Ketamine for Depression, but at What Cost? A Review of Ketamine’s Neurotoxic Effects From Preclinical and Human Studies
Songze Li, Kristina T. Kumpf, Julian Urrutia, John H. Krystal, Gerard Sanacora, Samuel T. Wilkinson
American Journal of Psychiatry September 10, 2025 DOI: 10.1176/appi.ajp.20250276 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Longitudinal Peer reviewed |
|---|---|
| Topics | Ketamine Depression Esketamine |
| Keywords | Cognition Observational study Clinical trial Animal studies Human studies Clinical significance Nmda receptor Anesthesia Pharmacology Neurology Neuropsychology Adverse effect |
| Citations | 13 |
| Key findings | Ketamine's neurotoxic potential depends on dose and frequency: high or repeated subanesthetic doses cause cognitive deficits in animals and human recreational users, while clinical esketamine doses are associated with maintained or slightly improved cognition. |
Abstract
This review examines ketamine's neurotoxic potential across preclinical and clinical studies. The authors synthesized data from preclinical models, then integrated findings from human clinical trials of esketamine and observational studies in recreational users. Animal studies have found that repeated or high-dose subanesthetic ketamine administration results in consistent excitotoxic neuronal damage and lasting cognitive deficits, especially in perinatal animals. Infrequently administered relatively low and moderate subanesthetic doses (<1 mg/kg approximate human intravenous equivalent) do not yield overt histopathology in rat and nonhuman primate models. In humans, observational studies in frequent high-dose (>1 g/day) ketamine users show memory and executive function impairments. In contrast, a large clinical trial found that intranasal esketamine at doses up to 84 mg, administered weekly or every other week for several years, is associated with maintained or slightly improved cognitive function in adults with major depression. Lower cognitive function (attention, processing speed) showed some potential worsening among elderly patients; the clinical significance of this is unknown. Direct comparisons of esketamine and off-label racemic ketamine at higher doses have not been done. These studies underscore the potential for neurotoxic effects when ketamine is used at doses or frequencies beyond those utilized in clinical trials, highlighting a critical need for robust longitudinal research. Clinicians are advised to exercise caution, particularly when prescribing ketamine off-label at doses significantly higher than those used in clinical trials. When deviating from this in clinical practice, strong consideration should be given to conducting repeated cognitive assessments. Funding agencies should incentivize preclinical researchers to conduct studies that further elucidate the threshold of ketamine's neurotoxicity.
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 11
- Interdisciplinary, Delphi-driven consensus guidelines on the use of intravenous ketamine infusions for depressive disorders from the American Society of Ketamine Physicians, Psychotherapists, and Practitioners (ASKP3). Journal of Affective Disorders May 16, 2026
- Non-inferiority, comparative effectiveness study of intravenous ketamine v. intranasal esketamine for treatment-resistant depression: The EQUIVALENCE trial protocol. Contemporary Clinical Trials March 2, 2026
- Treating addiction with an addictive drug: the ketamine paradox revisited Frontiers in Psychiatry July 9, 2026
- Combined Ketamine and Cognitive-Behavioral Therapy: Leveraging Metaplasticity to Enhance Treatment Outcomes FOCUS: The Journal of Lifelong Learning in Psychiatry July 1, 2026
- Evaluating the abuse liability of ketamine in the treatment of mood disorders: A systematic review. Journal of Psychopharmacology June 24, 2026
and 6 more in the library
Cites 32
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Ketamine Pharmacology: An Update (Pharmacodynamics and Molecular Aspects, Recent Findings) CNS Neuroscience & Therapeutics April 10, 2013
- Ketamine use: a review Addiction July 21, 2011
and 27 more in the library