The efficacy and safety of cannabinoids for the treatment of mental disorders and substance use disorders: a systematic review and meta-analysis

BACKGROUND: Mental disorders and substance use disorders (SUDs) are among the leading reasons for which the medical use of cannabinoids has been approved, but their efficacy and safety in treating these conditions is yet to be established. We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) testing the efficacy and safety of cannabinoids as the primary treatment for mental disorders or SUDs.

METHODS: We searched Ovid MEDLINE, PsychINFO, Cochrane Central Register of Controlled Clinical Trials, Cochrane Database of Systematic Reviews, and Embase for peer-reviewed articles published between Jan 1, 1980, and May 13, 2025, evaluating the efficacy of cannabinoids in reducing or treating mental disorders and SUDs as the primary indication. Primary outcomes were remission of disorder or reduction in disorder symptoms. Safety was assessed via synthesis of all-cause and serious adverse events, which was used to calculate the number needed to treat to harm (NNTH). Two independent reviewers screened all studies and performed data extraction. Evidence was synthesised as odds ratios (ORs) for dichotomous measures and standardised mean differences (SMDs) for continuous measures, via random-effects meta-analysis in Review Manager, version 5.4. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias 2.0 tool. We evaluated the quality of the primary outcomes using the GRADE framework. The study was registered with PROSPERO (CRD42023392718).

FINDINGS: 54 trials were identified for inclusion (2477 participants; 1713 [69%] males, 764 [31%] females; median age 33·3 years [IQR 28·1-38·05; ethnicity data not available). 24 (44%) of these trials had a high risk of bias, and the certainty of evidence for most outcomes was low. Our meta-analysis revealed that a combination of cannabidiol and delta-9-tetrahydrocannabinol reduced cannabis withdrawal symptoms (SMD -0·29, 95% CI -0·57 to -0·02) and weekly grams of cannabis use (-1·00, -1·69 to -0·30) among those with cannabis use disorder, and a reduction in tic severity among those with tic or Tourette's Syndrome (-0·68, -1·03 to -0·34) compared with placebo. Any cannabinoid type led to an increase in sleep time as recorded by an electronic device (0·54, 0·14 to 0·95) and sleep diary (0·55, 0·01 to 1·09) among those with insomnia. There was a reduction in autistic traits (-0·36, -0·66 to -0·07) among those with autism spectrum disorder. Cannabinoids led to an increase in cocaine craving among those with cocaine use disorder (0·69, 0·22 to 1·15) compared with placebo. There were no significant effects on outcomes associated with anxiety, anorexia nervosa, psychotic disorders, post-traumatic stress disorder, and opioid use disorder. There were insufficient data to meta-analyse studies of ADHD, bipolar disorder, obsessive-compulsive disorder, and tobacco use disorder. There was an absence of RCT evidence for the treatment of depression. Meta-analysis revealed higher odds of all-cause adverse events (OR 1·75, 95% CI 1·25 to 2·46) among those using cannabis versus control group (NNTH=7) but no higher odds of serious adverse events or study withdrawal.

INTERPRETATION: There was some evidence that cannabinoids can reduce symptoms of cannabis use disorder, insomnia, tic or Tourette's syndrome, and autism spectrum disorder, but the quality of this evidence was generally low. Cannabinoids were associated with a greater risk of any adverse events but not of serious adverse events. Overall, there is a crucial need for more high-quality research. Given the scarcity of evidence, the routine use of cannabinoids for the treatment of mental disorders and SUDs is currently rarely justified.

FUNDING: The National Health and Medical Research Council.