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There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT(2A) serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a beta-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT(2A) receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT(2A) activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects.
There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT(2A) serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a beta-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT(2A) receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT(2A) activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects.


The structural diversity of psychedelic drug actions revealed.,Gumpper RH, Jain MK, Kim K, Sun R, Sun N, Xu Z, DiBerto JF, Krumm BE, Kapolka NJ, Kaniskan HU, Nichols DE, Jin J, Fay JF, Roth BL Nat Commun. 2025 Mar 19;16(1):2734. doi: 10.1038/s41467-025-57956-7. PMID:40108183<ref>PMID:40108183</ref>
, PMID:40108183<ref>PMID:40108183</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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