The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.
Manish K Jain, Ryan H Gumpper, Samuel T Slocum, Gavin P Schmitz, Jakob S Madsen, Tia A Tummino, Carl-Mikael Suomivuori, Xi-Ping Huang, Laura Shub, Jeffrey F DiBerto, Kuglae Kim, Chelsea Deleon, Brain E Krumm, Jonathan F Fay, Michael Keiser, Alexander S Hauser, Ron O Dror, Brian Shoichet, David E Gloriam, David E Nichols, Bryan L Roth
Neuron July 15, 2025 DOI: 10.1016/j.neuron.2025.06.012 via PubMed
Summary
AI-generated from the abstractClassical psychedelics like LSD, psilocybin, and mescaline produce their mind-altering effects by activating the 5-HT2A serotonin receptor. Recent clinical studies indicate they may also help treat depression, anxiety, migraines, cluster headaches, drug abuse, and PTSD. This work examined 41 psychedelics from three chemical classes, testing them against 318 human G-protein-coupled receptors and, for LSD, over 450 human kinases. The compounds potently activated nearly every serotonin, dopamine, and adrenergic receptor. They also stimulated multiple signaling pathways through the 5-HT2A receptor, each linked to psychedelic-like effects in animals. The findings suggest that many molecular targets contribute to the overall actions of psychedelics.
Study at a glance
| Characteristics | Preclinical pharmacological profiling Peer reviewed |
|---|---|
| Keywords | G-protein-coupled receptors Dopamine receptors Hallucinogen Psychedelics Serotonin receptors |
| Citations | 42 |
| Key finding | Classical psychedelics activate nearly every serotonin, dopamine, and adrenergic receptor, and stimulate multiple 5-HT2AR transducers, each correlating with psychedelic-like actions in vivo. |
Abstract
The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT2A serotonin receptor (5-HT2AR). Recent clinical studies have suggested that classical psychedelics may additionally have therapeutic potential for many neuropsychiatric conditions including depression, anxiety, migraine and cluster headaches, drug abuse, and post-traumatic stress disorder. In this study, we investigated the pharmacology of 41 classical psychedelics from the tryptamine, phenethylamine, and lysergamide chemical classes. We profiled these compounds against 318 human G-protein-coupled receptors (GPCRs) to elucidate their target profiles, and in the case of LSD, against more than 450 human kinases. We found that psychedelics have potent and efficacious actions at nearly every serotonin, dopamine, and adrenergic receptor. We quantified their activation for multiple transducers and found that psychedelics stimulate multiple 5-HT2AR transducers, each of which correlates with psychedelic drug-like actions in vivo. Our results suggest that multiple molecular targets likely contribute to the actions of psychedelics.