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Cannabinoid Replacement Therapy (CRT):

Nabiximols (Sativex) as a Novel Treatment for
Cannabis Withdrawal
DJ Allsop1,2, N Lintzeris2,6, J Copeland3, A Dunlop4,5 and IS McGregor1
Cannabis is a common recreational drug that is generally
considered to have low addictive potential. However, an
increasing number of cannabis users are seeking treatment for
dependence on the drug. There is interest in using agonist
(substitution) pharmacotherapies to treat cannabis dependence
and here we outline a novel approach involving a buccal spray
(nabiximols) that contains tetrahydrocannabinol (THC) and
cannabidiol (CBD). We review recent research with nabiximols
and highlight ndings relevant to clinical practice.

CANNABIS DEPENDENCE AND WITHDRAWAL

Approximately 180 million people currently use cannabis worldwide. Cannabis dependence, dened as meeting three out of
seven diagnostic criteria according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)-Fourth Edition,1 develops
in 10% of people who ever try cannabis. Dependence is more
common with earlier age of initiation and higher levels of use,
and impaired control over cannabis use increases the risk of longterm health problems (e.g., cognitive decits, psychiatric, cardiovascular and respiratory disorders). Sudden cessation of regular
heavy cannabis use is associated with a distinctive withdrawal syndrome.2 This can include irritability, depression, anxiety, sleep
problems, restlessness, decreased appetite/weight loss, cravings,
and a range of physical symptoms (e.g., stomach pain, shakiness/
tremors, sweating, fever, chills, or headache).3 Cannabis withdrawal as a discrete diagnosis was added to the DSM-5 in 2014,
partly due to the recognition that it can drive relapse.1 The number of treatment episodes in which cannabis is the primary drug
of concern has increased markedly over recent years.1 Existing
treatments for cannabis use disorder involve psychosocial
approaches. However, only 20% of patients achieve continuous
abstinence, highlighting the need for better treatments.1

Agonist replacement therapy is a common approach to treating

other substance use disorders such as nicotine and opioid dependence, yet there are currently no approved pharmacotherapies for
cannabis dependence.1 Trials of several medications have
occurred over recent years. Laboratory-based approaches test
medication effects on acute craving and other parameters in small
numbers of non-treatment-seeking cannabis users. In addition, a
few randomized controlled trials (RCTs) and open-label studies
have been conducted in clinical populations.1 Medications tested
(see Table 1) include cannabinoid CB1 receptor agonists (e.g.,
THC, nabilone), antidepressants, mood stabilizers, anxiolytics,
a2-adrenergic agonists, anticonvulsants, and a glutamatergic modulator.4 Overall, results have shown only limited benets, particularly in clinical populations, with only gabapentin, Nacetylcysteine, and the CB1 receptor agonists demonstrating
some promise in specic patient groups.4
THE CASE FOR AGONIST (SUBSTITUTION) APPROACHES

The rationale for agonist substitution involves providing the

same or a similar drug to the problem drug, in a safer form with a
less hazardous route of administration. An agonist should reduce
illicit drug use by activating key receptor binding sites that the
drug of abuse activates, reducing withdrawal and cravings. Agonist therapy might also attenuate the acute effects of the primary
drug of addiction (via competition at receptor sites), and facilitate greater engagement in psychosocial interventions and reduce
criminal behavior. Together, these expected benets should
empower patients to make the necessary lifestyle changes to distance themselves from regular substance use, prior to tapering off
the agonist medication.
Recent studies suggest that an agonist approach holds some
promise in treating cannabis dependence. Dronabinol (Marinol),
which is an orally administered synthetic THC in capsule form,

Psychopharmacology Laboratory, School of Psychology, Faculty of Science, University of Sydney, NSW, Australia; 2Discipline of Addiction Medicine, Faculty of
Medicine, University of Sydney, NSW, Australia; 3National Cannabis Prevention and Information Centre, UNSW Medicine, Australia; 4Drug & Alcohol Clinical
Services, Hunter New England Local Health District, New South Wales Ministry of Health, Australia; 5School of Medicine and Public Health, Faculty of Health,
University of Newcastle, Australia; 6Drug and Alcohol Services, South East Sydney Local Health District, New South Wales Health, NSW, Australia.
Correspondence: DJ Allsop (david.allsop@sydney.edu.au)
Received 16 January 2015; accepted 5 March 2015; advance online publication 16 March 2015. doi:10.1002/cpt.109
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Table 1 Clinical pharmacotherapy randomized controlled trials research for cannabis withdrawal and dependence treatment (information extracted from ref. 4)
Drug name
(and sample size)

Comparator
(and sample size)

Cannabis use
reduced?a

Withdrawal
reduced?d

Adverse effects
increased?i

THC & CBD

Nabiximols
(n 5 27)

Cannabis
Withdrawal

Nob

Yes

No

THC

Outpatient

Cannabis
Dependence

No

Yes

No

Placebo
(n 5 36)

Outpatient

Cannabis
Dependence

No

Unknown

No

Escitalopram
(n 5 26)

Placebo
(n 5 26)

Outpatient

Cannabis
Dependence

Yesc

Unknown

Unknown

Mixed action
antidepressants

Nefazadone
(n 5 36)

Placebo
(n 5 30)

Outpatient

Cannabis
Dependence

Yes

Unknown

Yesj

Mixed action
antidepressants

Mirtazapine
(n not reported)

Placebo
(n not reported)

Outpatient

Cannabis
Dependence

No

Unknowne

Unknown

Mixed action
antidepressants

Venlafaxine
(n 5 51)

Placebo
(n 5 52)

Outpatient

Cannabis
Dependence

Opposite

Unknown

Unknown

Anticonvulsants
and mood
stabilizers

Divalproex
sodium (n 5 13)

Placebo
(n 5 12)

Outpatient

Cannabis
Dependence

Opposite

Unknownf

Unknown

Anticonvulsants
and mood
stabilizers

Gabapentin
(n 5 25)

Placebo
(n 5 25)

Outpatient

Cannabis
Dependence

Yes

Yes

No

Anticonvulsants
and mood
stabilizers

Lithium carbonate
(n 5 19)

Placebo
(n 5 19)

Inpatient

Cannabis
Withdrawal

No

Nog

No

Atypical
antidepressant

Bupropion
(n 5 12)

Placebo
(n 5 10)

Outpatient

Cannabis
Dependence

No

Yes

Yesk

Anxiolytic

Buspirone
(n 5 23)

Placebo
(n 5 27)

Outpatient

Cannabis
Dependence

No

No

Yes

Atomoxetine
(n 5 19)

Placebo
(n 5 19)

Outpatient

Cannabis
Dependence

No

Noh

Yesl

N-acetylcycteine
(n 5 58)

Placebo
(n 5 58)

Outpatient

Cannabis
Dependence

Yes

Unknown

No

Drug type

Setting

Indication

Placebo
(n 5 24)

Inpatient

Dronabinol
(n 5 79)

Placebo
(n 5 77)

Antidepressant
(SSRI)

Fluoxetine
(n 5 34)

Antidepressant
(SSRI)

Norepinephrine
reuptake inhibitor
Glutamatergic
modulator
a

Was cannabis use reduced in the active treatment group compared to in the placebo group at the end of the study compared to baseline? Yes, no, opposite. Opposite
means that cannabis use was greater in the active treatment group compared to placebo. bCannabis use was only assessed 1 month after the inpatient withdrawal treatment, NOT while the patients were receiving Nabiximols. cSmall sample size and very high drop out rates. dWas reported cannabis withdrawal intensity reduced in the
active group compared to the placebo group? If unknown is listed withdrawal intensity was either not reported or was reported for only a small subset of known withdrawal
symptoms. eOf the known cannabis withdrawal symptoms, only sleep disturbance was reported and was not improved by mirtazapine. fOf the known cannabis withdrawal
symptoms, only cravings were reported and they were not significantly different between the groups. gOverall Cannabis Withdrawal Scale scores were not reduced by lithium but specific withdrawal symptoms of loss of appetite, stomach aches, and nightmares or strange dreams were reduced by lithium. hOf the known cannabis withdrawal
symptoms, only cravings were reported and were not reduced by Atomoxetine. iWere adverse effects significantly higher in the active treatment group than in the placebo
group? jAdverse effects were more likely to be moderate or severe in the Nefazadone group but the overall number of AEs was not significantly different between the two
groups. kPatients receiving bupropion were more likely to experience AEs scored as moderate or severe. lSexual dysfunction and gastrointestinal side effects were more
common in the Atomoxetine group than in placebo.

dose-dependently reduced acute cannabis withdrawal in a laboratory study.1 However, a 12-week outpatient RCT of oral dronabinol (20 mg b.i.d.) in clinical populations did not reduce illicit
cannabis use.4 Subsequent laboratory research suggests that higher
single doses of dronabinol (60 or 120 mg) may be required to
reduce cannabis use.1 Aside from dosing, the clinical utility of dronabinol may be compromised by its poor bioavailability and slow
onset of action compared to smoked cannabis.1 Nabilone (Cesamet), a synthetic analog of THC, has superior bioavailability to
dronabinol and also reduced cannabis withdrawal in a human laboratory study but remains untested in clinical populations.1
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NABIXIMOLS IN THE TREATMENT OF CANNABIS

DEPENDENCE

Nabiximols is an oromucosal spray that is absorbed buccally. It

contains extracts from Cannabis sativa plants grown under
license in the UK by the company GW Pharmaceuticals. These
extracts contain 27 mg/ml THC and 25 mg/ml CBD per bottle,
with trace amounts of other plant-derived cannabinoids and terpenoids. Each spray of nabiximols delivers 100 mL (2.7 mg THC
and 2.5 mg CBD) doses. Buccal administration provides a more
rapid onset of action and more favorable pharmacokinetics than
oral THC.1 Nabiximols is available in 15 countries for
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Figure 1 Data from an inpatient trial of Sativex for cannabis withdrawal1: (a) Sativex suppresses cannabis withdrawal during inpatient cannabis detoxification and (b) retains patients in treatment longer during medication administration.

symptomatic relief of spasticity in multiple sclerosis (MS) and is

in development for cancer-related pain. Nabiximols has been
approved in a further 12 countries at the time of writing.
The THC component of nabiximols provides the agonist substitution and the buccal route of administration gives relatively low
and steady plasma THC concentrations relative to the large spikes
observed with smoked or vaporized cannabis. The CBD content
of nabiximols is potentially a major innovation over other CB1
receptor agonists such as dronabinol and nabilone, although direct
comparisons for cannabis dependence have not been carried out
yet. CBD has relatively poor afnity for CB1 and CB2 receptors
but possibly is an indirect agonist, either modulating receptor constitutional activities or increasing endocannabinoids via inhibition
of degradative enzymes. CBD affects numerous other drug targets
including transient receptor potential family channels, 5-HT1A
and PPARgamma receptors. CBD is present in varying degrees
across different cannabis strains, although it appears largely bred
out of modern illicit strains. CBD has no intoxicating effects, but
has notable anxiolytic, antidepressant, and antipsychotic properties,
and can attenuate paranoia and other adverse psychological effects
of THC in humans.1 Hence, the high CBD levels in Sativex may
introduce additional positive therapeutic effects and counteract the
anxiety, low mood, and cognitive decits associated with heavy
illicit cannabis use.1,3
Safety concerns with agonist medications usually include the
potential for abuse or diversion. A study examined the abuse
potential of nabiximols in a laboratory setting in which 23 recreational cannabis users were administered single doses of nabiximols (4, 8, and 16 sprays), dronabinol (20 and 40 mg), and
placebo in a crossover design.5 Nabiximols did not produce signicant adverse cognitive or psychomotor effects and showed
similar or lower abuse potential than dronabinol at lower doses.
However, both medications at the highest doses exhibited some
abuse potential, dened as self-reported drug liking compared
with placebo. This highlights the need for careful monitoring of
abuse and aberrant medication-related behaviors during future
research and clinical practice for cannabis withdrawal and
dependence treatment with nabiximols.

To date, there has been only one relevant study of nabiximols

for cannabis withdrawal (HNEHREC 10/12/15/3.02).1 A
double blind placebo-controlled RCT demonstrated that nabiximols suppressed cannabis withdrawal symptoms during inpatient abstinence (Figure 1a), and retained patients in
treatment longer than placebo during the drug administration
phase (Figure 1b).1 The drug was administered in doses of up
to 32 sprays (8 sprays q.i.d., 86.4 mg THC and 80 mg CBD)
daily on days 1 to 3, and was gradually tapered to zero over
days 4 to 7. Importantly, these high doses were well tolerated
by the participants, with no subjective reports of intoxication
or cognitive impairment.1
Despite the successful control of cannabis withdrawal, there
were high rates of relapse to cannabis following discharge from
the unit (69% at 1 month) in both groups. Thus, a 6-day inpatient nabiximols regimen is clearly not sufcient for maintenance
of continuous abstinence following discharge. This is not entirely
surprising: there is little evidence that any medication-assisted
withdrawal for any addiction promotes long-term abstinence
without ongoing psychosocial and/or clinical support. Consequently, a follow-up study examining longer-term (12 weeks) outpatient cannabis relapse prevention treatment using nabiximols is
now under way (Australian Government National Health and
Medical Research Council grant #1088902, 2015). The trial will
address a range of issues important in future translation of nabiximols for cannabis dependence into routine clinical practice,
including abuse liability, cognition, and psychomotor performance, toxicological detection of illicit cannabis use additional to
nabiximols, and cost effectiveness. A similar trial is under way in
Canada (NCT01747850). In MS trials the key safety concern
was the ability to tolerate the cannabis-like effects of nabiximols.
This is obviously less of a concern in treatment-seeking dependent cannabis users, who will be tolerant to cannabinoids. However, emerging safety concerns for the cannabis-dependent group
could include matters of compliance, diversion, and potentially
impaired driving.

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RECENT DEVELOPMENTS IN TREATING CANNABIS

DEPENDENCE WITH NABIXIMOLS

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CONCLUSIONS

The development of an effective medication for assisting in the

cessation of heavy cannabis use could have wide-reaching clinical
and public health benets. With no evidence-based medications
available currently, clinicians often prescribe off-label medications
for symptomatic relief, with neither consensus nor proof of efcacy. The use of nabiximols is innovative, given its favorable
pharmacokinetic prole and safety, although the high costs of the
drug may dissuade cannabis users from uptake, and it can only be
prescribed off-label at present in countries in which it is available
for other indications (nabiximols is not licensed in the USA).
The CBD content likely adds anxiolytic, antidepressant, and antipsychotic effects to the simple agonist THC substitution
approach, and facilitates the safe delivery of the high THC doses
needed to control cannabis cravings. While the approach may be
controversial in some quarters, from a harm reduction perspective
there can be little argument concerning the merits of agonist substitution for treating cannabis dependence given the mitigation
of respiratory, cardiovascular, and carcinogenic risk factors associated with smoking. However, changing the tide of opinion in the
medical profession and regulatory authorities requires much
effort to bring the drug to market for this ubiquitous indication.

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CONFLICT OF INTEREST
The authors declare no conflicts of interest.

C 2015 American Society for Clinical Pharmacology and Therapeutics

V

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