This study presents seven cryo-electron microscopy (cryo-EM) structures showing how different classes of psychedelic and non-psychedelic compounds interact with the serotonin (5-HT) 2A receptor—the primary target for classical psychedelics’ therapeutic effects—revealing both shared and distinct binding patterns that could guide the development of new therapeutic compounds with improved side effect profiles.
Abstract of The structural diversity of psychedelic drug actions revealed
“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.“
Authors: 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
Summary of The structural diversity of psychedelic drug actions revealed
Psychedelic compounds have gained increasing attention due to their potential therapeutic effects in treating psychiatric disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). These substances, including serotonin (5-HT) receptor agonists such as LSD, psilocybin, and DMT, interact with the brain’s serotonergic system, particularly the 5-HT2A receptor. While previous research has provided insights into their subjective effects and therapeutic potential, there remains a gap in understanding the structural and functional mechanisms underlying their action at the molecular level.
Gumpper and colleagues explore the structural diversity of psychedelic drug actions by investigating how different compounds interact with the 5-HT2A receptor and other related receptors. By integrating molecular pharmacology, structural biology, and computational techniques, the researchers aim to provide a detailed understanding of how different psychedelics engage with their targets. This study builds on previous findings that suggest psychedelics produce their effects through complex receptor conformations and downstream signalling pathways, rather than a single uniform mechanism of action.
Methods
The authors employed a combination of experimental and computational techniques to study the binding and functional properties of various psychedelic compounds.
Structural and Functional Analysis
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The structural diversity of psychedelic drug actions revealed
https://doi.org/10.1038/s41467-025-57956-7
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Cite this paper (APA)
Gumpper, R. H., Jain, M. K., Kim, K., Sun, R., Sun, N., Xu, Z., ... & Roth, B. L. (2025). The structural diversity of psychedelic drug actions revealed. Nature Communications, 16(1), 2734.