Psilocybin for treatment-resistant depression: no significant benefit at 6 weeks

The question

Does a single 25 mg dose of psilocybin, given alongside psychotherapy sessions, reduce symptoms in people whose depression has not responded to previous treatments?

What they did

The EPISODE trial was run at two centres in Germany, mostly in outpatient settings, with 144 adults aged 25 to 65 who had treatment-resistant depression and had come off their antidepressant medication. They were randomly assigned to receive either 25 mg of psilocybin, 5 mg of psilocybin, or an active placebo (100 mg nicotinamide, a form of vitamin B3), each given with psychotherapeutic sessions, followed by a second dose six weeks later. Participants, investigators and the clinicians rating symptoms were all kept unaware of who got what. The main measure was the share of people whose score on a standard clinician-rated depression scale (HAMD17) dropped by at least half by week 6, before the second dose.

What they found

Among the 142 people included in the main analysis, response rates at week 6 were 17.0% with 25 mg psilocybin, 12.5% with 5 mg, and 10.6% with the active placebo. The difference between 25 mg and placebo was not statistically significant (adjusted odds ratio 1.73; 95% CI, 0.53-6.23; P = .19), so the planned further statistical testing was stopped. Exploratory looks at average change in depression scores suggested a clinically meaningful effect of the 25 mg dose, but these were not confirmatory. Adverse events with 25 mg were mostly short-lived and occurred around dosing; reports of suicidal thinking on dosing days were higher (4%, versus 1% to 2% in the comparison groups), and two serious adverse reactions followed 25 mg psilocybin, including one case of hallucinogen persisting perception disorder (lasting visual disturbances after the drug has worn off).

The fine print

The trial did not meet its primary outcome, so the positive-looking secondary findings are exploratory and should not be read as proof of benefit. With roughly 47 people per group, the study may have been too small to detect a modest effect, and response rates were low across all arms. The primary time point was only six weeks, participants were recruited from two German sites, and intense drug effects can make blinding difficult even with an active placebo. This summary is based on the published abstract only.

What it means

In this carefully blinded trial, psilocybin with psychotherapy did not significantly outperform an active placebo on the main measure of depression response, and some safety signals were recorded. The results temper expectations and show that larger, longer trials are still needed.

Evidence grade: Moderate. A well-designed, triple-blind, active-placebo randomized trial, but with modest numbers per group (about 47 each), a single two-site setting and a short primary time point.

This summary is based on the study’s published abstract.