The American journal of psychiatrySep 10, 2025

Ketamine's Benefits for Depression and Possible Brain Toxicity from Animal and Human Studies

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Jun 28, 2026

Abstract

Essence

This review suggests ketamine’s neurotoxicity risk depends strongly on dose and frequency, with harm signals concentrated in repeated high-dose exposure rather than standard esketamine trial regimens.

Evidence

This narrative review synthesized preclinical models, human esketamine clinical trials, and observational studies of frequent recreational ketamine users, finding consistent neuronal damage and cognitive deficits in repeated or high-dose animal exposure and cognitive impairment in users taking more than 1 g/day, versus largely stable cognition in adults receiving intranasal esketamine up to 84 mg weekly or every other week.

Caveat

As a review combining animal studies, clinical trials, and observational user data, it cannot define a precise neurotoxicity threshold or directly compare approved esketamine with higher-dose off-label racemic ketamine.

Simplified

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.