sign in sign up
<<
Home , Nabiximols

PRACTICE

Cannabinoid Replacement Therapy (CRT): Nabiximols (Sativex) as a Novel Treatment for Withdrawal

DJ Allsop1,2, N Lintzeris2,6, J Copeland3, A Dunlop4,5 and IS McGregor1

Cannabis is a common recreational drug that is generally Agonist replacement therapy is a common approach to treating considered to have low addictive potential. However, an other substance use disorders such as nicotine and depend- increasing number of cannabis users are seeking treatment for ence, yet there are currently no approved pharmacotherapies for dependence on the drug. There is interest in using agonist cannabis dependence.1 Trials of several medications have (substitution) pharmacotherapies to treat cannabis dependence occurred over recent years. Laboratory-based approaches test and here we outline a novel approach involving a buccal spray medication effects on acute craving and other parameters in small (nabiximols) that contains (THC) and numbers of non-treatment-seeking cannabis users. In addition, a (CBD). We review recent research with nabiximols few randomized controlled trials (RCTs) and open-label studies and highlight findings relevant to clinical practice. have been conducted in clinical populations.1 Medications tested (see Table 1) include CB1 agonists (e.g., THC, ), antidepressants, mood stabilizers, anxiolytics, CANNABIS DEPENDENCE AND WITHDRAWAL a2-adrenergic agonists, anticonvulsants, and a glutamatergic mod- Approximately 180 million people currently use cannabis world- ulator.4 Overall, results have shown only limited benefits, particu- wide. Cannabis dependence, defined as meeting three out of larly in clinical populations, with only , N- seven diagnostic criteria according to the Diagnostic and Statisti- acetylcysteine, and the CB1 receptor agonists demonstrating 1 cal Manual of Mental Disorders (DSM)-Fourth Edition, develops some promise in specific patient groups.4 in 10% of people who ever try cannabis. Dependence is more common with earlier age of initiation and higher levels of use, THE CASE FOR AGONIST (SUBSTITUTION) APPROACHES and impaired control over cannabis use increases the risk of long- The rationale for agonist substitution involves providing the term health problems (e.g., cognitive deficits, psychiatric, cardio- same or a similar drug to the problem drug, in a safer form with a vascular and respiratory disorders). Sudden cessation of regular less hazardous route of administration. An agonist should reduce heavy cannabis use is associated with a distinctive withdrawal syn- illicit drug use by activating key receptor binding sites that the drome.2 This can include irritability, depression, anxiety, sleep drug of abuse activates, reducing withdrawal and cravings. Ago- problems, restlessness, decreased appetite/weight loss, cravings, nist therapy might also attenuate the acute effects of the primary and a range of physical symptoms (e.g., stomach pain, shakiness/ drug of addiction (via competition at receptor sites), and facili- tremors, sweating, fever, chills, or headache).3 Cannabis with- tate greater engagement in psychosocial interventions and reduce drawal as a discrete diagnosis was added to the DSM-5 in 2014, criminal behavior. Together, these expected benefits should partly due to the recognition that it can drive relapse.1 The num- empower patients to make the necessary lifestyle changes to dis- ber of treatment episodes in which cannabis is the primary drug tance themselves from regular substance use, prior to tapering off of concern has increased markedly over recent years.1 Existing the agonist medication. treatments for involve psychosocial Recent studies suggest that an agonist approach holds some approaches. However, only 20% of patients achieve continuous promise in treating cannabis dependence. (Marinol), abstinence, highlighting the need for better treatments.1 which is an orally administered synthetic THC in capsule form,

1Psychopharmacology 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 & 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 ([email protected]) Received 16 January 2015; accepted 5 March 2015; advance online publication 00 Month 2015. doi:10.1002/cpt.109

CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2015 1 PRACTICE

Table 1 Clinical pharmacotherapy randomized controlled trials research for cannabis withdrawal and dependence treatment (infor- mation extracted from ref. 4) Drug name Comparator Cannabis use Withdrawal Adverse effects Drug type (and sample size) (and sample size) Setting Indication reduced?a reduced?d increased?i THC & CBD Nabiximols Inpatient Cannabis Nob Yes No (n 5 27) (n 5 24) Withdrawal THC Dronabinol Placebo Outpatient Cannabis No Yes No (n 5 79) (n 5 77) Dependence Antidepressant Fluoxetine Placebo Outpatient Cannabis No Unknown No (SSRI) (n 5 34) (n 5 36) Dependence Antidepressant Escitalopram Placebo Outpatient Cannabis Yesc Unknown Unknown (SSRI) (n 5 26) (n 5 26) Dependence Mixed action Nefazadone Placebo Outpatient Cannabis Yes Unknown Yesj antidepressants (n 5 36) (n 5 30) Dependence Mixed action Mirtazapine Placebo Outpatient Cannabis No Unknowne Unknown antidepressants (n not reported) (n not reported) Dependence Mixed action Venlafaxine Placebo Outpatient Cannabis Opposite Unknown Unknown antidepressants (n 5 51) (n 5 52) Dependence Anticonvulsants Divalproex Placebo Outpatient Cannabis Opposite Unknownf Unknown and mood sodium (n 5 13) (n 5 12) Dependence stabilizers Anticonvulsants Gabapentin Placebo Outpatient Cannabis Yes Yes No and mood (n 5 25) (n 5 25) Dependence stabilizers Anticonvulsants Lithium carbonate Placebo Inpatient Cannabis No Nog No and mood (n 5 19) (n 5 19) Withdrawal stabilizers Atypical Bupropion Placebo Outpatient Cannabis No Yes Yesk antidepressant (n 5 12) (n 5 10) Dependence Anxiolytic Buspirone Placebo Outpatient Cannabis No No Yes (n 5 23) (n 5 27) Dependence Norepinephrine Atomoxetine Placebo Outpatient Cannabis No Noh Yesl reuptake inhibitor (n 5 19) (n 5 19) Dependence Glutamatergic N-acetylcycteine Placebo Outpatient Cannabis Yes Unknown No modulator (n 5 58) (n 5 58) Dependence aWas 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 treat- ment, 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 lith- ium 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 labora- NABIXIMOLS IN THE TREATMENT OF CANNABIS tory study.1 However, a 12-week outpatient RCT of oral dronabi- DEPENDENCE nol (20 mg b.i.d.) in clinical populations did not reduce illicit Nabiximols is an oromucosal spray that is absorbed buccally. It cannabis use.4 Subsequent laboratory research suggests that higher contains extracts from Cannabis sativa plants grown under single doses of dronabinol (60 or 120 mg) may be required to license in the UK by the company GW Pharmaceuticals. These reduce cannabis use.1 Aside from dosing, the clinical utility of dro- extracts contain 27 mg/ml THC and 25 mg/ml CBD per bottle, nabinol may be compromised by its poor bioavailability and slow with trace amounts of other plant-derived and ter- onset of action compared to smoked cannabis.1 Nabilone (Cesa- penoids. Each spray of nabiximols delivers 100 mL (2.7 mg THC met), a synthetic analog of THC, has superior bioavailability to and 2.5 mg CBD) doses. Buccal administration provides a more dronabinol and also reduced cannabis withdrawal in a human labo- rapid onset of action and more favorable pharmacokinetics than ratory study but remains untested in clinical populations.1 oral THC.1 Nabiximols is available in 15 countries for

2 VOLUME 00 NUMBER 00 | MONTH 2015 | www.wileyonlinelibrary/cpt PRACTICE

Figure 1 Data from an inpatient trial of Sativex for cannabis withdrawal1:(a) Sativex suppresses cannabis withdrawal during inpatient cannabis detoxifi- cation and (b) retains patients in treatment longer during medication administration. symptomatic relief of spasticity in (MS) and is RECENT DEVELOPMENTS IN TREATING CANNABIS in development for cancer-related pain. Nabiximols has been DEPENDENCE WITH NABIXIMOLS approved in a further 12 countries at the time of writing. To date, there has been only one relevant study of nabiximols The THC component of nabiximols provides the agonist substi- for cannabis withdrawal (HNEHREC 10/12/15/3.02).1 A tution and the buccal route of administration gives relatively low double blind placebo-controlled RCT demonstrated that nabix- and steady plasma THC concentrations relative to the large spikes imols suppressed cannabis withdrawal symptoms during inpa- observed with smoked or vaporized cannabis. The CBD content tient abstinence (Figure 1a), and retained patients in of nabiximols is potentially a major innovation over other CB1 treatment longer than placebo during the drug administration receptor agonists such as dronabinol and nabilone, although direct phase (Figure 1b).1 The drug was administered in doses of up comparisons for cannabis dependence have not been carried out to 32 sprays (8 sprays q.i.d., 86.4 mg THC and 80 mg CBD) yet. CBD has relatively poor affinity for CB1 and CB2 receptors daily on days 1 to 3, and was gradually tapered to zero over but possibly is an indirect agonist, either modulating receptor con- days 4 to 7. Importantly, these high doses were well tolerated stitutional activities or increasing endocannabinoids via inhibition by the participants, with no subjective reports of intoxication of degradative enzymes. CBD affects numerous other drug targets or cognitive impairment.1 including transient receptor potential family channels, 5-HT1A Despite the successful control of cannabis withdrawal, there and PPARgamma receptors. CBD is present in varying degrees were high rates of relapse to cannabis following discharge from across different cannabis strains, although it appears largely bred the unit (69% at 1 month) in both groups. Thus, a 6-day inpa- out of modern illicit strains. CBD has no intoxicating effects, but tient nabiximols regimen is clearly not sufficient for maintenance has notable anxiolytic, antidepressant, and antipsychotic properties, of continuous abstinence following discharge. This is not entirely and can attenuate paranoia and other adverse psychological effects surprising: there is little evidence that any medication-assisted of THC in humans.1 Hence, the high CBD levels in Sativex may withdrawal for any addiction promotes long-term abstinence introduce additional positive therapeutic effects and counteract the without ongoing psychosocial and/or clinical support. Conse- anxiety, low mood, and cognitive deficits associated with heavy quently, a follow-up study examining longer-term (12 weeks) out- illicit cannabis use.1,3 patient cannabis relapse prevention treatment using nabiximols is Safety concerns with agonist medications usually include the now under way (Australian Government National Health and potential for abuse or diversion. A study examined the abuse Medical Research Council grant #1088902, 2015). The trial will potential of nabiximols in a laboratory setting in which 23 recrea- address a range of issues important in future translation of nabixi- tional cannabis users were administered single doses of nabixi- mols for cannabis dependence into routine clinical practice, mols (4, 8, and 16 sprays), dronabinol (20 and 40 mg), and including abuse liability, cognition, and psychomotor perform- placebo in a crossover design.5 Nabiximols did not produce sig- ance, toxicological detection of illicit cannabis use additional to nificant adverse cognitive or psychomotor effects and showed nabiximols, and cost effectiveness. A similar trial is under way in similar or lower abuse potential than dronabinol at lower doses. Canada (NCT01747850). In MS trials the key safety concern However, both medications at the highest doses exhibited some was the ability to tolerate the cannabis-like effects of nabiximols. abuse potential, defined as self-reported drug liking compared This is obviously less of a concern in treatment-seeking depend- with placebo. This highlights the need for careful monitoring of ent cannabis users, who will be tolerant to cannabinoids. How- abuse and aberrant medication-related behaviors during future ever, emerging safety concerns for the cannabis-dependent group research and clinical practice for cannabis withdrawal and could include matters of compliance, diversion, and potentially dependence treatment with nabiximols. impaired driving.

CLINICAL PHARMACOLOGY & THERAPEUTICS | VOLUME 00 NUMBER 00 | MONTH 2015 3 PRACTICE

CONCLUSIONS CONFLICT OF INTEREST The development of an effective medication for assisting in the The authors declare no conflicts of interest. cessation of heavy cannabis use could have wide-reaching clinical and public health benefits. With no evidence-based medications available currently, clinicians often prescribe off-label medications C for symptomatic relief, with neither consensus nor proof of effi- V 2015 American Society for Clinical Pharmacology and Therapeutics cacy. The use of nabiximols is innovative, given its favorable pharmacokinetic profile and safety, although the high costs of the 1. Allsop, D.J. et al. Nabiximols as an agonist replacement therapy during drug may dissuade cannabis users from uptake, and it can only be cannabis withdrawal: a randomized . JAMA Psychiatry 71, prescribed off-label at present in countries in which it is available 281–291 (2014). 2. Degenhardt, L. et al. The global epidemiology and contribution of for other indications (nabiximols is not licensed in the USA). cannabis use and dependence to the global burden of disease: The CBD content likely adds anxiolytic, antidepressant, and anti- results from the GBD 2010 Study. PLoS One 8, e76635 (2013). psychotic effects to the simple agonist THC substitution 3. Allsop, D.J., Norberg, M.M., Copeland, J., Fu, S. & Budney, A.J. The approach, and facilitates the safe delivery of the high THC doses cannabis withdrawal scale development: patterns and predictors of cannabis withdrawal and distress. Drug Alcohol Depend. 119, 123– needed to control cannabis cravings. While the approach may be 129 (2011). controversial in some quarters, from a harm reduction perspective 4. Marshall, K., Gowing, L., Ali, R., Le Foll, B. Pharmacotherapies for there can be little argument concerning the merits of agonist sub- cannabis dependence. Cochrane Database Syst. Rev. 12, Cd008940 stitution for treating cannabis dependence given the mitigation (2014). of respiratory, cardiovascular, and carcinogenic risk factors associ- 5. Schoedel, K.A. et al. A randomized, double-blind, placebo-controlled, ated with smoking. However, changing the tide of opinion in the crossover study to evaluate the subjective abuse potential and cognitive effects of nabiximols oromucosal spray in subjects with a medical profession and regulatory authorities requires much history of recreational cannabis use. Hum. Psychopharmacol. 26, 224– effort to bring the drug to market for this ubiquitous indication. 236 (2011).

4 VOLUME 00 NUMBER 00 | MONTH 2015 | www.wileyonlinelibrary/cpt