There is limited evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, post-traumatic stress disorder (PTSD), or psychosis. The certainty of evidence was usually rated to be low or even very low. However, pharmaceutical tetrahydrocannabinol (THC, with or without cannabidiol) seems to show a small improvement in symptoms of anxiety among individuals with other medical conditions. There is insufficient evidence to provide clear guidance on the use of cannabinoids for treating mental disorders, e.g. within a regulatory framework. Bias in primary studies was addressed while interpreting the findings, but the criteria used for the observational studies were unclear. Further high-quality studies directly examining the eﬀect of cannabinoids on treating mental disorders are needed to support the current findings.
Overall summary Low risk of bias in the review
It was unclear which criteria were used for the methodological quality assessment of the observational studies. However, overall, no major issues were identified.
|A. Did the interpretation of findings address all of the concerns identified in Domains 1 to 4?||Probably yes|
|B. Was the relevance of identified studies to the review's research question appropriately considered?||Probably yes|
|C. Did the reviewers avoid emphasizing results on the basis of their statistical significance?||Probably yes|
|Risk of bias in the review||Low|
|Number of studies||83|
|Number of participants||8,547|
|Last search date||30 April 2018|
|Objective||To ascertain the eﬀectiveness and safety of all types of medicinal cannabinoids in treating symptoms of various mental disorders.|
|Population||Adults (aged ≥18 years) for treating depression, anxiety, ADHD, Tourette syndrome, PTSD, or psychosis, either as the primary condition or secondary to other medical conditions (such as chronic non-cancer pain).
Patients with neurocognitive disorders such as dementia were excluded.
|Interventions||Any type and formulation of a medicinal cannabinoid (THC and cannabidiol [CBD], combination THC plus CBD, cannabis sativa, and other cannabinoids [e.g. tetrahydrocannabinolic acid, cannabidiolic acid, cannabidivarin, and the synthetic Δ⁹-tetrahydrocannabinol formulations nabilone and dronabinol).|
|Comparator||Any type of comparator, including placebo, wait-list controls, and other interventions or no comparator.|
|Outcome||Primary outcome: remission from and changes in symptoms of mental disorders.
Secondary outcomes: changes in distal factors related to mental disorder, including global functioning (quality of life and patient or caregiver impression of change, and satisfaction with treatment), cardiovascular eﬀects, weight, sleep; and safety outcomes (including all-cause adverse events, serious adverse events, treatment-related adverse events, study withdrawals and study withdrawals due to adverse events).
|Study design||Experimental and observational study designs (i.e. randomised controlled trials [RCTs], non-RCTs, quasi-experimental studies, before-and-after studies, prospective and retrospective cohort studies, case-control studies, analytical cross-sectional studies, self-reported studies, and N-of-1 studies).
Reviews, editorials, commentaries and clinical overviews were excluded.
The meta-analysis of seven studies (n=252) reported that pharmaceutical THC (with or without CBD) significantly improved anxiety symptoms among individuals with other medical conditions (primarily chronic non-cancer pain and multiple sclerosis; standardised mean difference [SMD] -0.25, 95% confidence interval [CI] -0.49 to -0.01, very low certainty of evidence [COE]). However, pharmaceutical THC (with or without CBD) worsened negative symptoms of psychosis in a single study (SMD 0.36, 95% CI 0.10 to 0·62, n=24, very low COE).
Pharmaceutical THC (with or without CBD) did not significantly aﬀect any other primary outcomes for the mental disorders examined (change in depressive symptoms: SMD -0.05, 95% CI -0.20 to 0.11, 12 studies, n=1,656, very low COE; change in ADHD: SMD -0.67, 95% CI -1.41 to 0.07, 1 study, n=30, low COE; change in tic or Tourette symptoms: SMD -0.46, 95% CI -1.32 to 0.40, 2 studies, n=41, low COE; PTSD: not reported).
Compared to placebo, THC-CBD did increase the number of people who had adverse events (odds ratio [OR] 1.99, 95% CI 1.20 to 3.29, 10 studies, n=1,495, low COE) and withdrawals due to adverse events (OR 2.78, 95% CI 1.59 to 4.86, 11 studies, n=1,621, moderate COE) compared to the placebo group across all mental disorders examined. No significant differences were observed between pharmaceutical THC-CBD and comparators with regard to serious adverse events, treatment-related adverse events, or all-cause withdrawals.
A few randomised controlled trials found no significant differences between cannabidiol and active or placebo comparators in terms of adverse events or withdrawals due to adverse events (very low to low COE).
The research objective was clearly stated. Eligibility criteria were well described and appeared appropriate to address the present review question. No restrictions were applied to eligibility criteria based on study characteristics and sources of information.
|1.1 Did the review adhere to pre-defined objectives and eligibility criteria?||Probably yes|
|1.2 Were the eligibility criteria appropriate for the review question?||Probably yes|
|1.3 Were eligibility criteria unambiguous?||Probably yes|
|1.4 Were all restrictions in eligibility criteria based on study characteristics appropriate (e.g. date, sample size, study quality, outcomes measured)?||Yes|
|1.5 Were any restrictions in eligibility criteria based on sources of information appropriate (e.g. publication status or format, language, availability of data)?||Yes|
|Concerns regarding specification of study eligibility criteria||Low|
MEDLINE, EMBASE, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials and the Cochrane Database of Systematic Reviews via Ovid were searched for relevant studies. In addition, ClinicalTrials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry were searched for unpublished or ongoing studies. The reference lists of retrieved articles were handsearched for additional relevant studies. The search strategy was reported in full and appeared adequate. Searches were not restricted by date, publication format or language. Two review authors were independently involved in the study selection and disagreements were resolved by discussion or by consulting the third review author.
|2.1 Did the search include an appropriate range of databases/electronic sources for published and unpublished reports?||Yes|
|2.2 Were methods additional to database searching used to identify relevant reports?||Yes|
|2.3 Were the terms and structure of the search strategy likely to retrieve as many eligible studies as possible?||Probably yes|
|2.4 Were restrictions based on date, publication format, or language appropriate?||Yes|
|2.5 Were efforts made to minimise error in selection of studies?||Yes|
|Concerns regarding methods used to identify and/or select studies||Low|
Two review authors were involved in the data extraction process. Sufficient study characteristics appear to have been extracted to allow interpretation of results. Relevant study results appear to have been extracted. The quality of included randomised controlled studies was assessed using the Cochrane risk of bias tool for randomised controlled trials; however, it was unclear which criteria were used for the methodological quality assessment of the observational studies. Two reviewers independently assessed the risk of bias and any disagreements were resolved by discussion or by consulting the third review author.
|3.1 Were efforts made to minimise error in data collection?||Yes|
|3.2 Were sufficient study characteristics considered for both review authors and readers to be able to interpret the results?||Probably yes|
|3.3 Were all relevant study results collected for use in the synthesis?||Probably yes|
|3.4 Was risk of bias (or methodological quality) formally assessed using appropriate criteria?||Probably yes|
|3.5 Were efforts made to minimise error in risk of bias assessment?||Yes|
|Concerns regarding methods used to collect data and appraise studies||Low|
The synthesis included all relevant studies. The method of analysis was explained and appeared appropriate. There was evidence of substantial heterogeneity. Sensitivity analyses were performed to address the heterogeneity and robustness of the findings. The quality of individual studies was considered only for randomised controlled trials; however, unclear criteria were used for the observational studies (see domain 3).
|4.1 Did the synthesis include all studies that it should?||Probably yes|
|4.2 Were all pre-defined analyses reported or departures explained?||Probably yes|
|4.3 Was the synthesis appropriate given the degree of similarity in the research questions, study designs and outcomes across included studies?||Probably yes|
|4.4 Was between-study variation minimal or addressed in the synthesis?||Probably yes|
|4.5 Were the findings robust, e.g. as demonstrated through funnel plot or sensitivity analyses?||Probably yes|
|4.6 Were biases in primary studies minimal or addressed in the synthesis?||Probably yes|
|Concerns regarding synthesis and findings||Low|
Background Medicinal cannabinoids, including medicinal cannabis and pharmaceutical cannabinoids and their synthetic derivatives, such as tetrahydrocannabinol (THC) and cannabidiol (CBD), have been suggested to have a therapeutic role in certain mental disorders. We analysed the available evidence to ascertain the effectiveness and safety of all types of medicinal cannabinoids in treating symptoms of various mental disorders. Methods For this systematic review and meta-analysis we searched MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Clinical Trials, and the Cochrane Database of Systematic Reviews for studies published between Jan 1, 1980, and April 30, 2018. We also searched for unpublished or ongoing studies on ClinicalTrials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry. We considered all studies examining any type and formulation of a medicinal cannabinoid in adults (≥18 years) for treating depression, anxiety, attention-deficit hyperactivity disorder (ADHD), Tourette syndrome, post-traumatic stress disorder, or psychosis, either as the primary condition or secondary to other medical conditions. We placed no restrictions on language, publication status, or study type (ie, both experimental and observational study designs were included). Primary outcomes were remission from and changes in symptoms of these mental disorders. The safety of medicinal cannabinoids for these mental disorders was also examined. Evidence from randomised controlled trials was synthesised as odds ratios (ORs) for disorder remission, adverse events, and withdrawals and as standardised mean differences (SMDs) for change in symptoms, via random-effects meta-analyses. The quality of the evidence was assessed with the Cochrane risk of bias tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. This study is registered with PROSPERO (CRD42017059372, CRD42017059373, CRD42017059376, CRD42017064996, and CRD42018102977). Findings 83 eligible studies (40 randomised controlled trials, n=3067) were included: 42 for depression (23 randomised controlled trials; n=2551), 31 for anxiety (17 randomised controlled trials; n=605), eight for Tourette syndrome (two randomised controlled trials; n=36), three for ADHD (one randomised controlled trial; n=30), 12 for post-traumatic stress disorder (one randomised controlled trial; n=10), and 11 for psychosis (six randomised controlled trials; n=281). Pharmaceutical THC (with or without CBD) improved anxiety symptoms among individuals with other medical conditions (primarily chronic non-cancer pain and multiple sclerosis; SMD −0·25 [95% CI −0·49 to −0·01]; seven studies; n=252), although the evidence GRADE was very low. Pharmaceutical THC (with or without CBD) worsened negative symptoms of psychosis in a single study (SMD 0·36 [95% CI 0·10 to 0·62]; n=24). Pharmaceutical THC (with or without CBD) did not significantly affect any other primary outcomes for the mental disorders examined but did increase the number of people who had adverse events (OR 1·99 [95% CI 1·20 to 3·29]; ten studies; n=1495) and withdrawals due to adverse events (2·78 [1·59 to 4·86]; 11 studies; n=1621) compared with placebo across all mental disorders examined. Few randomised controlled trials examined the role of pharmaceutical CBD or medicinal cannabis. Interpretation There is scarce evidence to suggest that cannabinoids improve depressive disorders and symptoms, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder, or psychosis. There is very low quality evidence that pharmaceutical THC (with or without CBD) leads to a small improvement in symptoms of anxiety among individuals with other medical conditions. There remains insufficient evidence to provide guidance on the use of cannabinoids for treating mental disorders within a regulatory framework. Further high-quality studies directly examining the effect of cannabinoids on treating mental disorders are needed. Funding Therapeutic Goods Administration, Australia; Commonwealth Department of Health, Australia; Australian National Health and Medical Research Council; and US National Institutes of Health.