Medscape, CME / ABIM MOC / CE Released : 12/13/2019

https://www.medscape.org/viewarticle/922367

 

Clinical Context

The most common indication for the use of medicinal cannabis is pain, although the results of studies of cannabis products for chronic pain are mixed. Häuser and colleagues performed a review of systematic reviews of cannabis for chronic pain conditions, and their results were published in the October 15, 2017 issue of European Journal of Pain.^[1]

Reviewers evaluated 10 systematic reviews of cannabis for pain. Methodological quality was high in 4 of the reviews. There was mixed evidence regarding the efficacy of cannabis for neuropathic pain, and evidence was similarly unclear in one review of cannabis for painful spasms associated with multiple sclerosis (MS). There was insufficient evidence of the efficacy of cannabis in painful rheumatologic conditions or cancer pain.

Cannabis has been demonstrated to improve sleep among patients with chronic pain, and it has been advocated by pro-cannabis groups as a treatment of mental health disorders. But does cannabis effectively treat common mental health disorders? The current systematic review by Black and colleagues addresses this issue.

Study Synopsis and Perspective

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 Center, 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 Dr 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.^[2]

“Notable Absence of Evidence”

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

Specifically, they noted, “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.”

Nevertheless, juxtaposed to the limited evidence base, the authors noted “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 (RCTs) and more than 3000 adults.

Many of these studies were small. For some mental disorders, there was only one RCT. 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,” Dr 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 (ORs) 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 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 Cited as No. 1 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 Dr 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% CI: −0.49, −0.01), although the evidence was very low-quality, and the reduction in anxiety symptoms may have been the result of improvements in the primary medical condition: chronic noncancer pain or MS, the authors noted.

Across a small number of studies, there was no evidence that any type of cannabinoid significantly improved primary outcomes of attention-deficit/hyperactivity disorder (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: 0.1, 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 (AEs) (OR=1.99 [95% CI: 1.2, 3.29]) and study withdrawal because of AEs (OR=2.78 [95% CI: 1.59, 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 Dr 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 [RCTs].”

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

Hard to Justify

In an accompanying editorial,^[3] 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.

Although it could be argued these medications have little efficacy and come with significant AEs, “at least they were tested in adequately powered, large, double-blind, [RCTs] and then subjected to a rigorous regulatory approval process,” he wrote.

From a mechanistic standpoint, it is 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 noted.

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

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

“These factors will need to be accounted for when considering these compounds as long-term treatments for chronic psychiatric disorders,” he continued.

No APA Endorsement

The American Psychiatric Association (APA) does not endorse cannabis for medical use. In a position statement^[4] 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.

The APA position statement maintained, “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 noted that research on the use of cannabis-derived substances as medicine should be encouraged and facilitated by the US federal government.

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

Clinical Implications

• A previous review of systematic reviews by Häuser and colleagues found mixed results regarding the efficacy of cannabis in the treatment of neuropathic pain and painful cramps in patients with MS. There was insufficient evidence to judge efficacy of cannabis against cancer pain and pain associated with rheumatologic conditions.
• The current study by Black and colleagues finds some evidence that pharmaceutical THC-CBD is associated with improvements in anxiety, but it was ineffective in the treatment of depression, ADHD, and psychosis.
• Implications for the Healthcare Team: The current study finds little usefulness of medical cannabis in various forms for mental health disorders. The healthcare team should promote more evidence-based interventions for these illnesses.