Reconsidering evidence for psychedelic-induced psychosis: an overview of reviews, a systematic review, and meta-analysis of human studies.

Alban Glangetas, Kerem Böge, Katrin Preller, Gabriel Thorens, Federico Seragnoli, Louise Penzenstadler, Héléne Richard-Lepouriel, Logos Curtis, Marco De Pieri, Luc Mallet, Adi Sulstarova, Michel Sabé, Matthias Kirschner, Christoph U Correll, Marco Solmi, Stefan Leucht, Stefan Kaiser, Daniele Zullino

Journal: Molecular psychiatry 2025;30(3):1223-1255

PMID: 39592825

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Abstract

BACKGROUND

Persons with schizophrenia are excluded from psychedelic-assisted therapy due to concerns about the risk of triggering or worsening psychosis. However, there is limited meta-analytic data on the risk of psychedelic-induced psychosis in individuals with pre-existing psychotic disorders.

METHODS

We conducted a systematic review, meta-analysis, and overview of reviews to assess the incidence of psychedelic-induced psychosis and symptom exacerbation in schizophrenia. Our pre-registered protocol (CRD42023399591) covered: LSD, psilocybin, mescaline, DMT, and MDMA, using data from Embase, PubMed, PsyARTICLES, PsyINFO, and trial registries up to November 2023. A random-effects model was used to calculate psychosis incidence, with standardized assessments of study quality.

RESULTS

From 131 publications, we analyzed 14 systematic reviews, 20 reviews, 35 randomized-controlled trials (RCTs), 10 case-control studies, 30 uncontrolled trials (UCTs), and 22 cohort studies, most of which were low quality. Meta-analysis of nine studies showed an incidence of psychedelic-induced psychosis at 0.002% in population studies, 0.2% in UCTs, and 0.6% in RCTs. In UCTs including individuals with schizophrenia, 3.8% developed long-lasting psychotic symptoms. Of those with psychedelic-induced psychosis, 13.1% later developed schizophrenia. Sensitivity analyses confirmed the results.

CONCLUSION

In summary, the reviewed evidence suggests that schizophrenia might not be a definite exclusion criterion for clinical trials exploring safety and efficacy of psychedelics for treatment-resistant depression and negative symptoms. However, given the low quality and limited number of studies, more high-quality research is needed, and a conservative approach is recommended until further data is available.

Address: Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 2, Chemin du Petit-Bel-Air, CH-1226, Thonex, Switzerland. [email protected].; Faculty of Medicine, University of Geneva, Geneva, Switzerland. [email protected].; Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 2, Chemin du Petit-Bel-Air, CH-1226, Thonex, Switzerland.; Univ Paris-Est Créteil, DMU IMPACT, Département Médical-Universitaire de Psychiatrie et d'Addictologie, Hôpitaux Universitaires Henri Mondor - Albert Chenevier, Assistance Publique-Hôpitaux de Paris, Créteil, France.; Sorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Paris, France.; Department of Mental Health and Psychiatry, Global Health Institute, University of Geneva, Geneva, Switzerland.; Faculty of Medicine, University of Geneva, Geneva, Switzerland.; Young Adult Psychiatry Unit, Geneva University Hospitals, Geneva, Switzerland.; Faculty of Medicine, University of Geneva, Geneva, Switzerland.; Mood Disorder Unit, Psychiatric Specialties Service, Geneva University Hospital, Geneva, Switzerland.; Faculty of Medicine, University of Geneva, Geneva, Switzerland.; Division of Addiction Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 70, Grand-Pré, CH-1202, Geneva, Switzerland.; Division of Addiction Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 70, Grand-Pré, CH-1202, Geneva, Switzerland.; Department of Adult Psychiatry and Psychotherapy, Psychiatric University Clinic Zurich and University of Zurich, Zurich, Switzerland.; Department of Psychiatry and Psychotherapy, Campus Benjamin Franklin, Charité-Universitätsmedizin Berlin; and Freie Universität Berlin; and Humboldt-Universität zu Berlin; and Berlin Institute of Health, Berlin, Germany.; German Center of Mental Health (DZPG), Berlin, Germany.; Medical University Brandenburg-Theodor Fontane, Berlin, Germany.; Department of Psychiatry and Psychotherapy, School of Medicine, Technical University of Munich, Munich, Germany.; Klinik für Psychiatrie, Psychosomatik und Psychotherapie des Kindes- und Jugendalters, Charité-Universitätsmedizin Berlin, Campus Virchow, Augustenburger Platz 1, 13353, Berlin, Deutschland.; Department of Psychiatry and Molecular Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, USA.; Department of Psychiatry, The Zucker Hillside Hospital and Zucker School of Medicine at Hofstra/Northwell, New York, USA.; SIENCES lab, Department of Psychiatry, University of Ottawa, Ottawa, ON, Canada.; Department of Mental Health, The Ottawa Hospital, Ottawa, ON, Canada.; Ottawa Hospital Research Institute (OHRI) Clinical Epidemiology Program University of Ottawa, Ottawa, ON, Canada.; School of Epidemiology and Public Health, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.; Department of Child and Adolescent Psychiatry, Charité Universitätsmedizin, Berlin, Germany.; Division of Adult Psychiatry, Department of Psychiatry, University Hospitals of Geneva, 2, Chemin du Petit-Bel-Air, CH-1226, Thonex, Switzerland.; Faculty of Medicine, University of Geneva, Geneva, Switzerland.

DOI: 10.1038/s41380-024-02800-5

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MeSH Terms: Humans, Hallucinogens, Psychoses, Substance-Induced, Schizophrenia, Psychotic Disorders, Psilocybin, Lysergic Acid Diethylamide