Highlights
– A living systematic review and meta-analysis of 30 double-blind randomized controlled trials (n=1,480) examined MDMA and serotonergic psychedelics for mental disorders (Højlund et al., 2025).
– MDMA showed a large effect on PTSD symptoms versus control (SMD = -0.85; I2 = 0%; GRADE = low; moderate certainty vs placebo); serotonergic psychedelics (psilocybin, ayahuasca, LSD) showed moderate-to-large reductions in depressive and anxiety symptoms but with low/very low certainty.
– Safety as measured by all-cause discontinuation did not differ from controls; however, 83% of trials had high risk of bias and most included concurrent psychological support.
Background: Clinical context and unmet need
Post-traumatic stress disorder (PTSD), major depressive disorder (MDD), anxiety disorders, and substance use disorders account for a substantial global burden of morbidity, treatment resistance, and functional impairment. Existing pharmacotherapies and psychotherapies are effective for many but not all patients, and durability of response, side effects, and access remain major challenges. In this context, serotonergic psychedelics (principally psilocybin, lysergic acid diethylamide [LSD], and ayahuasca) and 3,4-methylenedioxymethamphetamine (MDMA) have been investigated as adjuncts to psychological support or psychotherapeutic models to produce rapid, sometimes durable symptom reductions. The biological rationale includes agonism at 5-HT2A receptors for classical psychedelics and potent serotonin / monoamine release with prosocial and fear-extinction–facilitating effects for MDMA.
Study design: Scope, methods, and outcomes
This report summarizes a living systematic review and random-effects meta-analysis (Højlund et al., 2025) that searched PubMed, Scopus, and trial registries through 08 July 2025 for double-blind randomized controlled trials (RCTs) of MDMA or serotonergic psychedelics in patients with diagnosed mental disorders. Key features:
- Included trials: 30 RCTs, total N = 1,480; female 45.8%; 83.3% of trials delivered study drug in combination with psychological support.
- Primary outcomes: change in disease-specific symptom scores (standardized mean differences, SMD) and all-cause discontinuation (relative risk, RR).
- Meta-analytic method: random-effects models; heterogeneity quantified with I2; risk of bias assessed with Cochrane RoB 2; certainty rated by GRADE.
- Notable quality metrics: 83.3% of trials judged high risk of bias; only comparisons of MDMA vs placebo in PTSD reached moderate certainty by GRADE when restricted to placebo-controlled trials.
Key findings: efficacy across disorders
Overall dataset
Thirty RCTs provided data for separate meta-analyses by indication and agent class (MDMA vs serotonergic psychedelics). Most trials paired study drugs with structured psychological support or therapy. Blinding and expectancy control were recurring methodological challenges.
PTSD — MDMA
Eleven RCTs of MDMA for PTSD were pooled. Compared with any control, MDMA substantially reduced clinician-rated PTSD symptom severity (k = 11; SMD = -0.85; 95% CI -1.09 to -0.60; I2 = 0%). This effect size corresponds to a large clinical effect. When analyses were restricted to MDMA versus inactive placebo, GRADE certainty improved to moderate, reflecting more robust evidence in controlled settings. Heterogeneity was negligible, suggesting consistent benefits across included PTSD trials, though the majority of studies were sponsored or supported by a relatively narrow set of research groups and commonly used adjunctive psychotherapy, which limits generalizability.
Major depressive disorder (MDD) — serotonergic psychedelics
Eight trials examining psilocybin, ayahuasca, or LSD in MDD and depressive symptomatology were pooled (k = 8). The combined effect favored psychedelics over control with a moderate-to-large SMD = -0.62 (95% CI -0.97 to -0.28). Heterogeneity was moderate (I2 = 55%), reflecting differences in agents, dosing, patient populations (treatment-resistant vs broader MDD), and psychotherapeutic models. The overall GRADE certainty was rated very low, driven by high RoB, small samples, and risk of expectancy effects.
Anxiety disorders
Pooled analyses included trials of both MDMA and classical psychedelics for anxiety-related indications. For MDMA, two trials yielded SMD = -1.18 (95% CI -2.04 to -0.32; I2 = 0%; k = 2) with GRADE = low. For serotonergic psychedelics (k = 5), SMD = -0.88 (95% CI -1.70 to -0.06; I2 = 54%) with GRADE = very low. These large point estimates are encouraging but imprecise and heterogeneous.
Substance use disorders
For alcohol use disorder, six trials of psilocybin and LSD did not find a statistically significant improvement in abstinence rates compared with controls (k = 6; RR = 1.42; 95% CI 0.89 to 2.26; I2 = 7%; GRADE = very low). The confidence interval crosses clinically important benefit as well as no effect, reflecting uncertainty. Limited high-quality trials and variable definitions of outcomes (abstinence vs reduced use) constrain interpretation.
Other indications
One small RCT tested LSD in attention-deficit hyperactivity disorder (ADHD) and found no benefit (k = 1; SMD = 0.22; 95% CI -0.32 to 0.76; GRADE = very low). Evidence in other disorders remains sparse.
Safety — all-cause discontinuation and tolerability
Across trials, MDMA and serotonergic psychedelics were not associated with increased all-cause discontinuation compared with controls (RRMDMA = 0.74; 95% CI 0.32 to 1.72; RRserotonergic = 0.81; 95% CI 0.56 to 1.15), suggesting comparable short-term tolerability. Adverse-event reporting varied between trials; serious adverse events were uncommon but monitoring windows were often short and sample sizes limited. Trials typically excluded medically vulnerable or high-risk psychiatric patients, which constrains generalizability to routine clinical populations.
Expert commentary: interpreting strengths and limitations
The living review provides a helpful, up-to-date quantitative summary showing clinically meaningful effect sizes for MDMA in PTSD and for serotonergic psychedelics in depression and anxiety. However, several methodological caveats temper enthusiasm:
- High risk of bias: 83.3% of included trials were rated high RoB, commonly due to inadequate blinding (functional unblinding from characteristic subjective effects), small sample sizes, and selective reporting.
- Role of psychological support: Over 80% of trials combined drug administration with psychotherapeutic support. The contribution of the drug versus psychotherapy (or their interaction) remains unresolved; head-to-head trials comparing drug-assisted therapy vs psychotherapy alone are rare.
- Expectancy and blinding: The intense subjective experiences produced by psychedelics and MDMA make effective blinding difficult. Inadequate blinding can inflate effect estimates via expectancy and therapeutic alliance effects.
- Short follow-up and limited functional outcomes: Many trials emphasize symptom scales at weeks to months; fewer provide durable, functional endpoints (return to work, social functioning) or long-term safety data required for regulatory evaluation.
- Generalisability: Most trials excluded complex comorbidities, suicidality, and medically unstable patients, and demographic representation (race, socioeconomic status) varied and was often limited.
Mechanistic plausibility remains strong. Classical psychedelics act primarily via 5-HT2A receptor agonism, facilitating changes in cognition, emotion processing, and plasticity; MDMA prompts serotonin release and increased oxytocin, which may enhance fear extinction and therapeutic engagement. These mechanisms align with observed effects in PTSD and treatment-resistant depression but do not obviate the need for rigorous clinical evidence.
Implications for practice and research
Current evidence supports the view that MDMA-assisted therapy is a promising intervention for PTSD, with moderate certainty in placebo-controlled comparisons. Serotonergic psychedelics show promising antidepressant and anxiolytic signals but require higher-quality, larger, and longer trials before routine clinical adoption. The following priorities emerge:
- Conduct large-scale, multi-site pragmatic RCTs with active comparators and longer follow-up to assess durability and functional outcomes.
- Design trials to mitigate expectancy and unblinding (e.g., active placebo, rigorous assessment of blinding success, objective functional endpoints).
- Evaluate the individual contribution of psychological support through factorial or head-to-head designs and define optimal psychotherapeutic models and training standards for therapists.
- Include diverse, real-world clinical populations and carefully monitor long-term safety, suicidality, cognitive outcomes, and substance use patterns.
- Identify predictors and moderators of response (biomarkers, neuroimaging, clinical phenotypes) to target interventions and personalize care.
Conclusion
The living meta-analysis by Højlund et al. (2025) synthesizes an emerging body of RCT evidence suggesting that MDMA and serotonergic psychedelics can produce moderate-to-large reductions in psychiatric symptoms—most convincingly for MDMA in PTSD. However, high risk of bias, small samples, challenges with blinding, and the frequent co-delivery of psychological support limit current certainty. Before broad clinical implementation and regulatory approval, the field needs larger, pragmatic, well-blinded trials with long-term follow-up, direct comparisons to established treatments, and clear delineation of the role of adjunctive psychotherapy.
Funding and clinicaltrials.gov
Details of trial funding vary across included studies; several trials were supported by academic institutions, philanthropic groups, and in some cases industry or advocacy organizations. The living review is maintained at https://ebipsyche-database.org/ for updates. Specific trial registrations are reported within the source review where individual RCTs are indexed; readers should consult trial registries (clinicaltrials.gov or equivalent) for trial-level funding and protocol details.
References
Højlund M, Kafali HY, Kırmızı B, Fusar-Poli P, Correll CU, Cortese S, Sabé M, Fiedorowicz J, Saraf G, Zein J, Berk M, Husain MI, Rosenblat JD, Rubaiyat R, Corace K, Wong S, Hatcher S, Kaluzienski M, Yatham LN, Cipriani A, Gosling CJ, Carhart-Harris R, Tanuseputro P, Myran DT, Fabiano N, Moher D, Mayo LM, Nicholls SG, White T, Prisco M, Radua J, Vieta E, Ladha KS, Katz J, Veroniki AA, Solmi M. Efficacy, all-cause discontinuation, and safety of serotonergic psychedelics and MDMA to treat mental disorders: A living systematic review with meta-analysis. Eur Neuropsychopharmacol. 2025 Nov 7;101:41-55. doi: 10.1016/j.euroneuro.2025.09.011. Epub ahead of print. PMID: 41205366.
