The structural diversity of psychedelic drug actions revealed

Nat Commun. 2025 Mar 19;16(1):2734. doi: 10.1038/s41467-025-57956-7.

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.

MeSH terms

  • Cryoelectron Microscopy
  • Hallucinogens* / chemistry
  • Hallucinogens* / pharmacology
  • Humans
  • Receptor, Serotonin, 5-HT2A* / chemistry
  • Receptor, Serotonin, 5-HT2A* / metabolism
  • Serotonin 5-HT2 Receptor Agonists* / chemistry
  • Serotonin 5-HT2 Receptor Agonists* / pharmacology
  • beta-Arrestins / chemistry
  • beta-Arrestins / metabolism

Substances

  • Hallucinogens
  • Receptor, Serotonin, 5-HT2A
  • Serotonin 5-HT2 Receptor Agonists
  • beta-Arrestins