Trajectory of Antidepressant Effects after Single- or Two-Dose Administration of Psilocybin: A Systematic Review and Multivariate Meta-Analysis

We examined the cardiovascular safety, acceptability, and trajectory of the antidepressant effects of psilocybin after single- or two-dose administration. Four major electronic databases were systematically searched. Data were pooled using a multivariate random-effects meta-analysis. Primary outcomes were changes in depressive symptoms. Secondary outcomes were cardiovascular safety and acceptability. Ten studies were included. The estimated effect sizes (standardized mean difference (SMD) with 95% confidence intervals) for psilocybin were -0.75 (-1.15 to -0.35) on day 1, -1.74 (-2.15 to -1.32) at 1 week, -1.35 (-1.77 to -0.93) at 1 month, -0.91 (-1.31 to -0.51) at 3 months, and -1.12 (-1.56 to -0.68) at 6 months. Higher doses and two sessions of psilocybin treatment were significantly associated with superior antidepressant effects. The all-cause discontinuation and heart rate after psilocybin administration were comparable to placebo; meanwhile, psilocybin increased systolic and diastolic blood pressure by 19.00 mmHg and 8.66 mmHg, respectively. There were no significant differences between SMD derived from placebo-controlled trials compared to those from pre-post changes and SMD in randomized controlled trials (RCTs) compared to those in non-RCTs. The present study demonstrates that single- or two-dose psilocybin administration has rapid and sustained antidepressant effects for up to 6 months, with favorable cardiovascular safety and acceptability.