The efficacy and safety of psilocybin-assisted therapy for major depressive disorder: a meta-analytic review of clinical outcomes

This systematic review and meta-analysis synthesized data from 13 clinical trials (n=606) evaluating psilocybin-assisted psychotherapy for major depressive disorder and treatment-resistant depression. Despite early enthusiasm, the pooled standardized mean difference (-0.79, 95% confidence interval: -3.98 to 2.40, p=0.63) revealed no statistically significant overall antidepressant effect, with extreme heterogeneity (I2=96.9%) across studies. Notably, the type of control group (active comparator vs. placebo/waitlist) accounted for 98.7% of between-study variance, with waitlist and low-dose comparators producing exaggerated effect sizes. Session frequency was a significant moderator: 2 to 5 psilocybin sessions yielded larger effects, while more intensive protocols attenuated benefit. Neither participant age nor follow-up duration significantly influenced outcomes. Evidence of reporting bias and small-study effects was detected (Egger’s test p=0.012). Sensitivity analyses demonstrated that no single study accounted for the non-significant pooled result. Overall, psilocybin’s antidepressant efficacy appears highly context-dependent-shaped by trial design, comparator, and session structure-rather than universally robust. These findings underscore the need for larger, rigorously controlled trials to clarify psilocybin’s therapeutic role in depression.