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Psychedelics: preclinical insights provide directions for future research

Abstract

Recently, psychedelics have emerged as promising therapeutics for numerous neuropsychiatric disorders. While their potential in the clinic has yet to be fully elucidated, understanding their molecular and biological mechanisms is imperative as these compounds are becoming widely used both in therapeutic and recreational contexts. This review examines the current understanding of basic biology, pharmacology, and structural biology in an attempt to reveal both the knowns and unknowns within the field.

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Fig. 1: Overview of the 5-HT (5-HT1-7) family of receptors and their canonical coupling pathways.
Fig. 2: Interactions with the widely used antagonists ketanserin, M100907, and pimavanserin against the 5-HT, dopamine, and alpha-adrenergic receptor families.
Fig. 3: Structures showing the molecular interactions over the entirety of the 5-HT2 family.
Fig. 4: Representative signaling cascades and complexes of the 5-HT2A receptor.
Fig. 5: Representative structures of the various possible interacting proteins with 5-HT2 receptors.

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Funding

Work in the Roth lab is supported by grants from the NIH and DARPA to BLR as well as the Michael Hooker Distinguished Professorship.

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BLR and RHG jointly wrote the paper and created the figures.

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Correspondence to Bryan L. Roth.

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BLR is a member of the Scientific Advisory Boards of Septerna Pharmaceuticals, Escient Pharmaceuticals and Onsero, Inc. As well, BLR is a scientific co-founder of Onsero and is listed as an inventor on patents related to the research in this review article. RHG declares no conflicts.

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Gumpper, R.H., Roth, B.L. Psychedelics: preclinical insights provide directions for future research. Neuropsychopharmacol. 49, 119–127 (2024). https://doi.org/10.1038/s41386-023-01567-7

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