{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T15:21:20Z","timestamp":1789572080102,"version":"build-2803163510"},"reference-count":42,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T00:00:00Z","timestamp":1766966400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Psychedelic-assisted therapy is gaining renewed attention as a potential treatment for various mental disorders. Despite increasing numbers of randomized controlled trials (RCTs) and meta-analyses, a comprehensive synthesis of the evidence across different substances and indications is lacking. This umbrella review aims to evaluate the effectiveness and safety of psychedelic-assisted therapy\u2014primarily psilocybin, MDMA, and LSD\u2014across major psychiatric disorders, including depression, post-traumatic stress disorder (PTSD), and substance use disorders. Methods: We systematically identified and synthesized data from 23 meta-analyses encompassing over 100 primary studies. Outcomes were standardized and re-expressed as Hedges\u2019 g to enable cross-study comparisons. Study quality was assessed using AMSTAR2, and certainty of evidence was evaluated via the GRADE framework. Results: The number of identified meta-analyses differed markedly depending on the substance and clinical indication: psilocybin for depression (n = 9) and MDMA for PTSD (n = 10) had the strongest evidence base, while fewer meta-analyses were available for LSD in alcohol use disorder (n = 2) and depression (n = 2), ayahuasca in depression (n = 2), and MDMA in autism spectrum disorder (n = 2). Psilocybin demonstrated large effect sizes in major depression (Hedges\u2019 g \u2248 1.05), with some evidence of sustained benefits up to six months. MDMA showed very large effects in reducing PTSD symptoms (Hedges\u2019 g \u2248 1.24), often after 2\u20133 sessions. LSD yielded short-term benefits for alcohol use disorder (OR \u2248 2.0), though effects declined over time. Across studies, adverse events were generally mild and transient, with no consistent signal for serious harm. Considerable methodological variability was observed, including small and sometimes overlapping samples, heterogeneity, risk of bias, and limited long-term data. These constraints should be taken into account when interpreting the overall findings. Conclusions: Current evidence supports the short-term efficacy and safety of psychedelic-assisted therapy for selected psychiatric disorders, particularly depression and PTSD. However, the low methodological quality of studies and most meta-analyses, as well gaps in long-term safety data highlight the need for high-quality studies.<\/jats:p>","DOI":"10.3390\/jcm15010253","type":"journal-article","created":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T14:33:25Z","timestamp":1767191605000},"page":"253","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Efficacy and Safety of Psychedelics in Mental Disorder Cases: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1423-2289","authenticated-orcid":false,"given":"Monika","family":"Dominiak","sequence":"first","affiliation":[{"name":"Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9312-2976","authenticated-orcid":false,"given":"Adam","family":"G\u0119dek","sequence":"additional","affiliation":[{"name":"Third Department of Psychiatry, Institute of Psychiatry and Neurology, 02-957 Warsaw, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-7688-9432","authenticated-orcid":false,"given":"Szymon","family":"Modrzejewski","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Medical University of Lublin, 20-059 Lublin, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnieszka","family":"Permoda-Pachuta","sequence":"additional","affiliation":[{"name":"Department of Neuroses, Personality Disorders and Eating Disorders, Institute of Psychiatry and Neurology, 02-957 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8570-4706","authenticated-orcid":false,"given":"Anna Zofia","family":"Antosik","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Faculty of Medicine, Collegium Medicum, Cardinal Wyszynski University in Warsaw, 01-938 Warszawa, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1080\/02791072.2023.2223195","article-title":"Psilocybin\u2019s Potential Mechanisms in the Treatment of Depression: A Systematic Review","volume":"56","author":"Lee","year":"2024","journal-title":"J. Psychoact. Drugs"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"116043","DOI":"10.1016\/j.psychres.2024.116043","article-title":"The Efficacy and Safety of MDMA-Assisted Psychotherapy for Treatment of Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis from Randomized Controlled Trials","volume":"339","author":"Yang","year":"2024","journal-title":"Psychiatry Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.jad.2021.09.041","article-title":"Dose Effect of Psilocybin on Primary and Secondary Depression: A Preliminary Systematic Review and Meta-Analysis","volume":"296","author":"Li","year":"2022","journal-title":"J. Affect. Disord."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Gon\u00e7alves, J., Lu\u00eds, A., Gallardo, E., and Duarte, A.P. (2023). A Systematic Review on the Therapeutic Effects of Ayahuasca. Plants, 12.","DOI":"10.3390\/plants12132573"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1177\/00048674221083868","article-title":"A Systematic Literature Review and Meta-Analysis of the Effect of Psilocybin and Methylenedioxymethamphetamine on Mental, Behavioural or Developmental Disorders","volume":"57","author":"Kisely","year":"2022","journal-title":"Aust. N. Z. J. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1080\/03007995.2023.2296968","article-title":"The Impact of Psychedelics on Patients with Alcohol Use Disorder: A Systematic Review with Meta-Analysis","volume":"40","author":"Sicignano","year":"2024","journal-title":"Curr. Med. Res. Opin."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"116337","DOI":"10.1016\/j.psychres.2024.116337","article-title":"Efficacy and Safety of Psilocybin in the Treatment of Major Depressive Disorder (MDD): A Dose-Response Network Meta-Analysis of Randomized Placebo-Controlled Clinical Trials","volume":"344","author":"Swieczkowski","year":"2025","journal-title":"Psychiatry Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.euroneuro.2023.07.011","article-title":"Psilocybin-Assisted Therapy for Depression: A Systematic Review and Dose-Response Meta-Analysis of Human Studies","volume":"76","author":"Perez","year":"2023","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"115960","DOI":"10.1016\/j.psychres.2024.115960","article-title":"Efficacy and Safety of Psilocybin on Treatment-Resistant Depression: A Systematic Review and Meta-Analysis","volume":"337","author":"Fang","year":"2024","journal-title":"Psychiatry Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Salvetti, G., Saccenti, D., Moro, A.S., Lamanna, J., and Ferro, M. (2024). Comparison between Single-Dose and Two-Dose Psilocybin Administration in the Treatment of Major Depression: A Systematic Review and Meta-Analysis of Current Clinical Trials. Brain Sci., 14.","DOI":"10.3390\/brainsci14080829"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1016\/j.jad.2022.09.168","article-title":"Psychedelic Therapy for Depressive Symptoms: A Systematic Review and Meta-Analysis","volume":"322","author":"Ko","year":"2023","journal-title":"J. Affect. Disord."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Fang, S.P., Yang, X., and Zhang, W. (2024). Efficacy and Acceptability of Psilocybin for Primary or Secondary Depression: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Front. Psychiatry, 15.","DOI":"10.3389\/fpsyt.2024.1359088"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1111\/acps.13778","article-title":"Randomized Controlled Trials of Psilocybin-Assisted Therapy in the Treatment of Major Depressive Disorder: Systematic Review and Meta-Analysis","volume":"151","author":"Menon","year":"2024","journal-title":"Acta Psychiatr. Scand."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"112749","DOI":"10.1016\/j.psychres.2020.112749","article-title":"The Experimental Effects of Psilocybin on Symptoms of Anxiety and Depression: A Meta-Analysis","volume":"284","author":"Goldberg","year":"2020","journal-title":"Psychiatry Res."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Aghajanian, S., Shafiee, A., Parvizi Omran, S., Rezaei Nejad, A., Jafarabady, K., Kohandel Gargari, O., Rajai, S., Mohammadi, I., Bahrami Babaheidari, T., and Bakhtiyari, M. (2024). Psilocybin for Major Depressive Disorder: An Updated Systematic Review and Meta-Analysis of Randomized Clinical Trials. J. Psychopharmacol.","DOI":"10.1177\/02698811241287542"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1177\/02698811211044688","article-title":"Assessing the Effects of Methodological Differences on Outcomes in the Use of Psychedelics in the Treatment of Anxiety and Depressive Disorders: A Systematic Review and Meta-Analysis","volume":"36","author":"Leger","year":"2022","journal-title":"J. Psychopharmacol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1802920","DOI":"10.1080\/20008198.2020.1802920","article-title":"Pharmacological Therapy for Post-Traumatic Stress Disorder: A Systematic Review and Meta-Analysis of Monotherapy, Augmentation and Head-to-Head Approaches","volume":"12","author":"Hoskins","year":"2021","journal-title":"Eur. J. Psychotraumatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1002\/npr2.12485","article-title":"MDMA-Assisted Psychotherapy for the Treatment of PTSD: A Systematic Review and Meta-Analysis of Randomized Controlled Trials (RCTs)","volume":"44","author":"Shahrour","year":"2024","journal-title":"Neuropsychopharmacol. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1177\/0269881120965915","article-title":"A Comparison of MDMA-Assisted Psychotherapy to Non-Assisted Psychotherapy in Treatment-Resistant PTSD: A Systematic Review and Meta-Analysis","volume":"35","author":"Illingworth","year":"2021","journal-title":"J. Psychopharmacol."},{"key":"ref_20","first-page":"392","article-title":"Efficacy of 3,4-Methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy for Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis","volume":"44","author":"Bahji","year":"2020","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1177\/0269881116642542","article-title":"Treating Posttraumatic Stress Disorder with MDMA-Assisted Psychotherapy: A Preliminary Meta-Analysis and Comparison to Prolonged Exposure Therapy","volume":"30","author":"Amoroso","year":"2016","journal-title":"J. Psychopharmacol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/02791072.2023.2278586","article-title":"Efficacy and Safety of Four Psychedelic-Assisted Therapies for Adults with Symptoms of Depression, Anxiety, and Posttraumatic Stress Disorder: A Systematic Review and Meta-Analysis","volume":"57","author":"Bahji","year":"2023","journal-title":"J. Psychoact. Drugs"},{"key":"ref_23","first-page":"e15070","article-title":"The Efficacy of MDMA (3,4-Methylenedioxymethamphetamine) for Post-Traumatic Stress Disorder in Humans: A Systematic Review and Meta-Analysis","volume":"13","author":"Tedesco","year":"2021","journal-title":"Cureus J. Med. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1038\/s41386-024-01865-8","article-title":"Side-Effects of Mdma-Assisted Psychotherapy: A Systematic Review and Meta-Analysis","volume":"49","author":"Colcott","year":"2024","journal-title":"Neuropsychopharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1080\/02791072.2020.1769878","article-title":"A Meta-Analysis of Placebo-Controlled Trials of Psychedelic-Assisted Therapy","volume":"52","author":"Luoma","year":"2020","journal-title":"J. Psychoact. Drugs"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"994","DOI":"10.1177\/0269881112439253","article-title":"Lysergic Acid Diethylamide (LSD) for Alcoholism: Meta-Analysis of Randomized Controlled Trials","volume":"26","author":"Krebs","year":"2012","journal-title":"J. Psychopharmacol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Regan, A., Margolis, S., de Wit, H., and Lyubomirsky, S. (2021). Does \u00b13,4-Methylenedioxymethamphetamine (Ecstasy) Induce Subjective Feelings of Social Connection in Humans? A Multilevel Meta-Analysis. PLoS ONE, 16.","DOI":"10.1371\/journal.pone.0258849"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1124\/pr.115.011478","article-title":"Psychedelics","volume":"68","author":"Nichols","year":"2016","journal-title":"Pharmacol. Rev."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Wojtas, A., and Go\u0142embiowska, K. (2023). Molecular and Medical Aspects of Psychedelics. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25010241"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"de Vos, C.M.H., Mason, N.L., and Kuypers, K.P.C. (2021). Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics. Front. Psychiatry, 12.","DOI":"10.3389\/fpsyt.2021.724606"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"108","DOI":"10.2174\/1570159X16666180125095902","article-title":"Ayahuasca: Psychological and Physiologic Effects, Pharmacology and Potential Uses in Addiction and Mental Illness","volume":"17","author":"Hamill","year":"2019","journal-title":"Curr. Neuropharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.neulet.2016.07.004","article-title":"MDMA and PTSD Treatment: \u201cPTSD: From Novel Pathophysiology to Innovative Therapeutics\u201d","volume":"649","author":"Sessa","year":"2017","journal-title":"Neurosci. Lett."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1038\/s41586-019-1075-9","article-title":"Oxytocin-Dependent Reopening of a Social Reward Learning Critical Period with MDMA","volume":"569","author":"Nardou","year":"2019","journal-title":"Nature"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"823","DOI":"10.12740\/PP\/OnlineFirst\/133919","article-title":"Will MDMA-Assisted Psychotherapy Become a Breakthrough in Treatment-Resistant Post-Traumatic Stress Disorder? A Critical Narrative Review","volume":"56","author":"Szafoni","year":"2022","journal-title":"Psychiatr. Pol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1079","DOI":"10.1177\/0269881120919957","article-title":"Efficacy of Psychedelic Treatments on Depressive Symptoms: A Meta-Analysis","volume":"34","author":"Romeo","year":"2020","journal-title":"J. Psychopharmacol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"104706","DOI":"10.1016\/j.neubiorev.2022.104706","article-title":"The Emerging Science of Microdosing: A Systematic Review of Research on Low Dose Psychedelics (1955\u20132021) and Recommendations for the Field","volume":"139","author":"Polito","year":"2022","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"102127","DOI":"10.1016\/j.eclinm.2023.102127","article-title":"Ketamine for the Treatment of Major Depression: A Systematic Review and Meta-Analysis","volume":"62","author":"Nikolin","year":"2023","journal-title":"EClinicalMedicine"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.neuropharm.2018.05.012","article-title":"The Abuse Potential of Medical Psilocybin According to the 8 Factors of the Controlled Substances Act","volume":"142","author":"Johnson","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Psiuk, D., Nowak, E.M., Dycha, N., Lopuszanska, U., Kurzepa, J., and Samardakiewicz, M. (2022). Esketamine and Psilocybin-The Comparison of Two Mind-Altering Agents in Depression Treatment: Systematic Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms231911450"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1177\/07067437221111371","article-title":"The Canadian Network for Mood and Anxiety Treatments (CANMAT) Task Force Report: Serotonergic Psychedelic Treatments for Major Depressive Disorder","volume":"68","author":"Rosenblat","year":"2023","journal-title":"Can. J. Psychiatry"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1177\/0269881116662634","article-title":"Survey Study of Challenging Experiences after Ingesting Psilocybin Mushrooms: Acute and Enduring Positive and Negative Consequences","volume":"30","author":"Carbonaro","year":"2016","journal-title":"J. Psychopharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1056\/NEJMoa2206443","article-title":"Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression","volume":"387","author":"Goodwin","year":"2022","journal-title":"N. Engl. J. Med."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/253\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T14:51:23Z","timestamp":1767192683000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/1\/253"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,29]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["jcm15010253"],"URL":"https:\/\/doi.org\/10.3390\/jcm15010253","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,29]]}}}