Cannabinoids for the treatment of mental disorders and symptoms of mental disorders : a systematic review and meta-analysis
Nicola Black, Emily Stockings, Gabrielle Campbell, Lucy T. Tran, Dino Zagic, Wayne D. Hall, Michael Farrell, Louisa Degenhardt
Lancet Psychiatry, 2019
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 We also searched for unpublished or ongoing studies on ClinicalTrials.gov, the EU Clinical Trials Register, and the Australian and New Zealand Clinical Trials Registry.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.
Research in context
Evidence before this study
We searched PubMed up to July 12, 2019, for reviews of cannabis use and mental health using the MeSH terms (((“medical marijuana”[MeSH Terms] OR (“medical”[All Fields] AND “marijuana”[All Fields]) OR “medical marijuana”[All Fields] OR (“medical”[All Fields] AND “cannabis”[All Fields]) OR “medical cannabis”[All Fields]) AND (“mental health”[MeSH Terms] OR (“mental”[All Fields] AND “health”[All Fields]) OR “mental health”[All Fields])) AND Review[ptyp]). This search led to 152 results, of which nine were relevant reviews (or summaries of reviews, as in the case of the US National Academies of Science) of cannabis or cannabinoids for mental health problems. The different reviews included varied study designs to examine the effects of cannabinoids on mental disorders; some concentrated on cross-sectional studies, others were limited to randomised controlled trials, and some were further limited to studies where the mental health symptoms were the primary indication for the cannabinoid. Some reviews pooled studies quantitatively on one outcome for a given mental disorder, but other features of their eligibility criteria and date of publication meant that few studies were included (eg, none for depression, one for anxiety, two for psychosis). All reviews concluded that the evidence was scarce but in many instances some concluded that no data yet existed for some mental health outcomes (eg, depression). No previous reviews defined a priori both primary and secondary outcomes of cannabinoids used for different mental disorders, nor did they systematically compile both randomised controlled trials and observational study designs. Most described potential adverse outcomes of cannabinoid use by relying on evidence from studies of people with recreational cannabis use or generally pooling adverse events from any study of medicinal cannabinoids, rather than specifically extracting and pooling data on adverse events and treatment withdrawals from the studies of cannabinoids in people with mental disorders. The clarity with which the specific cannabinoids were documented varied across the reviews, as did the characteristics of the study populations and the studies that were extracted and reported.
Added value of this study
Our systematic review and meta-analysis represents, to our knowledge, the most up to date and detailed analysis of the available evidence for the effectiveness of cannabinoids for treating mental health symptoms and disorders. We prespecified primary and secondary outcomes to examine for each mental disorder, included studies where the condition was primary or secondary, systematically collated evidence from study designs other than randomised controlled trials, and pooled all outcomes and adverse event data quantitatively wherever possible. We also specified which cannabinoids were studied and where the data and gaps were across primary and secondary outcomes. We conclude that the available evidence for the effectiveness of cannabinoids in improving symptoms of anxiety is of very low quality. There is inadequate evidence to suggest that cannabinoids improve depressive disorders, symptoms of depression, anxiety disorders, attention-deficit hyperactivity disorder, Tourette syndrome, post-traumatic stress disorder, or psychosis.
Implications of all the available evidence
Our findings have direct policy relevance. In countries where cannabis and cannabinoids are being made available for medicinal use, and in which mental health problems are a common reason for requesting access to cannabinoids for medicinal purposes, these findings clarify where the evidence exists and the quality of such evidence. This study also highlights the need for investment into high-quality research efforts to study the effects of different cannabinoids on a range of outcomes for people with mental disorders.
Countries are increasingly allowing cannabinoids to be made available for medicinal purposes, including for the treatment of mental disorders. In our study, based on previous agreed terminology,1 we use the term “medicinal cannabinoids” as an umbrella term encompassing all plant-derived and synthetic derivatives. We use “medicinal cannabis” to refer to any part of the cannabis plant and plant material, such as buds, leaves, or full plant extracts (eg, Cannabis sativa). We use the term “pharmaceutical cannabinoids” to refer to pharmaceutical-grade medicinal extracts with defined and standardised tetrahydrocannabinol (THC) with or without cannabidiol (CBD) content (eg, THC, CBD extract, or THC CBD combinations such as nabiximols) and synthetic cannabinoid derivatives.1 Given the increasing interest in CBD products for various medical conditions, we also separately grouped studies that only used pharmaceutical CBD.
After chronic non-cancer pain, mental health is one of the most common reasons for using medicinal cannabinoids.2 In terms of biological plausibility, a potential role exists of the endocannabinoid system (CB1 receptors) in reducing depressive and stress symptoms3 as well as the emotional and cognitive features of post-traumatic stress disorder.4 CBD has been proposed as an effective short-term treatment for individuals with social anxiety disorder.5 Medicinal cannabinoids have been reported to reduce tics in Tourette syndrome.6 Many surveys report increased rates of cannabis use among people living with depression, anxiety, post-traumatic stress disorder, and psychosis, and self-medication of symptoms is suggested to be a driver of some of this use.7,8
Given the interest in the use of medicinal cannabinoids for these purposes, a thorough review of the available evidence is needed to inform policy and clinical decisions. Previous systematic reviews have been limited in their coverage of mental disorders, study designs, and use of quantitative synthesis (ie, meta-analysis). A 2015 review by Whiting and colleagues,9 which included five randomised controlled trials of mental disorders, found no effect of medicinal cannabinoids on psychosis or depression, but noted low-quality evidence for some improvement in Tourette syndrome and anxiety. A 2016 review by Wilkinson and colleagues10 included 40 studies (randomised controlled trials and observational studies) of medicinal cannabinoids for post-traumatic stress disorder, Tourette syndrome, and Alzheimer’s disease. No randomised controlled trials were identified for any condition and no meta-analysis was done, so no conclusions were made about efficacy. Crucially, highly prevalent disorders for which medicinal cannabinoids are often sought, such as depression, anxiety, and psychosis, were not included. The 2017 National Academy of Sciences (NAS) review11 reported beneficial effects of medicinal cannabinoids for Tourette syndrome, anxiety, and post-traumatic stress disorder, and no effect on psychosis or depression; however, this review was based largely on findings reported by Whiting and colleagues.9 No review has, to date, considered all types of evidence, the potential differential effects of different types of medicinal cannabinoids, and the safety of using cannabinoids for mental disorders. Disentangling the evidence for different types of cannabinoids for specific mental disorders is needed to direct research efforts and provide clinical guidance.1
We aimed to examine the available evidence for all types of medicinal cannabinoids and all study designs (controlled and observational) to ascertain the impact of medicinal cannabinoids on remission from and symptoms of depression, anxiety, post-traumatic stress disorder, and psychosis, as well as symptoms of attentiondeficit hyperactivity disorder (ADHD) and Tourette syndrome, either as the primary disorder or secondary to other disorders; and the impact of medicinal cannabinoids on outcomes including global functioning, quality of life, and patient or caregiver impression of change. We also examined the safety of medicinal cannabinoids for mental health symptoms and disorders, including all-cause, serious, and treatment-related adverse events and study withdrawals.