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 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.