Psychiatry researchJan 4, 2025

Psilocybin's effectiveness and safety for major depression at different doses: A combined analysis of controlled clinical trials

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 3, 2026

Abstract

Psilocybin significantly reduced symptoms of Major Depressive Disorder by 9.55 points on average by Day 15 compared to placebo.

Three randomized controlled trials with 389 patients were analyzed to assess psilocybin's efficacy in treating MDD.
A 25 mg dose of psilocybin showed the highest effectiveness with a 92.25% probability of being the optimal dose.
Significant symptom reduction was observed at Day 8 and Day 15, while no significant changes were noted at Day 2.
Psilocybin was associated with a higher risk of adverse events, particularly nausea, with a relative risk of 8.35.
The findings support the importance of dose and timing in clinical trial design for psilocybin as a treatment for MDD.

Simplified

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.

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Funding

Competing interests

Declaration of competing interest Damian Swieczkowski: No conflict of interest. Aleksander Kwaśny: i) grants: Beckley Psytech, GH Research, MSD. Michal Pruc: No conflict of interest. Zuzanna Gaca: No conflict of interest. Lukasz Szarpak: No conflict of interest. Wiesław Jerzy Cubała: i) grants: Acadia, Alkermes, Allergan, Angelini, Auspex Pharmaceuticals, Beckley Psytech, BMS, Celon, Cephalon, Cortexyme, Ferrier, Forest Laboratories, Gedeon Richter, GH Research, GWPharmaceuticals, HMNC Brain Health, IntraCellular Therapies, Janssen, KCR, Lilly, Lundbeck, Minerva, MSD, NIH, Novartis, Orion, Otsuka, Sanofi, Servier; ii) honoraria: Adamed, Angelini, AstraZeneca, BMS, Celon, GSK, Janssen, KRKA, Lekam, Lundbeck, Minerva, NeuroCog, Novartis, Orion, Pfizer, Polfa Tarchomin, Sanofi, Servier, Zentiva; iii) advisory boards: Angelini, Celon (terminated), Douglas Pharmaceuticals, GH Research, Janssen, MSD, Novartis, Sanofi.

PubMed

Psilocybin's effectiveness and safety for major depression at different doses: A combined analysis of controlled clinical trials

Abstract

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Competing interests

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Abstract

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