Efficacy, all-cause discontinuation, and safety of serotonergic psychedelics and MDMA to treat mental disorders: a living systematic review with meta-analysis

Abstract

Serotonergic psychedelics and 3,4 methylendioxtmethamphetamine (MDMA) are promising treatments for mental disorders with a continuously evolving evidence base. We searched Pubmed/Scopus/clinical trial registries up to 08july2025 for double-blind randomized controlled trials (RCTs) testing MDMA or serotonergic psychedelics in patients with mental disorders. Primary outcomes were change in disease-specific symptoms and all-cause discontinuation. Standardized mean differences (SMD) and relative risk (RR) were estimated using random-effects meta-analysis. Risk of bias (RoB) was assessed with Cochrane’s RoB-tool version 2 and certainty of evidence with GRADE. The review is maintained as living systematic review (https://ebipsyche-database.org/). We included 30 RCTs (1,480 participants; female=45.8%;with psychological support=83.3%;high RoB=83.3%). In post-traumatic stress disorder (PTSD), MDMA reduced PTSD symptoms (k=9;SMD=-0.85[-1.09;-0.60];I2=0%;GRADE=low). In major depressive disorder (MDD), psilocybin/ayahuasca/LSD reduced depressive symptoms (k=7;SMD=-0.62[-0.97;-0.28];I2=55%;GRADE=very low). In anxiety disorders, both MDMA and serotonergic psychedelics reduced anxiety symptoms (SMDMDMA=-1.18[-2.04;-0.32];I2=0;k=2;GRADE=low and SMDserotonergic=-0.88[-1.70;-0.06];I2=54%;k=5;GRADE=very low). In alcohol use disorder, neither psilocybin nor LSD reduced abstinence rates (RR=1.42[0.89;2.26];I2=7%;GRADE=very low). In attention-deficit hyperactivity disorder (ADHD), LSD did not reduce ADHD symptoms (k=1;SMD=0.22[-0.32; 0.76];GRADE=very low). Moderate certainty in evidence was only found for MDMA on PTSD symptoms when compared to placebo. MDMA/serotonergic psychedelics were not associated with higher risk of all-cause discontinuation(RRMDMA=0.74[0.32;1.72];RRserotonergic=0.81[0.56;1.15]). Overall, MDMA/serotonergic psychedelics are promising for the treatment of PTSD, MDD, and anxiety disorders with moderate to large effect sizes. Pragmatic trials, long-term, head-to-head trials exploring the role of psychological support, aiming to identify predictors of response, and accounting for expectancy and functional unblinding are needed. Studies addressing these limitations will likely be required for regulatory approval of psychedelic drugs.

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ORCID for Samuele Cortese: orcid.org/0000-0001-5877-8075

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