Medical Cannabis for Mental Disorders
'Hard to Justify'

Pauline Anderson

October 28, 2019

There's little evidence to support the use of cannabinoids to treat psychiatric disorders such as depression, anxiety, posttraumatic stress disorder (PTSD), and psychosis, results of a new systematic review and meta-analysis suggest.

"Patients who are interested in using cannabinoids for mental disorders should understand that there's limited evidence for it, and if they do choose this intervention, there needs to be monitoring to check that it's helpful and is not causing harm," lead investigator Louisa Degenhardt, PhD, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, Australia, told Medscape Medical News.

A large body of evidence shows cannabis use can increase depression, anxiety, and psychotic symptoms, and lead to dependence, she noted.

"In many ways, we know more about the long-term risks of regular cannabis use than we do about its benefits for people with mental disorders," said Degenhardt. Meanwhile, she added, the trend toward legalization of cannabis has made it widely available on a global scale.

The study was published online today in Lancet Psychiatry.

"Notable Absence of Evidence"

The investigators point out there is a "notable absence of high-quality evidence where mental disorders are the primary target of [cannabinoid] treatment."

Specifically, they note, "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."

However, juxtaposed to the limited evidence base, the authors note "countries are increasingly allowing cannabinoids to be made available for medical purposes, including for the treatment of mental disorders."

To shed more light, the investigators conducted what they describe as "the most comprehensive systematic review and meta-analysis examining the available evidence for medicinal cannabinoids in treating mental disorders and symptoms."

Researchers carried out an extensive literature search of studies published from January 1980 to April 2018 of any type and formulation of medicinal cannabinoid including THC, CBD, or a combination of both, on various psychiatric conditions. The analysis included 40 randomized controlled trials and more than 3000 adult subjects.

Many of these studies were small. For some mental disorders, there was only one randomized controlled trial. In some studies, the psychiatric condition was the primary outcome, but in many cases, it was a secondary outcome, "so there's a lot of scope for more work to be done," Degenhardt noted.

The authors categorized the cannabis products into pharmaceutical grade THC, pharmaceutical grade CBD, and "medicinal cannabis" (any part of the cannabis plant and plant material such as buds, leaves or plant extracts). They synthesized the effect of cannabinoids as odds ratios for remission and standardized mean differences (SMDs) for symptom change.

The researchers evaluated the quality of the evidence using the Cochrane Risk of Bias tool and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

For depression, the analysis included 23 RCTs and more than 2500 participants. These studies were conducted in participants with depression secondary to chronic pain.

Depression the Number One Reason

Given that the most common reason Americans report using cannabinoids is to treat depression, "we were fairly surprised that there wasn't a single published study primarily aimed at looking at cannabinoids for people who had depression," said Degenhardt.

In these studies, there was no impact of pharmaceutical THC, either with or without CBD, on depressive symptoms.

There was a significantly greater reduction in anxiety symptoms with pharmaceutical THC, with or without CBD, vs placebo among individuals with other medical conditions (SMD –0.25 [95% confidence interval [CI] –0.49 to –0.01), although the evidence was very low quality.

However, the reduction in anxiety symptoms may have been the result of improvements in the primary medical condition, chronic noncancer pain or multiple sclerosis, the authors note.

Across a small number of studies, there was no evidence that any type of cannabinoid significantly improved primary outcomes of ADHD, Tourette syndrome, PTSD, or psychosis.

Indeed, results from one small study of patients with schizophrenia suggested that pharmaceutical THC, with or without CBD, worsened psychosis compared with placebo (SMD 0.36; 95% CI, 0.10 - 0.62). This study also showed that THC worsened cognitive functioning, which was a secondary outcome.

Compared with placebo and across all mental disorders, pharmaceutical THC, with or without CBD, increased the number of individuals with adverse events (odds ratio [OR] 1.99; 95% CI, 1.20 to 3.29]) and study withdrawal due to adverse events (OR, 2.78; 95% CI, 1.59 to 4.86).

Until now, there hasn't been a lot of "push" for drug companies to develop pharmaceutical grade cannabinoids except for conditions like epilepsy, said Degenhardt. However, this may be changing.

"My suspicion is that there may be increasing interest by some companies in examining cannabinoids," she said.

She noted the development of potentially therapeutic cannabinoids needs to be done by employing "carefully conducted randomized controlled trials."

Collecting this evidence is essential before clinical guidelines can be developed with respect to the medicinal use of cannabinoids for psychiatric disorders, the investigators note.

Hard to Justify

In an accompanying editorial, Deepak Cyril D'Souza, MD, Yale University School of Medicine, New Haven, Connecticut, said that in light of these new results, "it would be hard for practitioners to justify recommending the use of cannabinoids for psychiatric conditions at this time."

He pointed out that approved medications such as selective serotonin reuptake inhibitors and antipsychotics already exist for psychiatric conditions.

While it could be argued these medications have little efficacy and come with significant side effects, "at least they were tested in adequately powered, large, double-blind, randomized controlled trials and then subjected to a rigorous regulatory approval process," he writes.

From a mechanistic standpoint, it's uncertain how cannabinoids could be effective in treating conditions as diverse as depression, ADHD, psychosis, anxiety, and PTSD, which have no obvious common pathophysiology, D'Souza notes.

Before cannabinoids are integrated into clinical practice, it's important to determine the optimal doses for various conditions, the dosing frequency, the duration of treatment, and the ratio of THC to CBD, he adds.

In addition, many psychiatric conditions are chronic and long-term exposure to cannabinoids may lead to tolerance, dependence, and withdrawal upon discontinuation, D'Souza notes.

"These factors will need to be accounted for when considering these compounds as long-term treatments for chronic psychiatric disorders."

No APA Endorsement

The American Psychiatric Association (APA) does not endorse cannabis for medical use. In a position statement approved earlier this year, the APA noted there is no current scientific evidence that cannabis is in any way beneficial for the treatment of any psychiatric disorder.

"In contrast, current evidence supports, at minimum, a strong association of cannabis use with the onset of psychiatric disorders. Adolescents are particularly vulnerable to harm, given the effects of cannabis on neurological development."

The APA further notes that research on the use of cannabis-derived substances as medicine should be encouraged and facilitated by the US federal government.

Lancet Psychiatry. Published online October 28, 2019. Abstract, Editorial

The study authors and D'Souza have disclosed no relevant financial relationships.

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