The Missing Piece? A Case for Microglia's Prominent Role in the Therapeutic Action of Anesthetics, Ketamine, and Psychedelics.
Jared VanderZwaag, Torin Halvorson, Kira Dolhan, Eva Šimončičová, Benneth Ben-Azu, Marie-Ève Tremblay
Neurochemical Research April 1, 2023 DOI: 10.1007/s11064-022-03772-0 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine Neuroplasticity Esketamine |
| Keywords | Anesthetics Microglia Psychedelics Mental health Psychopharmacology Brain inflammation |
| Citations | 25 |
| Key findings | Psychedelic, anesthetic, and dissociative agents likely exert therapeutic effects through modulation of microglial phagocytic activity and inflammatory mediator release via sigma-1 receptors, serotonergic and GABA signaling, and tryptophan metabolism. |
Abstract
There is much excitement surrounding recent research of promising, mechanistically novel psychotherapeutics - psychedelic, anesthetic, and dissociative agents - as they have demonstrated surprising efficacy in treating central nervous system (CNS) disorders, such as mood disorders and addiction. However, the mechanisms by which these drugs provide such profound psychological benefits are still to be fully elucidated. Microglia, the CNS's resident innate immune cells, are emerging as a cellular target for psychiatric disorders because of their critical role in regulating neuroplasticity and the inflammatory environment of the brain. The following paper is a review of recent literature surrounding these neuropharmacological therapies and their demonstrated or hypothesized interactions with microglia. Through investigating the mechanism of action of psychedelics, such as psilocybin and lysergic acid diethylamide, ketamine, and propofol, we demonstrate a largely under-investigated role for microglia in much of the emerging research surrounding these pharmacological agents. Among others, we detail sigma-1 receptors, serotonergic and γ-aminobutyric acid signalling, and tryptophan metabolism as pathways through which these agents modulate microglial phagocytic activity and inflammatory mediator release, inducing their therapeutic effects. The current review includes a discussion on future directions in the field of microglial pharmacology and covers bidirectional implications of microglia and these novel pharmacological agents in aging and age-related disease, glial cell heterogeneity, and state-of-the-art methodologies in microglial research.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cited by 15
- Alleviating anxiety and taming trauma: Novel pharmacotherapeutics for anxiety disorders and posttraumatic stress disorder Neuropharmacology January 6, 2023
- Stimulant and hallucinogenic novel psychoactive substances; an update Expert Review of Clinical Pharmacology November 2, 2023
- Psilocybin’s effects on cognition and creativity: A scoping review Journal of Psychopharmacology July 1, 2023
- Psychedelics in neuroinflammation: Mechanisms and therapeutic potential Progress in Neuro-Psychopharmacology and Biological Psychiatry January 31, 2025
- Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents Neuroscience & Biobehavioral Reviews September 20, 2024
and 10 more in the library
Cites 82
- Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Archives of General Psychiatry March 1, 1994
- 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
- Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Journal of Neuroscience April 15, 1997
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
and 77 more in the library