Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics
Lily R. Aleksandrova, Anthony G. Phillips
TIPS - Trends in Pharmacological Sciences September 24, 2021 DOI: 10.1016/j.tips.2021.08.003 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Interventions | Ketamine Psilocybin Lysergic acid diethylamide (LSD) N N-dimethyltryptamine (DMT) |
| Topics | Ketamine Neuroplasticity Esketamine |
| Keywords | Mechanism biology Cognitive science Psychotherapist Cognitive psychology Epistemology |
| Citations | 255 |
| Key findings | Ketamine and classical psychedelics induce neuroplasticity through glutamate and serotonin receptor targets, leading to synaptic and structural changes that may underlie their fast-acting antidepressant effects. |
Abstract
The emerging therapeutic efficacy of ketamine and classical psychedelics for depression has inspired tremendous interest in the underlying neurobiological mechanisms. We review preclinical and clinical evidence supporting neuroplasticity as a convergent downstream mechanism of action for these novel fast-acting antidepressants. Through their primary glutamate or serotonin receptor targets, ketamine and psychedelics [psilocybin, lysergic acid diethylamide (LSD), and N,N-dimethyltryptamine (DMT)] induce synaptic, structural, and functional changes, particularly in pyramidal neurons in the prefrontal cortex. These include increased glutamate release, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) activation, brain-derived neurotrophic factor (BDNF) and mammalian target of rapamycin (mTOR)-mediated signaling, expression of synaptic proteins, and synaptogenesis. Such influences may facilitate adaptive rewiring of pathological neurocircuitry, thus providing a neuroplasticity-focused framework to explain the robust and sustained therapeutic effects of these compounds.
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 | |
| Psychedelics in Psychiatry: Neuroplastic, Immunomodulatory, and Neurotransmitter Mechanisms | 2020 | Review | |
| Biochemical Mechanisms Underlying Psychedelic-Induced Neuroplasticity. | 2022 | Review |
Citations in the library
Cited by 186
- Percentage of Heavy Drinking Days Following Psilocybin-Assisted Psychotherapy vs Placebo in the Treatment of Adult Patients With Alcohol Use Disorder JAMA Psychiatry August 24, 2022
- Towards an understanding of psychedelic-induced neuroplasticity. Neuropsychopharmacology 2023
- The neural basis of psychedelic action. Nature Neuroscience October 24, 2022
- Default Mode Network Modulation by Psychedelics: A Systematic Review The International Journal of Neuropsychopharmacology October 21, 2022
- Pharmacological, neural, and psychological mechanisms underlying psychedelics: a critical review Neuroscience & Biobehavioral Reviews September 1, 2022
and 181 more in the library
Cites 65
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- 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
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. The Lancet Psychiatry May 17, 2016
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
and 60 more in the library