title: Pharmacotherapies for cannabis dependence.
abstract: BACKGROUND
  Cannabis is the most prevalent illicit drug in the world. Demand for treatment of cannabis use disorders is increasing. There are currently no pharmacotherapies approved for treatment of cannabis use disorders.
  
  
  OBJECTIVE
  To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or supportive care for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use.
  
  
  METHODS
  We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (to 4 March 2014), MEDLINE (to week 3 February 2014), EMBASE (to 3 March 2014) and PsycINFO (to week 4 February 2014). We also searched reference lists of articles, electronic sources of ongoing trials and conference proceedings, and contacted selected researchers active in the area.
  
  
  METHODS
  Randomised and quasi-randomised controlled trials involving the use of medications to reduce the symptoms and signs of cannabis withdrawal or to promote cessation or reduction of cannabis use, or both, in comparison with other medications, placebo or no medication (supportive care) in participants diagnosed as cannabis dependent or who were likely to be dependent.
  
  
  METHODS
  We used standard methodological procedures expected by The Cochrane Collaboration. Two review authors assessed studies for inclusion and extracted data. All review authors confirmed the inclusion decisions and the overall process.
  
  
  RESULTS
  We included 14 randomised controlled trials involving 958 participants. For 10 studies the average age was 33 years; two studies targeted young people; and age data were not available for two studies. Approximately 80% of study participants were male. The studies were at low risk of selection, performance, detection and selective outcome reporting bias. Three studies were at risk of attrition bias.All studies involved comparison of active medication and placebo. The medications included preparations containing tetrahydrocannabinol (THC) (two studies), selective serotonin reuptake inhibitor (SSRI) antidepressants (two studies), mixed action antidepressants (three studies), anticonvulsants and mood stabilisers (three studies), an atypical antidepressant (two studies), an anxiolytic (one study), a norepinephrine reuptake inhibitor (one study) and a glutamatergic modulator (one study). One study examined more than one medication. Diversity in the medications and the outcomes reported limited the extent that analysis was possible. Insufficient data were available to assess the utility of most of the medications to promote cannabis abstinence at the end of treatment.There was moderate quality evidence that completion of treatment was more likely with preparations containing THC compared to placebo (RR 1.29, 95% CI 1.08 to 1.55; 2 studies, 207 participants, P = 0.006). There was some evidence that treatment with preparations containing THC was associated with reduced cannabis withdrawal symptoms and craving, but this latter outcome could not be quantified. For mixed action antidepressants compared with placebo (2 studies, 179 participants) there was very low quality evidence on the likelihood of abstinence from cannabis at the end of follow-up (RR 0.82, 95% CI 0.12 to 5.41), and moderate quality evidence on the likelihood of treatment completion (RR 0.93, 95% CI 0.71 to 1.21). For this same outcome there was very low quality evidence for the effects of SSRI antidepressants (RR 0.82, 95% CI 0.44 to 1.53; 2 studies, 122 participants), anticonvulsants and mood stabilisers (RR 0.78, 95% CI 0.42 to 1.46; 2 studies, 75 participants), and the atypical antidepressant, bupropion (RR 1.06, 95% CI 0.67 to 1.67; 2 studies, 92 participants). Available evidence on gabapentin (anticonvulsant) and N-acetylcysteine (glutamatergic modulator) was insufficient for quantitative estimates of their effectiveness, but these medications may be worth further investigation.
  
  
  CONCLUSIONS
  There is incomplete evidence for all of the pharmacotherapies investigated, and for many of the outcomes the quality was downgraded due to small sample sizes, inconsistency and risk of attrition bias. The quantitative analyses that were possible, combined with general findings of the studies reviewed, indicate that SSRI antidepressants, mixed action antidepressants, atypical antidepressants (bupropion), anxiolytics (buspirone) and norepinephrine reuptake inhibitors (atomoxetine) are probably of little value in the treatment of cannabis dependence. Preparations containing THC are of potential value but, given the limited evidence, this application of THC preparations should be considered still experimental. Further studies should compare different preparations of THC, dose and duration of treatment, adjunct medications and therapies. The evidence base for the anticonvulsant gabapentin and the glutamatergic modulator N-acetylcysteine is weak, but these medications are also worth further investigation.
authors.affiliation: Discipline of Pharmacology, University of Adelaide, Adelaide, Australia.
authors.forename: Kushani
authors.initials: K
authors.lastname: Marshall
authors.forename: Linda
authors.initials: L
authors.lastname: Gowing
authors.forename: Robert
authors.initials: R
authors.lastname: Ali
authors.forename: Bernard
authors.initials: B
authors.lastname: Le Foll
mesh_terms: D000328:Adult; D000927:Anticonvulsants / Q000627:therapeutic use; D000928:Antidepressive Agents / Q000627:therapeutic use; D013759:Dronabinol / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008297:Male; D002189:Marijuana Abuse / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D000928:Antidepressive Agents; D013759:Dronabinol; D017367:Selective Serotonin Reuptake Inhibitors