Psilocybin-assisted therapy for major depressive disorder: Perspective from meta-analysis

Objective This systematic review and meta-analysis of six randomized controlled trials aimed to investigate the temporal changes in the efficacy and safety of psilocybin treatment for major depressive disorder (MDD). Methods Separate meta-analyses were conducted for 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) subgroups. Control conditions included placebo, waiting-list control, niacin, or psilocybin 1 mg. Results Standard-dose psilocybin was superior to control in reducing depressive symptoms (standardized mean difference [SMD]: −1.05; 95% confidence intervals [CIs]: −1.60 to −0.50, p = 0.0002, I² = 75%, K = 4). Sensitivity analysis excluding studies with waiting-list controls supported the superiority of standard-dose psilocybin compared with control without considerable heterogeneity (SMD: −0.70; 95% CI: −1.03 to −0.36, p < 0.0001, I² = 43%, K = 2). This sensitivity analysis included two double-blind trials that incorporated manualized psilocybin-assisted psychotherapy. Compared with controls, standard-dose psilocybin was associated with higher response (risk ratio [RR]: 2.34; 95% CI: 1.52–3.60, p = 0.0001, I² = 0%) and remission rates at 2–3 weeks post-treatment (RR: 3.38; 95% CI: 1.88–6.08, p < 0.0001, I² = 0%), with response rate at 6–12 weeks post-treatment (RR: 2.61; 95% CI: 1.45–4.71, p = 0.001, I² = 0%). Moreover, standard-dose psilocybin was related to lower all-cause discontinuation compared with control (RR: 0.39; 95% CI: 0.18–0.87, p = 0.02, I² = 0%). Standard-dose psilocybin was associated with a higher incidence of headache (RR: 2.06; 95% CI: 1.11–3.81, p = 0.02, I² = 57%) and nausea within 1–9 days post-treatment (RR: 10.20; 95% CI: 3.80–27.39, p < 0.0001, I² = 0%) compared with the control; however, these symptoms resolved after this period. Low-dose psilocybin demonstrated no superior efficacy compared with the control group. Conclusions This meta-analysis indicates that standard-dose psilocybin may represent a promising therapeutic option for MDD treatment. Nonetheless, future research should address the considerable methodological heterogeneity across current trials.