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The promises and perils of psychedelic pharmacology for psychiatry

Abstract

Psychedelic drugs including psilocybin, N,Nʹ-dimethyltryptamine (DMT) and lysergic acid diethylamide (LSD) are undergoing a renaissance as potentially useful drugs for various neuropsychiatric diseases, with a rapid onset of therapeutic activity. Notably, phase II trials have shown that psilocybin can produce statistically significant clinical effects following one or two administrations in depression and anxiety. These findings have inspired a ‘gold rush’ of commercial interest, with nearly 60 companies already formed to explore opportunities for psychedelics in treating diverse diseases. Additionally, these remarkable phenomenological and clinical observations are informing hypotheses about potential molecular mechanisms of action that need elucidation to realize the full potential of this investigative space. In particular, despite compelling evidence that the 5-HT2A receptor is a critical mediator of the behavioural effects of psychedelic drugs, uncertainty remains about which aspects of 5-HT2A receptor activity in the central nervous system are responsible for therapeutic effects and to what degree they can be isolated by developing novel chemical probes with differing specificity and selectivity profiles. Here, we discuss this emerging area of therapeutics, covering both controversies and areas of consensus related to the opportunities and perils of psychedelic and psychedelic-inspired therapeutics. We highlight how basic science breakthroughs can guide the discovery and development of psychedelic-inspired medications with the potential for improved efficacy without hallucinogenic or rewarding actions.

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Fig. 1: Historical timeline of key events in psychedelic science.
Fig. 2: LSD has a complex polypharmacology.
Fig. 3: Current model for psychedelic drug actions.
Fig. 4: A crystal-clear view of psychedelic drug actions.
Fig. 5: The polypharmacology of the novel non-psychedelic drug TBG.

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Acknowledgements

B.L.R. was supported by grants from the National Institutes of Health (NIH), a cooperative agreement from the Defense Advanced Research Projects Agency (DARPA) and the Michael Hooker Distinguished Professorship. T.D.M.-B. is a programme manager in the DARPA Biological Technologies Office.

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FDA Breakthrough Therapy: https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy

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Psychedelic Stock Index: www.psychedelicinvest.com

Substance Abuse and Mental Health Service Administration — 2019 National Survey on Drug Use and Health Detailed Tables: https://www.samhsa.gov/data/report/2019-nsduh-detailed-tables

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McClure-Begley, T.D., Roth, B.L. The promises and perils of psychedelic pharmacology for psychiatry. Nat Rev Drug Discov 21, 463–473 (2022). https://doi.org/10.1038/s41573-022-00421-7

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