The structural diversity of psychedelic drug actions revealed.
Ryan H. Gumpper, Manish K. Jain, Kuglae Kim, Renhong Sun, Ning Sun, Zhongli Xu, Jeffrey F. Diberto, Brian E Krumm, Nicholas J. Kapolka, H. Ümit Kaniskan, David E. Nichols, Jian Jin, Jonathan F. Fay, Bryan L. Roth
Nat Commun March 19, 2025 DOI: 10.1038/s41467-025-57956-7 (opens in new tab) via PubMed Central
Summary
AI-generated from the abstractClassical psychedelics are being studied for treating depression, addiction, anxiety, and cluster headaches. Their therapeutic effects are thought to involve the 5-HT2A serotonin receptor. Seven cryo-EM structures were determined, covering major classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound. These structures reveal both common and distinct molecular interactions between different psychedelics and the receptor. The findings provide a mechanistic understanding of 5-HT2A activation that could aid development of new drugs with fewer side effects.
Study at a glance
| Characteristics | Structural biology study Peer reviewed |
|---|---|
| Keywords | Psychedelics Neuroscience Mental health Pharmacology Drug research |
| Citations | 31 |
| Key finding | Seven cryo-EM structures of hallucinogenic and non-hallucinogenic compounds bound to the 5-HT2A receptor reveal common and distinct molecular interactions that explain ligand specificity and signaling bias. |
Abstract
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-HT2A serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT2A receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT2A activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects. The authors present 7 cryo-EM structures of hallucinogenic and non-hallucinogenic compounds across multiple chemotypes bound to the 5-HT2A receptor, shedding light onto ligand specificity and signaling bias.