The intersection between psychedelics and schizophrenia spectrum disorders: Reevaluating risk and therapeutic potential

Evaluating the existing evidence on the risks and potential therapeutic use of psychedelics in people with schizophrenia spectrum disorders (SSDs).

In this review article, the authors reevaluate existing evidence on the risks and potential therapeutic use of psychedelics in people with schizophrenia spectrum disorders (SSDs).

• Current exclusion criteria may be overly broad: The authors argue that automatically excluding all people with schizophrenia spectrum disorders from psychedelic research may not be justified, although caution remains essential.

• Potential therapeutic benefits: Carefully selected, clinically stable patients may benefit from psychedelics for negative symptoms (e.g., reduced motivation, social withdrawal) and depression, using low-dose, closely supervised approaches.

• Psychosis risk remains important: Psychedelics can worsen or trigger psychotic symptoms in susceptible individuals, so careful patient selection, screening, and monitoring are critical.

• More research is needed: The authors recommend cautious, well-designed clinical trials to better define which patients, if any, might safely benefit from psychedelic therapies.

Overall conclusion: The review suggests that psychedelics should not automatically be ruled out for all people with schizophrenia spectrum disorders, but any therapeutic use should be approached conservatively and investigated only in carefully designed clinical research.

Abstract

In the past decade, interest in studying psychedelic compounds as potential therapeutic agents has resurged. These studies carefully exclude individuals at risk for developing psychotic symptoms in response to psychedelic use.

Given the potential for psychedelics to be established as treatments in psychiatry, it is important to more robustly understand their link with psychosis and schizophrenia spectrum disorders (SSDs). In this narrative review, we examine the historical and theoretical relationship between psychedelic drugs and SSDs, including the origins of the psychotomimetic hypothesis. For key psychedelic compounds, we review their phenomenological manifestations in relation to the experiential alterations characteristic of SSDs, revealing both areas of overlap and important qualitative differences that challenge the uniform psychotomimetic classification. We also review putative neural mechanisms underlying altered experiential states associated with psychedelic use and SSDs, with attention to serotonergic, dopaminergic, and glutamatergic contributions.

Clinical evidence demonstrates that psychedelics can exacerbate pre-existing psychotic illness and may trigger psychosis in vulnerable individuals, though the magnitude of these risks remains inadequately quantified. However, phenomenological and mechanistic distinctions suggest that potential therapeutic applications may exist for carefully selected symptoms (negative symptoms, depression) in stable patients using low-dose, controlled approaches. Based on published work, we provide recommendations regarding psychosis-related risk and potential avenues for the treatment of SSDs as psychedelics gain traction as therapeutics.

Brar PS, Price RB, Ross S, Tofighi B, Sarpal DK. The intersection between psychedelics and schizophrenia spectrum disorders: Reevaluating risk and therapeutic potential. Journal of Psychopharmacology. 2026;0(0). Read Paper

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