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Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review

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Abstract

Purpose of Review

Serotonergic psychedelics include psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and other agonists of the 5-HT2A receptor. While the efficacy and safety of psychedelics for depression have shown promising initial results in clinical trials, there is much to understand regarding how these effects occur. This narrative review provides an updated evaluation on the hypothesized neurobiology underlying the antidepressant effects of serotonergic psychedelics.

Recent Findings

Animal models indicate that the involvement of Gqɑ protein signaling pathway of 5-HT2A receptors rather than β-arrestin-2 is required to produce psychedelic effects. However, it is unclear if this pathway is necessary or sufficient for antidepressant effects. Antidepressant effects were observed in animal models despite the absence of hallucinogenic-like effects (e.g., head twitch). Proposed mechanisms of the antidepressant effects of serotonergic psychedelics include post-treatment changes in the default mode network (DMN) and increased neuroplasticity in the hippocampus and prefrontal cortex. Additionally, improved cognitive flexibility was observed after psychedelic administration which may facilitate the efficacy of psychotherapy.

Summary

Increases in neuroplasticity and cognitive flexibility are likely key mechanisms facilitating antidepressant effects of serotonergic psychedelics. Future research should further explore mechanisms of action. The role of 5-HT2A receptor activation, the psychedelic experience, and accompanying psychotherapy in the overall antidepressant efficacy are key areas of interest in elucidating neurobiological mechanisms of psychedelic treatments.

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Authors and Affiliations

  1. Mood Disorders Psychopharmacology Unit, Poul Hansen Family Depression Centre, University Health Network, 399 Bathurst Street, Main Pavilion 7-423, Toronto, ON, M5T 2S8, Canada

    Noah Chisamore HBSc, Erica Kaczmarek HBSc, Gia Han Le HBSc, Sabrina Wong HBSc, Diana K. Orsini MPH, Rodrigo Mansur MD, Roger S. McIntyre MD & Joshua D. Rosenblat MDMSc

  2. Department of Pharmacology, University of Toronto, Toronto, ON, Canada

    Noah Chisamore HBSc, Erica Kaczmarek HBSc, Sabrina Wong HBSc, Diana K. Orsini MPH & Roger S. McIntyre MD

  3. Institute of Medical Science, University of Toronto, Toronto, ON, Canada

    Gia Han Le HBSc, Rodrigo Mansur MD, Roger S. McIntyre MD & Joshua D. Rosenblat MDMSc

  4. Department of Psychiatry, University of Toronto, Toronto, ON, Canada

    Rodrigo Mansur MD, Roger S. McIntyre MD & Joshua D. Rosenblat MDMSc

  5. Brain and Cognition Discovery Foundation, Toronto, ON, Canada

    Gia Han Le HBSc, Sabrina Wong HBSc & Roger S. McIntyre MD

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Contributions

All authors revised and approved the final manuscript. N.C. wrote the main manuscript, N.C., E.K., D.O., G.H.L. and S.W. contributed to editing the manuscript, N.C. and G.H.L. helped prepare the figure. Conceptualization and supervision of the manuscript was done by J.R.

Corresponding author

Correspondence to Joshua D. Rosenblat MDMSc.

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Competing interests

Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He was previously the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health). Dr. Rodrigo. B. Mansur has received research grant support from the Canadian Institute of Health Research; Physicians’ Incorporated Foundation; the Baszucki Brain Research Fund; and the Academic Scholar Awards, Department of Psychiatry, University of Toronto. Dr. Roger McIntyre has received research grant support from Global Alliance for Chronic Diseases/Canadian Institutes of Health Research (CIHR)/National Natural Science Foundation of China’s Mental Health Team Grant; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp. N.C, E.K., G.H.L., S.W., and D.O. do not have any potential competing interests to disclose.

Conflict of Interest

Dr. Joshua D Rosenblat has received research grant support from the Canadian Institute of Health Research (CIHR), Physician Services Inc (PSI) Foundation, Labatt Brain Health Network, Brain and Cognition Discovery Foundation (BCDF), Canadian Cancer Society, Canadian Psychiatric Association, Academic Scholars Award, American Psychiatric Association, American Society of Psychopharmacology, University of Toronto, University Health Network Centre for Mental Health, Joseph M. West Family Memorial Fund and Timeposters Fellowship and industry funding for speaker/consultation/research fees from iGan, Boehringer Ingelheim, Janssen, Allergan, Lundbeck, Sunovion and COMPASS. He was previously the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health).

Dr. Rodrigo. B. Mansur has received research grant support from the Canadian Institute of Health Research; Physicians’ Incorporated Foundation; the Baszucki Brain Research Fund; and the Academic Scholar Awards, Department of Psychiatry, University of Toronto.

Dr. Roger McIntyre has received research grant support from Global Alliance for Chronic Diseases/Canadian Institutes of Health Research (CIHR)/National Natural Science Foundation of China’s Mental Health Team Grant; speaker/consultation fees from Lundbeck, Janssen, Purdue, Pfizer, Otsuka, Takeda, Neurocrine, Sunovion, Bausch Health, Novo Nordisk, Kris, Sanofi, Eisai, Intra-Cellular, NewBridge Pharmaceuticals, Abbvie. Dr. Roger McIntyre is a CEO of Braxia Scientific Corp.

N.C, E.K., G.H.L., S.W., and D.O. do not have any potential competing interests to disclose.

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Chisamore, N., Kaczmarek, E., Le, G.H. et al. Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review. Curr Treat Options Psych (2024). https://doi.org/10.1007/s40501-024-00319-8

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