Add 117 2075
Add 117 2075
Add 117 2075
DOI: 10.1111/add.15743
1
National Centre for Youth Substance Use Abstract
Research, The University of Queensland, St
Lucia, QLD, Australia Background and Aims: Cannabis withdrawal is a well-characterized phenomenon that
2
Discipline of Psychiatry, Faculty of Medicine, occurs in approximately half of regular and dependent cannabis users after abrupt cessa-
The University of Queensland, Herston, QLD,
tion or significant reductions in cannabis products that contain Δ9-tetrahydrocannabinol
Australia
3
Center for Technology and Behavioral Health,
(THC). This review describes the diagnosis, prevalence, course and management of can-
Geisel School of Medicine at Dartmouth, nabis withdrawal and highlights opportunities for future clinical research.
Lebanon, NH, USA
4
Methods: Narrative review of literature.
Translational Addiction Research Laboratory,
Campbell Family Mental Health Research Results: Symptom onset typically occurs 24–48 hours after cessation and most symp-
Institute, Centre for Addiction and Mental toms generally peak at days 2–6, with some symptoms lasting up to 3 weeks or more in
Health, University of Toronto, ON, Canada
5 heavy cannabis users. The most common features of cannabis withdrawal are anxiety,
Departments of Family and Community
Medicine, Psychiatry, Pharmacology and irritability, anger or aggression, disturbed sleep/dreaming, depressed mood and loss of
Toxicology, University of Toronto, ON,
appetite. Less common physical symptoms include chills, headaches, physical tension,
Canada
6
Queensland Alliance for Environmental sweating and stomach pain. Despite limited empirical evidence, supportive counselling
Health Sciences, The University of and psychoeducation are the first-line approaches in the management of cannabis with-
Queensland, Woolloongabba, QLD, Australia
drawal. There are no medications currently approved specifically for medically assisted
Correspondence withdrawal (MAW). Medications have been used to manage short-term symptoms
Professor Jason P. Connor, Director, National
(e.g. anxiety, sleep, nausea). A number of promising pharmacological agents have been
Centre for Youth Substance Use Research,
The University of Queensland, St Lucia, 4067 examined in controlled trials, but these have been underpowered and positive findings
QLD, Australia.
not reliably replicated. Some (e.g. cannabis agonists) are used ‘off-label’ in clinical prac-
Email: [email protected]
tice. Inpatient admission for MAW may be clinically indicated for patients who have sig-
Funding information nificant comorbid mental health disorders and polysubstance use to avoid severe
None.
complications.
Conclusions: The clinical significance of cannabis withdrawal is that its symptoms may
precipitate relapse to cannabis use. Complicated withdrawal may occur in people with
concurrent mental health and polysubstance use.
KEYWORDS
assessment, cannabis withdrawal syndrome, clinical management, pharmacology, prevalence, time
course
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any
medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
© 2021 The Authors. Addiction published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.
Description
Cannabis dependence
Cannabis withdrawal refers to symptoms that occur after abrupt
cessation or significant reductions in the use of cannabis products Individuals with cannabis use disorder (CUD) generally experience
containing Δ -tetrahydrocannabinol (THC), the main psychoactive
9
greater severity and duration of cannabis withdrawal symptoms than
component in cannabis. These symptoms occur most often in regu- those without CUD. This is most probably related to the greater fre-
lar and heavy cannabis users and the most common symptoms are quency and quantity of their cannabis use and their heavier exposure
anxiety, irritability, anger or aggression, disturbed sleep/dreaming, to THC [8]. CUD is characterized by persistent cannabis use despite
depressed mood and loss of appetite. Less commonly reported negative effects on the social functioning and physical or mental
physical symptoms include chills, headaches, physical tension, health of the user or the health of other individuals. Two diagnostic
sweating and stomach pain [1, 2]. Cessation of short-term systems classify and define the severity of the disorder: the Diagnos-
cannabidiol (CBD), a non-psychoactive cannabinoid, does not tic and Statistical Manual of Mental Disorders (DSM)-5 [1] and Inter-
appear to result in withdrawal [3]. national Classification of Diseases (ICD)-11 [9]. CUD severity is coded
Symptom onset typically occurs 24–48 hours after cessation and in DSM-5 as mild (presence of two to three symptoms), moderate
most symptoms generally peak at days 2–6. The duration and severity (presence of four to five symptoms) or severe (presence of six or more
of cannabis withdrawal is associated with the amount of cannabis symptoms). ICD-11 classifies cannabis use into hazardous cannabis
consumed before cessation, but can vary considerably. In heavy users use (potential to cause harm), harmful pattern of cannabis use (causing
withdrawal symptoms can occur for up to 2–3 weeks or longer. harm) and cannabis dependence.
A meta-analysis pooling studies of more than 20 000 regular and The cannabis plant contains approximately 120 cannabinoids, the
dependent cannabis users estimated that 47% of individuals reported most studied of which are THC and CBD. The body’s own endoge-
cannabis withdrawal measured by standardized scales [4]. The preva- nous cannabinoids act as partial agonists of the body’s CB1 and CB2
lence in community samples was 17%, increasing to 54% in outpatient receptors [10, 11], as does THC [12], whereas CBD acts as an alloste-
samples and 87% in inpatients [4]. ric modulator of these receptors [13, 14]. The psychoactive effects of
The prevalence of cannabis withdrawal symptoms is higher in THC are underpinned by its strong affinity for CB1 receptors, which
users with a history of daily cannabis use, concurrent cannabis and are predominantly distributed within the brain. CB1 antagonists, such
tobacco use and other substance use disorders [4]. as rimonabant, reduce the subjective effects of cannabis, demonstrat-
ing the role of CB1 binding in the psychoactive effects of cannabis
use [15]. THC has a much lower affinity for the CB2 receptor that is
Objectives of management predominantly found in immune cells. Conversely, CBD has a stronger
affinity for the CB2 receptor, but has a relatively much lower affinity
Cannabis withdrawal does not carry a high risk of severe adverse out- for either receptor than THC.
comes. The presence of medical or psychiatric comorbidities such as There are endogenous cannabinoid neurotransmitters in humans
polysubstance use and dependence may result in more severe compli- and other animals. The best-characterized are anandamide (AEA) and
cations and symptoms of cannabis withdrawal, necessitating addi- 2-arachidonoylglycerol (2-AG). These endocannabinoids are degraded
tional management. The clinical significance of cannabis withdrawal is by enzymes that include fatty acid amide hydrolase (FAAH) for ana-
that it may undermine abstinence by precipitating a relapse to canna- ndamine and monoacylglycerol lipase (MAGL) for 2-AG. THC is
bis use which immediately relieves these symptoms [5]. Irritability and metabolized by the enzymes CYP3A4 and CYP2C9 [16]. FAAH bind-
mood effects can also negatively impact personal relationships and ing is reduced in chronic and recent cannabis users [17], and inhibition
work productivity. of FAAH using PF-04457845 has been shown to reduce cannabis
Synthetic cannabinoids (SCBs) are classed as new psychoactive withdrawal [18].
substances (NPS) and are made in clandestine laboratories. Unlike There is good neurobiological and clinical evidence for a pharma-
cannabis, SCBs are a heterogeneous group that may contain multiple, cologically specific cannabis withdrawal syndrome. CB1 antagonists
typically synthetic compounds with broad structural diversity and are precipitate specific withdrawal symptoms in animal models of canna-
therefore not reviewed in this paper. SCBs can be 2–100 times more bis dependence [19]. In human studies, administration of CB1 agonists
potent than THC [6], are more likely to result in problematic use and (THC) blocks or relieves withdrawal symptoms [20–22]. Neurobiologi-
faster development of tolerance and potentially result in more severe cal and clinical studies indicate that symptoms of cannabis withdrawal
MANAGEMENT OF CANNABIS WITHDRAWAL 2077
are consistent with the core symptoms of other substance withdrawal complete concordance. An adaption of the MWC, the 14-item com-
syndromes and reflect neurochemical changes in the limbic system [2]. posite withdrawal scale (WDS [26]), corresponds more closely with
cannabis withdrawal symptoms described in the DSM-5. By compari-
son with other substance withdrawal scales (e.g. alcohol withdrawal
Cannabis withdrawal criteria DSM-5 and ICD-11 scale), there has been limited psychometric validation of the various
cannabis withdrawal scales.
Withdrawal was included as a distinct disorder and as a CUD diagnos-
tic criterion item in DSM-5. Cannabis withdrawal is also included in
ICD-11 (Table 1). Differential diagnosis
DSM-5 Cannabis withdrawal disorder (292.0) [1] ICD-11 Cannabis withdrawal (6C41.4) [9]
F I G U R E 1 Typical course of cannabis withdrawal. Adapted from Goodwin et al. [35] and Queensland Health (2012) [34, 90]. Typical urinary
tetrahydrocannabinol carboxylic acid (THC-COOH; the main secondary metabolite of THC) levels are drawn from Goodwin et al. [35] and reflect
high-range, chronic cannabis use
an incremental and slow reduction in cannabis intake and/or use of managing withdrawal. Most pharmacological studies of withdrawal
lower THC products over an extended period (weeks) may reduce the include some form of concurrent behavioural intervention, but the dif-
probability and severity of withdrawal symptoms. ferential efficacy of these behavioural approaches has not been
assessed (Table 2).
A 12-week single-arm cognitive behavioural therapy (CBT)
Risks/benefits study randomly assigned 13 regular cannabis users to selective
serotonin re-uptake inhibitors (SSRI) or placebo. It found no signifi-
There are few risks related directly to cannabis withdrawal. cant differences on the Clinical Institute Withdrawal Assessment
The greatest risk is relapse [5]. Previously highlighted in this review (CIWA) scores (adapted for cannabis) [39] between patients who
is elevated risk of polysubstance use and concurrent withdrawal relapsed and those who did not. Changes in CIWA scores in
from higher-risk substances. If cannabis withdrawal exacerbates response to CBT were not reported nor any differences between
depression ( suicide), anxiety and psychosis, then risks are those given SSRI or placebo [40].
increased and more regular monitoring and delay in detoxification Despite limited evidence, standard clinical practice typically
may be clinically indicated. All medications carry risk of side- includes psychoeducation on the course and symptoms of withdrawal,
effects. Consideration should be given to the potential side-effects coping with craving exercises, nutrition, hydration, physical exercise
of using pharmacotherapies that are largely untested in this popu- and sleep hygiene. It can also include motivational approaches and
lation, compared to the temporary uncomfortable withdrawal coping skills training [41]. Skills training in CBT such as relaxation
period. approaches, pleasant activity scheduling, managing stress/mood/
anger and goal-setting may be of clinical benefit.
Physical exercise has been associated with improved scores in the
Non-pharmacological interventions Marijuana Craving Questionnaire—short form (MCQ-SF) in a pilot
study (n = 10) of non-treatment-seeking, cannabis-dependent adults
To our knowledge, there are no high-quality studies on the most [42]. Standard sleep hygiene protocols [43] and CBT-insomnia (CBT-I
effective behavioural approaches and no studies that compare the [44]) may improve sleep in cannabis withdrawal, but this has not been
effectiveness of behavioural and pharmacological approaches to well studied [45].
TABLE 2 Pharmacotherapy studies for cannabis withdrawal
2080
Cannabis agonists
Dronabinol No Secondary [46, 54] Randomized, double-blind 12 week outpatient Replication RCTs required with cannabis
study of cannabis-dependent users [46]. withdrawal as a primary outcome. Greater than
Primary outcome was cannabis abstinence. one-third attrition among studies
Patients (n = 79) were titrated to 20 mg twice
daily over the period of 1 week, or placebo
(n = 77). Both groups received weekly coping
skills intervention and MET
Dronabinol increased treatment retention and
reduced cannabis withdrawal symptoms
(measured by the WDS) over time compared
to placebo. Medication was well tolerated and
no difference in side effects reported between
groups [46]
An RCT by the same authors as [46] found no Outcomes relied on self-report. Not possible to
benefit from adding lofexidine (a potent α2- examine dronabinol in absence of lofexidine
adrenergic receptor agonist with moderate
agonist effects) to dronabinol (n = 61) on
cannabis withdrawal (measured by the WDS),
compared to placebo (n = 61) in cannabis-
dependent individuals [54]
Nabiximols, Nabilone No Primary [48] Randomized, double-blind inpatient study of Larger-scale validation RCTs required to assess the
cannabis-dependent users (mean 22.98 g/ effectiveness of nabiximols in cannabis
week) [48]. Patients (n = 27) completed a 6- withdrawal, including dose–response data.
day regimen of nabiximols providing a maximal Treatment withdrawal high (> 1/3). Baseline
daily dose of 86.4 mg THC and 80 mg CBD or CWS score differed between groups
placebo (n = 24). Both groups received CBT-
based self-completed work-books during a 9-
day admission
Nabiximols reduced CWS scores for the duration
of treatment and improved retention relative
to placebo. No serious adverse events or
differences in side effects reported between
groups [48]
Secondary [56] Cannabis-dependent outpatients were randomized Pilot study with small sample size. High variability
(double-blind) to either as-needed (self- in amount of nabiximols self-administered
titrated) nabiximols spray (n = 20) up to
113.4 mg THC/105 mg CBD or placebo
(n = 20) daily for 12 weeks. Primary outcomes
were tolerability and cannabis abstinence.
Secondary outcomes were cannabis use,
(Continues)
CONNOR ET AL.
TABLE 2 (Continued)
(Continues)
TABLE 2 (Continued)
2082
(Continues)
TABLE 2 (Continued)
(Continues)
TABLE 2 (Continued)
2084
(Continues)
TABLE 2 (Continued)
2086
(Continues)
TABLE 2 (Continued)
(Continues)
MANAGEMENT OF CANNABIS WITHDRAWAL 2089
Medication of choice
report; MOS-SS = medical outcomes study—sleep scale; MWC and MWSC = marijuana withdrawal (symptom) checklist; POMS = profile of mood states; PSQI = Pittsburgh sleep quality index; RCT = randomized
controlled trial; REM = rapid eye movement; SIS = Snaith irritability scale; SMHSQ = St Mary’s Hospital sleep questionnaire; SSRI = selective serotonin re-uptake inhibitors; STAI = state–trait anxiety inventory;
scale; Hamilton anxiety questionnaire; HSC = Hopkins symptom checklist; ITT = intention to treat; MET = motivational enhancement therapy; MCQ = marijuana craving questionnaire; MCr = marijuana craving
BAI = Beck Anxiety Inventory; BDI and BDI–II = Beck Depression Inventory; CBD = cannabidiol; CBT = cognitive behavioural therapy; CWS = cannabis withdrawal scale; HAQ = HAM-A = Hamilton anxiety
Cannabis withdrawal pharmacotherapy
15 years, but remains less developed than for other drugs of abuse.
Nineteen placebo-controlled studies (17 Clinical; two experimen-
tal) and one open-label, non-placebo controlled trial have been
reported (Table 2). Sixteen were randomized designs. Fewer than half
(n = 9) report cannabis withdrawal (or individual cannabis withdrawal
symptoms) as a primary outcome and only three recruited more than
50 participants in the medication arm, two of which found a signifi-
cant benefit from medication over placebo (dronabinol [46],
quetiapine [47]). Attrition among the 17 clinical studies was typically
number of adverse events. Primary outcomes
than placebo. This was not true in all cases (e.g. divalproex did
not reduce irritability, depression and anxiety [63] and topiramate
did not improve mood [64]).
The research on medications for MAW in treatment-seeking,
cannabis-using populations is limited by the small number and low
quality of studies. Larger replication studies are required to test the
in study
TABLE 3 Examples of medication used in clinical practice • Psychiatric history: currently reports elevated anxiety and a history
General withdrawal and previous diagnosis of unipolar depression. Denies history of
features (off-label) Medications schizophrenia or psychotic disorders. [Clinician query: cannabis
withdrawal-induced psychosis.] Denies thoughts of self-harm.
• Dronabinol (one positive trial [46])a
• Nabiximols (two positive trials [48, 56]a • Medication: escitalopram 20 mg (non-compliant), captopril 25 mg
• Gabapentin (one positive trial [50]) (non-compliant), continuous positive airway pressure (CPAP) ther-
• Nabilone [62] apy (non-compliant).
Anxiety and agitation • Diazepam
Severe tremors • Diazepam Substance use history
Nausea/stomach pain • Metoclopramide The patient reports daily use of cannabis (average 2 g per day, or
• Hyoscine approximately eight joints), nicotine 15 ‘tailor-made’ manufactured
• Promethazine
cigarettes per day plus ‘spins’ loose tobacco with high THC content
• Non-opioid analgesia (e.g. paracetamol
assuming normal liver function) cannabis plant ‘buds’. He reports infrequent use of alcohol (average
three standard drinks peer week) and non-prescribed prescription opi-
Psychotic symptoms/ • Antipsychotics (e.g. olanzapine,
hallucinations quetiapine) oids (oxycodone 10 mg when available, typically one tablet per fort-
Sleep disturbances • Zolpidem, extended release [61] night). The patient states his longest drug-free period occurred
• Diazepam 15 years ago for 6 months after meeting his now partner (aged
• Promethazine 33 years). He scores 6 on the Alcohol Use Disorders Identification
a
May test positive to cannabinoids in drug-testing. Test (AUDIT) [67], where ≥ 16 is suggestive of alcohol-related prob-
lems, 13 on the Severity of Dependence Scale (SDS) [68], where ≥ 3
of 15 is indicative of cannabis-related problems and 10 (range = 0–10)
C O M P L E X CA S ES on the Fagerström Test for Nicotine Dependence (FTND [69]), indi-
cating a high level of dependence. He reports no history of significant
The case presented in this review reflects a common, complex substance withdrawal.
presentation.
Polysubstance use is common in cannabis users, with alcohol use
disorder (OR = 6.0) and nicotine use disorder (OR = 6.2) the most Withdrawal assessment
widely co-used substances [27]. Psychiatric comorbidity is also com-
mon, with the two most common mental health problems (besides Cannabis is commonly used with tobacco [70], and in treatment-
substance use disorders) mood and anxiety disorders [65, 66]. In can- seeking cannabis users approximately two-thirds also use tobacco
nabis use disorder the OR of having any mood disorder is 3.8 and for [71]. Tobacco withdrawal symptoms overlap with cannabis withdrawal
any anxiety disorder is 2.8 [27]. and may have a similar intensity and time-course [72, 73]. Table 4 out-
lines the withdrawal features observed in this complex case and possi-
ble management. Nicotine replacement therapy (NRT) may be
Presentation considered during the withdrawal period and post-detoxification if
the patient desires to quit nicotine.
A 48-year-old male presented to a primary care provider with stom- The decision to recommend inpatient admission or outpatient
ach cramps, headache and elevated anxiety symptoms that have withdrawal in this presentation relies upon an accurate assessment of
prevented him from working for 48 hours. He stated that while he has the brief psychotic episodes and their potential impact on the
been off work, he has heard infrequent but multiple unfamiliar voices patient’s functioning. Withdrawal from other substance use that may
telling him that he is going to lose his job. The patient reports that he increase risk of adverse outcomes (e.g. alcohol other CNS depres-
has been having relationship problems with his partner of 15 years, sants, opioids) is not present. The patient denies suicidal thoughts, but
primarily due to his substance use. He ceased all substance use reports dysthymic mood that is typical for him. He states that his can-
60 hours prior to the assessment. nabis use is heavier at night in an attempt to improve his sleep, and
Psychosocial history ceasing use has impaired sleep quality. He reports that his partner of
The patient is currently on sick leave but has a history of stable 15 years is highly supportive of his cessation attempt and committed
employment. He is married with no children. There are financial con- to a substance-free relationship.
cerns due to time off work. The patient reported a preference for home detoxification. He
attended with his partner, who reports that they can monitor him
• Medical history: he reports stomach cramps, headache, irritability/ closely over the next 5 days. The patient consented to attending
anger, loss of appetite, some chills and sweating. Previous history primary care appointments daily over the next week. The main
of hypertension, disturbed sleep, mild–moderate sleep apnoea; management approach to consider is a cannabinoid agonist
body mass index (BMI) is 35. (e.g. nabilone, off-label) that could be slowly titrated upwards. If
MANAGEMENT OF CANNABIS WITHDRAWAL 2091
TABLE 4 Complex case: observed and self-report symptoms and possible management
Withdrawal scale scores CWS [25] = 140 MNWS [91,92] = 14 Main management approach for cannabis withdrawal
(range = 0–190) (observer range = syndrome: cannabinoid agonist (e.g. nabilone,
0–16) off-label)
Nausea, abdominal cramps, muscle aches ++ + Metoclopramide
Non-opioid analgesia
Consider dronabinol (specific for nausea and general
for cannabis withdrawal)
Headache ++ ++ Non-opioid analgesia
Insomnia ++ ++ Sleep hygiene, CBT-I
Zolpidem, diazepam
Anxiety ++ ++ Supportive counselling
Diazepam
Recommence escitalopram
Psychosis (query cannabis withdrawal-induced) ++ – Quetiapine
Irritability + + Psychoeducation
Diazepam
Aggressive behaviour + + Psychoeducation
Diazepam
Restlessness + + Diazepam
Sweating and chills + + Supportive management
Decreased appetite + – Nutrition support
Consider dronabinol (specific for appetite and general
for cannabis withdrawal)
++ Strong withdrawal feature present; + withdrawal feature present; − withdrawal features not present; CBT-I = CBT-insomnia.
TABLE 5 Low-risk cannabis consumption guidelines evaluated in controlled research settings. Given the heterogeneity of
Using lower THC content products cannabis withdrawal features and substantial individual variations
Adopting methods other than inhalation (if inhaling, avoid ‘deep between patients, new developments in the management of cannabis
inhalation’) use disorder and withdrawal are likely to include more targeted
Refraining from daily or near-daily or binging on cannabis use behavioural approaches (e.g. [77, 88]). The provision of increased on-
Where available, using legal and quality-controlled cannabis products line and digital approaches to assist patients in managing cannabis
and devices withdrawal may improve accessibility and reduce costs, compared to
If cognitive performance is impaired, temporarily suspending or face-to-face health services.
substantially reducing intensity of use (e.g. frequency/potency) The legalization of non-medical cannabis use in a number of high-
Abstaining while pregnant or breastfeeding income countries has reduced cannabis prices and increased sales of
Avoiding cannabis while driving, using machinery or engaged in other high-potency cannabis products in these jurisdictions [89]. The canna-
high-risk activities bis industry is lobbying to reduce cannabis taxes, opposing restrictions
Exercising caution in combining other psychoactive substances with on maximum THC levels and promoting the sale of high-potency can-
cannabis use
nabis such as cannabis edibles, oils, extracts and waxes. Although the
Avoiding (or adjusting) use in the presence of psychosis, other effects of these changes have not yet been formally evaluated,
psychiatric comorbidities and/or a history of substance use
increased use of high-potency cannabis is likely to increase the risks
disorders
for CUD and the severity of withdrawal [77]. Public health messaging
should include independent information and advice on the risks of
using higher-potency cannabis.
[77]. However, many patients enter treatment with moderation goals
and clinicians must adapt their approaches to work effectively with DECLARATION OF INTERESTS
these patients. Reduced use is a common outcome in outpatient stud- J.P.C., D.S., A.J.B. and W.D.H. declare no competing interests. B.LeF.
ies, but how long these reductions are maintained and whether has obtained funding from Pfizer (GRAND Awards, including salary
reduced use improves psychosocial functioning remains unclear. To support) for investigator-initiated projects. B.LeF. has some in-kind
retain patients with a moderation goal in a therapeutic relationship donation of cannabis product from Aurora and medication donation
and reduce the risk of future cannabis related-problems, low-risk from Pfizer and Bioprojet and was provided a coil for TMS study from
guidelines have been endorsed by a number of health jurisdictions Brainsway. B.LeF. has obtained industry funding from Canopy
(e.g. [84]) and health experts [85] (see Table 5). (through research grants handled by CAMH or University of Toronto),
Most cannabis users also use other substances [27, 28]. Meta- Bioprojet, ACS and Alkermes. B.LeF. has received in kind donations of
analyses demonstrate that psychosocial treatments for polysubstance nabiximols from GW Pharma for past studies funded by CIHR and
use have weak efficacy compared to single-substance psychosocial NIH. He has been a consultant for Shionogi.
treatments [86]. There are insufficient studies to recommend either
treating multiple substances sequentially or concurrently. However, a AC KNOW LEDG EME NT S
recent meta-analysis found that combined tobacco and/or cannabis The Australian National Centre for Youth Substance Use Research
interventions had a modest effect on reducing cannabis but not (J.P.C., W.D.H., D.S.) is supported by funding from the Australian
tobacco. These combined interventions did not increase tobacco or Government provided under the Commonwealth Drug and Alcohol
cannabis cessation rates [87]. Program grant. B.LeF. is supported by CAMH, a clinician–scientist
award from the department of Family and Community Medicine of
the University of Toronto and a Chair in Addiction Psychiatry from
NEW DEVELOPMENTS the department of Psychiatry of University of Toronto. A.J.B. is
supported in part by US National Institute on Drug Abuse (NIDA)
The management of substance withdrawal typically includes pharma- grants P30DA029926, T32DA037202 and R01DA015186. The
cological agents which reduce clinically significant withdrawal symp- funding bodies had no role in the study design, collection, analysis or
toms. Cannabis does not have any approved medications for MAW, interpretation of the data, writing the manuscript, or the decision to
despite a well-recognized and clinically significant withdrawal profile. submit the paper for publication. We would like to thank Professor
A number of novel agents have been examined with some promising John B. Saunders for his expert review and feedback on previous
results (Table 2). This is an important avenue of future research, with versions of this manuscript.
some agents showing early efficacy. For this reason, cannabis agonists
have been cautiously used ‘off-label’ for cannabis withdrawal. AUTHOR CONTRIBU TIONS
The mainstay of cannabis withdrawal management has been psy- Jason Connor: Conceptualization; project administration; supervision.
chosocial education, supportive counselling and behavioural therapies. Daniel Stjepanovic: Conceptualization; data curation. Alan Budney:
Despite the wide use of these approaches in clinical practice, few Conceptualization. Bernard Le Foll: Conceptualization; data curation.
empirical studies have been conducted. These approaches need to be Wayne Hall: Conceptualization; supervision.
MANAGEMENT OF CANNABIS WITHDRAWAL 2093
ORCID 15. Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA,
Jason P. Connor https://orcid.org/0000-0002-7020-1196 Moolchan ET, et al. Blockade of effects of smoked marijuana by the
CB1-selective cannabinoid receptor antagonist SR141716. Arch Gen
Daniel Stjepanovic https://orcid.org/0000-0003-4307-423X
Psychiatry. 2001;58(4):322–28.
Alan J. Budney https://orcid.org/0000-0001-6308-6823 16. Cox EJ, Maharao N, Patilea-Vrana G, Unadkat JD, Rettie AE,
Bernard Le Foll https://orcid.org/0000-0002-6406-4973 McCune JS, et al. A marijuana-drug interaction primer: precipitants,
Wayne D. Hall https://orcid.org/0000-0003-1984-0096 pharmacology, and pharmacokinetics. Pharmacol Ther. 2019;201:
25–38.
17. Boileau I, Mansouri E, Williams B, Le Foll B, Rusjan P, Mizrahi R, et al.
RE FE R ENC E S Fatty acid amide hydrolase binding in brain of cannabis users: imag-
1. American Psychiatric Association. Diagnostic and Statistical Manual ing with the novel radiotracer [11C]CURB. Biol Psychiatry. 2016;80:
of Mental Disorders: DSM-5. 5th ed. Washington, DC: American 691–701.
Psychiatric Association; 2013. 18. D’Souza DC, Cortes-Briones J, Creatura G, Bluez G, Thurnauer H,
2. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Deaso E, et al. Efficacy and safety of a fatty acid amide hydrolase
Opin Psychiatry. 2006;19:233–8. inhibitor (PF-04457845) in the treatment of cannabis withdrawal
3. Taylor L, Crockett J, Tayo B, Checketts D, Sommerville K. Abrupt and dependence in men: a double-blind, placebo-controlled, parallel
withdrawal of cannabidiol (CBD): a randomized trial. Epilepsy Behav. group, phase 2a single-site randomised controlled trial. Lancet
2020;104:106938. Psychiatry. 2019;6:35–45.
4. Bahji A, Stephenson C, Tyo R, Hawken ER, Seitz DP. Prevalence of 19. Lichtman AH, Martin BR. Marijuana withdrawal syndrome in the
cannabis withdrawal symptoms among people with regular or depen- animal model. J Clin Pharmacol. 2002;42:20S–7S.
dent use of cannabinoids: a systematic review and meta-analysis. 20. Budney AJ. Review of the validity and significance of cannabis with-
JAMA Netw Open. 2020;3:e202370. drawal syndrome. Am J Psychiatry. 2004;161:1967–77.
5. Davis JP, Smith DC, Morphew JW, Lei X, Zhang S. Cannabis with- 21. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW.
drawal, posttreatment abstinence, and days to first cannabis use Abstinence symptoms following oral THC administration to humans.
among emerging adults in substance use treatment: a prospective Psychopharmacology. 1999;141:385–94.
study. J Drug Issues. 2016;46:64–83. 22. Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. Absti-
6. Castaneto MS, Gorelick DA, Desrosiers NA, Hartman RL, Pirard S, nence symptoms following smoked marijuana in humans. Psycho-
Huestis MA. Synthetic cannabinoids: epidemiology, pharmacody- pharmacology. 1999;141:395–404.
namics, and clinical implications. Drug Alcohol Depend. 2014;144: 23. Budney AJ, Moore BA, Vandrey RG, Hughes JR. The time course and
12–41. significance of cannabis withdrawal. J Abnorm Psychol. 2003;112:
7. Craft S, Ferris JA, Barratt MJ, Maier LJ, Lynskey MT, Winstock AR, 393–402.
et al. Clinical withdrawal symptom profile of synthetic cannabinoid 24. Budney AJ, Novy PL, Hughes JR. Marijuana withdrawal among adults
receptor agonists and comparison of effects with high potency can- seeking treatment for marijuana dependence. Addiction. 1999;94:
nabis. Psychopharmacology. 2021. Available at: https://doi.org/10. 1311–22.
1007/s00213-021-05945-1 25. Allsop DJ, Norberg MM, Copeland J, Fu S, Budney AJ. The Cannabis
8. Claus BB, Specka M, McAnally H, Scherbaum N, Schifano F, Withdrawal Scale development: patterns and predictors of cannabis
Bonnet U. Is the urine cannabinoid level measured via a commercial withdrawal and distress. Drug Alcohol Depend. 2011;119:123–9.
point-of-care semiquantitative immunoassay a cannabis withdrawal 26. Herrmann ES, Weerts EM, Vandrey R. Sex differences in cannabis
syndrome severity predictor? Front Psychiatry. 2020;11:1–11. withdrawal symptoms among treatment-seeking cannabis users. Exp
9. World Health Organization (WHO). International Classification of Clin Psychopharmacol. 2015;23:415–21.
Diseases for Mortality and Morbidity Statistics, 11th revision [inter- 27. Hasin DS, Kerridge BT, Saha TD, Huang B, Pickering R, Smith SM,
net]. Geneva, Switzerland: WHO; 2018. et al. Prevalence and correlates of DSM-5 cannabis use disorder,
10. Turner SE, Williams CM, Iversen L, Whalley BJ. Molecular pharma- 2012–2013: findings from the National Epidemiologic Survey on
cology of phytocannabinoids. In: Kinghorn AD, Falk H, Gibbons S, Alcohol and Related Conditions—III. Am J Psychiatry. 2016;173:
Kobayashi J, editorsPhytocannabinoids [internet], Progress in the 588–99.
Chemistry of Organic Natural Products 103 Cham: Springer Interna- 28. Connor JP, Feeney GFX, Kelly AB, Saunders JB. Polysubstance Use.
tional Publishing; 2017. p. 61–101 Available at: https://doi.org/10. In: The SAGE Handbook of Drug and Alcohol Studies. London, UK:
1007/978-3-319-45541-9_3 SAGE Publications Ltd; 2016. p. 283–305.
11. Morales P, Hurst DP, Reggio PH. Molecular targets of the 29. Antoniou T, Bodkin J, Ho JM-W. Drug interactions with cannabi-
phytocannabinoids: a complex picture. In: Kinghorn AD, Falk H, noids. Can Med Assoc J. 2020;192:E206–6.
Gibbons S, Kobayashi J, editorsPhytocannabinoids, Progress in the 30. Peters EN, Budney AJ, Carroll KM. Clinical correlates of co-occurring
Chemistry of Organic Natural Products 103 Cham: Springer Interna- cannabis and tobacco use: a systematic review: cannabis–tobacco
tional Publishing; 2017. p. 103–31. Available at: https://doi.org/10. clinical correlates. Addiction. 2012;107:1404–17.
1007/978-3-319-45541-9_4 31. Teesson M, Slade T, Swift W, Mills K, Memedovic S, Mewton L, et al.
12. Bow EW, Rimaldi JM. The structure–function relationships of classi- Prevalence, correlates and comorbidity of DSM-IV cannabis use and
cal cannabinoids: CB1/CB2 modulation. Perspect Med Chem. 2016; cannabis use disorders in Australia. Aust NZ J Psychiatry. 2012;46:
8:17–39. 1182–92.
13. Laprairie RB, Bagher AM, Kelly MEM, Denovan-Wright EM. 32. Hasan A, von Keller R, Friemel CM, Hall W, Schneider M, Koethe D,
Cannabidiol is a negative allosteric modulator of the cannabinoid et al. Cannabis use and psychosis: a review of reviews. Eur Arch
CB1 receptor: Negative allosteric modulation of CB1 by cannabidiol. Psychiatry Clin Neurosci. 2020;270:403–12.
Br J Pharmacol. 2015;172:4790–805. 33. Lerner A, Klein M. Dependence, withdrawal and rebound of CNS
14. Martínez-Pinilla E, Varani K, Reyes-Resina I, Angelats E, Vincenzi F, drugs: an update and regulatory considerations for new drugs
Ferreiro-Vera C, et al. Binding and signaling studies disclose a poten- development. Brain Commun. 2019;1(1):fcz025.
tial allosteric site for cannabidiol in cannabinoid CB2 receptors. Front 34. Queensland Health Queensland Alcohol and Drug Withdrawal
Pharmacol. 2017;23(8):1–10. Clinical Practice Guidelines [internet]. Herston, QLD: Mental Health,
2094 CONNOR ET AL.
Alcohol and Other Drugs Directorate; 2012, p. 128. Available at: 51. Budney AJ, Vandrey RG, Hughes JR, Moore BA, Bahrenburg B. Oral
https://insight.qld.edu.au/shop/queensland-alcohol-and-drug- delta-9-tetrahydrocannabinol suppresses cannabis withdrawal symp-
withdrawal-clinical-practice-guidelines-queensland-health-2012 toms. Drug Alcohol Depend. 2007;86:22–9.
accessed 10 August 2021. 52. Carpenter KM, McDowell D, Brooks DJ, Cheng WY, Levin FR. A pre-
35. Goodwin RS, Darwin WD, Chiang CN, Shih M, Li S-H, Huestis MA. liminary trial: double-blind comparison of nefazodone, bupropion-sr,
Urinary elimination of 11-nor-9-carboxy-Δ9-tetrahydrocannnabinol and placebo in the treatment of cannabis dependence. Am J Addict.
in cannabis users during continuously monitored abstinence. J Anal 2009;18:53–64.
Toxicol. 2008;32:562–9. 53. Johnston J, Lintzeris N, Allsop DJ, Suraev A, Booth J, Carson DS,
36. Verweij KJH, Agrawal A, Nat NO, Creemers HE, Huizink AC, et al. Lithium carbonate in the management of cannabis withdrawal:
Martin NG, et al. A genetic perspective on the proposed inclusion of a randomized placebo-controlled trial in an inpatient setting. Psycho-
cannabis withdrawal in DSM-5. Psychol Med. 2013;43:1713–22. pharmacology. 2014;231:4623–36.
37. Bedillion MF, Ansell EB. Differences in cannabis withdrawal symp- 54. Levin FR, Mariani JJ, Pavlicova M, Brooks D, Glass A, Mahony A,
toms for men and women over 21 days. Ann Behav Med. 2020;54: et al. Dronabinol and lofexidine for cannabis use disorder: a random-
S385–5. ized, double-blind, placebo-controlled trial. Drug Alcohol Depend.
38. Bonnet U, Preuss U. The cannabis withdrawal syndrome: current 2016;159:53–60.
insights. Subst Abuse Rehabil. 2017;8:9–37. 55. Penetar DM, Looby AR, Ryan ET, Maywalt MA, Lukas SE. Bupropion
39. Sullivan JT, Sykora K, Schneiderman J, Naranjo CA, Sellers EM. reduces some of the symptoms of marihuana withdrawal in chronic
Assessment of alcohol withdrawal: the revised clinical institute with- marihuana users: a pilot study. Subst Abuse. 2012;6:SART.S9706.
drawal assessment for alcohol scale (CIWA-Ar). Addiction. 1989;84: 56. Trigo JM, Soliman A, Quilty LC, Fischer B, Rehm J, Selby P, et al.
1353–7. Nabiximols combined with motivational enhancement/cognitive
40. Weinstein A, Miller H, Tal E, Avi IB, Herman I, Bar-Hamburger R, behavioral therapy for the treatment of cannabis dependence: a pilot
et al. Treatment of cannabis withdrawal syndrome using cognitive– randomized clinical trial. PLOS ONE. 2018;31(13):e0190768.
behavioral therapy and relapse prevention for cannabis dependence. 57. Vandrey R, Smith MT, McCann UD, Budney AJ, Curran EM. Sleep
J Group Addict Recov. 2010;5:240–63. disturbance and the effects of extended-release zolpidem during
41. Steinberg KL, Roffman RA, Carroll KM, McRee B, Babor TF, cannabis withdrawal. Drug Alcohol Depend. 2011;117:38–44.
Miller M, et al. Brief Counseling for Marijuana Dependence: A 58. Dakwar E, Mahony A, Choi CJ, Pavlicova M, Brooks D, Mariani JP,
Manual for Treating Adults. Report No.: HHS Publication no. (SMA) et al. Guanfacine extended-release for cannabis use disorder: a pilot
12-4211. Rockville, MD: Center for Substance Abuse Treatment, feasibility trial. Am J Drug Alcohol Abuse. 2020;46:44–8.
Substance Abuse and Mental Health Services Administration; 59. Weinstein AM, Miller H, Bluvstein I, Rapoport E, Schreiber S, Bar-
2005. p. 208. Hamburger R, et al. Treatment of cannabis dependence using
42. Buchowski MS, Meade NN, Charboneau E, Park S, Dietrich MS, escitalopram in combination with cognitive–behavior therapy: a
Cowan RL, et al. Aerobic exercise training reduces cannabis craving double-blind placebo-controlled study. Am J Drug Alcohol Abuse.
and use in non-treatment seeking cannabis-dependent adults. PLOS 2014;40:16–22.
ONE. 2011;6:e17465. 60. Herrmann ES, Cooper ZD, Bedi G, Ramesh D, Reed SC, Comer SD,
43. Posner D, Gehrman PR. Sleep hygiene. In: Behavioral Treatments et al. Varenicline and nabilone in tobacco and cannabis co-users:
for Sleep Disorders [internet]. London, UK: Elsevier; 2011 [cited effects on tobacco abstinence, withdrawal and a laboratory model of
2021 Aug 12], pp. 31–43. Available at: https://linkinghub.elsevier. cannabis relapse. Addict Biol. 2019;24:765–76.
com/retrieve/pii/B9780123815224000031 accessed 12 August 61. Herrmann ES, Cooper ZD, Bedi G, Ramesh D, Reed SC, Comer SD,
2021. et al. Effects of zolpidem alone and in combination with nabilone on
44. Trauer JM, Qian MY, Doyle JS, Rajaratnam SMW, Cunnington D. cannabis withdrawal and a laboratory model of relapse in cannabis
Cognitive behavioral therapy for chronic insomnia: a systematic users. Psychopharmacology. 2016;233:2469–78.
review and meta-analysis. Ann Intern Med. 2015;163:191–204. 62. Hill KP, Palastro MD, Gruber SA, Fitzmaurice GM, Greenfield SF,
45. Shahzadi M, Abbas Q. Individualised cognitive behaviour therapy in Lukas SE, et al. Nabilone pharmacotherapy for cannabis dependence:
patients of substance use disorders: three case studies. J Pak Med a randomized, controlled pilot study. Am J Addict. 2017;26:
Assoc. 2020;70:1657–60. 795–801.
46. Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV. 63. Levin FR, McDowell D, Evans SM, Nunes E, Akerele E, Donovan S,
Dronabinol for the treatment of cannabis dependence: a randomized, et al. Pharmacotherapy for marijuana dependence: a double-blind,
double-blind, placebo-controlled trial. Drug Alcohol Depend. 2011; placebo-controlled pilot study of divalproex sodium. Am J Addict.
116:142–50. 2004;13:21–32.
47. Mariani JJ, Pavlicova M, Jean Choi C, Basaraba C, Carpenter KM, 64. Miranda R, Treloar H, Blanchard A, Justus A, Monti PM, Chun T,
Mahony AL, et al. Quetiapine treatment for cannabis use disorder. et al. Topiramate and motivational enhancement therapy for canna-
Drug Alcohol Depend. 2021;218:108366. bis use among youth: a randomized placebo-controlled pilot study:
48. Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, topiramate and cannabis use. Addict Biol. 2017;22:779–90.
Sadler C, et al. Nabiximols as an agonist replacement therapy during 65. Rehm J, Shield KD. Global burden of disease and the impact of men-
cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry. tal and addictive disorders. Curr Psychiatry Rep. 2019;21:1–7.
2014;71:281–91. 66. World Health Organization. Depression and Other Common Mental
49. Trigo JM, Lagzdins D, Rehm J, Selby P, Gamaleddin I, Fischer B, et al. Disorders: Global Health Estimates [internet]. Geneva: World Health
Effects of fixed or self-titrated dosages of Sativex on cannabis Organization; 2017. Available at: https://www.who.int/publications/
withdrawal and cravings. Drug Alcohol Depend. 2016;161:298–306. i/item/depression-global-health-estimates accessed 21 September
50. Mason BJ, Crean R, Goodell V, Light JM, Quello S, Shadan F, et al. 2021.
A proof-of-concept randomized controlled study of gabapentin: 67. Saunders JB, Aasland OG, Babor TF, de la Fuente JR, Grant M.
effects on cannabis use, withdrawal and executive function deficits Development of the Alcohol Use Disorders Identification Test
in cannabis-dependent adults. Neuropsychopharmacology. 2012;37: (AUDIT): WHO collaborative project on early detection of persons
1689–98. with harmful alcohol consumption–II. Addiction. 1993;88:791–804.
MANAGEMENT OF CANNABIS WITHDRAWAL 2095
68. Swift W, Copeland J, Hall W. Choosing a diagnostic cut-off for 84. Fischer B, Russell C, Sabioni P, van den Brink W, Le Foll B, Hall W,
cannabis dependence. Addiction. 1998;93:1681–92. et al. Lower-risk cannabis use guidelines: a comprehensive update of
69. Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom K-O. The evidence and recommendations. Am J Public Health. 2017;107:
Fagerstrom Test for Nicotine Dependence: a revision of the e1–e12.
Fagerstrom Tolerance Questionnaire. Addiction. 1991;86:1119–27. 85. Fischer B, Robinson T, Bullen C, Curran V, Jutras-Aswad D, Medina-
70. Connor JP, Gullo MJ, White A, Kelly AB. Polysubstance use: diagnos- Mora ME, et al. Lower-Risk Cannabis Use Guidelines (LRCUG) for
tic challenges, patterns of use and health. Curr Opinion Psychiatry. reducing health harms from non-medical cannabis use: a comprehen-
2014;27:269–75. sive evidence and recommendations update. Int J Drug Policy. 2021;
71. Connor JP, Gullo MJ, Chan G, Young RMCD, Hall WD, Feeney GFX. 103381.
Polysubstance use in cannabis users referred for treatment: drug use 86. Dutra L, Stathopoulou G, Basden SL, Leyro TM, Powers MB,
profiles, psychiatric comorbidity and cannabis-related beliefs. Front Otto MW. A meta-analytic review of psychosocial interventions for
Psychiatry. 2013;4:1–7. substance use disorders. Am J Psychiatry. 2008;165:179–87.
72. Budney AJ, Vandrey RG, Hughes JR, Thostenson JD, Bursac Z. 87. Walsh H, McNeill A, Purssell E, Duaso M. A systematic review and
Comparison of cannabis and tobacco withdrawal: severity and Bayesian meta-analysis of interventions which target or assess co-
contribution to relapse. J Subst Abuse Treat. 2008;35:362–8. use of tobacco and cannabis in single- or multi-substance interven-
73. Vandrey RG, Budney AJ, Moore BA, Vandrey RG, Budney AJ, tions. Addiction. 2020;115:1800–14.
Moore BA, et al. A cross-study comparison of cannabis and tobacco 88. Gullo MJ, Papinczak ZE, Feeney GFX, Young RM, Connor JP.
withdrawal. Am J Addict. 2005;14:54–63. Precision mental health care for cannabis use disorder: utility of a
74. Arendt M, Rosenberg R, Foldager L, Sher L, Munk-Jørgensen P. biosocial cognitive theory to inform treatment. Front Psychiatry.
Withdrawal symptoms do not predict relapse among subjects treated 2021;12:643107.
for cannabis dependence. Am J Addict. 2007;16:461–7. 89. Smart R, Caulkins JP, Kilmer B, Davenport S, Midgette G. Variation in
75. Chung T, Martin CS, Cornelius JR, Clark DB. Cannabis withdrawal cannabis potency and prices in a newly legal market: evidence from
predicts severity of cannabis involvement at 1-year follow-up among 30 million cannabis sales in Washington State: legal cannabis
treated adolescents. Addiction. 2008;103:787–99. potency and price variation. Addiction. 2017;112:2167–77.
76. Greene MC, Kelly JF. The prevalence of cannabis withdrawal and its 90. Centre for Alcohol and Other Drugs Drug and Alcohol Withdrawal
influence on adolescents’ treatment response and outcomes: a Clinical Practice Guidelines [internet]. Sydney, NSW: NSW Depart-
12-month prospective investigation. J Addict Med. 2014;8:359–67. ment of Health; 2008 Jul p. 102. Available at: https://www1.health.
77. Connor JP, Stjepanovic D, Le Foll B, Hoch E, Budney AJ, Hall WD. nsw.gov.au/pds/ActivePDSDocuments/GL2008_011.pdf accessed
Cannabis use and cannabis use disorder. Nat Rev Dis Primers. 2021; 10 August 2021.
7:1–24. 91. Hughes JR. Signs and symptoms of tobacco withdrawal. Arch Gen
78. Cooper K, Chatters R, Kaltenthaler E, Wong R. Psychological and Psychiatry. 1986;43:289–94.
psychosocial interventions for cannabis cessation in adults: a system- 92. Hughes J, Hatsukami DK. Errors in using tobacco withdrawal scale.
atic review short report. Health Technol Assess. 2015;19:1–130. Tob Control. 1998;7:92–3.
79. Danovitch I, Gorelick DA. State of the art treatments for cannabis
dependence. Psychiatr Clin North Am. 2012;35:309–26.
SUPPORTING INFORMATION
80. Davis ML, Powers MB, Handelsman P, Medina JL, Zvolensky M,
Smits JA. Behavioral therapies for treatment-seeking cannabis users: Additional supporting information may be found in the online version
a meta-analysis of randomized controlled trials. Eval Health Prof. of the article at the publisher’s website.
2015;38:94–114.
81. Gates PJ, Sabioni P, Copeland J, Le Foll B, Gowing L. Psychosocial
interventions for cannabis use disorder. Cochrane Database Syst How to cite this article: Connor JP, Stjepanovic D, Budney AJ,
Rev. 2016;CD005336. Le Foll B, Hall WD. Clinical management of cannabis
82. Lévesque A, Le Foll B. When and how to treat possible cannabis use
withdrawal. Addiction. 2022;117:2075–95. https://doi.org/
disorder. Med Clin North Am. 2018;102:6676–81.
83. Sabioni P, Le Foll B. Psychosocial and pharmacological 10.1111/add.15743
interventions for the treatment of cannabis use disorder. Focus.
2019;17:163–8.