management of cannabis withdrawal - NCPIC by pengxuebo


									management of
cannabis withdrawal
Adam Winstock & Toby Lea
Sydney South West Area Health Service

introduction                                                 next revision of DSM (see Table 1 for proposed
                                                             cannabis withdrawal syndrome criteria) (Budney,
Cannabis is the most widely used illicit substance in        Hughes, Moore, & Vandrey, 2004). The authors
the world (UNODC, 2006). In the Australian National          recommend that the presence of four of the criteria
Survey of Mental Health and Wellbeing, nearly one            listed in Table 1 should constitute a diagnosis of
in 12 Australians had consumed cannabis more than            cannabis withdrawal.
five times in the preceding 12 months, and of those,
21% met criteria for cannabis dependence (Swift,             Table 1 Proposed cannabis withdrawal syndrome
Hall & Teesson, 2001) . While cannabis dependence            criteria for inclusion in DSM
is recognised in the International Classification of
                                                                                   Common symptoms
Diseases, 10th Revision (ICD-10) and the Diagnostic
and Statistical Manual of Mental Disorders, Fourth            Mood
Edition, Text Revision (DSM-IV-TR), the existence of               Anger or aggression
a specific withdrawal syndrome has been a more
highly debated issue (Smith, 2002). While a specific
cannabis withdrawal syndrome is not included in                    Nervousness/anxiety
the ICD-10 or DSM-IV-TR (“clinical significance yet to        Behavioural
be determined”), there is growing consensus of the
existence and clinical relevance of such a syndrome.               Decreased appetite or weight loss
A recent review by Budney et al. (2004:1967)                       Restlessness
concluded that the evidence indicates “...that a
                                                                   Sleep difficulties, including strange dreams
valid and clinically significant cannabis withdrawal
syndrome is prevalent in a substantial proportion                    Less common symptoms/equivocal symptoms
of heavy cannabis users”. Although none of the                Physical
symptoms comprising the proposed withdrawal                        Chills
syndrome are unique to cannabis and are frequently
seen in other substance withdrawal syndromes, they                 Stomach pain
are of clinical relevance to many dependent users                  Shakiness
and their recognition and management by clinicians
is an important area for consideration.
The proportion of patients reporting cannabis
                                                                   Depressed mood
withdrawal in recent treatment studies has ranged
from 50-95% (Budney & Hughes, 2006). Symptoms                Reproduced from Budney et al., 2004
commonly experienced include sleep difficulty;
decreased appetite and weight loss; irritability;            Given the inherent bias in treatment seeking
nervousness and anxiety; restlessness; and                   samples, for many dependent cannabis users
increased anger and aggression. The majority                 withdrawal may not be a significant hurdle to
of symptoms peak between day two and six of                  achieving a period of abstinence. However, even
abstinence and most return to baseline by day 14.            where withdrawal severity is of a similar magnitude
Sleep difficulty, anger/aggression, irritability and         to that experienced by people ceasing tobacco use
physical tension have persisted for three to four            (Vandrey, Budney, Hughes, & Liguori, 2008; Vandrey,
weeks in some studies (Budney, Moore, Vandrey,               Budney, Moore, & Hughes, 2005), withdrawal can
& Hughes, 2003; Kouri & Pope, 2000). Strange                 of course be a barrier to attaining abstinence. As
dreams failed to return to baseline during a 45-day          with other substances, the range and severity of
abstinence study (Budney et al., 2003).                      withdrawal symptoms lie on a spectrum and tend to
                                                             be greater among heavier, dependent users (Budney
Budney and colleagues propose that a specific                & Hughes, 2006). It is also probable that cannabis
cannabis withdrawal syndrome be included in the              withdrawal discomfort will be greater among people

                                                                                   management of cannabis withdrawal

with psychiatric comorbidity (Budney, Novy &                 Table 2 Variables likely to affect the severity of
Hughes, 1999), amongst whom continued use is also            cannabis withdrawal
most harmful (Hall, Degenhardt & Lynskey, 2001).
                                                              Psychiatric comorbidity including personality disorder
For many substance dependence problems, the                   Dose: amount and potency of preparation consumed
provision of medically assisted detoxification
services to address withdrawal symptoms (of                   Duration of current use
sufficient severity or risk to act as a barrier to            Mode of administration
achieving abstinence) is often the service that
                                                              Past or current other substance use
is most attractive to patients and may prompt
initial treatment seeking. It is possible that the            Expectation
absence of a range of effective interventions for             History of aggression or violence, other personality traits
cannabis withdrawal therefore represents a gap in
the provision of clinical services which may result           Setting: outpatient withdrawal may be more severe than
                                                              inpatient withdrawal
in overall lower levels of treatment seeking and
engagement.                                                   Context: voluntary vs involuntary

                                                              Support: professional, family, social
For a significant proportion of dependent cannabis
users the experience of cannabis withdrawal will              Population: more severe in treatment seekers
pose a significant barrier to achieving a period of           Rate of withdrawal (gradual reduction or sudden
abstinence (Hart, 2005). It is among this group               cessation)
of patients that specific interventions to manage
withdrawal may be required. Given the range of
long-term harms associated with chronic cannabis              Gender
consumption (Moore et al., 2007; Tashkin, Baldwin,
                                                             See for example Budney et al., 1999
Sarafian, Dubinett, & Roth, 2002), assisting cessation
of cannabis use may be associated with significant
benefits in social functioning, mental health and            cannabis withdrawal measures
physical health.                                             There is a lack of psychometrically validated
                                                             scales for the assessment of the symptomatology
evidence                                                     and severity of cannabis withdrawal. Haney and
                                                             colleagues, in studies assessing cannabis withdrawal
withdrawal severity                                          and subsequent medication treatment trials, used a
Withdrawal severity is likely to vary widely between         cannabis withdrawal scale adapted from a cocaine
individuals and may fluctuate over time depending            withdrawal scale (Haney, Ward, Comer, Foltin, &
on the severity of dependence, context of use and            Fischman, 1999). This scale has not undergone
cessation, and current life stressors. Factors that          psychometric testing in cannabis using populations.
may impact upon the severity of cannabis withdrawal          Budney and colleagues developed the Marijuana
are provided in Table 2, although it should be noted         Withdrawal Checklist (MWC), a 22-item scale
that research in this area is lacking as it relates          exploring the severity of mood, behavioural and
specifically to cannabis withdrawal.                         physical symptoms of cannabis withdrawal (Budney
                                                             et al., 1999) (see Table 3). The instrument can be
                                                             utilised for retrospective accounts of withdrawal
                                                             severity, or to assess withdrawal severity in a given
                                                             time period, typically the preceding 24 hours. A four-
                                                             point rating scale is used (0=no withdrawal; 1=mild
                                                             withdrawal; 2=moderate withdrawal; 3=severe
                                                             withdrawal). Revised versions of this scale have
                                                             been used in subsequent withdrawal studies and
                                                             clinical trials (e.g. Budney, Hughes, Moore, & Novy,
                                                             2001; Budney et al., 2003; Vandrey, Budney, Kamon,
                                                             & Stanger, 2005; Winstock, Lea & Copeland, 2007,
                                                             in press). The MWC is yet to be psychometrically
                                                             validated. The Marijuana Quit Questionnaire
                                                             (MJQQ) includes a section on cannabis withdrawal

                                                                                     management of cannabis withdrawal

(Copersino et al., 2006). Eighteen withdrawal items                was drawn from a randomised control trial of brief
are investigated (drawn from the MWC and one other                 cognitive behavioural interventions for cannabis
withdrawal study). Participants report whether the                 users (Copeland, Swift, Roffman, & Stephens, 2001).
symptom was experienced, symptom duration, and                     These issues will be discussed in more detail in the
any action taken to relieve the symptom. The Nepean                trigger paper addressing psychological interventions
Cannabis Withdrawal Scale (THCw-R) is a recently                   in cannabis treatment.
developed instrument that includes both a patient
self-report and clinician assessed withdrawal scale                gradual reduction
(Dawes, 2007). This scale is currently in the process
                                                                   The gradual reduction of an agonist substance of
of being psychometrically validated. In summary,
                                                                   dependence is typically associated with less severe
there are no psychometrically validated instruments
                                                                   and clinically significant withdrawal, because of the
to assess and guide the management of cannabis
                                                                   less abrupt reversal of neuroadaptive changes that
withdrawal in clinical populations. Until such scales
                                                                   a more gradual taper permits. Such an approach
are available, titration of medications against the
                                                                   underlies most pharmacologically assisted
symptoms most distressing to each patients and
                                                                   interventions for substance-related withdrawal
medication side effects (notably over sedation) is a
                                                                   (e.g., methadone and buprenorphine taper in opiate
sensible, practical approach.
                                                                   withdrawal, and benzodiazepine taper for alcohol
Table 3 Marijuana Withdrawal Checklist (MWC),                      and benzodiazepine withdrawal) (Alexander &
22 item version                                                    Perry, 1991; Lejoyeux, Solomon & Ades, 1998;
                                                                   NSW Department of Health, 2006). Although there
     Items from published                                          is no evidence in the literature about the effect of
      studies of cannabis        Items associated with other
          withdrawal                substance withdrawal           gradual dose reduction of cannabis on the severity
                                                                   of withdrawal symptoms, the relatively long plasma
 Irritability*                   Shakiness
                                                                   half-life of various active cannabis metabolites
 Nervousness                     Stuffy nose                       (typically cited as 1-4 days) (Johansson, Halldin,
 Depression                      Sweating                          Agurell, Hollister, & Gillespie, 1989; Wall & Perez-
                                                                   Reyes, 1981) suggests that a gradual reduction in
 Anger                           Hot flashes                       cannabis use would be an effective strategy for
 Craving                         Feverish                          people with cannabis dependence, where individuals
                                                                   are able to exert some control over their use or where
 Restlessness                    Diarrhoea
                                                                   access to their cannabis is regulated by a third party.
 Sleep problems                  Nausea                            This is supported by the apparent clinical utility of
 Decreased appetite              Muscle spasms                     oral THC in the management of cannabis withdrawal
                                                                   (Budney, Vandrey, Hughes, Moore, & Bahrenburg,
 Strange dreams                  Chills
                                                                   2007; Haney et al., 2004). Advice on gradual cannabis
 Increased appetite              Hiccups                           reduction may include smoking smaller bongs or
                                                                   joints, smoking fewer bongs or joints, commencing
 Violent outbursts
                                                                   use later in the day and having goals to cut down by a
 Headaches                                                         certain amount by the next review.
*Rating scale: 0=none, 1=mild, 2=moderate, 3=severe                Although it is likely that most people will experience
Reproduced from Budney et al., 1999
                                                                   less severe withdrawal if they gradually cut down,
                                                                   for many dependent users efforts at such control
psychosocial and psychoeducation                                   may often be unsuccessful. In such cases sudden
interventions                                                      cessation may be more successful, though its timing
The use of self-help booklets such as the National                 in relation to employment, education or parenting
Drug and Alcohol Research Centre’s cannabis brief                  responsibilities must be considered. There is some
intervention booklet Quitting Cannabis?, and the                   evidence to suggest that inpatient settings may be
Manly Drug Education and Counselling Centre’s                      associated with less severe withdrawal (Budney
Mulling it Over may be useful to support patients in               et al., 2004; Haney et al., 1999). This may provide
managing withdrawal and craving. Quitting Cannabis?                patients with time away from home and the removal
recommends a self-help strategy of distracting,                    of behavioural cues associated with cannabis use.
delaying, de-catastrophising and de-stressing to
manage withdrawal and craving. This approach

                                                                                management of cannabis withdrawal

pharmacotherapy trials                                         medications have not been investigated as
                                                               potential therapeutic agents in the management of
There are currently no evidence-based
                                                               cannabis withdrawal.
pharmacotherapy treatments for cannabis
withdrawal. In recent years a number of clinical trials
have been conducted investigating the effect of
pharmacotherapy treatments for cannabis withdrawal
in adult humans (see Table 4). Medications were
chosen on the basis of their previous use in
the management of mood disorders and other
substance withdrawal, and their potential efficacy
in the treatment of symptoms common to cannabis
withdrawal. Medications investigated have included
bupropion (Haney et al., 2001), buspirone (McRae,
Brady & Carter, 2006), divalproex sodium (Haney
et al., 2004; Levin et al., 2004), lithium carbonate
(Bowen, McIlwrick, Baetz, & Zhang, 2005; Winstock et
al., 2007, in press), nefazodone (Haney, Hart, Ward,
& Foltin, 2003) and oral THC (Budney et al., 2007;
Haney et al., 2004). The rationale for using oral THC, a
cannabinoid agonist, has been described above.

These studies utilised either a placebo controlled
crossover design or an open-label design. Aside
from the methodological limitations of open-label
designs and crossover designs, these studies
share some common limitations. All had small
samples and were comprised almost exclusively of
males. People with psychiatric comorbidity or other
substance use disorders were excluded. Many of
the studies involved medication regimes of longer
duration than the time course of the majority of
cannabis withdrawal symptoms. In addition, the
reported studies utilised different withdrawal
and other outcomes measures thereby reducing
the comparability of different trials. No studies
to date have explored variations in individual
pharmacogenetics on the potential efficacy of
different medications in managing withdrawal. To
date no sufficiently large clinical trials have been
conducted to support the routine use in clinical
practice of any of the medications investigated
so far, although the results of the preliminary
studies suggest that further research is warranted
among some.

Perhaps surprisingly, while benzodiazepines are
probably the most commonly prescribed medications
for the symptomatic relief of cannabis withdrawal,
the efficacy of this drug class in the management
of cannabis withdrawal is yet to be investigated in
human clinical trials (Hart, 2005). Commonly used in
detoxification from alcohol, stimulants and opioids
(Baker, Lee & Jenner, 2004; Kosten & O’Connor,
2003), their general calmative, sedative and
antispasmodic effects may be useful. Antipsychotic

                                                                                                Duration     Treatment                                                      Further
                                                           Inclusion                  Daily        per      completion                                                     research
    Investigators           Design               n          criteria   Medication     dose      condition      (n, %)                        Results                       required
    Haney et al.,   Randomised, double-      10           Regular      Bupropion    300mg       4 weeks     9 (90%)      Ratings of irritability, restlessness,            No
    2001            blind, placebo           (8 male)     cannabis                                                       depression and sleep difficulty worsened
                    controlled, crossover;                use                                                            by bupropion compared to placebo
                    outpatient 11 days/
                    inpatient 17 days
    Haney et al.,   Randomised, double-      11           Regular      Nefazodone   450mg       26 days     7 (64%)      Ratings of anxiety and muscle pain reduced        Some
    2003            blind, placebo           (8 male)     cannabis                                                       by nefazodone but had no effect on other          evidence
                    controlled, crossover;                use                                                            withdrawal symptoms
                    outpatient 9 days/
                    inpatient 17 days
    Haney et al.,   Randomised, double-      11           Regular      Oral THC     50mg        5 days      7 (64%)      Oral THC reduced ratings of marijuana             Yes
                                                                                                                                                                                      cannabis withdrawal in adult humans

    2004            blind, placebo           (all male)   cannabis                              active;                  craving, anxiety, feeling miserable, sleep
    [Study 1]       controlled, crossover;                use                                   25 days                  problems, chills, and increased food intake
                    inpatient 15 days/                                                          placebo
                    outpatient 5 days/
                    inpatient 15 days
    Haney et al.,   Randomised, double-      8            Regular      Divalproex   1500mg      29 days     7 (88%)      Divalproex reduced marijuana craving but          No
    2004            blind, placebo           (7 male)     cannabis     sodium                                            worsened ratings of anxiety, irritability,
                    controlled, crossover;                use                                                            ‘bad effect’, and tiredness

    [Study 2]
                    outpatient 14 days/
                    inpatient 15 days
    Levin et al.,   Randomised, double-      25           DSM-IV       Divalproex   1500-       6 weeks     9 (36%)      Reductions in irritability reported in both       No
    2004            blind, placebo           (23 male)    cannabis     sodium       2000mg                               the divalproex and placebo condition
                    controlled, crossover;                dependence
    Bowen et al.,   Open-label; outpatient   9            DSM-IV       Lithium      600-        6 days      9 (100%)     Four participants reported improvements           Yes
    2005                                     (7 male)     cannabis     carbonate    900mg                                in withdrawal symptoms they attributed to
                                                          dependence                                                     lithium
    McRae et al.,   Open-label; outpatient   11           DSM-IV       Buspirone    10-60mg     12 weeks    2 (18%)      Significant reductions in marijuana craving,      Some
    2006                                     (10 male)    cannabis                                                       irritability and anxiety at a median 23 days      evidence
                                                          dependence                                                     post-baseline
    Budney et       Randomised, double-      22           Regular      Oral THC     Condition   5 days      8 (36%)      Low dose oral THC reduced overall                 Yes
    al., 2007       blind, placebo           (16 male)    cannabis                  1: 30mg                              withdrawal discomfort, aggression,
                    controlled, crossover;                use                       Condition                            irritability and sleep difficulty. In addition,
                    outpatient                                                      2: 90mg                              high dose oral THC reduced depressed
                                                                                                                         mood and craving
    Winstock et     Open-label; inpatient    20           DSM-IV       Lithium      1000mg      7 days      12 (60%)     ≥6 withdrawal symptoms of at least                Yes
                                                                                                                                                                                      Table 4 Studies that have investigated the effects of pharmacotherapy treatments for the management of

    al., 2007, in                            (19 male)    cannabis     carbonate                                         moderate severity on ≥1 day (n=7). ≥4
    press                                                 dependence                                                     symptoms as severe on ≥1 day (n=3).
                                                                                                                         Significant reductions in symptoms of
                                                                                                                                                                                                                                                                                               management of cannabis withdrawal

                                                                                                                         depression and anxiety
                                                                                management of cannabis withdrawal

concurrent tobacco use                                        to providing alternative licit analgesia or other coping
                                                              strategies before commencing cannabis reduction.
The majority of cannabis smokers in Australia smoke
tobacco either in combination with their cannabis             Young people
(91%) or separately as cigarettes (43%) (Copeland,
                                                              The very early onset of cannabis use among young
Swift & Rees, 2001). Both substances impart a poor
                                                              people may be a marker for other psychosocial
prognosis for successful cessation for the other
                                                              problems and is often seen in conjunction with other
and thus any approach to addressing to the use
                                                              substance use or psychiatric disorders (Fergusson,
of cannabis will in most instances appropriately
                                                              Horwood & Swain-Campbell, 2002; Patton et al.,
address tobacco (Ford, Vu & Anthony, 2002; Stuyt,
                                                              2002). Aggression and hostility may be particularly
1997; Sullivan & Covey, 2002). All forms of Nicotine
                                                              common in younger male users with pre-morbid
Replacement Therapy (NRT) are likely to be of some
                                                              aggressive personalities. This may be a particular
use among tobacco using cannabis dependent
                                                              issue among people in juvenile detention centres.
patients regardless of whether they use tobacco
independently or in combination with cannabis,
although available evidence suggests generally                depressive symptoms in cannabis users
poorer outcomes than among non cannabis users.                The incidence of depression and anxiety is higher
Interestingly, although one might expect an increase          in people with cannabis dependence than in the
in tobacco consumption during the period of cannabis          general population (Arendt, Rosenberg, Foldager,
withdrawal, the limited evidence available suggests           Perto, & Munk-Jorgensen, 2007; Copeland, Swift &
this is not the case (Budney et al., 2003; Winstock et        Rees, 2001). Therefore symptoms suggestive of a
al., 2007, in press).                                         mood disorder may be a presenting complaint and a
                                                              specific patient-initiated request for antidepressants
issues in managing withdrawal in                              may be made of the treating practitioner. However,
special groups                                                precipitous prescription and diagnosis should
                                                              generally be avoided at a first presentation since
Impact of cannabis cessation on underlying
                                                              there are a range of psychological and behavioural
health conditions and/or the efficacy of prescribed
                                                              symptoms that may be seen in association with
                                                              the chronic consumption of cannabis that might
People self-medicate with cannabis for a number               be interpreted as depression, including low level
of medical conditions including HIV cachexia,                 paranoia and the ‘amotivational syndrome’. A
chemotherapy induced nausea, chronic pain,                    significant reduction or cessation of cannabis use
arthritis, spasticity, and multiple sclerosis (Chong et       may be associated with improvements in ratings
al., 2006; Swift, Gates & Dillon, 2005). Cessation of         of mood, negating a diagnosis of depression and
cannabis use may leave symptoms associated with               the need for medication. That persistent cannabis
these conditions untreated which may be associated            intoxication may lead to a presumptive diagnosis of
with acute exacerbation.                                      a depressive illness is supported by findings from a
                                                              recent study of 20 dependent cannabis users enrolled
Cannabis has been shown to affect the metabolism
                                                              in a withdrawal study, where 85% scored at least
of some classes of medication such as antipsychotics
                                                              moderate scores on the Beck Depression Inventory
(Silvestri et al., 2000), necessitating the prescribing
                                                              (BDI-II) (Beck, Steer & Brown, 1996) at baseline but at
of higher doses in regular cannabis smokers. In
                                                              day 107 follow-up moderate depression scores were
such cases cessation of cannabis use may lead to
                                                              persistent in only two participants (Winstock et al.,
inadvertent toxicity. Examples include induction of
                                                              2007, in press).
P450 isoenzyme CYP 1A, which may impact on the
metabolism of clozapine and olanzapine, by tobacco            In addition to the difficulty of making an accurate
and cannabis (de Leon, 2004).                                 diagnosis of a psychiatric disorder in the context
                                                              of continued cannabis use, compliance is likely to
Chronic pain
                                                              be poor (McLellan, Lewis, O’Brien, & Kleber, 2000).
Cannabis and its derivatives may be effective                 Furthering the initiation of some antidepressants
analgesics in a range of painful conditions,                  (SSRIs) early in cannabis withdrawal may worsen
with particular benefits accrued in those with                symptoms, as was the case with buproprion (Haney
musculoskeletal/spasm/arthritic disorders such                et al., 2001). Finally, if psychotropic medication is
as multiple sclerosis (Chong et al., 2006). For some          commenced precipitously patients may attribute
patients careful consideration will need to be given          improvements in mood to medication rather than

                                                                                 management of cannabis withdrawal

the cessation of cannabis use. The motivation for              Table 5 Assessing the significance and nature of
continued abstinence may be removed if patients fail           cannabis withdrawal
to attribute improvements in mood to the cessation of
cannabis use.                                                   •	 range and severity of individual symptoms
                                                                   (predominant symptoms)

recommendations                                                 •	 specific risks of withdrawal to self or others
identification and assessment                                      (e.g., violence)

Inquiry into drug and alcohol use should form part              •	 previous approaches to self-management
of any routine assessment with a patient. Although
some dependent cannabis users may approach                      •	 duration of withdrawal
specialist services directly, in many cases it is likely        •	 other substance use/mental health disorders
that cannabis use problems will be identified during               that may affect clinical progression of
presentation to another health care professional                   withdrawal
either incidentally or as part of the presenting
complaint, for example within primary care or mental            •	 prescribed medications (which may exacerbate
health settings. Once a cannabis use disorder has                  withdrawal or whose metabolism may be altered
been identified (see trigger paper on screening                    on cessation of cannabis use)
and assessment) it will be important to identify
the severity, nature and clinical significance of any           •	 patient expectations and preference
withdrawal discomfort that has been experienced                 •	 environmental factors conducive or not
(see Table 5). Patients may identify withdrawal as a               conducive to achieving withdrawal – including
barrier to attaining abstinence either spontaneously               safety of others
or on direct questioning about prior withdrawal
experiences. Determining the nature of withdrawal
                                                               initial advice and harm reduction advice
may be assisted in some cases by the use of
standardised withdrawal measures. The presence                 including cutting down
of coexisting physical health problems (e.g. pain),            A range of cannabis use reduction strategies exist
psychiatric comorbidity, and other substance use               that can be adopted to support the goal of achieving
disorders should also be determined since any                  abstinence from cannabis or a significant reduction
intervention aimed at assisting the patient to reduce          in use (Swift, Copeland & Lenton, 2000). For most
or cease using cannabis will need to be considered             dependent cannabis users, initial advice should
in the context of their use of other substances                include education on the less harmful ways of
and prescribed medications. When assessing                     consuming cannabis (e.g., reduce daily intake, avoid
retrospective accounts of withdrawal discomfort, it is         tobacco, avoid using bongs) and if time, clinical
important to identify situational, temporal and other          setting or individual circumstances of the person
psychosocial variables that may have influenced the            permit, advice to gradually reduce the amount they
withdrawal experience. For example, did the patient            use over a few days or weeks prior to cessation of
quit suddenly, was it voluntary or enforced (e.g., due         use. Whether controlled use of cannabis is a clinically
to incarceration). Corroborative information from              attainable and clinically useful goal for dependent
family or others close to the patient may also inform          cannabis users has yet to be investigated. Advice
the clinical picture as well as highlight the potential        should also be provided on avoiding an increase in
effect of withdrawal on people around the individual.          the consumption of other psychoactive substances,
Identification of helpful and less useful strategies           since this may lead to the risk of greater abuse.
used during previous attempts should be explored
and positive initiatives built upon.                           concurrent tobacco use
                                                               For patients who smoke cannabis and use tobacco
                                                               independently, there is no evidence to guide
                                                               clinicians that one should be stopped before the
                                                               other. For patients who smoke cannabis mixed with
                                                               tobacco and do not smoke tobacco independently,
                                                               the advice should be that they cease both
                                                               simultaneously with the provision of NRT considered.
                                                               For those patients considering buproprion, clinicians

                                                                                 management of cannabis withdrawal

should take heed of the exacerbating effect of this            only after a thorough exploration of the individual
anti-smoking drug in a trial of its use in cannabis            patient’s symptom profile and circumstances.
withdrawal (Haney et al., 2001). Thus, if buproprion is        Most commonly used are a range of medications
considered clinically appropriate in tobacco smoking           targeted at providing symptomatic relief, typically
cannabis users, treatment should be commenced at               involving sedation. In Australia, the most widely used
least 1-2 weeks prior to cessation of both cannabis            medications are diazepam (or other benzodiazepines)
and tobacco.                                                   and sedating antihistamines such as promethazine
                                                               and pericyazine, although there has been no formal
pharmacotherapies for cannabis withdrawal                      evaluation of their effectiveness (Hart, 2005).
Of the medications investigated in controlled studies,         For each medication class recommended below (see
only oral THC has been found to be effective in                Table 6), determining the precise therapeutic regime
reducing a broad selection of cannabis withdrawal              to assist in the management for cannabis withdrawal
symptoms. There is evidence of a dose-response                 there are five main considerations:
relationship between oral THC and reduction of
withdrawal symptoms (Budney et al., 2007). Further             •	 timing and duration of any medications during the
investigation of oral-THC is required. The results of             acute withdrawal period
the open-label trial of lithium conducted by Winstock
                                                               •	 relative safety profile of any medications used
et al., 2007, in support of an earlier preclinical trial
                                                                  and the incidence of adverse effects given that
(Cui et al., 2001) and small open-label human pilot
                                                                  the symptoms that are being treated are not life-
(Bowen et al., 2005), provides preliminary evidence
                                                                  threatening or typically severe
of the potential role of this medication in the
management of cannabis withdrawal and suggests                 •	 abuse liability of any medication prescribed and
that a controlled trial of lithium is warranted.                  the ability to safely monitor the use of these
Nefazodone and buspirone may benefit from further                 medications
investigation in controlled studies of shorter duration
of dosing than investigated to date, congruent with            •	 potential for cessation of cannabis use to
the time course in which the majority of cannabis                 exacerbate underlying medical or mental health
withdrawal symptoms would return to baseline (1–2                 conditions or alterations in the efficacy of other
weeks).                                                           prescribed medications through changes in
symptoms focused approach
                                                               Finally, although the vast majority of patients
In the absence of a body of published literature or            requiring assistance for withdrawal can be safely and
other clinical evidence demonstrating the efficacy of          effectively supported in the community, for people
any one class of medication or prescribing schedule            dependent on other substances (especially alcohol)
over another for the relief of any particular symptom          or people with psychiatric comorbidity or premorbid
cluster, a menu of prescribing options should be               aggressive traits, inpatient admission may be
considered using a symptoms focused approach                   appropriate. The inpatient setting may reduce the risk
(see Table 6). Importantly, it is recommended that             for others who share the patient’s home environment.
mood stabilisers, antipsychotics and antidepressants
are not used for the management of acute cannabis              timing and duration of medication provision
withdrawal. In addition, it is recommended that
                                                               Prescriptions should generally provide 4-7 days
psychotropic medications are not initiated for the
                                                               worth of medication. Where early side effects
management of psychiatric disorders first diagnosed
                                                               are unlikely to exacerbate withdrawal symptoms
during a period of dependent use or withdrawal.
                                                               medications are in most cases most appropriately
In those with a well documented pre-existing
                                                               commenced on the day of cessation. Patients
psychiatric diagnosis requiring for example SSRIs,
                                                               should be advised of potential interactions
medication may be commenced after the first few
                                                               between prescribed medications and cannabis
days of withdrawal have been managed, since earlier
                                                               (e,g., increased sedation) and should be advised to
introduction may worsen symptoms of nervousness
                                                               refrain from taking prescribed medications should
and insomnia.
                                                               they continue to consume cannabis. A seven day
Given the wide interpersonal variability in the                medication schedule will cover the main period where
experience of withdrawal, dosages and prescribing              withdrawal symptoms are of significant severity in
schedules will most effectively be decided upon                the majority of patients. More prolonged symptoms

                                                                                management of cannabis withdrawal

such as sleep difficulty and strange dreams may be           abuse liability of any medication
prolonged if anxiolytics are continued beyond 1-2
                                                             Where there are concerns of a patient not taking
weeks. Persistent sleep problems related to cannabis
                                                             medication as directed or where there are other
withdrawal are more appropriately addressed through
                                                             concerns regarding the abuse liability of the
non pharmacological approaches such as effective
                                                             medication, the doctor should utilise frequent
sleep hygiene and relaxation techniques. Medication
                                                             script reviews and short dispensing windows from
should only be extended beyond 7-10 days if the
                                                             the pharmacy or outpatient unit to ensure that
patient is reviewed and specific withdrawal symptoms
                                                             medication is taken as directed. Review by a practice
are still present. Consideration should then be given
                                                             nurse or an outpatient drug and alcohol specialist
to the possibility that persistent mood symptoms may
                                                             may also be beneficial. Benzodiazepines are best
be reflective of an underlying psychiatric disorder as
                                                             avoided in patients with a history of dependence
opposed to cannabis withdrawal. Typically a period of
                                                             or abuse of alcohol or other CNS depressants and
two to four weeks of abstinence from cannabis should
                                                             should generally not be provided for more than
pass before a psychiatric diagnosis is made and
                                                             two weeks.
treatment commenced.

relative safety profile of any medications
Given that cannabis withdrawal symptoms are not
dangerous or life-threatening, medications with
good safety profiles and few adverse effects are
optimally chosen. This would generally exclude most
of the common psychotropic classes and high dose
sedatives, as well as consideration of the potential
interaction with prescribed medications and other
substance use.

Table 6 Symptom focused approach to managing cannabis withdrawal

                 Symptom                            Medication                        Psychosocial intervention
 Insomnia                            Benzodiazepines (e.g., oxazepam            Sleep hygiene advice, stimulant control
                                     30mg o.d, or temezapam 10-20mg o.d),       procedures, Progressive Muscular
                                     zopiclone (7.5-15mg o.d), zolpidem (10mg   Relaxation
                                     o.d) promethazine (25-50mg)

 Irritability, restlessness,         Benzodiazepines (e.g., diazepam            Meditation, exercise, relaxation
 nervousness/anxiety                 5mg t.i.d)                                 techniques, family support and

 Headache, muscular ache, spasms     Paracetamol (1g q.i.d), NSAIDs (e.g.,      Avoid caffeine and dehydration
 and pain                            ibuprofen 400mg t.i.d), magnesium

 Sweating, chills                    Paracetamol, appropriate hydration and
                                     appropriate clothing

 Nausea, nasal congestion            Antihistamine (e.g., promethazine,
                                     25-50mg) metoclopramide (10mg b.d),
                                     prochlorperazine (25mg b.d)

                                                                                 management of cannabis withdrawal

insomnia and anxiety-related symptoms                           In cases where patients prescribed antipsychotic
                                                                medications cease using cannabis, consideration
As the most commonly used class of drugs in
                                                                should be given to reviewing the medication
managing substance use withdrawal syndromes,
                                                                response, and where appropriate, to reducing
benzodiazepines have a potentially useful short-
                                                                the dose to avoid the development of toxicity or
term (4-7 days) role in assisting with anxiety-
                                                                worsening of side effects such as sedation. This is
related symptoms and insomnia. The prescribing of
                                                                particularly important in the case of people with
benzodiazepines should be avoided where there is a
                                                                schizophrenia who use cannabis and who tend to be
high abuse liability, for example to people with other
                                                                on higher doses of neuroleptics.
substance use disorders. In such cases alternative
night sedation such as promethazine or zopiclone
may be used. Night sedation may be all that is                  diagnosing and managing depressive
required (e.g., diazepam 10mg or temazepam 20mg                 symptoms in cannabis users
but where necessary may be supplemented by low                  It is recommended that complaints of anorexia,
doses of diazepam during the day (5mg b.d or t.i.d).            insomnia, agitation and hostility in the context of
Short-term, benzodiazepines may provide effective               acute withdrawal need to be considered and reviewed
relief from anxiety and insomnia, but their continued           after a few days. The diagnosis and initiation of any
use should be avoided because of risk of abuse                  antidepressant medication should be deferred until
and dependence.                                                 after detoxification and withdrawal has subsided.
                                                                In cases where a patient’s clinical history is well
Antipsychotics have a number of potentially
                                                                known to the treating clinician or where the patient
significant side effects and the only symptomatic
                                                                has a well documented primary depressive illness,
benefits they appear to provide in the initial period of
                                                                for example, it would be appropriate to commence
their consumption are ones of anxiolysis and sedation
                                                                an antidepressant (initially at half a dose to avoid
- both adequately and safely catered for by judicious
                                                                early side effects) 1-2 weeks following cessation
use of benzodiazepines. In Australia, atypical
                                                                of cannabis use. Clear advice should also be given
antipsychotics if prescribed for the management of
                                                                to the patient concerning the sudden cessation
cannabis withdrawal are being used off PBS listing. It
                                                                of antidepressant medication in cannabis users
is recommended that antipsychotics are not routinely
                                                                since a discontinuation syndrome associated with
used for the management of cannabis withdrawal.
                                                                cessation of antidepressants may exacerbate
Their use during withdrawal in those with underlying
                                                                cannabis withdrawal or their underlying mental
psychotic illness of course may be indicated, though
                                                                health problems.
dose reduction may be indicated following cessation
of cannabis and tobacco.
headache, muscular ache and pain                                Cannabis withdrawal represents a constellation
Simple analgesia and antipyretics such as                       of symptoms that is of clinical relevance in a
paracetamol and NSAIDs may be effective.                        large proportion of dependent cannabis users.
                                                                Withdrawal symptoms may be a barrier to attaining
                                                                abstinence and are likely to be more pronounced
                                                                in heavy dependent users and in people with
A sedating or non-sedating antihistamine or                     underlying psychiatric comorbidity. Appetite and
metoclopramide are all appropriate. Promethazine                sleep disturbance predominate with symptoms of
50mg at night can be an effective sedative but may              restlessness, anxiety, aggression and a number of
have persistent sedative effects on waking.                     less common moderate physical complaints. Typically
                                                                lasting 1-2 weeks, the appropriate use of medication
Impact of cannabis cessation on underlying health
                                                                when combined with psychoeducation and sleep
conditions and/or the efficacy of prescribed
                                                                hygiene may be helpful in minimising discomfort
                                                                and risks associated with cessation of use. With
In cases where cannabis is used to self-manage                  no evidenced-based pharmacological approach
medical conditions including MS and chronic pain,               currently identified and no psychometrically validated
consideration should be given to the commencement               withdrawal scale available, the default management
of alternative management approaches (whether                   approach for cannabis withdrawal for most
medication based or not) to support ongoing                     patients should be accurate information provision,
cessation of use.                                               psychological support, sleep hygiene advice, nicotine

                                                                                  management of cannabis withdrawal

replacement where indicated and minimal medication              Budney, A.J., Novy, P.L. & Hughes, J.R. (1999).
provided using a symptoms focused approach. The                 Marijuana withdrawal among adults seeking
impact of cessation upon underlying psychiatric                 treatment for marijuana dependence. Addiction 94,
and physical conditions should be considered                    1311-1322.
prior to commencing withdrawal management. The
diagnosis of psychiatric disorders and the initiation of        Budney, A.J., Vandrey, R.G., Hughes, J.R., Moore,
psychiatric medications at a first presentation should          B.A., & Bahrenburg, B. (2007). Oral delta-9-
be avoided in order to permit greater diagnostic                tetrahydrocannabinol suppresses cannabis
accuracy, appropriate patient attribution and                   withdrawal symptoms. Drug and Alcohol Dependence
improved clinical outcomes.                                     86, 22-29.

                                                                Chong, M.S., Wolff, K., Wise, K., Tanton, C.,
references                                                      Winstock, A., & Silber, E. (2006). Cannabis use in
Alexander, B. & Perry, P.J. (1991). Detoxification from         patients with multiple sclerosis. Multiple Sclerosis 12,
benzodiazepines: Schedules and strategies. Journal              646-651.
of Substance Abuse Treatment 8, 9-17.                           Copeland, J., Swift, W. & Rees, V. (2001). Clinical
Arendt, M., Rosenberg, R., Foldager, L., Perto, G.,             profile of participants in a brief intervention for
& Munk-Jorgensen, P. (2007). Psychopathology                    cannabis use disorder. Journal of Substance Abuse
among cannabis-dependent treatment seekers and                  Treatment 20, 45-52.
association with later substance abuse treatment.               Copeland, J., Swift, W., Roffman, R., & Stephens,
Journal of Substance Abuse Treatment 32, 113-119.               R. (2001). A randomized controlled trial of brief
Baker, A., Lee, N.K. & Jenner, L. (eds.). (2004). Models        cognitive-behavioral interventions for cannabis use
of intervention and care for psychostimulant users,             disorder. Journal of Substance Abuse Treatment 21,
2nd Edition. National Drug Strategy Monograph                   55-64.
Series No. 51.                                                  Copersino, M., Boyd, S., Tashkin, D., Huestis,
Beck, A.T., Steer, R.A. & Brown, G.K. (1996). BDI-II            M., Heishman, S., Dermand, J., Simmons, M., &
Manual (2nd ed). San Antonio, TX: Psychological                 Gorelick, D. (2006). Cannabis withdrawal among non-
Corporation.                                                    treatment-seeking adult cannabis users. American
                                                                Journal on Addictions 15, 8-14.
Bowen, R., McIlwrick, J., Baetz, M., & Zhang, X.
(2005). Lithium and marijuana withdrawal. Canadian              Cui, S.S., Bowen, R.C., Gu, G.B., Hannesson, D.K., Yu,
Journal of Psychiatry 50, 240-241.                              P.H., & Zhang, X. (2001). Prevention of cannabinoid
                                                                withdrawal syndrome by lithium: Involvement
Budney, A.J. & Hughes, J.R. (2006). The cannabis                of oxytocinergic neuronal activation. Journal of
withdrawal syndrome. Current Opinion in Psychiatry              Neuroscience 21, 9867-9876.
19, 233-238.
                                                                Dawes, G. (2007). Improving the measurement and
Budney, A.J., Hughes, J.R., Moore, B.A., & Novy, P.L.           treatment of cannabis withdrawal. Paper presented
(2001). Marijuana abstinence effects in marijuana               at the Two Nations, Ten Cultures? Combined APSAD
smokers maintained in their home environment.                   and Cutting Edge Addiction Conference, Auckland,
Archives of General Psychiatry 58, 917-924.                     New Zealand.

Budney, A.J., Hughes, J.R., Moore, B.A., & Vandrey,             de Leon, J. (2004). Atypical antipsychotic dosing:
R. (2004). Review of the validity and significance of           The effect of smoking and caffeine. Psychiatric
cannabis withdrawal syndrome. American Journal of               Services 55, 491-493.
Psychiatry 161, 1967-1977.
                                                                Fergusson, D.M., Horwood, L.J. & Swain-Campbell, N.
Budney, A.J., Moore, B.A., Vandrey, R.G., & Hughes,             (2002). Cannabis use and psychosocial adjustment
J.R. (2003). The time course and significance of                in adolescence and young adulthood. Addiction 97,
cannabis withdrawal. Journal of Abnormal Psychology             1123-1135.
112, 393-402.
                                                                Ford, D.E., Vu, H.T. & Anthony, J.C. (2002). Marijuana
                                                                use and cessation of tobacco smoking in adults from
                                                                a community sample. Drug and Alcohol Dependence
                                                                67, 243-248.

                                                                                 management of cannabis withdrawal

Hall, W., Degenhardt, L. & Lynskey, M. (2001). The             McLellan, A.T., Lewis, D.C., O’Brien, C.P., & Kleber,
health and psychological effects of cannabis use.              H.D. (2000). Drug dependence, a chronic mental
Monograph Series No. 44. Canberra: Commonwealth                illness: Implications for treatment, insurance and
of Australia.                                                  outcomes evaluation. JAMA 284, 1689-1695.

Haney, M., Hart, C.L., Vosburg, S.K., Nasser, J.,              McRae, A.L., Brady, K.T. & Carter, R.E. (2006).
Bennett, A., Zubaran, C., & Foltin, R.W. (2004).               Buspirone for treatment of marijuana dependence: A
Marijuana withdrawal in humans: Effects of oral THC            pilot study. American Journal on Addictions 15, 404.
or divalproex. Neuropsychopharmacology 29,
158-170.                                                       Moore, T.H.M., Zammit, S., Lingford-Hughes, A.,
                                                               Barnes, T.R.E., Jones, P.B., Burke, M., & Lewis, G.
Haney, M., Hart, C.L., Ward, A.S., & Foltin,                   (2007). Cannabis use and risk of psychotic or affective
R.W. (2003). Nefazodone decreases anxiety                      mental health outcomes: A systematic review. Lancet
during marijuana withdrawal in humans.                         370, 319-328.
Psychopharmacology 165, 157-165.
                                                               NSW Department of Health. (2006). New South Wales
Haney, M., Ward, A.S., Comer, S.D., Foltin,                    opioid treatment program clinical guidelines for
R.W., & Fischman, M.W. (1999). Abstinence                      methadone and buprenorphine treatment of opioid
symptoms following smoked marijuana in humans.                 dependence. Sydney: NSW Department of Health.
Psychopharmacology 141, 395-404.
                                                               Patton, G.C., Coffey, C., Carlin, J.B., Degenhardt, L.,
Haney, M., Ward, A.S., Comer, S.D., Hart, C.L.,                Lynskey, M., & Hall, W. (2002). Cannabis use and
Foltin, R.W., & Fischman, M.W. (2001). Bupropion               mental health in young people: Cohort study. BMJ
SR worsens mood during marijuana withdrawal in                 325, 1195-1198.
humans. Psychopharmacology 155, 171-179.
                                                               Silvestri, S., Seeman, M.V., Negrete, J.C., Houle, S.,
Hart, C.L. (2005). Increasing treatment options                Shammi, C.M., Remington, G.J., Kapur, S., Zipursky,
for cannabis dependence: A review of potential                 R.B., Wilson, A.A., Christensen B.K., & Seeman, P.
pharmacotherapies. Drug and Alcohol Dependence                 (2000). Increased dopamine D2 receptor binding after
80, 147-159.                                                   long-term treatment with antipsychotics in humans: A
                                                               clinical PET study. Psychopharmacology 152, 174-180.
Johansson, E., Halldin, M.M., Agurell, S., Hollister,
L.E., & Gillespie, H.K. (1989). Terminal elimination           Smith, N.T. (2002). A review of the published
plasma half-life of delta 1-tetrahydrocannabinol (delta        literature into cannabis withdrawal symptoms in
1-THC) in heavy users of marijuana. European Journal           human users. Addiction 97, 621-632.
of Clinical Pharmacology 37, 273-277.
                                                               Stuyt, E.B. (1997). Recovery rates after treatment for
Kosten, T.R. & O’Connor, P.G. (2003). Management of            alcohol/drug dependence. Tobacco users vs. non-
drug and alcohol withdrawal. New England Journal of            tobacco users. American Journal on Addictions 6,
Medicine 348, 1786-1795.                                       159-167.

Kouri, E.M. & Pope, H.G.J. (2000). Abstinence                  Sullivan, M.A. & Covey, L.S. (2002). Current
symptoms during withdrawal from chronic marijuana              perspectives on smoking cessation among substance
use. Experimental and Clinical Psychopharmacology              abusers. Current Psychiatry Reports 4, 388-396.
8, 483-492.
                                                               Swift, W., Copeland, J. & Lenton, S. (2000). Cannabis
Lejoyeux, M., Solomon, J. & Ades, J. (1998).                   and harm reduction. Drug and Alcohol Review 19,
Benzodiazepine treatment for alcohol-dependent                 101-112.
patients. Alcohol and Alcoholism 33, 563-575.
                                                               Swift, W., Gates, P. & Dillon, P. (2005). Survey of
Levin, F.R., McDowell, D., Evans, S.M., Nunes, E.,             Australians using cannabis for medical purposes.
Akerele, E., Donovan, S., & Vosburg, S.K. (2004).              Harm Reduction Journal 18, doi:10.1186/1477-7517-
Pharmacotherapy for marijuana dependence: A                    1182-1118.
double-blind, placebo-controlled pilot study of
Divalproex Sodium. American Journal on Addictions              Swift, W., Hall, W. & Teesson, M. (2001). Cannabis
13, 10.1080/10550490490265280.                                 use and dependence among Australian adults:
                                                               Results from the National Survey of Mental Health
                                                               and Wellbeing. Addiction 96, 737-748.

                                                               management of cannabis withdrawal

Tashkin, D., Baldwin, G.C., Sarafian, T., Dubinett, S.,
& Roth, M.D. (2002). Respiratory and immunologic
consequences of marijuana smoking. Journal of
Clinical Pharmacology 42, 71S-81S.

UNODC. (2006). World Drug Report 2006. New York:
United Nations Office on Drugs and Crime.

Vandrey, R.G., Budney, A.J., Hughes, J.R., & Liguori,
A. (2008). A within-subject comparison of withdrawal
symptoms during abstinence from cannabis, tobacco,
and both substances. Drug and Alcohol Dependence
92, 48-54.

Vandrey, R.G., Budney, A.J., Kamon, J.L., & Stanger,
C. (2005). Cannabis withdrawal in adolescent
treatment seekers. Drug and Alcohol Dependence 78,

Vandrey, R.G., Budney, A.J., Moore, B.A., & Hughes,
J.R. (2005). A cross-study comparison of cannabis and
tobacco withdrawal. American Journal on Addictions
14, 54-63.

Wall, M.E. & Perez-Reyes, M. (1981). The
metabolism of delta 9-tetrahydrocannabinol and
related cannabinoids in man. Journal of Clinical
Pharmacology 21, 178S-189S.

Winstock, A.R., Lea, T. & Copeland, J. (2009).
Lithium carbonate in the management of cannabis
withdrawal in humans: An open label study. Journal of
Psychopharmacology 23, 84-93.


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