REVIEW

Clonazepam: Indications, Side Effects, and Potential

for Nonmedical Use
Vinícius Dokkedal-Silva, MSc, Laís Fernanda Berro, PhD, José Carlos Fernandes Galduróz, PhD,
Sergio Tufik, MD, PhD, and Monica Levy Andersen, PhD

Learning objectives: After participating in this activity, learners should be better able to:
• Assess the misuse potential of clonazepam
• Characterize the nonmedical use of clonazepam
• Identify the health problems associated with long-term use of clonazepam
Abstract: Clonazepam, a benzodiazepine, is commonly used in treating various conditions, including anxiety disorders
and epileptic seizures. Due to its low price and easy availability, however, it has become a commonly misused medication,
both in medical and recreational contexts. In this review, we aim to highlight the behavioral and pharmacological aspects of
clonazepam and its history following its approval for human use. We examine the circumstances commonly associated
with the nonmedical use of clonazepam and raise points of particular concern. Clonazepam, alone or in combination with
other psychoactive substances, can lead to unwanted effects on health, such as motor and cognitive impairment, sleep dis-
orders, and aggravation of mood and anxiety disorders. Prolonged use of clonazepam may lead to physical dependence
and tolerance. There is therefore a need to find safer therapeutic alternatives for treating seizures and anxiety disorders.
Greater awareness of its frequent nonmedical use is also needed to achieve safer overall use of this medication.
Keywords: anxiety disorders, clonazepam, drug misuse, mood disorders, sleep, sleep disorders

W
hen they first emerged, benzodiazepine medications withdrawal-like effects have been reported in experiments with
represented an improvement on the barbiturate rodents,4 nonhuman primates,5,6 and humans.7 In addition,
tranquilizers being used at the time.1 Benzodiaze- the association of benzodiazepines and other drugs, such as
pines were safer than barbiturates, whose border between thera- alcohol and opioids, can be a dangerous combination, lead-
peutic and toxic dosages had never been completely established.2 ing to marked impairments in cognition and motor function,
As benzodiazepines became more popular, however, negative lethal overdose, and poor treatment outcomes.8,9
implications of their use started to arise. It is now known that Among the many different benzodiazepine drugs, clonaze-
tolerance and physical dependence can quickly develop and that pam has become one of the most popular compounds for
they can be related to withdrawal symptoms.3 Benzodiazepine treating anxiety-related disorders and seizures.10,11 Clonaze-
pam is a high-potency, intermediate- to long-acting GABAA
From Departamento de Psicobiologia, Universidade Federal de São Paulo receptor positive allosteric modulator that is marketed world-
(Mr. Dokkedal-Silva and Drs. Galduróz, Tufik, and Andersen) (Brazil); Depart-
ment of Psychiatry and Human Behavior, University of Mississippi Medical wide. It is commonly prescribed for treating a range of disor-
Center, Jackson, MS (Dr. Berro). ders for which it had not originally been approved, including
Supported by grants from the Associação Fundo de Incentivo à Pesquisa; by sleep-related disorders, withdrawal from other benzodiaze-
grant no. 133397/2017-3 received from, and by fellowships awarded by pines, and pain management.12 Among its effects, clonazepam
(Drs. Galduróz, Tufik, and Andersen), the National Council for Scientific
and Technological Development. is known to cause mild and short-lived euphoria at therapeutic
Original manuscript received 30 July 2018; revised manuscript received 4 doses. The intensification of euphoric effects with an increased
December 2018, accepted for publication subject to revision 14 January dose might have a connection to its common nonmedical use
2019; revised manuscript received 6 February 2019. and to its frequent use for recreational purposes.13,14 Clonaze-
Correspondence: Monica Levy Andersen, Departamento de Psicobiologia, pam dependence may arise in a third of the patients after only
Universidade Federal de São Paulo (UNIFESP), Rua Napoleão de Barros,
925, São Paulo, 04024-002, Brazil. Email: ml.andersen12@gmail.com four weeks of treatment15—a major concern in view of the un-
Harvard Review of Psychiatry offers CME for readers who complete controlled, unprescribed use of this medication.
questions about featured articles. Questions can be accessed from the Reports of clonazepam’s nonmedical use have surfaced
Harvard Review of Psychiatry website (www.harvardreviewofpsychiatry.org) only in recent years, despite it being a benzodiazepine sold
by clicking the CME tab. Please read the featured article and then log into
the website for this educational offering. If you are already online, click here since 1975. Clonazepam sets itself apart from other benzodi-
to go directly to the CME page for further information. azepines by combining high potency with a long duration of
© 2019 President and Fellows of Harvard College action. Additionally, clonazepam is an easily accessible, widely
DOI: 10.1097/HRP.0000000000000227 prescribed medication, and as noted above, reports of its use in

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V. Dokkedal-Silva et al.

a multitude of conditions for which it was not approved have classified as either fast or slow—the two predominant pheno-
become widespread.16–23 Consequently, clonazepam has be- types in the general population.36 The metabolic pathway of
come a best-selling medication around the world. In the clonazepam and its phenotypic variations thus plays an essen-
United States it is only surpassed by alprazolam among ben- tial role in the success of treatment and the development of side
zodiazepines, and in Brazil it has become one of the most pre- effects. Until recently, the detection of clonazepam and its me-
scribed drugs of the country, according to some studies.24,25 tabolites after use was believed to be relatively difficult and
Its affordability must also be considered. The wholesale cost only possible for a short time.37 A 2015 study by Nordal and
of clonazepam in the United States is 40 cents for each pill.26 colleagues,38 however, revealed that clonazepam can be de-
In developing countries, the cost can fall below one cent tected in oral fluid for up to six days after use.
(USD).27 Taken together, its accessibility, affordability, phar- Clonazepam’s strong affinity for α1 and α2 subunits of the
macological properties, and rise in popularity as a misused GABA-A receptor is responsible for its anxiolytic and anti-
drug justify a specific, in-depth investigation of the reasons convulsant properties.39 Therefore, clonazepam has fre-
that led to this rise, the implications for a drug-misusing quently been prescribed for the treatment and control of
scenario, and potentially different neural mechanisms affected anxiety crises11 and seizure episodes,40 as well as for insom-
by this particular molecule. The present review examines data nia and sleep-related problems commonly associated with
on the nonmedical use of clonazepam, the populations af- other conditions, such as Parkinson’s disease.41 It is com-
fected by it, and the changes in how it has been perceived over monly used for treating REM sleep behavior disorder.42,43
time. We aim to summarize evidence on the addictive potential Clonazepam has also been proven effective for treating a
of clonazepam, its different forms of nonmedical use, and the multitude of other health problems—alleviating symptoms
health problems associated with its long-term use, either alone of conditions for which it was not originally prescribed.16
or in combination with other drugs. These conditions include movement disorders, such as rest-
less legs syndrome and neuroleptic-induced akathisia;17–19
CLONAZEPAM: HISTORY AND GENERAL ASPECTS neuropathic pain and burning mouth syndrome;20 multi-
Clonazepam, initially patented in 1964, has been sold in infarct dementia;21 tinnitus;22 and depression (in combina-
the United States since 1975.28 It is considered a potent tion with antidepressants).23
benzodiazepine—about 20 times more potent than diaze- Despite its therapeutic potential, the use of benzodiaze-
pam.29 Clonazepam combines such high potency with longer pines is not without risks. Clonazepam is no exception, as it
action, setting itself apart from other benzodiazepines, which might lead to several adverse effects, including motor and
commonly do not share both these traits. Its half-life is be- psychiatric symptoms, especially with prolonged use. One
tween 19 and 60 hours, with peak blood concentrations of the most prominent acute observed effects is psychomotor
reached between 1 and 8 hours. Its duration of action is com- impairment,16,44 though this effect may subside after toler-
monly set at 6–12 hours (longer than other benzodiazepines ance develops.45 Psychomotor impairment is especially
of similar potency used for anxiolytic purposes, such as al- present in the elderly,1 who may already experience motor
prazolam10), which makes clonazepam an intermediate- to and coordination impairment due to neurological condi-
long-acting benzodiazepine. This combination of features tions and the natural aging processes. Amnesic effects are
contributes to its wide range of potential uses. Another un- not normally reported with clonazepam; in this respect its
common trait is its demonstrated serotonergic action,30 properties differ from other benzodiazepines.39 Midazo-
which is believed to play a role in its anxiolytic properties lam, for example, is used as an anesthetic, with its capacity
and to be related to its potential for nonmedical use.31 to generate anterograde amnesia contributing to its utility.1
Clonazepam undergoes metabolism by CYP3A4, through As with other benzodiazepines, there are reports of clonaz-
nitro reduction, generating 7-amino-clonazepam, its first me- epam treatment causing paradoxical disinhibition; in-
tabolite, which is acetylated afterward by NAT2 enzymes, creased aggression, hostility, and excitability; and loss of
forming 7-acetamido-clonazepam32,33—a unique reaction general social restraints.46–49 Benzodiazepines can lead
among benzodiazepines. Both metabolites and the parent to emotional blunting and depressive symptoms,50 which
compound can also undergo hydroxylation.34 It must be have been associated with higher rates of suicidal ideation.1
noted that CYP3A4 activity on clonazepam and its metabolites Depressive symptoms may appear with elevated doses and can
can vary up to 100 times from one individual to another.35 diminish when benzodiazepine treatment is discontinued.51
This variation is responsible for the differences in manifesta- At the doses of 8 and 12 mg, clonazepam has been re-
tion of adverse effects, as it directly affects the availability of ported to induce euphoria and to have the potential for
7-amino-clonazepam, which, although a mild partial agonist nonmedical abuse.52 While at first it was believed that
for GABA-A receptors, can alter activity of clonazepam. Of clonazepam-induced euphoria would not be substantial
note, 7-amino-clonazepam levels can be higher in clonazepam enough to encourage nonmedical use,53 this position was
users than its parent compound and may affect the appearance disproved during the 1990s and 2000s. Clonazepam became
and persistence of withdrawal symptoms.32,36 These concen- a popularly misused drug because of its mood-enhancing ef-
trations are affected by the acetylation process, which may be fects.52 Clonazepam-induced reinforcing effects are similar

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 Use and Abuse of Clonazepam

to those induced by opioids, making clonazepam an attrac- United States), clonazepam can lead to more pronounced re-
tive substitute in the absence of other preferable drugs.54 Se- sidual effects. Clonazepam has become one of the most suc-
rotonergic affinity, which is not a commonly observed effect cessful benzodiazepines in terms of sales in several countries,
of benzodiazepines, seems to influence the recreational use constantly being one of the top three most commonly pre-
of clonazepam,31 which decreases the utilization of serotonin scribed medications of this class.1,63,64 It has a solid reputation
by the brain.55 Studies in animal models demonstrated a de- thanks to its elevated safety level (low chance of overdose and
crease in serotonin turnover rate after clonazepam injec- of side effects that represent immediate danger) and the multi-
tions30 and attributed the anxiolytic effects of clonazepam tude of disorders it can treat—which made it popular among
to the excitation of presynaptic serotonergic receptors.56 both physicians and patients. Clonazepam is also extremely ac-
Thus, despite its therapeutic effects, clonazepam is now cessible, having a low wholesale cost and being affordable in
known to have the potential for nonmedical use and has been different presentations as a generic medication, as are benzodi-
increasingly used for recreational purposes. According to azepines in general.65 This accessibility, however, may be one
Hernandez and Nelson,31 different expressions are used to of the factors related to its increasing popularity among those
classify the nonmedical use of medications. These categories with substance use disorders. It is currently one of the most fre-
can overlap at varying points, which may generate misunder- quently sold benzodiazepines in the streets.66 Clonazepam de-
standings. The different terms reflect differences in drug dos- pendence is also reported, with withdrawal symptoms being
age, means of acquisition of the drug, motivation to use, and especially likely after abrupt discontinuation.32,67 There are
different forms of misuse. Nonmedical use includes drug mis- also occasional reports of nonmedical use leading to subse-
use or recreational use, which is the use of a drug to intention- quent dependence of clonazepam,15,59,68 which suggests that
ally alter perception, behavior, and other aspects of the individuals making recreational use of clonazepam might be
organism. It is also important to highlight nonprescribed equally or even more exposed to the risk of developing psycho-
use of the drug, with reasons that may vary, including self- logical and physical dependence.
medication due to a health problem, rather than recreation. During the early 2000s, a similar drug from the same class,
Recreational use and self-medication are the two main rea- flunitrazepam, became extremely popular in Europe because
sons for the recent rise in the nonmedical use of clonazepam. of its hypnotic effects.69 Flunitrazepam quickly became a pre-
Overdose by clonazepam alone is not lethal,1 but its com- ferred drug of misuse, was detected in blood samples from in-
bination with other drugs such as opioids is life-threatening—a toxicated drivers, and was sold in the streets. Its nonmedical
trait shared by the benzodiazepines in general.8,57,58 In addi- use became so problematic that the drug was rescheduled,
tion to the misuse-related effects, several factors associated and measures were taken to interrupt its diversion from licit
with clonazepam’s nonmedical use may lead to severe health manufacturers. While the use of flunitrazepam decreased af-
consequences. Besides its interaction with other psychotropic ter these measures, the use of clonazepam started to increase
substances, clonazepam has tolerance potential, which can be in the same population, indicating a shift in nonmedical use
associated with a withdrawal syndrome and can cause vary- from flunitrazepam to clonazepam.70 The same study points
ing side effects.3,51 Withdrawal symptoms arising after cessa- to the decrease in the number of people making legal use of
tion of high doses of clonazepam are commonly observed.59 clonazepam (from 2.81 to 2.31 per 1000 inhabitants) even
Symptoms of clonazepam (and, to an extent, benzodiazepine) as seizures of illegally sold clonazepam tablets have increased
withdrawal are well established and may involve irritability, dramatically (a staggering increase from 8077 in 2004 to
aggressiveness, anxiety, and hallucinations.60 From a psycho- 681,718 in 2013). In addition to street sales, another, increas-
logical perspective, prolonged benzodiazepine treatment may ingly popular mode of acquiring clonazepam is through
cause loss of confidence and the appearance of an exacer- “doctor shopping,” enabling individuals to obtain clonaze-
bated reliance on the drug’s effects to provide a degree of pam prescriptions from potentially numerous physicians.12
psychological comfort.1 It may also be associated with inten- The nonmedical use of benzodiazepines in general, as well
sification of the nonmedical use of other drugs in addition to as other prescription drugs, is a growing trend among univer-
the potential for addiction of clonazepam alone.61 sity students.71 In 1990, Cole and Chiarello53 reviewed an in-
crease in the use of benzodiazepines by university students but
RISE OF POPULARITY AND NONMEDICAL USE did not predict that the practice would become increasingly
While reports of nonmedical use can be found for most ben- popular. The study found that the nonmedical use of benzodi-
zodiazepines, particular aspects of clonazepam need to be azepines in general was mainly to decrease anxiety and that
considered when analyzing its abuse liability. Visits to emer- they were not being used for recreational purposes. A previ-
gency departments for the nonmedical use of clonazepam ous increase in the nonmedical use of benzodiazepines had al-
are second in frequency (only to alprazolam) among benzodi- ready been observed in 1977 among high school students.72
azepines in the United States.62 Clonazepam has a high Cole and Chiarello53 conceded that inferring only a minor
nonmedical use liability and can lead to severe withdrawal potential for nonmedical use might be a misconception
symptoms. Additionally, due to its longer duration of action than based on lack of studies. In fact, studies reporting an in-
alprazolam (the most frequently abused benzodiazepine in the crease in the nonmedical use of benzodiazepines became

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V. Dokkedal-Silva et al.

more frequent. For instance, in 1996, Calhoun and col- sampled population may not match what is reported. Also,
leagues73 reported patterns of nonmedical use of clonazepam, the studied population was fairly specific, as Brandt and col-
flunitrazepam, and other benzodiazepines in Austin, Texas. leagues pointed out; a wider population range would be
In 2005, McCabe74 published an extensive study reporting needed to obtain a better overall estimate of the nonmedical
and analyzing patterns of nonmedical use of prescription use of drugs. Nevertheless, their results are suggestive re-
drugs, in general, and benzodiazepines, in particular, by garding the present, nonmedical use of clonazepam and
college students. The study found that about one-tenth of other prescription drugs, and may serve as a useful back-
the students in North American universities had used anxio- ground for designing future studies with larger samples
lytic benzodiazepines without prescription. Benzodiazepine and objective measurements.
nonmedical use seems to be associated with sexual behavior. A similar potential for nonmedical use was observed
In McCabe’s study,74 students who were sexually active with in animal studies. Self-administration of clonazepam
both same- and opposite-sex partners were more than three has been reported in nonhuman primates in a trial-based
times more likely to use benzodiazepines nonmedically experiment consisting of repetitive lever pressing as a
than were those were sexually active only with same- or op- response requirement.78,79
posite-sex partners.74 One of the possible explanations Clonazepam, together with alprazolam and bromazepam,
raised by the author was that benzodiazepine misusers has been described as a drug with an intermediate risk of non-
present higher sensation-seeking behavior, which would lead medical use.80 One of the main reasons why clonazepam is
to experimenting not only with different substances but also frequently used as a self-medication or even improperly pre-
with sexual experiences. Nevertheless, the relationship be- scribed by physicians is that clonazepam exerts hypnotic ef-
tween clonazepam and sensation-seeking behavior still needs fects.44 Given the growing frequency of sleep disturbances
to be specifically investigated. Additionally, the link between in modern society,81,82 the use of clonazepam as a sleep aid
clonazepam and alterations in sexual behavior has been ex- has become popular and, as discussed below, seems to be
plored mostly through anecdotal reports, in which clonazepam one of the gateways for clonazepam addiction, alone or in as-
led to sexual disinhibition.75,76 sociation with other drugs of misuse.
According to the 2012 edition of Observation des Produits
Psychotropes Illicites ou Détournés de leur Utilisation
Médicamenteuse (OPPIDUM) national survey, clonazepam CLONAZEPAM AND SLEEP: A GATEWAY
was among the three most illegally acquired drugs, together FOR ADDICTION
with the opioids buprenorphine and methadone.77 Reports Benzodiazepines are commonly used as hypnotic drugs to
from the Drug Abuse Warning Network62 indicate that the treat sleep-related problems. Although specific benzodiaze-
number of visits to emergency departments associated with pines, such as flurazepam, triazolam, and temazepam,83–86
the nonmedical use of clonazepam in the United States in- have been approved for treating insomnia, all benzodiazepine
creased 117% from 2004 to 2011, surpassing levels reported drugs exert hypnotic effects due to their mechanisms of action
for other drugs of misuse, such as amphetamines. Clonaze- as GABAA receptor positive allosteric modulators.87 As for
pam contributed to nearly 18% of the annual emergency clonazepam, although it is mainly used as an anxiolytic and
room visits associated with the nonmedical use of benzodiaz- anticonvulsant drug, it has become a popular option for
epines. In addition, 29% of visits involving suicide attempts treating sleep-related problems,32 especially REM sleep be-
were associated with the use of benzodiazepines (a percentage havior disorder. As Schenck and colleagues42,88 have demon-
similar to that found for alcohol-present suicide attempts and strated, clonazepam alleviates symptoms associated with this
higher than any other class of drug), with an increase of 81% disorder, diminishing aggressive behavior (and consequently
from 2005 to 2011. In this scenario, clonazepam alone has reducing the need for restraint) in affected patients.
shown an increase in 132%. Previous guidelines have even highlighted the effectiveness
In a more recent study, Wilens and colleagues14 assessed of clonazepam in improving insomnia symptoms if the du-
the nonmedical use of different prescription medications in ration of action matches the symptom presentation.89
association with opioids, showing that clonazepam has been Contreras-Gonzalez and colleagues16 have shown, how-
consistently reported as one of the most widely misused ever, that insomnia patients treated with clonazepam per-
drugs, even when considering other benzodiazepines. Clonaz- formed worse on executive function–oriented tasks. The use
epam was also the third most frequently consumed medica- of clonazepam might lead to general motor impairment and
tion at doses higher than those prescribed, and first among anterograde amnesia—residual effects that affect daytime ac-
the medications taken without prescription. In another study, tivities.90,91 Therefore, even though clonazepam seems to be
by Brandt and colleagues,13 clonazepam was shown to be effective for treating REM sleep behavior disorder and to im-
among the most misused prescription tranquilizers, second prove insomnia symptoms, there is little evidence of its effec-
only to alprazolam. The use of self-report and survey-based tiveness as a hypnotic, and studies in this area generally do
methods can lead, however, to a degree of subjectivity; the not consider the use of clonazepam and other benzodiaze-
actual range and extent of different substances used by the pines as sleep inducers to be appropriate in most cases.92

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 Use and Abuse of Clonazepam

The use of benzodiazepines to treat insomnia should be COMBINATION WITH OTHER DRUGS
maintained only for short periods, and the initial treatment It is well known that clonazepam is rarely misused alone. The
should, in any event, be stopped after four continuous practice of mixing clonazepam with other drugs is frequently
weeks.93 Benzodiazepines are known to alter sleep patterns observed and reported in the literature.66 An example would
and have been reported, mainly with prolonged use, to exac- be a report of a fatality caused by the combination of clonaz-
erbate the sleep disturbances for which they were initially epam with oxycodone.58 The victim had consumed both sub-
prescribed.87 Extended use of clonazepam, for example, is stances at a much higher concentration than the therapeutic
commonly associated with poor sleep quality.94 Regarding doses—in addition to other substances such as nicotine, can-
EEG sleep patterns, benzodiazepines increase sigma-band nabinoids, and trazodone. While being anecdotal and provid-
power and reduce the presence of frequencies lower than ing limited evidence regarding the benzodiazepine-opioid
10 Hz, which has been characterized as the “GABA- combination, this case may serve to illustrate both the risk
benzodiazepine signature.”95 Benzodiazepines can also in- of combining benzodiazepines with other drugs and the kind
crease the concentration of sleep spindles during sleep stage of polydrug use that might be detected in large-scale studies.
N2 and suppress rapid eye movement (REM) sleep.96 The In a recent study using urine samples collected from individ-
changes observed in sleep architecture may be reversible.97 uals with substance use disorder, Heikman and colleagues114
Moreover, extended benzodiazepine use can result in the de- reported the use of clonazepam in association with several
velopment of tolerance and loss of hypnotic effect, even if other drugs, such as methadone, amphetamines, and other
suppression of REM sleep is still observed.98,99 Evidence benzodiazepines. The study focused primarily not on benzo-
shows that the use of benzodiazepines can lead to difficulty diazepines, however, but on the use of new psychoactive sub-
in inducing and maintaining sleep and also to early morning stances. The self-reported use of different drugs was also
insomnia.100 Treatment discontinuation increases sleep somewhat unreliable since patients sometimes reported the
quality and ameliorates sleep architecture measures.99 use of drugs that were not detected in their samples; as the au-
Although benzodiazepines are commonly used to treat thors noted, users rarely know the exact composition of the
various sleep-related problems, it is well known that benzodi- drugs they consume.
azepines aggravate obstructive sleep apnea syndrome symp- The association of benzodiazepines with opioids is partic-
toms because of a reduction in muscle tone and decreased ularly common, as anxiolytic benzodiazepines can amplify
response to hypoxia.101 Of note, sleep apnea is very preva- the effects caused by opioids115 or even replace them tempo-
lent, found in about 32.9% of the population.102 Previous rarily, as when no opioid drugs are available.54 A common
studies have revealed that clonazepam seems to decrease cen- feature of all drugs with the potential for nonmedical use is
tral sleep apnea events at the cost of increasing obstructive their ability to increase mesolimbic dopamine levels, particu-
events.103 The worsening of obstructive sleep apnea syn- larly in the nucleus accumbens.116 Opioids induce an increase
drome symptoms, which can already influence daytime sleep- in dopamine signaling by binding to mu-opioid receptors lo-
iness and impair movement, might occur with administration cated on GABAergic interneurons in the ventral tegmental
of clonazepam, and should be considered when treating REM area (VTA), inhibiting the activity of GABAergic interneurons
sleep behavior disorder.104 and thereby disinhibiting VTA dopamine neurons that inner-
A point of interest regarding clonazepam in treating sleep- vate the nucleus accumbens.117 Although the mechanisms un-
related problems is its use as a self-medication to block the un- derlying the nonmedical use of benzodiazepines are not yet
wanted effects of other drugs. Stimulants like cocaine and fully understood, recent studies have shed light on the possi-
methylenedioxymethamphetamine (MDMA) induce marked ble neural basis for the addictive properties of benzodiaze-
sleep and mood disturbances.105–107 Administration of pines, suggesting a mechanism of action similar to that of
clonazepam and other benzodiazepines has become a fre- opioids. According to a review by Tan and colleagues,117 ben-
quent practice to alleviate those side effects.108–110 Nonethe- zodiazepines are thought to increase the firing of dopamine
less, while this self-medication practice is documented in the neurons in the VTA by binding to GABAA receptors located
literature, studies assessing it directly are still uncommon; in VTA GABAergic interneurons, thereby causing a disinhi-
most studies address, instead, the potentially therapeutic use bition of VTA dopamine neurons that innervate the nucleus
of benzodiazepines in face of the acute toxic effects of recrea- accumbens. Thus, benzodiazepines and opioids seem to ex-
tional drugs such as stimulants in general.111–113 Research on ert reinforcing properties through a similar mechanism de-
the nonmedical use and the self-treatment of unwanted side fined as disinhibition.117 Studies have proposed that GABAA
effects with clonazepam and other benzodiazepines remains receptors coexist with opioid receptors in VTA GABA inter-
necessary. In addition to being used in association with stim- neurons, as well as on dendrites present in GABAergic neurons
ulants to mitigate stimulant-induced sleep impairment, the in the nucleus accumbens.118,119 More recently, the reinforcing
use and misuse of clonazepam in association with other drugs properties of benzodiazepines have also been attributed to the
has been extensively reported (though not studied); of partic- presence of alpha-2 subunits in GABAA receptors of neurons
ular prominence in this context is its combination with other present in the nucleus accumbens.120 Finally, benzodiazepines
drugs of misuse. may also modulate the metabolism of opioids; previous studies

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V. Dokkedal-Silva et al.

demonstrated that diazepam, for example, is a noncompetitive and flunitrazepam, as well as with high doses of buprenorphine,
inhibitor of the methadone metabolic chain.8 As CYP3A4 par- a powerful opioid.12 Clonazepam in association with other
ticipates in clonazepam metabolism, there is a considerable benzodiazepines is commonly consumed in combination with
possibility that a similar interaction might occur. Studies in other drugs.66 Benzodiazepine use has been described in associ-
nonhuman primates have even shown that subjects prefer an ation with the nonmedical use of cocaine to modulate the effects
opioid-benzodiazepine mixture over opioids alone.121 of cocaine74—including the use of snorted benzodiazepines in
Based on a similar mechanism of action, studies have re- association with snorted crack.132 Grouped in a category of an-
peatedly reported a co-misuse of opioids and benzodiaze- xiolytic medications, benzodiazepines were found to be used in
pines. Combining benzodiazepines and prescribed opioids is combination with drugs such as cannabis, alcohol, lysergic acid
a popular practice.8 The use of clonazepam by individuals diethylamide (LSD), and ecstasy.13 As reported for cocaine, ben-
with methadone use disorder has been assessed in a rehabili- zodiazepine use has also been described in association with
tation clinic, where 11 out of 21 participants recognized clo- amphetamine-like stimulants in order to reduce the aftereffects
nazepam as a drug of misuse, and 8 knew its street value.122 (as described by the expression coming down from speed).66
Clonazepam use, with or without a prescription, at doses For example, the use of clonazepam has been reported in asso-
much higher than recommended, has been extensively associ- ciation with amphetamine and methamphetamine in blood
ated with the nonmedical use of opioids.14 The combination samples from intoxicated drivers arrested in Norway.70 Benzo-
with other drugs of misuse, especially opioids, is probably diazepines are also frequently used to reverse adverse effects
the most life-threatening risk associated with clonazepam’s from hallucinogens (so-called bad trips), mainly because of
nonmedical use. In a cohort study that assessed the risk of their capacity to interrupt or decrease the effects of halluci-
death in veterans who took combined benzodiazepines and nogenic drugs.133,134 Clonazepam has already been shown
opioids, Park and colleagues123 observed that the use of clo- to treat hallucinogen persisting perception disorder (HPPD)
nazepam and the vast majority of benzodiazepines is corre- caused by LSD.135
lated with an increased risk of death among patients using
opioids. When combined with the opioid tramadol, clonaze- ALTERNATIVES, PREVENTIVE MEASURES, AND
pam has also been shown to lead to an increase in neurons TREATMENT OF SIDE EFFECTS
that are associated with apoptosis, hemorrhage, perivascular Despite the growing need for different options that can at
space, and overall lethality.124 least partially replace the use of clonazepam and other benzo-
Studies have reported a high prevalence of concurrent use diazepines, the development of new medications that can ef-
of alcohol and benzodiazepines.125 According to the Treat- fectively treat the same conditions for which clonazepam is
ment Episode Data Set (TEDS) report, treatment admissions frequently prescribed is a slow-moving process. In the context
for the nonmedical use of benzodiazepines increased almost of sleep, non-benzodiazepine drugs for treating sleep im-
threefold between 1998 and 2008, with the co-misuse of opi- pairment and insomnia, the so-called Z-drugs, have gained
ates representing the majority of admissions, followed by al- increasing popularity in recent years.136 Importantly,
cohol.126 As a central nervous system depressant, alcohol zolpidem, one of the most prominent Z-drugs, is recom-
acts by binding to GABAA receptors, an effect that is likely mended by the American Academy of Sleep Medicine for
an important mechanism underlying its behavioral effects in treating insomnia.137 Although studies suggest the poten-
humans.127 Thus, alcohol and benzodiazepines seem to share tial for nonmedical use,138,139 Z-drugs have been proven
similar mechanisms of action that could account for the high to be safer than benzodiazepines for treating insomnia,
prevalence of concurrent use of those substances. In a study with a lower risk of habit formation and physical depen-
by Pauly and colleagues,128 almost 45% of individuals using dence.140 There is also compelling evidence on alternatives
clonazepam nonmedically also showed concomitant alcohol to clonazepam for treating REM sleep behavior disorder.
use. Due to their similarities, clonazepam has been shown to While clonazepam is still the standard treatment, evidence
be effective in treating acute alcohol withdrawal in humans.129 suggests zopiclone or zolpidem (two of the compounds
Data from the Drug Abuse Warning Network (DAWN) from the class of Z-drugs) are effective substitutes for treating
has shown that in combination with opioids or alcohol, ben- that disorder.141 Rivastigmine, a medication for treating
zodiazepines produce a 24%–55% increase in the predicted Alzheimer’s disease, has also been shown to be effective.142
risk of more serious outcomes arising from emergency depart- In addition to the sleep-related effects, alternatives to using
ment visits, including hospitalization and death.130 In addition clonazepam in anxiety and depression have also been investi-
to alcohol and opioids, other central nervous system depres- gated. Selective serotonin reuptake inhibitors are still the first-
sants, such as barbiturates, potentiate the effects of clonaze- line treatment for depressive episodes.143,144 Other treatment
pam.15 Benzodiazepines increase the frequency with which options include the antidepressant trazodone, which has been
chloride channels open, while barbiturates promote a longer shown to be a safe alternative to using clonazepam in depres-
opening interval,131 resulting in a synergistic interaction. sion and does not differ in efficacy from SSRIs.145,146 The use
The use of clonazepam has also been observed in associa- of benzodiazepines for anxiety is a matter of concern, as
tion with other benzodiazepine drugs, such as bromazepam self-medication to treat anxiety disorders is considered a

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Copyright © 2019 President and Fellows of Harvard College. Unauthorized reproduction of this article is prohibited.
 Use and Abuse of Clonazepam

common reason for using benzodiazepines nonmedically,146 monitoring showed encouraging positive results;59 by regu-
and very few substitutes are currently available. Much of the larly measuring serum concentrations of the used medication,
literature on ceasing benzodiazepine treatment focuses on suc- this form of monitoring “allows tailoring the treatment to the
cessfully controlling withdrawal symptoms and on ceasing specific needs of individual patients,” including through dose
benzodiazepine treatment without offering substitutes.59 It is adjustment over the course of withdrawal. The success of this
well known, however, that benzodiazepine-dependent patients treatment approach suggests that non-pharmacological ther-
are frequently unable to maintain long-term abstinence.147 In apies might be useful for treating clonazepam addiction. Fur-
this setting, alternatives that can act as clonazepam substi- ther investigation remains necessary, however, to evaluate
tutes should be investigated. Buspirone has become a promis- long-term remission.
ing alternative for treating anxiety disorders, but reports also Finally, considering that the primary source of illicit benzo-
indicate that it is effective as an antidepressant, either in diazepines is from doctors’ prescriptions, caution should be
monotherapy or as adjunctive treatment.148–150 Interest is taken when prescribing the use of clonazepam and other ben-
also growing in the use of valerian, a phytotherapeutic that zodiazepines for treating conditions such as anxiety and sleep
may have positive effects on both insomnia and anxiety, as impairment. With the nonmedical use of benzodiazepines be-
demonstrated in animal studies.151,152 Evidence for its anxio- ing a growing public health concern, the present review has
lytic properties in patients, however, still needs to be devel- emphasized the need for raising awareness about the nonmed-
oped.153,154 Next-generation antidepressants, such as ical use of clonazepam and also other benzodiazepines. The
vortioxetine, may also be effective in treating anxiety lack of knowledge and understanding regarding this phenom-
symptoms.155 Vilazodone, a serotonin 5-HT1A receptor enon represents a significant problem that demands serious
partial agonist, has been shown to be effective in reducing consideration from health professionals and policy makers.
mean scores in the Hamilton Anxiety Rating Scale, compared
to placebo, in a pool of 708 patients diagnosed with anxious CONCLUSIONS
depression.156 Besides the already available pharmacother- The broad pharmacological action of clonazepam translates
apies, studies have also been focusing on developing new into therapeutic efficacy; for example, it has been proven ef-
compounds with distinct intrinsic efficacy at α1, α2, α3, fective for treating several clinical conditions, including
and α5 subunit–containing GABAA receptors; the aim is to REM sleep behavior disorder, anxiety, and depression. But
determine the role of distinct GABAA receptor subtypes in there is also a high risk of abuse and nonmedical use, poten-
benzodiazepine-induced anxiolytic, sedative, and reinforcing tially resulting in seriously adverse health outcomes, includ-
effects, potentially leading to the identification of selective ing motor and memory impairment, physical dependence,
treatment options.5,157–160 tolerance, and withdrawal symptoms. Given such effects
To reduce the abuse of clonazepam, better law enforce- and the easy access to this drug, controlling its availability
ment to reduce illegal sales of clonazepam is required, as are and use—that is, achieving a balance between the associated
efforts to curb the practice of obtaining clonazepam prescrip- benefits and risks—presents a major challenge. Investing in
tions from different physicians for later diversion. Frauger measures to control access to clonazepam and reduce its illegal
and colleagues12 reported measures taken by the French gov- distribution is essential. The establishment of harm-reduction
ernment to diminish illegal sales of clonazepam (and previ- strategies, the development of alternatives to clonazepam,
ously flunitrazepam). The study used the general health and improved treatments for those who abuse clonazepam
insurance system, a database that includes the majority of or who use it nonmedically remain important goals.
the unemployed and salaried population, to track down the
number of clonazepam deliveries, number of clonazepam pre- Declaration of interest: The authors report no conflicts of in-
scriptions, pharmacies visited, and estimated mean daily dose terest. The authors alone are responsible for the content and
of clonazepam (the defined daily dose) used by each individ- writing of the article.
ual.12 Through this monitoring, it was possible to track down
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