Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms
Antonio Inserra, Danilo de Gregorio, Gabriella Gobbi
Pharmacological Reviews December 16, 2020 DOI: 10.1124/pharmrev.120.000056 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Neuroplasticity Serotonin |
| Keywords | Glutamatergic Dopaminergic Ampa receptor Pharmacology Hallucinogen Gabaergic Glutamate receptor |
| Citations | 227 |
| Key findings | Psychedelics' therapeutic mechanisms likely involve modulation of serotonergic and glutamatergic systems, neuroplasticity, immunomodulation, and neurotransmitter system regulation. |
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.
Comparable studies
Other narrative reviews on neuroplasticity, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A neurotrophic hypothesis of depression: role of synaptogenesis in the actions of NMDA receptor antagonists | 2012 | Review | |
| Towards an understanding of psychedelic-induced neuroplasticity. Review of preclinical and clinical studies | 2023 | Review | |
| Buddha's Brain: Neuroplasticity and Meditation [In the Spotlight] | 2008 | Review | |
| Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics | 2021 | Review | |
| Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity. | 2022 | Review |
Citations in the library
Cited by 186
- Psilocybin therapy increases cognitive and neural flexibility in patients with major depressive disorder. Translational Psychiatry November 8, 2021
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- Psychedelics and Neuroplasticity: A Systematic Review Unraveling the Biological Underpinnings of Psychedelics Frontiers in Psychiatry September 10, 2021
- Hallucinogens in Mental Health: Preclinical and Clinical Studies on LSD, Psilocybin, MDMA, and Ketamine Journal of Neuroscience November 30, 2020
- Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics TIPS - Trends in Pharmacological Sciences September 24, 2021
and 181 more in the library
Cites 469
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- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
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and 464 more in the library