Journal of Dual Diagnosis

research and practice in substance abuse comorbidity

ISSN: 1550-4263 (Print) 1550-4271 (Online) Journal homepage: https://www.tandfonline.com/loi/wjdd20

Cannabis Use and the Risk of Psychosis and

Affective Disorders

Lucia Sideli, Harriet Quigley, Caterina La Cascia & Robin M. Murray

To cite this article: Lucia Sideli, Harriet Quigley, Caterina La Cascia & Robin M. Murray (2019):
Cannabis Use and the Risk of Psychosis and Affective Disorders, Journal of Dual Diagnosis, DOI:
10.1080/15504263.2019.1674991

To link to this article: https://doi.org/10.1080/15504263.2019.1674991

Published online: 24 Oct 2019.

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JOURNAL OF DUAL DIAGNOSIS
https://doi.org/10.1080/15504263.2019.1674991

Cannabis Use and the Risk of Psychosis and Affective Disorders

Lucia Sideli, PhDa,b , Harriet Quigley, MBBS, MRes, MRCPsycha,c , Caterina La Cascia, PhDb , and
Robin M. Murray, MD, FRSa,b,c
a
Institute of Psychiatry, Psychology, and Neuroscience, King’s College, London, UK; bDepartment of Biomedicine, Neurosciences, and
Advanced Diagnostic, University of Palermo, Palermo, Italy; cSouth London and Maudsley NHS Trust Biomedical Research Centre,
London, UK

ABSTRACT KEYWORDS
Objective: This review discusses the relationship between cannabis use and psychotic, bipo- Cannabis; marijuana;
lar, depressive, and anxiety disorders, as well as suicide. It summarizes epidemiological evi- psychosis; mania;
dence from cross-sectional and long-term prospective studies and considers possible depression; anxiety; brain
structure; genetic
etiological mechanisms. Methods: Systematic reviews and methodologically robust studies predisposition; early
in the field (from inception to February 2019) were identified using a comprehensive search adolescence; interaction
of Medline, PsychINFO, and Embase and summarized using a narrative synthesis. Results:
Consistent evidence, both from observational and experimental studies, has confirmed the
important role of cannabis use in the initiation and persistence of psychotic disorders. The
size of the effect is related to the extent of cannabis use, with greater risk for early cannabis
use and use of high-potency varieties and synthetic cannabinoids. Accumulating evidence
suggests that frequent cannabis use also increases the risk for mania as well as for suicide.
However, the effect on depression is less clear and findings on anxiety are contradictory
with only a few methodologically robust studies. Furthermore, the relationship with com-
mon mental disorders may involve reverse causality, as depression and anxiety are reported
to lead to greater cannabis consumption in some studies. Pathogenetic mechanisms focus
on the effect of tetrahydrocannabinol (THC, the main psychoactive ingredient of cannabis)
interacting with genetic predisposition and perhaps other environmental risk factors.
Cannabidiol (CBD), the other important ingredient of traditional cannabis, ameliorates the
psychotogenic effects of THC but is absent from the high-potency varieties that are increas-
ingly available. Conclusions: The evidence that heavy use of high-THC/low-CBD types of
cannabis increases the risk of psychosis is sufficiently strong to merit public health educa-
tion. Evidence of similar but smaller effects in mania and suicide is growing, but is not con-
vincing for depression and anxiety. There is much current interest in the possibility that
CBD may be therapeutically useful.

Introduction scientific research into the long-term effects of canna-

bis on psychiatric disorders plays little part in deter-
In all European countries, across all age groups, can-
mining public policy.
nabis is the most popular illicit substance; the overall
In this narrative review, we will briefly review the
prevalence of use is approximately five times that of
cannabis plant, the endocannabinoid system, and the
other substances (European Monitoring Centre for
changing nature of recreational cannabinoids before
Drugs & Drug Addiction, 2016). In Portugal, posses-
focusing on cannabis use and psychotic, depressive,
sion of small quantities of cannabis has been officially
decriminalized, while in the Netherlands cannabis can bipolar, and anxiety disorders.
be legally obtained in so-called “coffee shops.” In
many other countries such as the United Kingdom,
Methods
the police generally turn a blind eye to personal use.
Currently, several European countries are reviewing The summarized evidence here comes from systematic
their legislation, prompted by the liberalization in reviews and meta-analyses published in English from
North America. However, as in North America, inception to February 2019, which investigated the

CONTACT Lucia Sideli lucia.sideli@gmail.com Institute of Psychiatry, Psychology, and Neuroscience, King’s College, De Crespigny Park, London, SE5
8AF, UK.
ß 2019 Taylor & Francis Group, LLC
2 L. SIDELI ET AL.

effect of cannabis use or its active compounds on & Freund, 2012). It was initially thought that the CB2
psychotic, depressive, bipolar, and anxiety disorders. receptor was expressed solely in peripheral tissues and
The following keywords were used to screen Medline, immune cells (Piomelli, 2003); however, more recently
PsychINFO, and Embase: (cannabis OR hash OR it has also been found in the cerebellum and brain-
marijuana) AND (psychosis OR FEP OR depression stem. Other receptors have been found to be involved
OR bipolar OR mania OR suicide OR anxiety). in endocannabinoid signaling. These include orphan
We sought to describe the detrimental effects of G protein-coupled receptors GPR119 (expressed pre-
cannabis, with particular attention to the adolescence dominately in the digestive tract) and GPR55 (central
period, but also potential therapeutic applications. nervous system [CNS] and bone), as well as transient
When systematic reviews were not available, large receptor potential vanilloid 1 receptors (TRPV1),
prospective controlled studies, both observational and which are activated by endogenous cannabinoids in
experimental, were included. However, since the paper the CNS (Balenga, Henstridge, Kargl, & Waldhoer,
was conceived as a narrative review, the coverage of 2011; Brown, 2007; Henstridge et al., 2011; Starowicz,
the literature did not pretend to be exhaustive. Cristino, & Di Marzo, 2008). CBD is capable of bind-
More attention has been devoted to the relationship ing to TRPV1 (Bisogno et al., 2001), and endocanna-
between cannabis and psychosis than with other psy- binoids have also been shown also activate TRPV1
chiatric disorders. Consequently, in relation to psych- (Brown, 2007), which has been shown to influence
otic disorders, we summarize the evidence, which is both dopaminergic (Tzavara et al., 2006) and glutama-
well-reviewed elsewhere, that heavy use of cannabis tergic neurotransmission (Fawley, Hofmann, &
can induce psychosis, and discuss possible mecha- Andresen, 2014).
nisms as well as objections to this hypothesis. As there THC is responsible for the “high” that users enjoy,
are far fewer studies investigating the relationship the feelings of euphoria, increased sociability, insight-
between cannabis and mood disorders and anxiety, fulness, and sharpening of senses. It is a partial agon-
here we shall also consider individual studies. ist at the CB1 receptor. With continued use, its
binding overwhelms the endogenous endocannabinoid
Results system and results in downregulation of the CB1
receptor and lower levels of endogenous cannabinoids
Cannabinoids and the endocannabinoid system (e.g., AEA), which are synthesized in an activity-
The cannabis plant contains numerous cannabinoid dependent manner (Ceccarini et al., 2015; D’Souza
compounds (Hanu
s, 2009) which are produced in et al., 2016; Hirvonen et al., 2012).
crystal formations around the flowering tops of the The mechanism of action of CBD is not fully
plant, the most important of which are tetrahydro- understood (Boggs, Nguyen, Morgenson, Taffe, &
cannabinol (THC) and cannabidiol (CBD). There are Ranganathan, 2018; Pertwee, 2005). CBD has little
approximately 400 other compounds such as terpe- affinity for the CB1 receptor but may act antagonistic-
noids and flavonoids (Atakan, 2012). ally against CB1 agonists via a non-orthosteric bind-
Cannabinoids interact with the endocannabinoid ing site (McPartland, Duncan, Di Marzo, & Pertwee,
system to exert their effects. This biological system is 2015; Morales, Goya, Jagerovic, & Hernandez-Folgado,
composed of endocannabinoids (endogenous lipid- 2016). Moreover, some studies suggest that CBD
based ligands), their receptors, and the enzymes that interacts with serotonin 1A (5-HT1A) receptors, with
synthesize and degrade them (Mechoulam & Parker, similar effects as 5-HT1A agonists (Boggs et al., 2018),
2013). The most important endocannabinoids are N- increases the availability of endogenous AEA (Bisogno
arachidonoylethanolamide (anandamide, AEA) and 2- et al., 2001), and acts as allosteric modulator of mu-
arachidonoylglycerol (2-AG), which are synthesized and delta-opioid receptors (Kathmann, Flau, Redmer,
postsynaptically “on demand” and cleared by a Tr€ankle, & Schlicker, 2006).
reuptake mechanism and enzymatic hydrolysis. There There is evidence that CBD is able to block or at
are two types of endocannabinoid receptors: canna- least ameliorate many of the effects of THC (Pertwee,
binoid receptor type-1 (CB1) and cannabinoid recep- 2008). For instance, in an experimental study of 48
tor type-2 (CB2). The CB1 receptors are located healthy volunteers, pretreatment with 600 mg oral
presynaptically and can be found throughout the CBD before 1.5 mg of intravenous THC significantly
brain, with highest concentrations in the neocortex, reduced the occurrence of psychotic symptoms and
basal ganglia, and hippocampus (Howlett et al., 1990), detrimental effects of THC on memory (Englund
where they modulate neurotransmitter release (Katona et al., 2012). Morgan and Curran tested hair samples
 JOURNAL OF DUAL DIAGNOSIS 3

for cannabinoids and showed that those cannabis (i.e., the greater psychotogenic effect of high THC and
users with both THC and CBD in their hair had fewer the lack of the moderating influence of CBD). An
psychotic symptoms than those with THC alone increasing assortment of cannabis products including
detected in their hair (Morgan & Curran, 2008). oils and “edibles” such as chocolates and cakes are
available via the Internet.
Changes in recreational cannabinoids In the late 2000s, synthetic cannabinoid compounds
Cannabis for recreational use is available as either started to be used in Germany as “legal highs,” often
herb (marijuana, grass, weed) or resin (hashish, hash). referred to collectively as “Spice” or “K2.” Use rapidly
In many parts of the world such as the United States, increased, with more than 200 synthetic cannabinoids
it is commonly smoked on its own, whereas in with slightly different molecular structures now avail-
Europe it tends to be smoked in a “joint” with able online. Most synthetic cannabinoids are full ago-
tobacco (Hindocha, Freeman, Ferris, Lynskey, & nists for the CB1 receptor and consequently have
Winstock, 2016). The effects of cannabis are felt after more powerful effects than THC, which is a partial
a few minutes if smoked or inhaled (e.g., from a agonist; they therefore pose a greater health risk com-
bong) and last 2 to 3 hours; if eaten, the effects can pared to plant cannabis (Tait, Caldicott, Mountain,
take 2 hours to come on and they can last up to Hill, & Lenton, 2016). Side effects are unpredictable;
8 hours. Cannabis remains in the body for several acute physical reactions include nausea and vomiting,
weeks, and withdrawal symptoms are therefore rela- shortness of breath, hypertension, tachycardia, chest
tively mild; craving, anxiety, irritability, insomnia, pain, and occasionally acute renal failure. Synthetic
appetite disturbance, dysphoria, and depression have
cannabinoids are not readily detectable in routine
been reported. Approximately 10% of traditional can-
drug screening tests, making them particularly popular
nabis users experience dependency (Budney, Roffman,
among certain groups such as prisoners.
Stephens, & Walker, 2007), with some studies suggest-
ing that this figure could be as high as 17% in those
who start using cannabis during adolescence (Volkow, Cannabis and psychosis
Baler, Compton, & Weiss, 2014). High-potency canna-
Prospective epidemiological studies have consistently
bis is associated with a particularly increased risk of
demonstrated that cannabis use is associated with an
dependence (Freeman & Winstock, 2015). The latter
increased risk of subsequently experiencing psychotic
may be why, according to the US NESARC study, the
symptoms and developing schizophrenia-like psycho-
prevalence of cannabis use disorders (CUD) is now
ses. In the first study to examine whether cannabis
up to 30% among past-year cannabis users (Hasin
might be causally related to psychosis, Andreasson,
et al., 2015).
Engstr€om, Allebeck, and Rydberg (1987) conducted a
Sinsemilla is a Spanish term that means “without
seeds” and refers to a type of cannabis where the longitudinal prospective study by following up 45,750
female plant is left unfertilized so that so it does not young men who had been questioned about their use
produce seeds and thus converts more of its energy of substances when they were conscripted into the
into cannabinoids (in particular, increased THC); it is Swedish army (Andreasson et al., 1987). Those men
known by a vast number of colloquial terms but most who had used cannabis more than 50 times were six
commonly in Europe as “skunk” as it has a strong times more likely to experience schizophrenia in the
smell. In the 1960s, the average proportion of THC in next 15 years than those who had never used it. There
herbal cannabis (marijuana) and resin (hashish) in has since been a raft of longitudinal prospective stud-
Europe was about 2% to 3%; however, there has been ies. These have been extensively reviewed over time
a move toward high-potency cannabis and by the (Arseneault, Cannon, Witton, & Murray, 2004; Gage,
early 21st century this had risen to an average of 14% Hickman, & Zammit, 2016; McLaren, Silins,
in England (Hardwick Leslie, 2008), 20% in Holland Hutchinson, Mattick, & Hall, 2010; Moore et al., 2007;
(Pijlman, Rigter, Hoek, Goldschmidt, & Niesink, Murray, Quigley, Quattrone, Englund, & Di Forti,
2005), 15% in Australia (Swift, Wong, Li, Arnold, & 2016; Murray et al., 2017), so we will not reiterate all
McGregor, 2013), and 12% in the United States the evidence here (see Table 1). Suffice it to say that,
(ElSohly et al., 2016). Plants bred to produce a high in the current state of knowledge, of 13 prospective
concentration of THC cannot simultaneously produce longitudinal studies, 10 showed that cannabis users
a lot of CBD; thus, there are two reasons for the had a significantly increased risk of psychosis com-
resultant cannabis having stronger psychoactive effects pared with nonusers, while two of the remaining three
4 L. SIDELI ET AL.

showed a trend in the same direction (Murray et al., Critical period of adolescence
2016, 2017). Psychotic disorders such as schizophrenia are widely
There is consistent evidence of a dose–response accepted as being neurodevelopmental in origin, with
relationship between the risk for psychosis and the prodromal symptoms often emerging in adolescence
amount of cannabis consumed. In a first meta-analysis and early adulthood (Murray et al., 2017; Murray &
of six studies, Moore et al. (2007) estimated a more Lewis, 1987). Neurodevelopmental processes that take
than doubled risk among those with the most frequent place during this time may be important in the
pattern of cannabis use, but in a following meta- expression of latent vulnerability for psychosis and
analysis, Marconi, Di Forti, Lewis, Murray, and may be susceptible to the influence of drugs such as
Vassos (2016) found that in 10 studies, the odds ratio cannabis. Thus, exposure to exogenous cannabinoids
for risk of psychosis-related outcomes reached almost might permanently impair the endocannabinoid sys-
4 among the heaviest cannabis users compared to tem, which plays a role in neural development and
the nonusers. impacts adversely on brain and neurotransmitter func-
Higher-potency types of cannabis carry more risk tion (Volkow, Wang et al., 2014). As already men-
than traditional forms. Di Forti, Marconi et al. (2015) tioned, the risk of cannabis dependence and of
studied 410 patients with their first episode of psych- psychosis is especially increased if use was initiated
osis and 390 healthy controls and found that those during adolescence. In the Dunedin cohort, those who
using high-potency cannabis on a daily basis were five started to use cannabis at age 18 or older showed only
times more likely than nonusers to experience a a small, nonsignificant increase in the risk of schizo-
psychotic disorder; use of cannabis resin was not phrenia-like psychosis by age 26; the risk increased
related to an increased risk of psychosis, likely due to fourfold, however, among those starting at age 15 or
the lower THC concentration and the presence of an younger (Arseneault et al., 2002).
equivalent amount of CBD (Di Forti, Marconi There is an association between age at onset of
et al., 2015). cannabis use and levels of striatal dopamine in adult
Psychotic episodes have been reported secondary to life (Bloomfield et al., 2014; Urban et al., 2012). Some
use of synthetic cannabinoids. Papanti et al. carried imaging studies have claimed to find structural brain
out a systematic review and reported that agitation, changes in those who started heavy cannabis use in
anxiety, paranoia, and psychosis can result from even adolescence: global reduction in gray matter volume
brief use of synthetic cannabinoids; these reactions are (Mathew, Turkington, Hawk, Coleman, & Provenzale,
sometimes referred to as “spiceophrenia” (Papanti 2000), reduced fractional anisotropy in a number of
et al., 2013). Increasing evidence suggests that more white matter tracts (Gruber, Dahlgren, Sagar, G€ onenç,
chronic psychotic disorders can also occur (Deng, & Lukas, 2014), reduced parahippocampal volume
Verrico, Kosten, & Nielsen, 2018). (Battistella et al., 2014), and greater white matter
Higher rates of cannabis use and CUDs were alterations (Gruber et al., 2014). These findings are
also found among individuals at ultra high risk discussed in detail elsewhere in this issue.
(Carney, Cotter, Firth, Bradshaw, & Yung, 2017;
Kraan et al., 2016) and with a first episode of Criticisms of the causal hypothesis
psychosis (Myles, Myles, & Large, 2016). Psychotic Most European and Australasian experts are now con-
patients who use cannabis have an earlier illness vinced that cannabis is one of a number of contribu-
onset than nonusing psychotic patients (Di Forti, tory causes of schizophrenia. However, less attention
Marconi et al., 2015; Large, Sharma, Compton, has been paid to this issue in North America,
Slade, & Nielssen, 2011). They also have higher IQ although a very recent book aimed at the general
and better neurocognition than nonusing patients, population has induced considerable discussion
as well as higher premorbid IQ and better premor- (Berenson, 2019). The main criticisms of the causal
bid social function (Ferraro et al., 2013, 2019; Y€ ucel hypothesis are as follows:
et al., 2010); cannabis-using patients with psychosis
are less likely to show neurological soft signs than 1. Confounding by other drug use: A number of
nonusing patients (Ruiz-Veguilla, Callado, & Ferrin, studies have addressed this question and not
2012). It may be that these surprising findings found the effect of other drugs sufficient to negate
reflect the fact that cannabis-using psychotic patients the psychotogenic impact of cannabis (Arseneault
have less neurodevelopmental impairment than non- et al., 2002; Di Forti, Marconi et al., 2015; Di
using psychotic patients. Forti et al., 2009).
 JOURNAL OF DUAL DIAGNOSIS 5

2. “Psychological deviancy”: The Dunedin study and psychotic disorders. It had been assumed that
controlled for psychotic symptoms at age 11 and tobacco smoking was secondary to the illness
still found that cannabis use increased the risk of itself, either through self-medication or a process
later psychotic symptoms (Arseneault et al., of institutionalization, or could be explained by
2002). Two studies using data collected as part of confounding. More recently, a bidirectional rela-
the Swedish Army Study controlled for so-called tionship has been implicated wherein tobacco
“disturbed behavior” (including truancy, contact smoking may be causally related to the risk of
with police/childcare authority, running away psychosis (Gurillo, Jauhar, Murray, &
from home), and both found that after adjust- MacCabe, 2015).
ment cannabis use still significantly increased the Tobacco smoking increases the amount of THC
risk of schizophrenia (Manrique-Garcia et al., inhaled per gram, thus enhancing the subjective effect
2011; Zammit, 2002). of cannabis (Van Der Kooy, Pomahacova, &
3. Reverse causation/self-medication: It has been Verpoorte, 2008), and may mediate the relationship
hypothesized that psychotic patients may use can- between cannabis use and cannabis dependence,
nabis to counteract negative symptoms in people which could be explained by the more addictive prop-
with the illness, or even allay anxiety in the pro- erties of nicotine (Hindocha et al., 2015). Tobacco
drome, but there are few empirical data to sup- smoking has also been shown to offset the effects of
port this (Mustonen et al., 2018). Indeed, one cannabis on delayed verbal recall, thereby perpetuat-
study by Fergusson et al. showed that people tend ing use (Hindocha, Freeman, Xia, Shaban, & Curran,
to smoke less cannabis after the onset of psych- 2017). Thus, tobacco smoking might facilitate canna-
otic symptoms (Fergusson, Horwood, & Ridder, bis dependence, compounding the risk of experiencing
2005), and the finding was confirmed by subse- a psychotic disorder. There is also some evidence to
quent studies (Myles et al., 2016). Also, THC has suggest a synergistic effect whereby the combination
been shown experimentally to worsen positive of tobacco and cannabis gives rise to symptoms of
symptoms in those with schizophrenia. Psychotic psychosis (Jones et al., 2018).
patients cite enjoyment and pleasure as reasons
for using cannabis, the same as in the rest of the 6. Shared genetic vulnerability has been a popular
population (Bianconi et al., 2016). explanation for the association between cannabis
4. It is often said that there has not been an increase use and psychosis. It is now possible to examine
in the prevalence of schizophrenia, despite an the relationship between predisposition to psych-
increase in cannabis use; however, there is little osis, as measured by the polygenic risk score for
reliable information on temporal trends in the schizophrenia (PRS-Sz), and cannabis use. The
incidence of schizophrenia, so it is difficult to PRS-Sz was reported to be associated with
examine this question. One study using consistent increased use of cannabis (Power et al., 2014), but
diagnostic criteria for schizophrenia reported that was responsible for only a small proportion (5%)
the incidence in South London doubled between of the variance in cannabis use. Similarly, Verweij
1965 and 1999 (Boydell et al., 2006). Very et al. (2017) showed that the PRS-Sz explained a
recently, a large European study (the EU-GEI small proportion of the variance in lifetime can-
study) has shown an eightfold variation in the nabis use in almost 7,000 individuals (Verweij
incidence of psychosis across 17 centers; the high- et al., 2017). Gage, Hickman et al. (2015) sug-
est rates were found in London and Amsterdam, gested that those who use high-potency cannabis
which also reported the greatest use of high- might be genetically predisposed to psychosis
potency cannabis (Di Forti et al., 2019). Indeed in (Gage, Munaf o, MacLeod, Hickman, & Smith,
these two cities, the use of high-potency cannabis 2015), but Di Forti, Vassos, Lynskey, Craig, and
accounted for almost one-third and one-half, Murray (2015) examined the PRS-Sz in users of
respectively, of all new cases of psychosis. low- and high-potency cannabis and found no
5. A high proportion of cannabis users smoke evidence of this (Di Forti, Marconi et al., 2015).
tobacco, either concurrently (co-use) or as a com-
ponent of cannabis joints (simultaneous use; Gage’s Mendelian randomization (MR) study of
Hindocha et al., 2016), and the relationship cannabis initiation and schizophrenia risk reported
between the two is difficult to disentangle. There evidence for causal pathways operating in both direc-
is a strong association between cigarette smoking tions (Gage et al., 2017). Pasman et al. (2018) used
6 L. SIDELI ET AL.

MR to show evidence for a causal positive influence between candidate genes and cannabis use must how-
of schizophrenia risk on cannabis use (Pasman et al., ever be regarded as unproven until larger studies
2018). Vaucher et al. adopted the opposite approach are reported.
and examined whether genetic predisposition to can-
nabis use increased risk of schizophrenia, conducting Outcome and treatment of psychotic disorders
an MR analysis of the association of genetically deter- Psychotic patients who continue to use cannabis, espe-
mined cannabis use on risk of schizophrenia in 34,241 cially high-potency forms, have higher relapse rates,
cases and 45,604 controls and concluding strong sup- longer hospital admissions (suggesting more severe
port for a causal association between genetically deter- relapses which take longer to stabilize), and more
mined use of cannabis and risk of schizophrenia severe positive symptoms than either former users
(Vaucher et al., 2018). who discontinued or never-users (Schoeler et al.,
In summary, genetic predisposition to schizophre- 2016; Zammit et al., 2008) (see Table 1). These find-
nia accounts for only a small proportion of variance ings emphasize the importance of addressing cannabis
in cannabis use; furthermore, this effect on cannabis use in the treatment of psychosis.
use is shared with an effect on other drugs not associ- A variety of interventions have been tried to
ated with psychosis such as alcohol and heroin, indi- address continued cannabis use by psychotic patients,
cating that although this may play a small role, it is including cognitive behavioral therapy, motivational
not the major reason for the association between can- interviewing/motivational enhancement, and contin-
nabis and psychosis. gency management (e.g., giving shopping coupons for
Of course, it may be that individuals vary in their urine free of cannabis). These have had little success
susceptibility to the psychotogenic effects of cannabis. (Hjorthoj, Baker, Fohlmann, & Nordentoft, 2014). Of
To our knowledge, only one published study has antipsychotics trialed, one study has shown clozapine
looked at a possible interaction between the polygenic to have a useful effect in reducing craving (Brunette
risk score for schizophrenia and cannabis in causing et al., 2011).
psychosis. This showed an additive interaction of
molecular genetic risk for schizophrenia with regular Therapeutic use of CBD in psychosis
cannabis use (Guloksuz et al., 2019). French et al. Research on the therapeutic effects of cannabinoids is
(2015) also examined this in relation to structural still preliminary (McLoughlin et al., 2014). A German
brain imaging in adolescents and showed that canna- clinical trial found that CBD had antipsychotic actions
bis use before the age of 16 was associated with equivalent to a standard antipsychotic, amisulpride, in
reduced global cortical thickness, suggesting that can- patients with schizophrenia (Klosterk€ otter et al.,
nabis exposure may alter cortical morphometry, but 2012). More recently, McGuire et al. showed that
only in males with a high schizophrenia polygenic CBD has beneficial effects as an adjunct to conven-
risk score (French et al., 2015). tional antipsychotics in patients with schizophrenia
The interaction between cannabis use and candi- (McGuire et al., 2017). However, there are unpub-
date genes has also been studied. Caspi et al. (2005) lished negative studies, and further evidence is
reported that the Val-Met functional polymorphism of required before CBD can be considered as a new
the COMT gene, which plays a role in the metabolism treatment for schizophrenia.
of dopamine in the prefrontal cortex, appeared to
moderate liability to cannabis-associated psychosis,
Cannabis and bipolar disorder (BD)
but this has not been generally replicated (Vaessen
et al., 2018). A variant of AKT1 has been reported to One study estimated that 30% of individuals affected
increase the risk of psychotic illness among cannabis with BD have used cannabis in their life and as many
users in two case-control studies, and a third study as 20% have comorbid CUD (Pinto et al., 2019). A
has shown that those who carry this variant show a meta-analysis of the few longitudinal studies found
greater psychotogenic response to smoked cannabis that cannabis use was related to a nearly threefold
(Di Forti et al., 2012; Morgan, Freeman, Powell, & increased risk of the onset of mania in community
Curran, 2016; van Winkel et al., 2011). A variant in and high-risk samples (Gibbs et al., 2014). According
the D2 receptor gene may also increase psychosis risk; to another systematic review (Marangoni, Hernandez,
the risk was reported to be even greater in those who & Faedda, 2016) of prospective studies, the odds of
carry both this variant and the AKT1 risk allele BD were between 2.5 and 9 times higher among indi-
(Colizzi et al., 2015). These findings of interactions viduals who smoked cannabis at least weekly,
 JOURNAL OF DUAL DIAGNOSIS 7

compared to unexposed participants (Feingold, Cannabis and depression

Weiser, Rehm, & Lev-Ran, 2015; Van Laar, Van According to the first meta-analysis (Moore et al.,
Dorsselaer, Monshouwer, & De Graaf, 2007) (see 2007) based on eight prospective studies, the risk of
Table 1). Among the studies included, a dose–res- depression among individuals with the most frequent
ponse relationship was observed in the Netherlands cannabis use (i.e., individuals affected with CUD or
Mental Health Survey and Incidence Study smoking cannabis at least on weekly basis) was
(NEMESIS; Van Laar et al., 2007) and the National slightly greater than among nonusers (OR ¼ 1.49, 95%
Epidemiologic Survey on Alcohol and Related CI [1.15, 1.94]), with evidence of a dose–response
Conditions study (NESARC; Feingold et al., 2015), relationship between low- and high-frequency smok-
with nearly doubled odds of BD among weekly but ers. The findings were replicated by Lev-Ran et al.
oddly not daily consumers. (2014), who observed a marginally significant greater
The relation with hypomania has been less explored risk of depression in relation to cannabis use
in the literature (Baethge et al., 2008; Rottanburg, Ben- (OR ¼ 1.17, 95% CI [1.05, 1.30]), which was slightly
Arie, Robins, Teggin, & Elk, 1982; Weinstein, Rosca, increased for those with the most frequent pattern of
Fattore, & London, 2017). But in a large sample of teen- use (OR ¼ 1.62, 95% CI [1.21, 2.16]) (see Table 2).
agers, Marwaha, Winsper, Bebbington, and Smith Among the most recent studies, in a male cohort
(2018) have recently found evidence of a risk increasing of children at higher risk for behavioral problems,
effect of ever use and, more strongly, of weekly canna- cannabis use in childhood and adolescence was related
bis use, adjusted odds ratio (OR) ¼ 2.21, 95% confi- to increased risk of major depressive disorder (MDD)
dence interval [CI] [1.49, 3.28]. by 48 years, with a fourfold risk among frequent
smokers, after accounting for behavioral and mood
Course and outcome of BD disorders and other substance use (Schoeler et al.,
Two systematic reviews of prospective studies with a 2018). In the Seattle Social Developmental Project,
maximum follow-up of 5 years (Gibbs et al., 2014; persistent regular cannabis use in adulthood, but not
Mammen et al., 2018) found that continued cannabis in adolescence, more than doubled the risk for MDD
use was associated with recurrence of manic episodes at age 33 (Guttmannova et al., 2017). A relation
and reduced response to treatment (see Table 1). between problematic cannabis use and depressive
Specifically, patients with comorbid CUD showed a symptoms was observed also in a large Swiss prospect-
more rapid-cycling course than the nonusers ive study (Baggio et al., 2014), with a stronger effect
(Strakowski et al., 2007) and cannabis smokers for early and persistent cannabis use (vs. nonuse or
reported greater manic and psychotic symptoms, late onset).
although no effect was observed on depressive symp- In contrast with these findings, the 3-year prospect-
toms (Baethge et al., 2008; Van Rossum, Boomsma, ive NESARC study found that cannabis use, at any
Tenback, Reed, & Van Os, 2009). In other studies, frequency, was unrelated to the incidence of MDD
current and continued cannabis use was related to (Feingold et al., 2015). Other prospective studies sug-
worse global and social functioning (Kvitland et al., gested that the effect of cannabis use on depression
2015; Zorrilla et al., 2015), a greater risk of recurrence may be reduced when potential confounders (includ-
(Zorrilla et al., 2015), and a reduced remission rate ing other substance use) are taken into account. For
(Kim et al., 2015). instance, an integrative meta-analysis of three
Australian cohorts reported a dose–response relation-
ship between frequency of cannabis use and moderate
Cannabis and depressive and anxiety disorders
to severe depression, but the trend became nonsignifi-
and suicide
cant after adjusting for covariates (Silins et al., 2014).
The effect of cannabis use on depression (Cairns, Yap, Lack of effect of lifetime cannabis use was found also
Pilkington, & Jorm, 2014; Chadwick, Miller, & Hurd, in the ALSPAC study (Gage, Hickman et al., 2015)
2013; Degenhardt, Hall, & Lynskey, 2003; Hanna, and in a Swedish prospective study (Danielsson,
Perez, & Ghose, 2017; Hosseini & Oremus, 2018; Lev- Lundin, Agardh, Allebeck, & Forsell, 2016).
Ran et al., 2014; Lowe, Sasiadek, Coles, & George,
2019; Moore et al., 2007) and anxiety (Hosseini & Cannabis and anxiety
Oremus, 2018; Kedzior & Laeber, 2014; Moore et al., According to systematic reviews, only two out of six
2007; Twomey, 2017) has begun to receive prospective studies found evidence of a relationship
greater attention. between cannabis use and later anxiety (Hosseini &
8 L. SIDELI ET AL.

Oremus, 2018; Moore et al., 2007). A meta-analysis 2019) focusing on adolescent cannabis use, and
(Kedzior & Laeber, 2014) of five cohort studies, the accounting for the effect of baseline suicidal thoughts,
majority of which adjusted for demographic and clin- stated that cannabis smokers have a one and a half
ical confounders, estimated that the odds ratio for times greater risk (OR ¼ 1.50, 95% CI [1.11, 2.03]) of
anxiety symptoms in cannabis smokers was 1.28 (95% suicidal ideation and a more than three times greater
CI [1.06, 1.54]); the finding was substantially repli- risk of suicidal attempts (OR ¼ 3.46, 95% CI [1.53,
cated by a larger, more recent meta-analysis 7.84]) (see Table 2). The risk tends to be higher for
(Twomey, 2017). However, the evidence became those who started smoking cannabis before 15 years
inconsistent when the analyses were limited only to of age (Gobbi et al., 2019) and for heavy cannabis
studies with the categorical diagnosis of anxiety disor- users (Borges, Bagge, & Orozco, 2016). Furthermore,
ders (Kedzior & Laeber, 2014; Twomey, 2017), and no the effect of cannabis in increasing risk for suicide
effect was found when only high-quality studies were was also observed among individuals with psychotic
examined (Twomey, 2017) (see Table 2). (Coentre, Talina, G ois, & Figueira, 2017) and bipolar
Among the most recent studies, the NESARC sur- disorders (Leite et al., 2015; Pinto et al., 2019).
vey found that neither cannabis use nor CUD was
related to greater risk of anxiety disorders (adjusted Pathogenetic mechanisms
OR ¼ 1.12, 95% CI [0.63, 0.98]), although the effect of Researchers have hypothesized that cannabis use exerts
frequent cannabis use on social anxiety approached a direct effect on mood throughout the action of its
significance (Feingold, Weiser, Rehm, & Lev-Ran, main ingredients (THC and CBD) on the endocannabi-
2016). In the Seattle Social Development Project noid, dopamine, serotonin, and other neurotransmitter
(Guttmannova et al., 2017), adolescent and adult regu- systems (Chadwick et al., 2013; Degenhardt et al., 2003;
lar marijuana use (vs. nonuse) was associated with Gibbs et al., 2014; Lev-Ran et al., 2014). The small
increased risk of generalized anxiety symptoms, but amount of evidence supporting these speculations
not social anxiety. A prospective Hispanic cohort includes clinical trials reporting increased depression
study showed a relationship between baseline cannabis following acute and chronic administration of the CB1
use and greater anxiety severity at the 1-year follow antagonist rimonabant (see Lev-Ran et al., 2014) and
up, even after accounting for depression and use of preclinical studies showing that THC administration
legal drugs (Duperrouzel et al., 2018). produces anhedonia- and depressive-like symptoms in
rats (see Chadwick et al., 2013). In addition, THC
Course and outcome of depression and anxiety administration has been associated with relaxation,
The role of cannabis use on the outcomes of depres- euphoria, and dysphoria in healthy volunteers, as well
sion and anxiety is controversial (Mammen et al., as with mood improvement and pain relief in individu-
2018) (see Table 2). In the NESARC study, both can- als with chronic diseases, such as cancer or multiple
nabis use and CUD were related to an earlier onset of sclerosis (Ashton, Moore, Gallagher, & Young, 2005;
MDD (Feingold, Rehm, & Lev-Ran, 2017), but no Ashton & Moore, 2011). THC administration produced
effect was found on the course either of MDD a transient amotivational state in occasional smokers
(Feingold et al., 2017) or of any anxiety disorders (Lawn et al., 2016) and a reduced response in the infer-
(Feingold, Rehm, Factor, Redler, & Lev-Ran, 2018). In ior parietal and temporal cortex during reward activities
a substance use intervention trial on an outpatient (van Hell et al., 2012). This preliminary evidence sug-
sample with depression, cannabis use was related to gests that the effect of cannabis on mood disorders may
increased depression and anxiety (Bahorik et al., depend on the modulation exerted by the endocannabi-
2017). In another medication trial for cannabis cessa- noid receptors on the striatal neurons involved in
tion, cannabis reduction predicted decreased anxiety reward functioning (Baskin-Sommers & Foti, 2015;
and depressive symptoms (Hser et al., 2017). Berridge, Robinson, & Aldridge, 2009; Volkow,
Hampson, & Baler, 2017). However, further experimen-
Cannabis and suicide tal studies are needed to corroborate the hypothesis, as
Accumulating evidence suggests that cannabis use negative findings were also reported. In contrast to
may increase the risk of suicidal ideation and behav- psychosis, laboratory studies suggested that the THC/
iors. A first meta-analysis of prospective studies CBD ratio was not related to depression scores in can-
(Moore et al., 2007) estimated the risk increasing nabis smokers (Schubart et al., 2011) and acute admin-
effect on suicidal ideation as 4.55 (95% CI [1.37, istration of THC did not trigger depressive symptoms
15.11]). A more recent meta-analysis (Gobbi et al., in healthy individuals (Englund et al., 2016).
 JOURNAL OF DUAL DIAGNOSIS 9

The route from cannabis use to anxiety is contro- gender, age (Fattore & Fratta, 2010), poor education
versial, with animal models suggesting that, depending achievement (Cerda, 2017) and other types of social
on the quantity, the potency, and the timing of disadvantage (Daniel et al., 2009), and other substance
administration, cannabis might produce either an use (De Luca et al., 2017). Compared to psychosis, the
anxiolytic or an anxiogenic effect (Boggs et al., 2018; combined effect of cannabis and other exposures has
Chadwick et al., 2013; Crippa et al., 2009). According been less explored in mood and anxiety. The effect of
to preclinical studies, low doses of THC or other CB1 cannabis use on later depression was claimed (but not
receptor agonists, such as nabilone or CP 55,940 had yet replicated) to be moderated by the serotonin
anxiolytic-like effects in rodents, while higher doses transporter gene, with greater risk for those carrying
triggered anxious behaviors, especially after exposure the short allele of the 5-HTTLPR genotype (Otten &
to novel and challenging environments (Crippa et al., Engels, 2013), and a similar effect was found on anx-
2009). Furthermore, chronic administration during iety (Otten, Huizink, Monshouwer, Creemers, &
the prepubertal period was found to have anxiogenic Onrust, 2017). A weak age x cannabis interaction was
effects on rats exposed to situational stressors, while found in a study of four Australian cohorts, suggest-
postpuberal administration reduced anxiety, suggest- ing a greater risk for adolescent cannabis use
ing that the anxiogenic effect may depend on the (Horwood et al., 2012). Furthermore, the synergistic
effect of cannabinoids during a critical period for effect of cannabis use and childhood maltreatment
brain development (Chadwick et al., 2013; Kedzior & increased the risk of earlier onset, rapid cycling, and
Laeber, 2014). In addition, it is conceivable that the suicide attempt in BD (Aas et al., 2014).
effect of cannabis on anxiety is partially influenced by
the type of stressors, as cannabinoid agonists seemed Criticism of the causal hypothesis
to maintain an anxiogenic effect on social stressors The systematic reviews of longitudinal studies sum-
even during the postpubertal period (see Chadwick marized above suggest that cannabis use, particularly
et al., 2013). if frequent, has a weak or no effect on later develop-
Some evidence suggests that anxiety symptoms may ment of depression (Lev-Ran et al., 2014; Moore et al.,
result from the interplay between the endocannabi- 2007) and anxiety (Kedzior & Laeber, 2014; Twomey,
noid and the serotonin and noradrenaline systems. 2017), but a stronger effect on mania (Gibbs et al.,
For instance, in rats early exposure to the cannabinoid 2014) and suicide (Gobbi et al., 2019; Moore et al.,
receptor agonist WIN-55,212-2 was associated with 2007). It is possible that the weak relationship might
hyperactivity of noradrenergic neurons in the locus be partially explained by the heterogeneity of defin-
coeruleus and concomitant hypoactivity of serotoner- ition and level of measure of both exposure and out-
gic neurons, which were predictive of affective-like come (Kedzior & Laeber, 2014; Moore et al., 2007),
symptoms (Bambico, Nguyen, Katz, & Gobbi, 2010; which is consistent with the finding of an increase in
Page et al., 2007). Accordingly, both in rodents and the effect size when a narrower definition of cannabis
primate studies, the anxiolytic effect of CBD was use was employed (Lev-Ran et al., 2014; Moore et al.,
related to its interaction with 5-HT1A receptors, with 2007). Additional caveats in the discussion of the pos-
agonists of 5-HT1A preventing the anxiolytic effects of sible effects of cannabis on mood and anxiety include
CBD (Campos & Guimar~aes, 2008; Fogaça, Reis, the following:
Campos, & Guimar~aes, 2014). Less documented is the
effect of cannabis on the glutamate and the GABA 1. Reversal causality: There may be a bidirectional
systems (Boggs et al., 2018; Crippa et al., 2009). As in relationship between cannabis use and depression
the case of psychotogenic effects, some animal and and anxiety. A recent review of the relationship
human studies have indicated that CBD administra- between cannabis use and emotions in daily life,
tion may counteract THC-induced anxiety, although assessed throughout momentary assessment meth-
the findings have not been consistently replicated (see ods, found partial evidence in favor of the self-
Boggs et al., 2018). medication hypothesis (Wycoff, Metrik, & Trull,
Besides its direct effect on the endocannabinoid 2018); the most robust findings were related to a
and the other neurotransmitters, cannabis use may reduction of negative affect and anger/hostility
impact mood and anxiety via its association with among patients with psychiatric disorders, thus
other risk factors, which may mediate or moderate the supporting a negative reinforcement hypothesis of
effect of cannabis on affective outcomes (Degenhardt cannabis use as a means to relieve negative inner
et al., 2003; Lev-Ran et al., 2014). These include states (Wycoff et al., 2018).
 10

Table 1. Relevant Systematic Reviews or Meta-Analyses Concerning the Relationship Between Cannabis and the Onset and Course of Psychosis or Bipolar Disorder
Type of Number of Level of assessment of Level of assessment of
Authors, year included studies included studies cannabis use the outcome Main findings
Arseneault, Cannon, Longitudinal, N¼5 Any cannabis use Psychotic symptoms Cannabis use was related to a twofold risk of later
Witton, & prospective and disorders psychosis (OR ¼ 2.34, 95% CI [1.69, 2.95]). The incidence of psychosis would
Murray, 2004 be reduced by about 8% upon the elimination of cannabis use.
Carney et al., 2017 Longitudinal, cross- N ¼ 29 Lifetime, current Psychotic symptoms Individuals at UHR had a greater prevalence of lifetime (52.8%) and current
sectional, cannabis use, CUDs in UHR status (26.7%) cannabis use, as well as CUDs (12.8%). The odds of psychosis
L. SIDELI ET AL.

and randomized among cannabis users was 2.09 (95% CI [1.04, 4.18]) and was nearly
control trials doubled among people affected with CUDs (5.49, 95% CI [1.97, 15.32]).
Deng et al., 2018 Cross-sectional, case N ¼ 42 Any synthetic Onset of psychotic New-onset psychotic symptoms after synthetic cannabinoid use were reported
report/case series cannabinoid use symptoms or by several case reports and a few cross-sectional surveys. However, some
psychotic relapse studies suggested that the effect of synthetic cannabinoids tend to resolve
after discontinuation, and studies on psychotic relapse led to
inconsistent findings.
Gage et al., 2016 Longitudinal, N ¼ 10 Any cannabis use Psychotic symptoms Evidence of a relationship between cannabis use and psychosis was replicated
prospective and disorders across the studies, with a pooled OR of 1.46 (95% CI [1.24, 1.72]).
Gibbs et al., 2014 Longitudinal, N ¼ 12 (n ¼ 6 in the Any cannabis use Onset and recurrence Cannabis use was associated with recurrence of manic symptoms in patients
prospective meta-analysis) of manic symptoms with bipolar disorders. There is also evidence that cannabis increased the
risk of manic symptoms in individuals without previous bipolar disorders
(OR ¼ 2.97, 95% CI [1.80, 4.90]).
Kraan et al., 2016 Longitudinal, N¼7 Lifetime cannabis Transition to psychosis CUD was associated with a nearly doubled risk for transition to psychosis (OR
prospective use, CUDs in UHR ¼ 1.75, 95% CI [1.13, 2.71]). No risk was related to lifetime cannabis use
(OR ¼ 1.14, 95% CI [0.86, 1.52]).
Large et al., 2011 Cohort, case-control, N ¼ 41 Any cannabis use Age at onset of On average, the age at onset of psychosis was 2.70 years earlier (SMD
cross sectional psychotic disorder 0.414) among cannabis users than among nonusers.
Mammen et al., 2018 Longitudinal, N ¼ 12 (n ¼ 5 on Recent cannabis use Symptomatic course Recent cannabis use was associated with greater symptom severity at
prospective bipolar disorders) or outcome follow-up.
of mania
Marangoni Longitudinal cohort or N ¼ 22 (n ¼ 3 on Any cannabis use Onset of Cannabis use was associated with greater risk of bipolar disorders both in
et al., 2016 case-control cannabis use) bipolar disorders community samples and in a clinical sample of patients with major
depressive disorders. ORs ranged from 2.12 (95% CI [1.10, 4.08]) to 8.93
(95% CI [2.77, 28.82]).
Marconi et al., 2016 Cohort and N ¼ 12 (n ¼ 10 in the Heaviest pattern of Psychotic symptoms All studies confirmed a dose–response relationship between the level of
cross-sectional meta-analysis) cannabis use in and disorders cannabis use and the risk of psychosis. The estimate of the effect was 3.90
terms of either (95% CI [2.84, 5.34]).
frequency or
amount used
or severity
McLaren et al., 2010 Longitudinal, N ¼ 10 Any cannabis use Psychotic symptoms Evidence of an effect of any cannabis use was found in 9/10 studies. A
prospective and disorders greater risk was reported for individuals with early cannabis use or greater
frequency of cannabis use.
Moore et al., 2007 Longitudinal cohort or N ¼ 24 (n ¼ 11 Any cannabis use, Psychotic symptoms Evidence of an effect of any cannabis use was found in 4/7 studies (OR ¼ 1.41,
case-control on psychosis) most frequent and disorders 95% CI [1.20, 1.65]). Five out of six studies suggested a dose–response
pattern of relationship with greater risk among people who used cannabis most
cannabis use frequently (OR ¼ 2.09, 95% CI [1.54, 2.84]).
Murray et al., 2017 Longitudinal, N ¼ 13 Any cannabis use Psychotic symptoms Cannabis use was associated with an increased risk of psychotic symptoms or
prospective and disorders disorder in 10 studies with ORs ranging from 1.7 (95% CI [1.1, 1.5]) to 4.5
(95% CI [1.1, 18.2]). The other three studies showed a trend in the
same direction.
Myles et al., 2016 Cohort, case-control, N ¼ 37 Any cannabis use Age at onset of About one-third of individuals with a first episode of psychosis have smoked
cross-sectional psychotic disorder cannabis in their lifetime (33.7%, 95% CI [31, 39%]). On average, the
(Continued)
 JOURNAL OF DUAL DIAGNOSIS 11

These findings are consistent with large prospective

initiation of regular cannabis use was 6.3 years (SMD ¼ 1.56) antecedent to

transient psychosis and, to a lesser extent, to persistent psychotic disorders

admissions compared to nonuse (d ¼ 0.36, 95% CI [0.13, 0.58]). Continued

No longitudinal studies were found. Evidence from case reports and surveys

rehospitalization (3/3 studies), and reduced adherence to treatments (3/3

the onset of psychosis. Odds for continued cannabis use within 10 years
studies reporting an increased risk of cannabis use

psychosis (Cohen’s d ¼ 0.36, 95% CI [0.22, 0.50]) and to longer hospital

cannabis users showed also a higher rate of relapse than discontinued

suggest an association between synthetic cannabinoid use and acute

studies). Evidence was less consistent for the symptomatic outcome.

Continued cannabis use was associated with a higher risk of relapse of
and CUD in patients with MDD (Feingold et al.,
2015; Wittchen et al., 2007) and depressive symptoms

Cannabis use was associated with increased relapse (4/4 studies),

at age 13 to 15 predicting CUD at age 18 (Rhew
et al., 2017). By contrast, in two large U.S. cohorts,
the effect of cannabis use in the peer network on fre-
quency of youth cannabis use was attenuated by ado-
from the onset was 0.56 (95% CI [0.40, 0.79]).
Main findings

lescent depressive symptoms, which might render

them more isolated or less susceptible to peer influ-

users (d ¼ 0.28, 95% CI [0.12, 0.44]).

ence (Pollard, Tucker, Green, de la Haye, & Espelage,
2018) Similar results were found by the Cambridge
Study in Delinquent Development (CSDD; Schoeler
et al., 2018), while no influence of mood symptoms
or psychotic relapse.

on later cannabis use was found in other studies

(Baggio et al., 2014; Danielsson et al., 2016; Womack,
Shaw, Weaver, & Forbes, 2016).
As far as mania and BD are concerned, in the
Early Developmental Stages of Psychopathology
Note. CI ¼ confidence interval; CUD ¼ cannabis use disorder; SMD ¼ standardized mean difference; OR ¼ odds ratio; UHR ¼ ultra-high risk.

(ESDP) study (Wittchen et al., 2007), hypomania/

mania was associated with a marginally significant
Level of assessment of

psychotic symptom

psychotic disorder
Hospital readmission
Psychotic symptoms

greater risk for cannabis use, but other studies found

the outcome

and disorders

or relapse of

no prospective relationship between manic symptoms

or disorder

Outcome of

or BD and cannabis use during follow-up (Baethge

et al., 2008; Feingold et al., 2015; Henquet,
Krabbendam, de Graaf, ten Have, & van Os, 2006;
Strakowski et al., 2007).
Level of assessment of

Although cannabis may be used to relieve occasional

discontinued use
Continued cannabis
cannabinoid use
cannabis use

Any cannabis use

or persistent feelings of anxiety (Crippa et al., 2009;

Any synthetic

vs. nonuse

Kedzior & Laeber, 2014), longitudinal studies on the

use vs.

overall effect of anxiety disorders on later cannabis use

reported mixed findings, with evidence of effect in the
Great Smoky Mountains cohort (Hill, Shanahan,
Costello, & Copeland, 2017), but not in the NESARC
study (Feingold et al., 2016) or in two other samples
included studies
Number of

(Brook, Rosen, & Brook, 2001; Duperrouzel et al., 2018).

There is some evidence regarding the effect of panic dis-
order on increased rate of marijuana use (Feingold
N ¼ 41

N ¼ 24

N ¼ 10

et al., 2016; Wittchen et al., 2007) and generalized anx-

iety disorder on cannabis use (Stapinski, Montgomery,
series, retrospective

& Araya, 2016) and CUD (Wittchen et al., 2007). The

toxicology surveys,
laboratory studies
included studies

and surveys on

role of social anxiety on later cannabis use is controver-

Case reports/case

self-reported
Type of

sial, with one study reporting an effect on cannabis

unwanted

Longitudinal

Longitudinal

dependence but not on abuse (Buckner et al., 2008), and

effects

others suggesting even a protective role (Feingold et al.,

2016; Nelemans et al., 2016).
Table 1. Continued.

In summary, there are some indications that the

Schoeler et al., 2016

Zammit et al., 2008

Papanti et al., 2013

putative risk-increasing effect of cannabis on the

development of mood and anxiety might be con-
Authors, year

founded by the self-medicating use of the substance.

In some cases, early symptoms of depression and anx-
iety might even protect against cannabis use. More
 12
L. SIDELI ET AL.

Table 2. Relevant Systematic Reviews or Meta-Analyses Concerning the Relationship Between Cannabis and the Onset and Course of Depression and Anxiety Disorders
Number of Level of assessment of Level of assessment of
Authors, year Type of included studies included studies cannabis use the outcome Main findings
Gobbi et al., 2019 Longitudinal, prospective N ¼ 11 (n ¼ 7 on Any cannabis use Depressive and Cannabis smokers had a modest increase in risk for depression
depression, n ¼ 3 before age 18 anxiety disorders (OR ¼ 1.37, 95% CI [1.16, 1.62]) but not for anxiety (OR ¼ 1.18,
on anxiety, n ¼ 3 between 18 and 32 95% CI [0.84, 1.67]). Furthermore, cannabis use was associated
on suicidal years of age with one and a half times greater risk (OR ¼ 1.50, 95% CI [1.11,
ideation, n ¼ 3 on 2.03]) of suicidal ideation and a more than 3 times greater risk
suicidal attempts) of suicide attempts (OR ¼ 3.46, 95% CI [1.53, 7.84]).
Hosseini & Cohort, cross-sectional, N ¼ 23 (n ¼ 11 on Any cannabis use Depressive and Only two out of six prospective studies found evidence of a
Oremus, 2018 and case-control depression anxiety symptoms relationship between cannabis use and later depression or
and anxiety) and disorders anxiety. A moderate relationship with depression was found in
three out of four cross-sectional or case-control studies.
Lev-Ran et al., 2014 Longitudinal, prospective N ¼ 14 Any cannabis use, Depressive symptoms Any cannabis use (OR ¼ 1.17, 95% CI [1.05, 1.30]) and the most
most frequent and disorders frequent cannabis use (OR ¼ 1.62, 95% CI [1.21, 2.16]) were
pattern of related to increased risk of depression.
cannabis use
Kedzior & Cohort and N ¼ 31 Lifetime cannabis use, Anxiety symptoms Anxiety was associated with cannabis use (OR ¼ 1.24, 95% CI
Laeber, 2014 cross-sectional past-year cannabis and disorders [1.06, 1.45]) and CUD (OR ¼ 1.68, 95% CI [1.23, 2.31]). A further
use, cannabis use association was found between cannabis use and comorbid
disorders anxiety and depression (OR ¼ 1.68, 95% CI [1.17, 2.40]). The
association between cannabis use and anxiety was replicated
in the subgroup of the five prospective studies (OR ¼ 1.28,
95% CI [1.06, 1.54]).
Mammen et al., 2018 Longitudinal, prospective N ¼ 12 (n ¼ 2 on Recent cannabis use Symptomatic course Recent cannabis use was associated with greater symptom
depressive or outcome severity at follow-up.
disorder) of depression
Moore et al., 2007 Longitudinal cohort or N ¼ 24 (n ¼ 15 on Any cannabis use, Depressive and The most frequent cannabis use was related to increased risk of
case-control depression, n ¼ 7 most frequent anxiety symptoms depression (OR ¼ 1.49, 95% CI [1.15, 1.94]). Any cannabis use
on anxiety, n ¼ 6 pattern of and disorders, was related to depression in 4/11studies, to anxiety in 2/7
on suicide) cannabis use suicidal ideation studies, and to suicidal ideation in 3/5 studies.
and attempt
Twomey, 2017 Longitudinal, prospective N ¼ 10 Any cannabis use Anxiety symptoms Cannabis use was associated with a small increase in the risk of
and disorders anxiety (OR ¼ 1.15, 95% CI [1.03, 1.29]), but no association was
found when the meta-analysis was restricted to high-quality
studies (OR ¼ 1.04, 95% CI [0.91, 1.19]).
Note. CI ¼ confidence interval; CUD ¼ cannabis use disorder; OR ¼ odds ratio.
 JOURNAL OF DUAL DIAGNOSIS 13

recent systematic reviews reported that a growing investigation of the effect on CBD on mood and anxiety
number of studies have attempted to take into symptoms reported negative results and highlighted the
account the possibility of reverse causality, either need for further studies (Crippa, Guimar~aes, Campos,
excluding participants with baseline affective symp- & Zuardi, 2018). Another review suggests that CBD
toms or controlling for baseline symptom severity premedication might reduce the anxiety arising from
(Lev-Ran et al., 2014; Twomey, 2017). public speaking, but studies on other anxiogenic tasks
led to inconsistent findings, and the efficacy on anxiety
2. Confounding effect of intoxication: The acute disorders needs to be further assessed (White, 2019).
effect of cannabis may increase the impact on psy-
chiatric symptoms (Moore et al., 2007), particu-
larly in studies with a short length of follow-up. Conclusions
In order to reduce the confounding effect of There is extensive evidence that heavy use of high-
intoxication, some studies (see Cairns et al., 2014; potency cannabis increases the risk of psychotic symp-
Lev-Ran et al., 2014; Moore et al., 2007) employed toms and schizophrenia-like psychosis. Fewer studies
assessment measures that enable the investigators have examined mania and suicide, but reports suggest
to disentangle affective symptoms due to sub- that exposure to frequent cannabis use may similarly
stance misuse, such as the Diagnostic Interview increase the risk of these conditions. Whether there is a
Schedule (DIS), the Diagnostic Interview Schedule risk-increasing effect on depression is much less clear,
for Children (DISC), the Composite International and there are few longitudinal controlled studies on
Diagnostic Interview (CIDI), or the Hypomania anxiety. Large cohort studies, carefully assessing the
CheckList (HCL-32). Another strategy involved pattern of cannabis use, controlling for potential con-
controlling the analysis for baseline substance founders, are required to clarify the effect of cannabis
misuse, as was done in about one-half of the stud- on common mental disorders and to highlight any
ies included in the meta-analyses of Lev-Ran et al. potential dose–response relationships and possible syn-
(2014) and Twomey (2017). ergism with other genetic or environmental risk factors.
3. Shared risk factors for cannabis use and common
Furthermore, while psychotic symptoms do not appear
mental disorders, BD, and suicide may attenuate
to facilitate cannabis use, self-medication may play a
the effect of cannabis use. However, previous
role in depression and anxiety where unpleasant symp-
meta-analyses showed that a weak effect was still
toms may encourage greater cannabis consumption. It
present in most of the studies after controlling for
is vital to distinguish between the effects of THC and
demographic and other substance misuse (Gibbs
CBD; for example, in experimental studies, the former
et al., 2014; Gobbi et al., 2019; Kedzior & Laeber,
can induce psychotic symptoms which can be blocked
2014; Lev-Ran et al., 2014; Moore et al., 2007;
by the latter. Interestingly, CBD may have potential as
Twomey, 2017), suggesting that these factors do
an adjunctive treatment in psychosis and in anxiety/
not entirely explain the association between can-
nabis and these mental health outcomes. Among depression, but more studies are required before these
the most recent studies, an analysis of three large preliminary findings can be accepted.
Australian twin cohorts found that the effect of
frequent cannabis use on MDD and suicidal idea- Disclosures
tion was still significant after controlling for early
LS, HQ, and CLC report no financial relationships
substance misuse, childhood abuse, and conduct
with commercial interests in relation to this study.
disorder. Furthermore, the effect was of similar
size both within monozygotic and dizygotic twin RMM has attended one Canopy Health advisory
pairs, suggesting that the effect of frequent canna- board meeting on the use of CBD in pain and has
bis use is not fully accounted by genes and early received honoraria for lectures from Janssen, Otsuka,
environmental exposures (Agrawal et al., 2017). Sunovion, and Lundbeck.

Therapeutic use of CBD for mood and anx- ORCID

iety disorders
Lucia Sideli http://orcid.org/0000-0001-6124-6897
Although there are numerous anecdotal reports that Harriet Quigley http://orcid.org/0000-0003-3204-1707
cannabis may benefit mood and/or anxiety disorders, Caterina La Cascia http://orcid.org/0000-0002-2078-0214
there are few systematic studies. One recent Robin M. Murray http://orcid.org/0000-0003-0829-0519
14 L. SIDELI ET AL.

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