Efficacy, all-cause discontinuation, and safety of serotonergic psychedelics and MDMA to treat mental disorders: A living systematic review with meta-analysis.
Mikkel Højlund, Helin Y. Kafali, Begüm Kırmızı, Paolo Fusar‐poli, Christoph U Correll, Samuele Cortese, Michel Sabé, Jess G. Fiedorowicz, Gayatri Saraf, Josephine Zein, Michael Berk, Muhammad I Husain, Joshua D. Rosenblat, Ruby Rubaiyat, Kim Corace, Stanley Wong, Simon Hatcher, Mark Kaluzienski, Lakshmi N. Yatham, Andrea Cipriani, Corentin J. Gosling, Robin Carhart-Harris, Peter Tanuseputro, Daniel T. Myran, Nicholas Fabiano, David Moher, Leah M. Mayo, Stuart G. Nicholls, Tracy White, Michele de Prisco, Joaquim Radua, Eduard Vieta, Karim S Ladha, Jay Katz, Areti A. Veroniki, Marco Solmi
European Neuropsychopharmacology November 7, 2025 DOI: 10.1016/j.euroneuro.2025.09.011 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis (living systematic review) Randomized Double-blind Peer reviewed |
|---|---|
| Sample size | 1,480 |
| Population | Patients with mental disorders enrolled in double-blind randomized controlled trials of MDMA or serotonergic psychedelics |
| Interventions | MDMA psilocybin ayahuasca LSD |
| Topics | Psychedelic-assisted therapy MDMA Serotonin |
| Keywords | MDMA Therapy Psychedelic medicine Entheogenic therapy Psycholytic treatment Mental health treatment Mental healthcare Psychiatric treatment Mental disorder therapy Behavioral health Clinical trials Medical research Efficacy studies Safety profiles Treatment evaluation Drug trials |
| Citations | 12 |
| Key findings | MDMA and serotonergic psychedelics showed moderate to large symptom reductions in PTSD, major depressive disorder, and anxiety disorders, with the strongest and most certain evidence for MDMA in PTSD (SMD -0.85, moderate certainty versus placebo). Evidence was weaker or null for alcohol use disorder abstinence and ADHD symptoms, and certainty was low to very low for most outcomes. The authors conclude these treatments are promising but that pragmatic, long-term, head-to-head trials addressing expectancy and functional unblinding are needed for regulatory approval. |
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 (1480 participants; female=45.8 %; with psychological support=83.3 %; high RoB=83.3 %). In post-traumatic stress disorder (PTSD), MDMA reduced PTSD symptoms compared to any control (k = 11; SMD=-0.85 [-1.09; -0.60]; I2=0 %; GRADE=low). In major depressive disorder (MDD), psilocybin/ayahuasca/LSD reduced depressive symptoms (k = 8; 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 (k = 6; 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.
Comparable studies
Other systematic reviews and meta-analyses on MDMA and psychedelic-assisted therapy, most cited first.