The structural diversity of psychedelic drug actions revealed.
Nature communications – March 19, 2025
Source: PubMed
Summary
Recent insights into psychedelics reveal their diverse actions on the 5-HT2A serotonin receptor, a key player in treating conditions like depression and anxiety. By analyzing various compounds, researchers identified unique molecular interactions, paving the way for new therapies that could offer benefits with fewer side effects.
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.