Efficacy and safety of psilocybin in the treatment of Major Depressive Disorder (MDD): A dose-response network meta-analysis of randomized placebo-controlled clinical trials

Selecting the optimal dose of psilocybin for treating Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD) is crucial for clinical development and regulatory approval. This meta-analysis evaluates psilocybin's efficacy and safety in treating MDD to determine the optimal dose and timing for clinical trials. A systematic review and Dose-Response Network Meta-Analysis (NMA) of Randomized Placebo-Controlled Clinical Trials (RCTs) registered with PROSPERO was conducted. Databases searched included Embase, PubMed, Cochrane Library, Scopus, Web of Science, and Google Scholar, up to July 2024. The PICOS framework defined eligibility criteria: P: adult patients with MDD; I: psilocybin; C: placebo; O: changes in MADRS scores at Days 2, 8 and 15, and adverse events; S: RCT. Independent researchers performed data extraction and bias assessment. From 5419 search results, three RCTs involving 389 patients were included. Psilocybin significantly reduced symptoms compared to placebo at Day 8 (MD = -7.42; 95 % CI:10.07 to -4.78; p < 0.001) and Day 15 (MD = -9.55; 95 % CI:12.44 to -6.65; p < 0.001), without significant effects on Day 2. The NMA indicated that a 25 mg dose was the most effective, with a SUCRA value of 92.25 %, compared to doses of 0.215 mg/kg and 10 mg. However, psilocybin was associated with a higher risk of adverse events, particularly nausea (RR = 8.35; p < 0.001). This meta-analysis supports psilocybin's efficacy in treating MDD, particularly at a 25 mg dose, showing a time-dependent therapeutic effect. The recommended timing of efficacy evaluation by regulatory authorities is validated by this evidence, underscoring its importance in clinical trial design for psychedelic substances.