Ketamine use disorder: preclinical, clinical, and neuroimaging evidence to support proposed mechanisms of actions
Leah Vines, Diana Sotelo, Allison Johnson, Evan Dennis, Peter Manza, Nora D. Volkow, Gene‐Jack Wang
Intelligent Medicine March 7, 2022 DOI: 10.1016/j.imed.2022.03.001 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Depression Ketamine Serotonin Esketamine |
| Keywords | Disinhibition Mechanism biology Monoaminergic Nmda receptor Antidepressant Ampa receptor Functional neuroimaging Hippocampus Amygdala |
| Citations | 21 |
| Key findings | Argues that ketamine's antidepressant mechanisms involve combined NMDA receptor inhibition/disinhibition, AMPA receptor activation, and monoaminergic enhancement, and that long-term misuse causes brain impairments, with machine learning potentially identifying KUD biotypes. |
Abstract
Ketamine, a noncompetitive NMDA receptor antagonist, has been exclusively used as an anesthetic in medicine and has led to new insights into the pathophysiology of neuropsychiatric disorders. Clinical studies have shown that low subanesthetic doses of ketamine produce antidepressant effects for individuals with depression. However, its use as a treatment for psychiatric disorders has been limited due to its reinforcing effects and high potential for diversion and misuse. Preclinical studies have focused on understanding the molecular mechanisms underlying ketamine's antidepressant effects, but a precise mechanism had yet to be elucidated. Here we review different hypotheses for ketamine's mechanism of action including the direct inhibition and disinhibition of NMDA receptors, AMPAR activation, and heightened activation of monoaminergic systems. The proposed mechanisms are not mutually exclusive, and their combined influence may exert the observed structural and functional neural impairments. Long term use of ketamine induces brain structural, functional impairments, and neurodevelopmental effects in both rodents and humans. Its misuse has increased rapidly in the past 20 years and is one of the most common addictive drugs used in Asia. The proposed mechanisms of action and supporting neuroimaging data allow for the development of tools to identify 'biotypes' of ketamine use disorder (KUD) using machine learning approaches, which could inform intervention and treatment.
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 9
- At-home, telehealth-supported ketamine treatment for depression: Findings from longitudinal, machine learning and symptom network analysis of real-world data. Journal of Affective Disorders September 15, 2024
- [Psychedelic and dissociative agents in psychiatry: challenges in the treatment]. Der Nervenarzt September 1, 2024
- Neurobiological Mechanisms of Ketamine Use, its Addiction, and Withdrawal: A Mini Review. Current reviews in clinical and experimental pharmacology March 3, 2025
- The Dark Side of Ketamine: Brain, Bladder, and Beyond: a Focused Clinical Review for Emergency Medicine Clinicians Anatolian Journal of Emergency Medicine June 28, 2026
- Beyond the High: A Narrative Review of the Chronic Complications of Recreational Ketamine Use. British journal of hospital medicine (London, England : 2005) May 18, 2026
and 4 more in the library
Cites 29
- 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
- The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate British Journal of Pharmacology June 1, 1983
- Glutamate and the Neural Basis of the Subjective Effects of Ketamine Archives of General Psychiatry February 1, 2008
- Reviewing the ketamine model for schizophrenia Journal of Psychopharmacology November 20, 2013
and 24 more in the library