Psych Congress NetworkPsilocybin Produces Mixed Outcomes in Phase 2b MDD Study

A phase 2b RCT of 144 adults with treatment-resistant depression finds psilocybin 25 mg failed its primary endpoint of 50% HAMD17 response at 6 weeks. Secondary measures showed clinically meaningful symptom reductions versus placebo, but serious adverse events in 2 patients and severe reactions in 28% complicate the picture.

Clinical Considerations

• The primary endpoint was negative: 17% response with psilocybin 25 mg versus 10.6% with placebo, a nonsignificant difference that limits efficacy claims
• Secondary scales diverged sharply: BDI-II response reached 23.4% with psilocybin 25 mg versus 6.3% with low-dose and 10.6% with placebo
• Severe adverse events occurred in 28% of psilocybin 25 mg patients on day 0, versus 4% with low-dose and 8% with placebo
• Symptom improvements appeared as early as week 1, suggesting a real biological signal that underpowered enrollment may have obscured

Practice Applications

• Counsel patients that psilocybin remains investigational for TRD; secondary signals are promising but not confirmatory
• Monitor closely for serious adverse events if patients access psilocybin through clinical trials or legal therapeutic programs
• Document treatment-resistance history thoroughly now, as patient selection criteria will likely tighten in future confirmatory trials
• Avoid citing secondary outcomes as proof of efficacy; distinguish between signal generation and regulatory-grade evidence

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