Neuroplasticity as a convergent mechanism of ketamine and classical psychedelics
Lily R. Aleksandrova, Anthony G. Phillips
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.