Neuroimaging & Brain MeasuresEquity and EthicsMedicinal Chemistry & Drug Development

The neural basis of psychedelic action

This comprehensive review (2022) explains the neural basis of how psychedelics work. It covers serotonin receptors, changes in structural plasticity, and the long-term effects of psychedelics. The discussion covers the future of psychedelics, including non-hallucinogenic compounds.

Authors

  • Katrin Preller
  • David Olson
  • Bryan Roth

Published

Nature Medicine
meta Study

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 signalling 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 behaviour.

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Research Summary of 'The neural basis of psychedelic action'

Introduction

Psychedelics are primarily serotonin 2A (5-HT2A) receptor agonists that can produce large alterations in perception, cognition and mood. Earlier research established their striking subjective and therapeutic potential, and recent phase II clinical trials report durable symptom reductions after only a few sessions of psychedelic-assisted psychotherapy. However, many mechanistic questions remain about how molecular interactions at receptors scale up to changes in neuronal activity, network dynamics and ultimately behaviour and clinical outcomes. Kwan and colleagues set out to synthesise current knowledge across chemical, molecular, cellular and network levels to provide an integrative perspective on the neural mechanisms of psychedelic action. The review focuses on chemistry and pharmacokinetics, serotonin receptor pharmacology and downstream signalling, effects on neuronal spiking and plasticity across brain regions, and human neuroimaging evidence that informs mechanistic theories. The authors emphasise basic neurobiology and aim to link these multiple levels to help guide future drug discovery and mechanistic research.

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References (51)

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Dong, C., Ly, C., Dunlap, L. E. et al. · Cell (2021)

In vivo production of psilocybin in E. coli

Adams, A. M., Kaplan, N. A., Wei, Z. et al. · Metabolic Engineering (2019)

Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action

Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)

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Preller, K. H., Herdener, M., Pokorny, T. et al. · Current Biology (2017)

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Show all 51 references
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Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behavior

Gonza ´lez-Maeso, J., Weisstaub, N. V., Zhou, M. et al. · Neuron (2007)

818 cited
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Shao, L-X,, Liao, C., Gregg, I. et al. · Neuron (2021)

Crystal Structure of an LSD-Bound Human Serotonin Receptor

Wacker, D., Wang, S., Mccorvy, J. D. et al. · Cell (2017)

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Rodriguiz, R. M., Nadkarni, V., Means, C. R. et al. · Scientific Reports (2021)

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Olson, J. A. · Neuroscience Insights (2018)

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De La, M., Revenga, F., Zhu, B. et al. · Cell Reports (2021)

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Psychedelics promote structural and functional neural plasticity

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Positron emission tomography and fluorodeoxyglucose studies of metabolic hyperfrontality and psychopathology in the psilocybin model of psychosis

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Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin

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Two dose investigation of the 5-HT-agonist psilocybin on relative and global cerebral blood flow

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Effective connectivity changes in LSD-induced altered states of consciousness in humans

Preller, K. H., Razi, A., Zeidman, P. et al. · PNAS (2019)

Whole-brain multimodal neuroimaging model using serotonin receptor maps explains non-linear functional effects of LSD

Deco, G., Cruzat, J., Cabral, J. et al. · Current Biology (2018)

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Burt, J. B., Preller, K. H., Demirtaş, M. et al. · eLife (2021)

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McCulloch, D. E-W., Madsen, M. K., Stenbæk, D. S. et al. · Journal of Psychopharmacology (2021)

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Barrett, F. S., Doss, M. K., Sepeda, N. D. et al. · Scientific Reports (2020)

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Stenbæk, D. S., Madsen, M. K., Ozenne, B. et al. · Journal of Psychopharmacology (2020)

REBUS and the Anarchic Brain: Toward a Unified Model of the Brain Action of Psychedelics

Carhart-Harris, R. L., Friston, K. J. · Pharmacological Reviews (2019)

Models of psychedelic drug action: modulation of cortical-subcortical circuits

Doss, M. K., Madden, M. B., Gaddis, A. et al. · Brain (2021)

Acute effects of lysergic acid diethylamide in healthy subjects

Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)

LSD alters eyes-closed functional connectivity within the early visual cortex in a retinotopic fashion

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Increased spontaneous MEG signal diversity for psychoactive doses of ketamine, LSD and psilocybin

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Psilocybin acutely alters the functional connectivity of the claustrum with brain networks that support perception, memory, and attention

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A review of the clinical effects of psychotomimetic agents

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MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

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