NIDA IRP Technology Resource Initiative Featured Paper

The polypharmacology of psychedelics reveals multiple targets for potential therapeutics

Published in Neuron.

Authors

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

Paper presented by Dr. Oscar Soli Castrejon and selected by the NIDA TDI Paper of the Month Committee

Publication Brief Description

This study provides one of the most comprehensive pharmacological analyses of classical psychedelics to date. The authors profiled 41 psychedelic compounds across more than 300 GPCRs and showed that these drugs act on multiple serotonin, dopamine, and adrenergic receptors rather than only the 5-HT2A receptor. They also identified signaling pathways associated with psychedelic effects and highlighted activation of the 5-HT2B receptor as a potential safety concern. This work provides a comprehensive dataset that will be useful for understanding the mechanisms of psychedelics and for the development of new therapeutic compounds.

Jain, Manish K; Gumpper, Ryan H; Slocum, Samuel T; Schmitz, Gavin P; Madsen, Jakob S; Tummino, Tia A; Suomivuori, Carl-Mikael; Huang, Xi-Ping; Shub, Laura; DiBerto, Jeffrey F; Kim, Kuglae; DeLeon, Chelsea; Krumm, Brain E; Fay, Jonathan F; Keiser, Michael; Hauser, Alexander S; Dror, Ron O; Shoichet, Brian; Gloriam, David E; Nichols, David E; Roth, Bryan L

The polypharmacology of psychedelics reveals multiple targets for potential therapeutics Journal Article

In: Neuron, vol. 113, no. 19, pp. 3129–3142.e9, 2025, ISSN: 1097-4199.

Abstract | Links

@article{pmid40683247,

title = {The polypharmacology of psychedelics reveals multiple targets for potential therapeutics},

author = {Manish K Jain and Ryan H Gumpper and Samuel T Slocum and Gavin P Schmitz and Jakob S Madsen and Tia A Tummino and Carl-Mikael Suomivuori and Xi-Ping Huang and Laura Shub and Jeffrey F DiBerto and Kuglae Kim and Chelsea DeLeon and Brain E Krumm and Jonathan F Fay and Michael Keiser and Alexander S Hauser and Ron O Dror and Brian Shoichet and David E Gloriam and David E Nichols and Bryan L Roth},

url = {https://pubmed.ncbi.nlm.nih.gov/40683247/},

doi = {10.1016/j.neuron.2025.06.012},

issn = {1097-4199},

year  = {2025},

date = {2025-10-01},

urldate = {2025-10-01},

journal = {Neuron},

volume = {113},

number = {19},

pages = {3129--3142.e9},

abstract = {The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT serotonin receptor (5-HTR). 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-HTR 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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}