Among Psychedelics, Only Psilocybin Has Demonstrated Benefit to Treat Depression

Are psychedelic drugs effective for the treatment of depression?

Only high-dose psilocybin was more effective than placebo, and it was only slightly better, on average, than treatment with an antidepressant. (Level of Evidence = 1a−)

In this network meta-analysis, the investigators searched four literature databases, including Cochrane CENTRAL, and two clinical trial databases. They identified 15 randomized controlled trials of psychedelics in a total of 811 adults with depressive symptoms. They also included four studies of escitalopram to use as an indirect comparison. Two authors independently extracted the data and evaluated the research for risk of bias. Because psychedelics produce a rapid and noticeable effect, the investigators evaluated the issue of unmasking separately and found that the placebo response was less in the trials of psychedelics than in the studies of escitalopram. For the primary outcome—a change in depression, as measured by the Hamilton Depression Rating Scale—high-dose psilocybin, which has the most research, was better than placebo and only slightly better (effect size = 0.31) than escitalopram in patients with moderate to severe depression. Other psychedelics, including 3,4-methylenedioxymethamphetamine (MDMA), lysergic acid diethylamide (LSD), and ayahuasca, were not more effective than placebo.

Study design: Meta-analysis (randomized controlled trials)

Funding source: Government

Setting: Various (meta-analysis)

Reference: Hsu TW, Tsai CK, Kao YC, et al. Comparative oral monotherapy of psilocybin, lysergic acid diethylamide, 3,4-methylenedioxymethamphetamine, ayahuasca, and escitalopram for depressive symptoms: systematic review and Bayesian network meta-analysis. BMJ. 2024;386:e078607.

Editor's Note: Dr. Shaughnessy is an assistant medical editor for AFP.