A significant benefit of psilocybin on depression scores was observed in a meta-analysis of 436 participants, with a treatment effect size of 0.66.
Psilocybin treatment was associated with a greater reduction in depression scores compared to placebo or non-psychoactive drugs.
Secondary depression showed a larger treatment effect size of =0.88.
Self-report scales indicated improved outcomes, correlating with older age and previous psychedelic use.
All included studies had a moderate risk of bias, leading to a moderate certainty rating for the evidence.
Further research is needed to explore the impact of expectation effects and other moderating factors.
Simplified
OBJECTIVE: To determine the efficacy of psilocybin as an antidepressant compared with placebo or non-psychoactive drugs.
DESIGN: Systematic review and meta-analysis.
DATA SOURCES: Five electronic databases of published literature (Cochrane Central Register of Controlled Trials, Medline, Embase, Science Citation Index and Conference Proceedings Citation Index, and PsycInfo) and four databases of unpublished and international literature (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, ProQuest Dissertations and Theses Global, and PsycEXTRA), and handsearching of reference lists, conference proceedings, and abstracts.
DATA SYNTHESIS AND STUDY QUALITY: Information on potential treatment effect moderators was extracted, including depression type (primary or secondary), previous use of psychedelics, psilocybin dosage, type of outcome measure (clinician rated or self-reported), and personal characteristics (eg, age, sex). Data were synthesised using a random effects meta-analysis model, and observed heterogeneity and the effect of covariates were investigated with subgroup analyses and metaregression. was used as a measure of treatment effect size, to account for small sample effects and substantial differences between the included studies' sample sizes. Study quality was appraised using Cochrane's Risk of Bias 2 tool, and the quality of the aggregated evidence was evaluated using GRADE guidelines.
ELIGIBILITY CRITERIA: Randomised trials in which psilocybin was administered as a standalone treatment for adults with clinically significant symptoms of depression and change in symptoms was measured using a validated clinician rated or self-report scale. Studies with directive psychotherapy were included if the psychotherapeutic component was present in both experimental and control conditions. Participants with depression regardless of comorbidities (eg, cancer) were eligible.
RESULTS: Meta-analysis on 436 participants (228 female participants), average age 36-60 years, from seven of the nine included studies showed a significant benefit of psilocybin (Hedges' g=0.66, 95% confidence interval (CI) 0.46 to 0.86, P<0.001) on change in depression scores compared with comparator treatment. Exploratory subgroup analyses and metaregressions indicated that having secondary depression (Hedges' g=0.88, 95% CI 0.42 to 1.33), being assessed with self-report depression scales such as the Beck depression inventory (0.88, 0.42 to 1.33), and older age and previous use of psychedelics (metaregression coefficient 0.13, 95% CI 0.02 to 0.23 and 6.00, 2.48 to 9.53, respectively) were correlated with greater improvements in symptoms. All studies had a moderate risk of bias, but the change from baseline metric was associated with low heterogeneity and a statistically non-significant risk of small study bias, resulting in a moderate certainty of evidence rating.
CONCLUSION: Treatment effects of psilocybin were significantly larger among patients with secondary depression, when self-report scales were used to measure symptoms of depression, and when participants had previously used psychedelics. Further research is thus required to delineate the influence of expectancy effects, moderating factors, and treatment delivery on the efficacy of psilocybin as an antidepressant.
Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: no support from any organisation for the submitted work; AMM is employed by IDEA Pharma, which does consultancy work for pharmaceutical companies developing drugs for physical and mental health conditions; MC was the supervisor for AMM’s University of Oxford MSc dissertation, which forms the basis for this paper; no other relationships or activities that could appear to have influenced the submitted work.
