From the Journals

Evidence lacking for using cannabinoids to treat mental disorders

Systematic review and meta-analysis concluded more ‘high-quality studies’ needed

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Cannabinoids should undergo rigorous safety, efficacy testing

The results from Black et al. demonstrate that use of cannabinoids is unsupported for treating ADHD, PTSD, Tourette syndrome, psychosis, and depressive and anxiety disorders and symptoms, especially given that other approved medications for these conditions already exist, Deepak D’Souza, MBBS, MD, wrote in a related editorial.

“In light of the paucity of evidence, the absence of good quality evidence for efficacy, and the known risk of cannabinoids, their use as treatments for psychiatric disorders cannot be justified at present,” said Dr. D’Souza.

In addition, the conditions examined in the systematic review by Dr. Black, Dr. Stockings, and colleagues are distinct, and it is unclear how cannabinoids could treat these various conditions unless cannabinoids’ effects are similar to those of benzodiazepines, Dr. D’Souza noted. Another issue is that information on safety and efficacy of cannabinoids is also unknown, and factors such as optimal dosing, treatment duration, and tetrahydrocannabinol (THC) to cannabidiol (CBD) ratio must also be established to begin trials. Finally, cannabinoids are also subject to tolerance issues with long-term exposure and would need to be considered for use with chronic psychiatric disorders.

“With cannabinoids, it seems that the cart (use) is before the horse (evidence),” Dr. D’Souza concluded. “If cannabinoids are to be used in the treatment of psychiatric disorders, they should first be tested in randomized controlled trials and subjected to the same regulatory approval process as other prescription medications.”

Dr. D’Souza is affiliated with the department of psychiatry at Yale University in New Haven, Conn. He reported receiving grants from the National Institutes of Health, Veterans Health Administration Office of Research and Development, Heffter Foundation, Wallace Foundation, and Takeda. He also reported serving on the physicians advisory board of the medical marijuana program for the state of Connecticut.



Scant evidence exists to recommend medical cannabinoids and derivatives such as tetrahydrocannabinol and cannabidiol to patients with depressive disorders, anxiety, or other mental disorders, suggested research in a recent systematic review and meta-analysis published in The Lancet Psychiatry.

In their review, Nicola Black, PhD, Emily Stockings, PhD,and colleagues performed a search of the MEDLINE, Embase, PsycINFO, Cochrane Central Register of Controlled Clinical Trials, and Cochrane Database of Systematic Reviews and identified 83 studies between January 1980 and April 2018 in which adult patients were treated with a medical cannabinoid for primary or secondary depression, anxiety, ADHD, Tourette syndrome, PTSD, or psychosis.

The researchers examined symptom changes, symptom remission, and the safety of medicinal cannabinoids in each study. Overall, there were 3,067 participants across the 83 studies, including 42 trials for depression, 31 trials for anxiety, 11 for psychosis, 8 for Tourette syndrome, 3 for ADHD, and 12 trials for PTSD. Of those, 23 were randomized controlled trials (RCTs) for depression (2,551 participants), 17 were RCTs for anxiety (605 participants), and six were RCTs for psychosis (281 participants). In addition, one RCT was for Tourette syndrome (36 participants), one RCT was for ADHD (30 participants), and one RCT was for PTSD (10 participants), reported Dr. Black and Dr. Stockings, both of the National Drug and Alcohol Research Centre (NDARC) at the University of New South Wales in Sydney and colleagues.

In patients with anxiety in seven RCTs (252 participants), there was a “very low” evidence assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach that pharmaceutical tetrahydrocannabinol (THC) with and without cannabidiol (CBD) in standardized mean differences in symptoms (SMD, –0.25; 95% confidence interval, –0.49 to –0.01); however, researchers noted that most patients in this study had other medical conditions, such as noncancer pain and multiple sclerosis, which might have affected results. Patients with psychosis in one study (24 participants) had significantly worse outcomes after use of pharmaceutical THC with and without CBD (SMD, 0.36; 95% CI, 0.10-0.62).

In 10 studies (1,495 participants), a pooled analysis across all mental disorders showed pharmaceutical THC with and without CBD did not improve the primary outcome and was associated with significantly increased adverse events, compared with placebo (odds ratio, 1.99; 95% CI, 1.20-3.29). It led to study withdrawal from adverse events (OR, 2.78; 95% CI, 1.59-4.86) in 11 studies (1,621 participants), compared with placebo. While there were not many RCTs that examined adverse events after use of pharmaceutical CBD or medicinal cannabis, the studies that did examine the association did not find an increased risk of adverse events or adverse events leading to study withdrawal, compared with placebo.

“Our findings have important implications in countries where cannabis and cannabinoids are being made available for medical use,” one of the authors, Louisa Degenhardt, PhD, said in a press release. “There is a notable absence of high-quality evidence to properly assess the effectiveness and safety of medicinal cannabinoids, compared with placebo, and until evidence from randomized, controlled trials is available, clinical guidelines cannot be drawn up around their use in mental health disorders.”

“In countries where medicinal cannabinoids are already legal, doctors and patients must be aware of the limitations of existing evidence and the risks of cannabinoids,” said Dr. Degenhardt, who also is with NDARC. “These must be weighed when considering use to treat symptoms of common mental health disorders. Those who decide to proceed should be carefully monitored for positive and negative mental health effects of using medicinal cannabinoids.”

Among the limitations cited by investigators were the small amount of medical data. More “high-quality studies” are needed, they wrote.

The study was supported in part by funding from the Health Products Regulation Group, research fellowship grants from the National Health and Medical Research Council, and a grant from the National Institutes of Health National Institute on Drug Abuse. Two authors reported serving as investigators for studies funded by Indivior, Reckitt Benckiser, Mundipharma, and Seqirus; another also reported being an investigator for studies funded by Indivior. The remaining authors reported no relevant conflicts of interest.

SOURCE: Black N et al. Lancet Psychiatry. 2019. doi: 10.1016/S2215-0355(19)30401-8.

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