 28, 31, 38, 39, 40, 41, 42, sesquiterpenoid, 78
43, 44, 45, 47, 51, 55, 58, 69, 93, 103, 120, 138, sewage, 29, 50
143, 147, 152, 179, 182, 183, 184, 185, 186, 191, sex, 69, 208, 212, 218
201, 204, 208, 211, 213, 215, 216, 218, 219, 223, sexual abuse, 235
230, 245 sexual behavior, 218
RNA, 77 sexual health, 37, 50
Romania, 30, 182 sexual intercourse, 97
Russia, 30 sexuality, 244
shape, 181
short-term memory, 41, 78, 208
S showing, 14, 124, 176
sickle cell, 195
safety, 5, 49, 52, 61, 91, 99, 102, 103, 109, 110, 123,
side chain, 72
128, 153, 155, 156, 177, 182, 202, 205, 227, 228,
230
 Index 263

side effects, 3, 11, 12, 14, 36, 51, 114, 120, 137, 143, stroke, 33, 181
155, 156, 176, 181, 192, 194, 196, 203, 209, 228 structure, 8, 9, 35, 55, 58, 70, 71, 79, 218, 229
signalling, 99 substance abuse, 41, 51, 93, 143, 186, 212, 216, 219
signs, 31, 215 substance use, 16, 40, 42, 56, 57, 59, 60, 91, 92, 183,
silk, 150 212, 218, 219, 245
sinusitis, 36 substance use disorders, 16, 40, 56, 57, 60
skeletal muscle, 114 substitution, 23
skeleton, 80 substrates, 77
skin, 190 suicidal ideation, 69
sleep deprivation, 96 suicide, 44, 45, 47, 58, 215, 223, 225, 235, 244
smoking, 10, 23, 27, 31, 35, 36, 38, 39, 40, 42, 44, suicide rate, 223
45, 46, 48, 51, 54, 55, 75, 76, 81, 88, 96, 103, supervision, 45, 143
109, 110, 121, 123, 129, 130, 131, 133, 137, 138, suppliers, 33, 230
140, 142, 147, 150, 152, 175, 176, 181, 194, 199, supply chain, 33
200, 201, 202, 203, 204, 208, 209, 211, 222, 231 suppository, 24
social anxiety, 34, 45, 59 suppression, 33, 35, 36, 114
social behavior, 47 survival, 4, 127
social change, 211 susceptibility, 41
social interaction, 67 Sweden, 30, 161, 241
social situations, 45 sweeteners, 23
society, 45, 217, 223, 229, 239 swelling, 208
solubility, 24, 77 Switzerland, 30, 116
solvents, 150, 151 sympathy, 230
somnolence, 137, 139 symptoms, xix, 23, 39, 42, 44, 49, 53, 55, 57, 77, 85,
South America, 18 88, 89, 91, 92, 95, 96, 97, 99, 100, 122, 124, 127,
Southeast Asia, 51 140, 177, 179, 181, 195, 200, 201, 208, 209, 213,
Spain, 182 218, 227, 228, 229, 245
spastic, 157 synaptic plasticity, 100
spasticity, 7, 26, 49, 52, 100, 103, 114, 135, 137, synaptic transmission, 197
138, 146, 148, 149, 151, 178, 180, 182, 201, 222 syndrome, 8, 9, 34, 37, 39, 42, 48, 49, 54, 55, 57, 58,
species, 4, 5, 7, 20, 53, 71, 74, 78, 147, 148, 149, 152 60, 96, 97, 102, 103, 114, 115, 123, 124, 126,
spinal cord, 67, 106, 145, 177 127, 128, 148, 149, 181, 209, 210
spinal cord injury, 145, 177 synergistic effect, 77
spleen, 67, 68 synthesis, 22, 79, 113, 125, 130
Spring, 100, 205 Synthetic cannabinoids, 35, 53, 66, 69, 70, 107, 108,
squamous cell, 38, 54 111, 131, 182, 192, 193, 196, 204
squamous cell carcinoma, 38, 54 synthetic opioids, xvii
stability, 224
standardization, 109, 124, 125
starvation, 122
T
states, 11, 18, 28, 29, 105, 109, 145, 147, 148, 149,
T lymphocytes, 106
179, 182, 183, 186, 190, 203, 207, 209, 223
tachycardia, 37, 181, 208
stigma, 99, 101, 102, 109, 202, 230
tar, 38, 110, 130
stigmatized, 103, 111, 202
target, 16, 32, 78, 122, 126, 213, 214, 215, 216
stimulation, 74, 91, 114, 116, 118, 120, 123, 125,
taxonomy, 102
126, 127, 130, 148, 201
teachers, 215, 219
stimulus, 137
techniques, 12, 20, 23, 36, 45, 48, 66, 68
stomach, 19, 24, 74, 75
technologies, xviii
storage, 4, 35, 72, 79, 199, 202, 224
technology, 82
stress, 46, 48, 53, 78, 96, 100, 105, 106
teens, 184, 207
striatum, 32, 57
telephone, 45, 59, 149
264 Index

temperature, 31, 110 transportation, 190

temporal lobe, 52 trauma, 138, 156
tension, 204 treaties, 70
terminal illness, 227 tremor, 49
terpenes, 71, 77, 78, 79 trial, 8, 9, 11, 52, 59, 102, 107, 108, 118, 119, 120,
territorial, 199 122, 123, 127, 128, 133, 134, 135, 137, 143, 145,
testing, xviii, 35, 36, 53, 143, 174, 223 146, 172, 177, 178, 191, 192, 194, 196
testis, 80 tricyclic antidepressants, 191
testosterone, 35, 181, 208, 210 triggers, 46
tetanus, 19, 125 tuberculosis, 38, 245
texture, 150 tumor, 52, 114, 116, 118, 122, 228, 229
Thailand, 82 tumors, 8
therapeutic benefits, xviii, 110, 130 twins, 59
therapeutic effects, 51, 106, 114, 194 type 2 diabetes, 9
therapeutic goal, 203 tyrosine, 8
therapeutic relationship, 199, 200, 202, 204, 229
therapeutic targets, 81
therapeutic use, 5, 19, 25, 66, 68, 69, 70, 113, 115,
U
125, 131, 223
U.S. policy, 206
therapeutics, 15
Ukraine, 30
therapy, xix, 14, 16, 27, 45, 46, 47, 49, 52, 59, 82,
United Kingdom, 7, 30, 158, 159, 162, 163, 165,
99, 100, 109, 114, 122, 124, 139, 148, 149, 177,
168, 173, 182, 197, 218, 241
178, 180, 184, 191, 194, 196, 201, 205, 207, 222,
United Nations, xix, 15, 103
244
United States (USA) , xvii, xviii, 14, 15, 16, 19, 27,
thermoregulation, 209
28, 29, 47, 65, 69, 105, 109, 115, 116, 147, 151,
thoughts, 224
158, 159, 163, 169, 171, 172, 182, 183, 186, 196,
threats, 223
203, 206, 207, 211, 218, 224, 236, 240
thrombosis, 114
unmasking, 141
thrush, 89
urban, 218
thyroid, 36, 54, 208
urinalysis, 146
Tibet, 18, 25, 92
urinary dysfunction, 49, 100
time use, 12, 193
urine, 31, 35, 36, 39, 40, 68, 69, 70, 93, 143, 203
tincture, 96
Uruguay, 182
tissue, 3, 10, 32, 36, 42, 67, 68, 74
US Department of Health and Human Services, 219
titanium, 133, 143
utilization, 29, 69, 92, 179, 180, 182, 185
TNF-α, 75
tobacco, 10, 29, 31, 35, 36, 38, 44, 46, 51, 54, 55, 57,
59, 88, 142, 146, 150, 176, 200, 201, 204, 205, V
218, 222
tobacco smoke, 38, 88, 142, 205 vacuum, 151
toxic effect, 121 validation, 11, 16, 50, 53, 189
toxicity, 11, 14, 19, 82, 118, 120, 123, 223 vapor, 151
toxicology, 16, 25, 53, 70, 81, 127 vaporization, xviii, 23, 26, 96, 109, 111, 121, 145
trade, 18 variables, 91
trafficking, 223 varieties, 20, 33, 96
training, 109, 149, 235, 240 vascular system, 9
trait anxiety, 218 vasodilation, 228
traits, 20, 23, 24 vector, 128
translation, 6, 235 vegetables, 78
transmission, 43, 192 vehicles, 39
transport, 77 venlafaxine, 191
 Index 265

ventilation, 206 weight loss, 97, 105, 110, 113, 114, 115, 116, 117,
Venus, xiv, 211 118, 119, 120, 122, 126, 127, 128, 182, 209
vertebrates, 99, 114 weight reduction, 115
vesicle, 74 weight status, 124
victims, 193, 235 welfare, 236, 239
violent behavior, 37, 57 well-being, 95, 97, 218, 236
violent crime, 218, 223 Western Europe, 19
viscosity, 23 whiplash, xix
volunteerism, 235 white matter, 41, 45, 218
vomiting, xiv, 7, 34, 37, 100, 105, 106, 107, 108, withdrawal symptoms, 31, 35, 42, 43, 46, 57, 181,
109, 110, 111, 114, 115, 126, 130, 148, 174, 181, 196, 209
182, 209 workers, 202
vulnerability, 50, 227 working memory, 212
workplace, 202
World Anti-Doping Agency, 40
W World Bank, 16
World Health Organization (WHO), 4, 152, 193, 197
waiver, 202
worldwide, 11, 130, 207
walking, 97
war, 10
warts, 7 Y
Washington, 16, 25, 28, 51, 92, 219
waste water, 29 yield, 5, 20, 23, 122
water, 11, 24, 30, 37, 38, 54, 97, 124, 137, 150, 209 young adults, 16, 29, 36, 39, 42, 45, 47, 65, 128, 180,
weakness, 173, 181 185, 186, 201, 218
websites, 194 young people, 218
weight gain, 36, 120, 122, 123, 124 Youth program, 216