Cannabis is the most used illicit drug in the world, and the adverse effects associated with the drug are well documented (Budney et al 2007). Long term or heavy use of cannabis can increase the risk of dependence, with 10% of people who have used cannabis at least once expected to develop dependence (Wagner 2002).

The current recommended treatment for cannabis dependence is psychological therapies, such as motivational enhancement therapy or cognitive-behavioural therapy. Whilst pharmacotherapies (medications) are available for dependence on other substances, such as nicotine and opiates, there is currently no medication recommended by the guidelines to help people with dependence on cannabis.

A recent Cochrane systematic review (Marshall K et al, 2014) sought to identify trials that have tested whether pharmacotherapies can be effective in reducing the effects of cannabis withdrawal and promoting abstinence or reduced use.

Method

To identify papers for inclusion in the review the authors searched databases, electronic sources of ongoing trials, reference lists and conference proceedings, and contacted experts in the field. They searched for both English and non-English language papers, although only English language papers were identified.

Fourteen randomised control trials (RCT’s) were included with a total of 958 participants. Where data was available on demographics of the samples, around 80% were male and the average age was 33 years. There was generally a low risk of bias in most areas across papers. However, there was often a high risk of attrition bias.

All 14 studies compared a medication with placebo and a range of medications were trialled, including:

• Medications containing tetrahydrocannabinol (THC): dronabinol (Levin 2011) and nabiximols (Allsop 2014);
• Selective serotonin reuptake inhibitor (SSRI) antidepressants: fluoxetine (Cornelius 2010) and escitalopram (Weinstein 2014)
• Mixed action antidepressants: nefazodone (Carpenter 2009), mirtazapine (Frewen 2007) and venlafaxine (Levin 2013)
• Anticonvulsant and mood stabilisers: divalproex sodium (Levin 2004), gabapentin (Mason 2012) and lithium (Johnston 2012)
• Atypical antidepressants: bupropion (Carpenter 2009; Penetar 2012)
• Anxiolytics: buspirone (McRae-Clark 2009)
• Selective norepinephrine reuptake inhibitor: atomoxetine (McRae-Clark 2010)
• A supplement promoting glutamate release and modulating N-methyl-D-aspartate (NMDA) receptor: N-acetylcysteine (Gray 2012)

The primary outcomes for the review were abstinence, intensity of withdrawal, adverse effects and completion of the treatment regime. Due to the range of medications tested and the outcomes reported, analysis was difficult and meta-analysis was often not possible.

Results

Abstinence

Data relating to abstinence was available for 4 types of medication (medications containing THC, SSRIs, mixed action antidepressants and anticonvulsants or mood stabilisers).

There was no significant difference in the likelihood of abstinence from cannabis at the end of treatment for any of the medications compared to placebo. However, two individual papers suggested positive effects on reduction compared to placebo, for both gabapentin and n-acetylcysteine.

Intensity of withdrawal

Due to variation and small numbers, meta-analysis was not possible on the data for intensity of cannabis withdrawal. However, several studies individually reported significant results:

• For medications containing THC, nabiximols resulted in significantly lower levels of cravings, irritability, anger and aggression compared to placebo, and dronabinol resulted in significantly less withdrawal discomfort than placebo
• Gabapentin showed a significant reduction in withdrawal symptoms compared to placebo
• Withdrawal discomfort scores were significantly higher in those taking placebo compared to those taking bupropion

No other medications showed significant differences compared to placebo.

Adverse effects

There is data to suggest that the adverse effects were greater in the medication group compared to the placebo group in trials of compounds containing THC, buspirone and atomexetine; however, the data was insufficient to make any conclusions.

Completion of treatment

Completion of treatment was more likely for those taking a medication containing THC than those taking placebo (2 RCTs; 207 participants; RR 1.29, 95% CI 1.08 to 1.55, p=0.006).

There was no significant difference in completion of treatment between any other medication and placebo.

Conclusion

There is a lack of evidence for all medications included in the review. As a result, it is difficult to make any conclusions about the effectiveness of pharmacotherapies for cannabis dependence.

From the limited evidence that is available, it appears that compounds containing THC showed the most promise, due to their potential to reduce the effects of withdrawal and improve treatment adherence (although they had no significant effect on abstinence or reduction). Gabapentin, N-acetylcysteine and bupropion also showed some beneficial effects, whist all other medications included in the review have no evidence to support their use.

Although some benefits for certain medications were seen, the evidence is insufficient to inform clinical practice and more research is needed on these pharmacotherapies; specifically testing different combinations and doses of medication with longer durations of treatment.

The review was unclear about whether or not the participants of the various studies were receiving any form of psychological treatment for cannabis use, in addition to the medication, which could have potentially influenced the results. To increase the reliability of these studies, and to be able to say with confidence that medications have beneficial results, they should be trialled in people receiving no additional treatment.

On the other hand, whilst medication can be useful, and is often the first line of treatment for many disorders, it would make sense if medications for cannabis dependence were trialled alongside psychological therapies, as increasing motivation to change and developing relapse prevention strategies are fundamental aspects of treatment which cannot be gained through taking a medication alone.

Links

Marshall K, Gowing L, Ali R, Le Foll B. Pharmacotherapies for cannabis dependence. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD008940. DOI: 10.1002/14651858.CD008940.pub2

Budney AJ, Roffman R, Stephens RS, Walker D. Marijuana dependence and its treatment. Addiction Science & Clinical Practice 2007; Vol. 4, issue 1:4–16.

Wagner FA, Anthony JC. From first drug use to drug dependence; developmental periods of risk for dependence upon marijuana, cocaine, and alcohol. Neuropsychopharmacology 2002; Vol. 26, issue 4:479–88.

Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry 2014; 71 (3):281–91. DOI: 10.1001/jamapsychiatry.2013.3947 [Pubmed abstract]

Carpenter KM, McDowell D, Brooks DJ, Cheng WY, Levin FR. A preliminary trial: double-blind comparison of nefazodone, bupropion-SR, and placebo in the treatment of cannabis dependence. American Journal on Addictions 2009; 18 (1):53–64.

Cornelius JR, Bukstein OG, Douaihy AB, Clark DB, Chung TA, et al. Double-blind fluoxetine trial in comorbid MDD-CUD youth and young adults. Drug and Alcohol Dependence 2010; 112 (1-2):39–45.

Frewen A, Montebello ME, Baillie A, Rea F. Effects of mirtazapine on withdrawal from dependent cannabis use. Proceedings of the 69th Annual Scientific Meeting of the College on Problems of Drug Dependence; June 16-21; Quebec City, Canada 2007. 21.

Gray KM, Carpenter MJ, Baker NL, DeSantis SM, Kryway E, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. American Journal of Psychiatry 2012; 169(8):805–12. DOI: 10.1176/appi.ajp.2012.12010055

Johnston J, Lintzeris N, McGregor I, Guastella A, Allsop D, Helliwell D, Winstock A. Preliminary findings from a double blind, randomised, placebo controlled trial of lithium carbonate for the management of cannabis withdrawal [conference abstract]. Drug and Alcohol Review 2012; 31:45.

Levin FR, McDowell D, Evans SM, Nunes E, Akerele E, Donovan S, et al. Pharmacotherapy for marijuana dependence: a double-blind, placebo-controlled pilot study of divalproex sodium. American Journal on Addictions 2004; 13:21–32.

Levin FR, Mariani JJ, Brooks DJ, Pavlicova M, Cheng W, Nunes EV. Dronabinol for the treatment of cannabis dependence: A randomized, double-blind, placebo-controlled trial. Drug and Alcohol  Dependence 2011; 116:142–50. DOI: 10.1016/j.drugalcdep.2010.12.010

Levin FR, Mariani J, Brooks DJ, Pavlicova M, Nunes EV, et al. A randomized double-blind, placebo-controlled trial of venlafaxine-extended release for co-occurring cannabis dependence and depressive disorders. Addiction 2013; 108 (6):1084–94. DOI: 10.1111/add.12108

Mason BJ, Crean R, Goodell V, Light JM, Quello S, Shadan F, et al. A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology 2012; 37:1689–98. DOI:10.1038/npp.2012.14

McRae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, Wahlquist AE, Simpson SA, Brady KT. A placebo-controlled trial of buspirone for the treatment of marijuana dependence. Drug and Alcohol Dependence 2009; 105:132–8. DOI: 10.1016/j.drugalcdep.2009.06.022

McRae-Clark AL, Carter RE, Killeen TK, Carpenter MJ, White KG, Brady KT. A placebo-controlled trial of atomoxetine in marijuana-dependent individuals with attention deficit hyperactivity disorder. American Journal on Addictions 2010; 19(6):481–9.

Penetar DM, Looby AR, Ryan ET, Maywalt MA, Lukas SE. Bupropion reduces some of the symptoms of marihuana withdrawal in chronic marihuana users: A pilot study. Substance Abuse: Research and Treatment 2012; 6:63–71.

Weinstein AM, Miller H, Bluvstein I, Rapoport E, Schreiber S, et al. Treatment of cannabis dependence using escitalopram in combination with cognitive-behavior therapy: A double-blind placebo-controlled study. American Journal of Drug and Alcohol Abuse 2014; 40(1):16–22. DOI: 10.3109/00952990.2013.819362 [Pubmed abstract]