Abstract: We included 21 RCTs involving 1755 participants: 18 studies recruited adults (mean age 22 to 41 years); three studies targeted young people (mean age 20 years). Most (75%) participants were male. The studies were at low risk of performance, detection and selective outcome reporting bias. One study was at risk of selection bias, and three studies were at risk of attrition bias. All studies involved comparison of active medication and placebo. The medications were diverse, as were the outcomes reported, which limited the extent of analysis. Abstinence at end of treatment was no more likely with Δ9-tetrahydrocannabinol (THC) preparations than with placebo (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.64 to 1.52; 305 participants; 3 studies; moderate-quality evidence). For selective serotonin reuptake inhibitor (SSRI) antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine, there was no difference in the likelihood of abstinence at end of treatment compared to placebo (low- to very low-quality evidence). There was qualitative evidence of reduced intensity of withdrawal symptoms with THC preparations compared to placebo. For other pharmacotherapies, this outcome was either not examined, or no significant differences was reported. Adverse effects were no more likely with THC preparations (RR 1.02, 95% CI 0.89 to 1.17; 318 participants; 3 studies) or N-acetylcysteine (RR 0.94, 95% CI 0.71 to 1.23; 418 participants; 2 studies) compared to placebo (moderate-quality evidence). For SSRI antidepressants, mixed action antidepressants, buspirone and N-acetylcysteine, there was no difference in adverse effects compared to placebo (low- to very low-quality evidence). There was no difference in the likelihood of withdrawal from treatment due to adverse effects with THC preparations, SSRIs antidepressants, mixed action antidepressants, anticonvulsants and mood stabilisers, buspirone and N-acetylcysteine compared to placebo (low- to very low-quality evidence). There was no difference in the likelihood of treatment completion with THC preparations, SSRI antidepressants, mixed action antidepressants and buspirone compared to placebo (low- to very low-quality evidence) or with N-acetylcysteine compared to placebo (RR 1.06, 95% CI 0.93 to 1.21; 418 participants; 2 studies; moderate-quality evidence). Anticonvulsants and mood stabilisers appeared to reduce the likelihood of treatment completion (RR 0.66, 95% CI 0.47 to 0.92; 141 participants; 3 studies; low-quality evidence). Available evidence on gabapentin (anticonvulsant), oxytocin (neuropeptide) and atomoxetine was insufficient for estimates of effectiveness. There is incomplete evidence for all of the pharmacotherapies investigated, and for many outcomes the quality of the evidence was low or very low. Findings indicate that SSRI antidepressants, mixed action antidepressants, bupropion, buspirone and atomoxetine are probably of little value in the treatment of cannabis dependence. Given the limited evidence of efficacy, THC preparations should be considered still experimental, with some positive effects on withdrawal symptoms and craving. The evidence base for the anticonvulsant gabapentin, oxytocin, and N-acetylcysteine is weak, but these medications are also worth further investigation.

Plain-language summary: We identified 21 randomised controlled trials (clinical studies where people are allocated at random to one of two or more treatment groups) involving 909 participants treated with active medicines, and 846 who received placebo (a pretend treatment). Key features of dependent drug use are compulsive use, loss of control over use and withdrawal symptoms on cessation of drug use. This review included studies where participants were described as dependent or were likely to be dependent based on cannabis use occurring several days a week, or daily. The mean age of participants in individual studies ranged from 22 to 41 years, excluding three studies that targeted young people. Most (75%) study participants were male. Most (16) of the studies were undertaken in the USA, with three occurring in Australia, one in Canada and one in Israel. The studies tested a wide range of medicines to reduce the symptoms of cannabis withdrawal and to promote cessation or reduction of cannabis use. Four studies received study medicines from the manufacturing pharmaceutical company but none were funded by pharmaceutical companies. One study did not report funding or medicine source. For the outcome of abstinence at the end of treatment, Δ9-tetrahydrocannabinol (THC, the major constituent in cannabis) preparations were probably ineffective; antidepressants called selective serotonin reuptake inhibitors, mixed action antidepressants, a medicine called buspirone and a medicine called N-acetylcysteine may also have been ineffective; and we are uncertain about the effect of anticonvulsants and mood stabilisers. For the outcome of completion of the scheduled period of treatment, THC preparations, mixed action antidepressants, anticonvulsants and mood stabilisers may not have been effective, we were uncertain about the effect of SSRI antidepressants, and N-acetylcysteine probably did not support treatment completion. The use of anticonvulsants and mood stabilisers may have increased the likelihood that people left treatment early. THC preparations and N-acetylcysteine were probably no more likely to cause side effects than placebo, mixed action antidepressants and buspirone may have been no more likely to cause side effects than placebo, and we were uncertain about SSRI antidepressants. Based on current research, all medicines should be considered still experimental. The quality of the evidence for many of the outcomes in this review was low or very low because each medicine was investigated by a small number of studies (ranging from one to four), each study involved small numbers of participants, there was some inconsistency in the findings and there was a risk of bias due to study participants dropping out of treatment.