Psilocybin-assisted therapy for major depressive disorder: Perspective from meta-analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis of randomized controlled trials
PubMed 41876058 · doi:10.1016/j.jad.2026.121675
What was done
This systematic review and meta-analysis of 6 randomized controlled trials evaluated the efficacy and safety of psilocybin for major depressive disorder (MDD). Studies were analyzed by dose: standard-dose psilocybin (25 mg/session or 20–30 mg/70 kg/session) and low-dose psilocybin (10 mg/session or 15.05 mg/70 kg/session). Control conditions included placebo, waiting-list control, niacin, or 1 mg psilocybin.
What was found
Standard-dose psilocybin was superior to control in reducing depressive symptoms (standardized mean difference [SMD]: -1.05; 95% CI: -1.60 to -0.50, p = 0.0002, I² = 75%, K = 4). Excluding waiting-list controls maintained superiority with lower heterogeneity (SMD: -0.70; 95% CI: -1.03 to -0.36, p < 0.0001, I² = 43%, K = 2). Standard-dose psilocybin showed higher response at 2–3 weeks (RR: 2.34; 95% CI: 1.52–3.60, p = 0.0001) and 6–12 weeks (RR: 2.61; 95% CI: 1.45–4.71, p = 0.001), higher remission at 2–3 weeks (RR: 3.38; 95% CI: 1.88–6.08, p < 0.0001), and lower all-cause discontinuation (RR: 0.39; 95% CI: 0.18–0.87, p = 0.02). Standard doses increased transient headache (RR: 2.06; 95% CI: 1.11–3.81, p = 0.02) and nausea (RR: 10.20; 95% CI: 3.80–27.39, p < 0.0001) within 1–9 days post-treatment. Low-dose psilocybin demonstrated no superior efficacy over controls.
Why it matters
This meta-analysis demonstrates that standard clinical doses of psilocybin offer substantial short- to medium-term efficacy for MDD with acceptable tolerability, while low doses appear ineffective.
Limits
The total evidence base was small (6 trials), with individual meta-analyses relying on only 2 to 4 studies. Control conditions varied considerably across trials, and the abstract did not report total participant sample sizes or outcomes beyond 12 weeks.
Cited by
- supports In clinical trials for major depression that has not responded to other treatments, high-dose psilocybin-assisted psychotherapy yields significant relief or remission in 60% to 70% of patients.