A Systematic and Meta-Analytic Review on Psilocybin and 3,4-Methylenedioxymethamphetamine in the Treatment of Mental Illnesses: Effects of Dosage, Psychotherapeutic Support, and Antidepressant Use on Treatment Efficacy

Background: The therapeutic use of 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin has gained interest due to their potential efficacy in treating mental illness. We systematically reviewed the efficacy of MDMA and psilocybin in treating mental illness and explored the moderating effects of dosage, psychotherapeutic support, and concurrent antidepressant use.

Methods: In this systematic review and meta-analysis, we searched PubMed, Web of Science, and PsycINFO from inception to June 1, 2024, for randomized controlled trials and quantitative studies using MDMA or psilocybin to treat mental illnesses in humans. Primary outcomes were change in psychopathology severity. Meta-regressions explored the effects of preparation and integration sessions, dose, and concurrent antidepressant use. The study was registered with PROSPERO (CRD42024554450).

Findings: Of 29,255 identified records, 25 were included in the systematic review and 12 in meta-analyses (six MDMA trials in post-traumatic stress disorder (PTSD) and six psilocybin trials in major depressive disorder/treatment-resistant depression). The meta-analyses for MDMA-assisted therapy found significant efficacy in reducing PTSD symptoms both between-groups (Hedge’s g=2.1, 95% CI[1.43,2.77], I²=80.29%) and within-groups (Hedge’s g=0.72, 95% CI[0.45,1.06], I²=80.29%). In psilocybin-assisted therapy for major/treatment-resistant depression, the between-groups meta-analysis did not reach statistical significance, while the within-groups meta-analysis showed significant symptom reduction (Hedge’s g=1.72, 95% CI[1.25,2.19], I²=92.65%). Multivariate meta-regressions indicated that more integration sessions improved outcomes for both substances, while concurrent antidepressant use in psilocybin-assisted therapy did not affect outcomes. Higher MDMA doses were linked to lesser improvements, and more preparation sessions reduced improvements in psilocybin therapy. Risk of bias primarily arose from challenges in using blinding.

Interpretation: Our findings highlight the therapeutic potential of MDMA- and psilocybin-assisted therapies. However, they also emphasize the necessity for standardized treatment protocols to balance safety and efficacy. This is crucial for integrating these therapies into clinical practice, where they could provide valuable alternatives for patients with severe or treatment-resistant conditions.Funding: LO was supported by a National Health and Medical Research Council (NHMRC) Investigator grant (2007718), a strategic award from the School of Psychology at the 24 University of Queensland, and a start-up fund from the AIBN at the University of Queensland.Declaration of Interest: SP is the Trial Psychiatrist on a clinical trial (in progress) that has been supported by Woke Pharmaceuticals. In the last five years, SP has received research funding or honoraria within the past five years from Johnson & Johnson and CSL Seqirus. The other authors declare no competing interests.