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Open Access

Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms

Antonio Inserra, Danilo De Gregorio and Gabriella Gobbi
Michael Nader, ASSOCIATE EDITOR
Pharmacological Reviews January 2021, 73 (1) 202-277; DOI: https://doi.org/10.1124/pharmrev.120.000056
Antonio Inserra
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
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Danilo De Gregorio
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
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Gabriella Gobbi
Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University, Montreal, Quebec, Canada
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Michael Nader
Roles: ASSOCIATE EDITOR
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Abstract

Mounting evidence suggests safety and efficacy of psychedelic compounds as potential novel therapeutics in psychiatry. Ketamine has been approved by the Food and Drug Administration in a new class of antidepressants, and 3,4-methylenedioxymethamphetamine (MDMA) is undergoing phase III clinical trials for post-traumatic stress disorder. Psilocybin and lysergic acid diethylamide (LSD) are being investigated in several phase II and phase I clinical trials. Hence, the concept of psychedelics as therapeutics may be incorporated into modern society. Here, we discuss the main known neurobiological therapeutic mechanisms of psychedelics, which are thought to be mediated by the effects of these compounds on the serotonergic (via 5-HT2A and 5-HT1A receptors) and glutamatergic [via N-methyl-d-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors] systems. We focus on 1) neuroplasticity mediated by the modulation of mammalian target of rapamycin–, brain-derived neurotrophic factor–, and early growth response–related pathways; 2) immunomodulation via effects on the hypothalamic-pituitary-adrenal axis, nuclear factor ĸB, and cytokines such as tumor necrosis factor-α and interleukin 1, 6, and 10 production and release; and 3) modulation of serotonergic, dopaminergic, glutamatergic, GABAergic, and norepinephrinergic receptors, transporters, and turnover systems. We discuss arising concerns and ways to assess potential neurobiological changes, dependence, and immunosuppression. Although larger cohorts are required to corroborate preliminary findings, the results obtained so far are promising and represent a critical opportunity for improvement of pharmacotherapies in psychiatry, an area that has seen limited therapeutic advancement in the last 20 years. Studies are underway that are trying to decouple the psychedelic effects from the therapeutic effects of these compounds.

Significance Statement Psychedelic compounds are emerging as potential novel therapeutics in psychiatry. However, understanding of molecular mechanisms mediating improvement remains limited. This paper reviews the available evidence concerning the effects of psychedelic compounds on pathways that modulate neuroplasticity, immunity, and neurotransmitter systems. This work aims to be a reference for psychiatrists who may soon be faced with the possibility of prescribing psychedelic compounds as medications, helping them assess which compound(s) and regimen could be most useful for decreasing specific psychiatric symptoms.

Footnotes

  • This work was supported by the Canadian Institute for Health Research (CIHR) [Grant # 436986] and by the Réseau Québécois sur le Suicide, les Troubles de l’Humeur et les Troubles Associés (RQSHA) [Grant # 268065]. D.D.G. is recipient of Fond Recherche Québec-Santé (FRQS) and Canadian Institutes for Health Research (CIHR) postdoctoral fellowships.

  • G.G. is a consultant for Diamond Therapeutic Inc. The other authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

  • https://doi.org/10.1124/pharmrev.120.000056.

  • ↵Embedded ImageThis article has supplemental material available at pharmrev.aspetjournals.org.

  • Copyright © 2020 by The Author(s)

This is an open access article distributed under the CC BY-NC Attribution 4.0 International license.

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Pharmacological Reviews: 73 (1)
Pharmacological Reviews
Vol. 73, Issue 1
1 Jan 2021
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Review ArticleReview Article

Psychedelics in Psychiatry: Therapeutic Mechanisms

Antonio Inserra, Danilo De Gregorio and Gabriella Gobbi
Pharmacological Reviews January 1, 2021, 73 (1) 202-277; DOI: https://doi.org/10.1124/pharmrev.120.000056

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Review ArticleReview Article

Psychedelics in Psychiatry: Therapeutic Mechanisms

Antonio Inserra, Danilo De Gregorio and Gabriella Gobbi
Pharmacological Reviews January 1, 2021, 73 (1) 202-277; DOI: https://doi.org/10.1124/pharmrev.120.000056
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  • Article
    • Abstract
    • I. Introduction
    • II. Psychedelic Compounds as Neuroplastic Agents
    • III. Psychedelic Compounds as Immunomodulatory and Anti-Inflammatory Agents
    • IV. Psychedelic Compounds as Modulators of Neurotransmitter Systems
    • V. Biased Signaling, Biased Phosphoproteomics, and Psychedelic Compounds
    • VI. Going Beyond Receptors: Neuronal Circuits Activated by Psychedelic Drugs
    • VII. Effects of Psychedelics on Sleep
    • VIII. Long-Term Neurobiological and Psychological Effects of Psychedelic Compounds
    • IX. Side Effects of Psychedelic Compounds
    • X. Recommendations for Future Research
    • XI. Conclusion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
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