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The neural basis of psychedelic action

Nature Neuroscience volume 25, pages 1407–1419 (2022)Cite this article

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Abstract

Psychedelics are serotonin 2A receptor agonists that can lead to profound changes in perception, cognition and mood. In this review, we focus on the basic neurobiology underlying the action of psychedelic drugs. We first discuss chemistry, highlighting the diversity of psychoactive molecules and the principles that govern their potency and pharmacokinetics. We describe the roles of serotonin receptors and their downstream molecular signaling pathways, emphasizing key elements for drug discovery. We consider the impact of psychedelics on neuronal spiking dynamics in several cortical and subcortical regions, along with transcriptional changes and sustained effects on structural plasticity. Finally, we summarize neuroimaging results that pinpoint effects on association cortices and thalamocortical functional connectivity, which inform current theories of psychedelic action. By synthesizing knowledge across the chemical, molecular, neuronal, and network levels, we hope to provide an integrative perspective on the neural mechanisms responsible for the acute and enduring effects of psychedelics on behavior.

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Fig. 1: Chemical phylogeny of psychedelics.
Fig. 2: The 5-HT2A receptors and molecular signaling pathways.
Fig. 3: Regional differences in psychedelic action on neurophysiology.
Fig. 4: Network-level models of psychedelic action.

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Acknowledgements

A.C.K. thanks N. Savalia, P. Davoudian and P. Corlett and D.E.O. thanks L. Dunlap, H. Warren and D. Nichols for helpful conversations. A.C.K. was supported by the Yale Program in Psychedelic Science, an One Mind - COMPASS Rising Star Award, and NIH/NIMH grants R01MH121848 and R01MH128217. D.E.O. was supported by NIH/NIDA grant R01DA056365, NIH/NIGMS grant R01GM128997 and the Camille and Henry Dreyfus Foundation. B.L.R. was supported by grants from NIH/NIMH, NIH/NIDA, DARPA and the Michael Hooker Distinguished Professorship.

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Authors and Affiliations

  1. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

    Alex C. Kwan

  2. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    Alex C. Kwan

  3. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    Alex C. Kwan

  4. Department of Chemistry, University of California, Davis, Davis, CA, USA

    David E. Olson

  5. Department of Biochemistry & Molecular Medicine, School of Medicine, University of California, Davis, Sacramento, CA, USA

    David E. Olson

  6. Center for Neuroscience, University of California, Davis, Davis, CA, USA

    David E. Olson

  7. Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Hospital, University of Zurich, Zurich, Switzerland

    Katrin H. Preller

  8. Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC, USA

    Bryan L. Roth

  9. Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA

    Bryan L. Roth

  10. Psychoactive Drug Screening Program, National Institute of Mental Health, School of Medicine, University of North Carolina, Chapel Hill, NC, USA

    Bryan L. Roth

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Competing interests

A.C.K. is a member of the Scientific Advisory Board of Empyrean Neuroscience and Freedom Biosciences. A.C.K. has consulted for Biohaven Pharmaceuticals. No-cost compounds were provided to A.C.K. for research by Usona Institute. D.E.O. is a cofounder of Delix Therapeutics, Inc., and serves as the Chief Innovation Officer and Head of the Scientific Advisory Board. K.H.P. is currently an employee of Boehringer Ingelheim GmbH & Co. KG. B.L.R. is a member of the Scientific Advisory Board of Septerna Pharmaceuticals and Escient Pharmaceuticals. These duties had no influence on the content of this article.

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Kwan, A.C., Olson, D.E., Preller, K.H. et al. The neural basis of psychedelic action. Nat Neurosci 25, 1407–1419 (2022). https://doi.org/10.1038/s41593-022-01177-4

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