Non-hallucinogenic psychedelics for mood and anxiety disorders: A systematic review

A review of pre-clinical and clinical studies on non-hallucinatory psychedelics (NHPs) for mood and anxiety disorders found five animal studies showing antidepressant-like effects, assessed via forced swim test and open field test, without the head-twitch response that indicates hallucination. One case report described a patient who inadvertently combined trazodone and psilocybin and experienced potent antidepressant effects without psychedelic effects. These preliminary findings suggest that antidepressant benefits of psychedelics may be separable from hallucinatory effects, providing impetus for rigorous clinical trials in humans.

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Abstract

Psychedelics have re-emerged as promising treatments for mood disorders. The current model provides a moderate-to-high dose of a psychedelic agent (e.g., psilocybin) to reliably induce an altered state of consciousness. Unfortunately, the hallucinatory effects limit the treatment's potential scalability given patients' vulnerability and extensive monitoring costs, leading to growing interest in non-hallucinatory psychedelics (NHPs). This review's objective was to identify, summarize and synthesize all published pre-clinical and clinical studies evaluating NHPs for mood and anxiety disorders. We included five animal studies demonstrating antidepressant-like effects through assessments like forced swim test (FST) and open field test (OFT) without observing head-twitch response (HTR), and one case report that identified a patient who inadvertently combined trazodone and psilocybin and experienced potent antidepressant effects without psychedelic effects. These preliminary findings provide a strong impetus for further investigation in human samples with rigorously designed clinical trials that may delineate the potential antidepressant effects of psychedelics without hallucinatory effects.