The polypharmacology of psychedelics reveals multiple targets for potential therapeutics

Manish K Jain¹, Ryan H Gumpper¹, Samuel T Slocum¹, Gavin P Schmitz¹, Jakob S Madsen², Tia A Tummino³, Carl-Mikael Suomivuori⁴, Xi-Ping Huang⁵, Laura Shub⁶, Jeffrey F DiBerto¹, Kuglae Kim⁷, Chelsea DeLeon¹, Brain E Krumm¹, Jonathan F Fay⁸, Michael Keiser⁶, Alexander S Hauser², Ron O Dror⁴, Brian Shoichet³, David E Gloriam², David E Nichols¹, Bryan L Roth⁹

Affiliations

¹ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
² Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark.
³ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94304, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
⁵ National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
⁶ Institute of Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA.
⁷ Department of System Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
⁸ Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
⁹ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA; National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA; Divison of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA. Electronic address: bryan_roth@med.unc.edu.

PMID: 40683247
DOI: 10.1016/j.neuron.2025.06.012

The polypharmacology of psychedelics reveals multiple targets for potential therapeutics

Manish K Jain et al. Neuron. 2025.

. 2025 Jul 15:S0896-6273(25)00470-2.

doi: 10.1016/j.neuron.2025.06.012. Online ahead of print.

Authors

Affiliations

¹ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
² Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark.
³ Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94304, USA; Department of Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA 94305, USA.
⁵ National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.
⁶ Institute of Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA.
⁷ Department of System Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.
⁸ Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.
⁹ Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA; National Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA; Divison of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7360, USA. Electronic address: bryan_roth@med.unc.edu.

PMID: 40683247
DOI: 10.1016/j.neuron.2025.06.012

Abstract

The classical psychedelics (+)-lysergic acid diethylamide (LSD), psilocybin, and mescaline exert their psychedelic effects via activation of the 5-HT_2A serotonin receptor (5-HT_2AR). 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-HT_2AR 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: G-protein-coupled receptors; dopamine receptors; hallucinogen; psychedelics; serotonin receptors.

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Conflict of interest statement

Declaration of interests R.O.D. is an SAB member of Septerna. B.L.R. is an SAB member of Septerna and Escient Pharmaceuticals. R.H.G. is a consultant for 2A Biosciences.

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The polypharmacology of psychedelics reveals multiple targets for potential therapeutics

Affiliations

The polypharmacology of psychedelics reveals multiple targets for potential therapeutics

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Affiliations

Abstract

Conflict of interest statement

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