Reconsidering evidence for psychedelic-induced psychosis: an overview of reviews, a systematic review, and meta-analysis of human studies
This systematic review (2024) and meta-analysis (s=131) examines the incidence of psychedelic-induced psychosis, focusing on individuals with schizophrenia. It finds an incidence of 0.002% in population studies, 0.2% in UCTs, and 0.6% in RCTs, with 3.8% of UCT participants with schizophrenia developing long-lasting psychotic symptoms. It also reports that 13.1% of those with psychedelic-induced psychosis later developed schizophrenia.
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.
Research Summary of 'Reconsidering evidence for psychedelic-induced psychosis: an overview of reviews, a systematic review, and meta-analysis of human studies'
Introduction
Interest in the therapeutic potential of serotonergic psychedelics is rapidly expanding, driven by promising results in treatment-resistant conditions such as depression, substance use disorders, anxiety and PTSD. However, patients with schizophrenia and bipolar disorder have generally been excluded from psychedelic research because of concerns that these drugs might trigger acute or long-lasting psychotic symptoms. Earlier theories, such as the serotonin-2A overactivity hypothesis, and historical clinical use of LSD in the 1950s–60s contributed to debate about whether serotonergic psychedelics can precipitate or worsen psychosis; at the same time, more recent work points to other substances (for example cannabis and stimulants) as stronger drivers of psychosis risk than classic psychedelics. Sabé and colleagues set out to clarify the evidence linking serotonergic psychedelics (LSD, psilocybin, mescaline, DMT, and MDMA) to incident psychosis, exacerbation of pre-existing psychotic disorders, and subsequent transition to schizophrenia. The study combined an overview of existing reviews with a systematic review and meta-analysis, aiming to estimate the incidence of long-lasting (>48 hours) psychotic symptoms after psychedelic use across several populations (general/indigenous populations, healthy volunteers, patients with depression, and people with schizophrenia) and to quantify conversion rates from substance-induced psychotic disorder (SIPD) to schizophrenia.
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Sabé, M., Sulstarova, A., Glangetas, A., De Pieri, M., Mallet, L., Curtis, L., Richard-Lepouriel, H., Penzenstadler, L., Seragnoli, F., Thorens, G., Zullino, D., Preller, K., Böge, K., Leucht, S., Correll, C. U., Solmi, M., Kaiser, S., & Kirschner, M. (2025). Reconsidering evidence for psychedelic-induced psychosis: an overview of reviews, a systematic review, and meta-analysis of human studies. Molecular Psychiatry, 30(3), 1223-1255. https://doi.org/10.1038/s41380-024-02800-5
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