The polypharmacology of psychedelics reveals multiple targets for potential therapeutics.

ObservationalPubMedOctober 2, 2025PMID: 40683247 DOI

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.

Authors (21)

LeadDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.

Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.

Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark.

Tia A TumminoDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.

Carl-Mikael SuomivuoriDepartment 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.

Xi-Ping HuangNational Institute of Mental Health Psychoactive Drug Screening Program, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.

Laura ShubInstitute of Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA.

Jeffrey F DiBertoDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.

Kuglae KimDepartment of System Biology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, South Korea.

Chelsea DeLeonDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.

Brain E KrummDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.

Jonathan F FayDepartment of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA.

Michael KeiserInstitute of Neurodegenerative Diseases, University of California, San Francisco, San Francisco, CA 94158, USA.

Alexander S HauserDepartment of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark.

Ron O DrorDepartment 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.

Brian ShoichetDepartment of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.

David E GloriamDepartment of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark.

David E NicholsDepartment of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7365, USA.

Bryan L RothDepartment 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.

MeSH Terms

HallucinogensHumansPolypharmacologyAnimalsTryptaminesLysergic Acid DiethylamideReceptor, Serotonin, 5-HT2AReceptors, G-Protein-Coupled

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Metadata

Study TypeObservational

SourcePubMed

Publication DateOctober 2, 2025

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