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Review
. 2023 Feb 10:13:1076459.
doi: 10.3389/fpsyt.2022.1076459. eCollection 2022.

Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action?

Muhammad Ishrat Husain  1   2 , Nicole Ledwos  3 , Elise Fellows  3 , Jenna Baer  3 , Joshua D Rosenblat  2   4 , Daniel M Blumberger  1   2 , Benoit H Mulsant  1   2 , David J Castle  2   3
Affiliations
Review

Serotonergic psychedelics for depression: What do we know about neurobiological mechanisms of action?

Muhammad Ishrat Husain et al. Front Psychiatry. .

Abstract

Introduction: Current treatment options for major depressive disorder (MDD) have limited efficacy and are associated with adverse effects. Recent studies investigating the antidepressant effect of serotonergic psychedelics-also known as classic psychedelics-have promising preliminary results with large effect sizes. In this context, we conducted a review of the putative neurobiological underpinnings of the mechanism of antidepressant action of these drugs.

Methods: A narrative review was conducted using PubMed to identify published articles evaluating the antidepressant mechanism of action of serotonergic psychedelics.

Results: Serotonergic psychedelics have serotonin (5HT)2A agonist or partial agonist effects. Their rapid antidepressant effects may be mediated-in part-by their potent 5HT2A agonism, leading to rapid receptor downregulation. In addition, these psychedelics impact brain derived neurotrophic factor and immunomodulatory responses, both of which may play a role in their antidepressant effect. Several neuroimaging and neurophysiology studies evaluating mechanistic change from a network perspective can help us to further understand their mechanism of action. Some, but not all, data suggest that psychedelics may exert their effects, in part, by disrupting the activity of the default mode network, which is involved in both introspection and self-referential thinking and is over-active in MDD.

Conclusion: The mechanisms of action underlying the antidepressant effect of serotonergic psychedelics remains an active area of research. Several competing theories are being evaluated and more research is needed to determine which ones are supported by the most robust evidence.

Keywords: LSD; ayahuasca; connectivity; depression; hallucinogen; neurobiology; psilocybin; psychedelics.

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Conflict of interest statement

MIH received research support from the Brain and Behavior Research Foundation, Canadian Institutes of Health Research (CIHR), CAMH Foundation, Grand Challenges Canada, the PSI Foundation, and the University of Toronto and provided consultancy to Mindset Pharma, PsychEd Therapeutics, and Wake Network. JR 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 is the Chief Medical and Scientific Officer of Braxia Scientific and the medical director of the Canadian Rapid Treatment Centre of Excellence (Braxia Health). BM hold and received support from the Labatt Family Chair in Biology of Depression in Late-Life Adults at the University of Toronto and currently receives or has received with the past 5 years research support from Brain Canada, the Canadian Institutes of Health Research, the CAMH Foundation, the Patient-Centered Outcomes Research Institute (PCORI), the US National Institute of Health (NIH), Capital Solution Design LLC (software used in a study founded by CAMH Foundation), and HAPPYneuron (software used in a study founded by Brain Canada); has also been an unpaid consultant to Myriad Neuroscience. DC (past 36 months: September 2022) received grant monies for research from Servier, Boehringer Ingelheim; Travel Support and Honoraria for Talks and Consultancy from Servier, Seqirus, and Lundbeck. He is a founder of the Optimal Health Program (OHP), and holds 50% of the IP for OHP; and is part owner (5%) of Clarity Healthcare. He is an Advisory Board Chair of an Australian not-for-profit institute specializing in psychedelic medicines research. He does not knowingly have stocks or shares in any pharmaceutical company. DB received research support from the Canadian Institutes of Health Research (CIHR), National Institutes of Health—US (NIH), Brain Canada Foundation and the Temerty Family through the CAMH Foundation, and the Campbell Family Research Institute. He received research support and in-kind equipment support for an investigator-initiated study from Brainsway Ltd. and he was the site principal investigator for three sponsor-initiated studies for Brainsway Ltd. He received in-kind equipment support from Magventure for investigator-initiated studies. He received medication supplies for an investigator-initiated trial from Indivior. He participated in an advisory board for Janssen. He participated in an advisory board for Welcony Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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