JAMA Netw Open

Have psilocybin trials overestimated its antidepressant efficacy?

August 1, 2025

Study details: This meta-analysis pooled data from 17 double-blind randomized trials evaluating psilocybin (n=373), SSRIs (n=4,014), and esketamine (n=573) for major depressive disorder (MDD) or treatment-resistant depression (TRD). All studies used the Montgomery-Åsberg Depression Rating Scale (MADRS) to assess depressive symptoms, and only parallel-arm trials of at least two weeks’ duration were included. Data were pooled using random-effects models, and standardized mean change (SMC) and standardized mean difference (SMD) were calculated for within- and between-group effects, respectively.

Results: Control group SMCs (pretreatment to posttreatment) were 0.50 for psilocybin, 1.00 for SSRIs, and 1.12 for esketamine, indicating less improvement in control arms of psilocybin trials. The study population significantly moderated between-group SMDs (Omnibus Test of Moderators [QM]=10.7, P=0.005). MADRS response rates for control groups were 14 percentage points higher in SSRI trials and 23 points higher in esketamine trials compared with psilocybin trials. Dropout rates were lower in psilocybin and esketamine trials than in SSRI trials.

Clinical impact: The poor control treatment outcomes in psilocybin trials suggest that it may not be as broadly effective for depression as estimated.

Source:

Hieronymus F, et al. (2025, July 30). JAMA Netw Open. Control Group Outcomes in Trials of Psilocybin, SSRIs, or Esketamine for Depression: A Meta-Analysis. https://pubmed.ncbi.nlm.nih.gov/40736734/