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Psychedelics and schizophrenia: a double-edged sword

Molecular Psychiatry volume 30, pages 679–692 (2025)Cite this article

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Abstract

Psychedelics have shown promising effects in several psychiatric diseases as demonstrated by multiple clinical trials. However, no clinical experiments on patients with schizophrenia have been conducted up to date, except for some old semi-anecdotal studies mainly performed in the time-span ‘50s-‘60s. Notably, these studies reported interesting findings, particularly on the improvement of negative symptoms and social cognition. With no doubts the lack of modern clinical studies is due to the psychomimetic properties of psychedelics, a noteworthy downside that could worsen positive symptoms. However, a rapidly increasing body of evidence has suggested that the mechanisms of action of such compounds partially overlaps with the pathogenic underpinnings of schizophrenia but in an opposite way. These findings suggest that, despite being a controversial issue, the use of psychedelics in the treatment of schizophrenia would be based on a strong biological rationale. Therefore, the aim of our perspective paper is to provide a background on the old experiments with psychedelics performed on patients with schizophrenia, interpreting them in the light of recent molecular findings on their ability to induce neuroplasticity and modulate connectivity, the immune and TAARs systems, neurotransmitters, and neurotropic factors. No systematic approach was adopted in reviewing the evidence given the difficulty to retrieve and interpret old findings. Interestingly, we identified a therapeutic potential of psychedelics in schizophrenia adopting a critical point of view, particularly on negative symptoms and social cognition, and we summarized all the relevant findings. We also identified an eligible subpopulation of chronic patients predominantly burdened by negative symptoms, outlining possible therapeutic strategies which encompass very low doses of psychedelics (microdosing), carefully considering safety and feasibility, to pave the way to future clinical trials.

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Fig. 1: Biological targets of psychedelics.
Fig. 2: Protocol flowchart; expected biological and clinical changes; and murine model: translational findings.

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Funding

This work was supported by The Zardi-Gori Foundation, to DDG.

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Author notes

  1. These authors contributed equally: Danilo De Gregorio, Marta Bosia.

Authors and Affiliations

  1. IRCCS San Raffaele Scientific Institute, Milan, Italy

    Jacopo Sapienza, Francesca Martini, Stefano Comai, Roberto Cavallaro, Marco Spangaro, Danilo De Gregorio & Marta Bosia

  2. Department of Humanities and Life Sciences, University School for Advanced Studies IUSS, Pavia, Italy

    Jacopo Sapienza

  3. Department of Pharmaceutical and Pharmacological Sciences, University of Padua, Padua, Italy

    Stefano Comai

  4. Department of Psychiatry, McGill University, Montreal, QC, Canada

    Stefano Comai

  5. Department of Biomedical Sciences, University of Padua, Padua, Italy

    Stefano Comai

  6. School of medicine, Vita-Salute San Raffaele University, Milan, Italy

    Roberto Cavallaro, Danilo De Gregorio & Marta Bosia

Authors
  1. Jacopo Sapienza
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  2. Francesca Martini
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  3. Stefano Comai
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  4. Roberto Cavallaro
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  5. Marco Spangaro
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  6. Danilo De Gregorio
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  7. Marta Bosia
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Contributions

JS: Conceptualization; Writing original draft; Writing – review & editing; Methodology, literature review. FM: Writing – review & editing; Supervision; Methodology, literature review. SC: Writing – review & editing; Supervision. RC: Validation. MS: Validation. DDG: Conceptualization; Writing – review & editing; Validation; Funding acquisition. MB: Conceptualization; Writing – review & editing; Validation. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Francesca Martini.

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Competing interests

DDG has a provisional patent on the therapeutic use of LSD to treat anxiety disorders. The other authors declare no conflict of interest.

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Sapienza, J., Martini, F., Comai, S. et al. Psychedelics and schizophrenia: a double-edged sword. Mol Psychiatry 30, 679–692 (2025). https://doi.org/10.1038/s41380-024-02743-x

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  • DOI: https://doi.org/10.1038/s41380-024-02743-x

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