Ketamine as a potential cognitive enhancer in neurological disorders: evidence from preclinical and clinical studies
Jose E. Leon-Rojas, Guido Mascialino, Lizeth Vinueza Mera, Mario S. Hinojosa-Figueroa, Cristina F. Navas Arias, Cadena Barberis, Amanda Sacks-Zimmerman
Frontiers in Neurology March 30, 2026 DOI: 10.3389/fneur.2026.1786249 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Population | Animal models and one human study of neurological diseases and injuries |
| Intervention | Ketamine |
| Topics | Esketamine Ketamine |
| Citations | 2 |
| Key findings | In animal models, ketamine showed positive cognitive effects in 93.2% of rodent subjects, particularly in working memory and spatial learning, but the only human study reported short-term, dose-dependent cognitive worsening. Human evidence remains too limited to support clinical cognitive enhancement. |
Abstract
Subanesthetic ketamine shows rapid neuroplastic and antidepressant effects in psychiatric conditions, prompting interest in its potential relevance for cognitive dysfunction in neurological disorders. Cognitive deficits are widespread across traumatic brain injury, stroke, epilepsy, and neurodegenerative diseases, yet treatments remain primarily compensatory. Ketamine's actions on glutamatergic signaling, synaptogenesis, and neuroinflammation suggest possible cognitive implications, but its specific effects on cognition in neurological populations remain unclear. This systematic review evaluated evidence on the effects of ketamine on cognitive functioning in neurological diseases and injuries characterized by cognitive impairment. A systematic search of three databases through February 10, 2024, was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis 2020 guidelines, including animal or human studies administering ketamine or its derivatives with cognitive outcome measures. Twenty-two studies met inclusion criteria: twenty-one animal studies and one human study. In animal models of traumatic brain injury, epilepsy, cerebrovascular disease, Parkinson's disease, and infectious encephalopathy, a subject-level vote count in rodents indicated positive cognitive effects in 93.2% of subjects, particularly in working memory and spatial learning, while null effects appeared in 4.1% and negative effects in 2.7%. The only human study, conducted in patients with Huntington's disease, reported short-term, dose-dependent cognitive worsening after escalating intravenous ketamine. Overall, preclinical evidence indicates potential cognitive effects in animal models of neurological injury; however, human evidence remains extremely limited and does not currently support clinical cognitive enhancement. Further controlled clinical studies are needed to clarify safety, mechanisms, and translational relevance in neurological rehabilitation.
Comparable studies
Other systematic reviews and meta-analyses on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis Depressed patients with suicidal ideation at baseline | 2017 | Systematic review and individual participant data meta-analysis | n = 167 |
| Ketamine use: a review Ketamine users | 2011 | Systematic review | |
| Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression Participants with major depression in placebo-controlled, double-blind, randomized... | 2015 | Systematic review and meta-analysis | |
| Ketamine and postoperative pain – a quantitative systematic review of randomised trials Surgical patients from 25 countries | 2004 | Systematic review | n = 2,839 |
| Side-effects associated with ketamine use in depression: a systematic review. Patients with depression | 2018 | Systematic review |
Citations in the library
Cites 18
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- BDNF Release Is Required for the Behavioral Actions of Ketamine The International Journal of Neuropsychopharmacology October 31, 2014
- Ketamine: NMDA Receptors and Beyond Journal of Neuroscience November 2, 2016
- A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide. Psychopharmacology Bulletin March 4, 2024
- Ketamine Assisted Psychotherapy (KAP): Patient Demographics, Clinical Data and Outcomes in Three Large Practices Administering Ketamine with Psychotherapy Journal of Psychoactive Drugs March 15, 2019
and 13 more in the library