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.

Funding

Competing interests

Dr. Krystal has received payments related the VA’s and Yale University’s share of patents for antidepressant and antisuicide effects of ketamine that were licensed to Janssen Pharmaceuticals; he has stock or stock options in Biohaven Pharmaceuticals, Cartego Therapeutics, Damona Pharmaceuticals, EpiVario, Freedom Biosciences, Neumora Therapeutics, Response Pharmaceuticals, Rest Therapeutics, Spring Health, Tempero Bio, Terran Biosciences, and Tetricus; he has served as a consultant or adviser for AbbVie, Aptinyx, Biogen, Bionomics, Boehringer Ingelheim, Cerevel Pharmaceuticals, Eisei Pharmaceuticals, Epiodyne, Idec, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Johnson & Johnson, Neurocrine Biosciences, Novartis Pharmaceuticals, Psychogenics, Otsuka America Pharmaceuticals, and Takeda Pharmaceuticals; and he has conducted research with drugs supplied by Cerevel Pharmaceuticals and BioXcel Pharmaceuticals. Dr. Sanacora has served as a consultant for Actinogen Medical, Alto Neuroscience, Aptinyx, Atai, Axsome Therapeutics, Biogen, Biohaven Pharmaceuticals, Boehringer Ingelheim, Bristol Myers Squibb, Clexio, Daiichi Sankyo, Denovo Biopharma, EMA Wellness, Embark, Engrail Therapeutics, Freedom Biosciences, Gilgamesh, Holmusk, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Lundbeck, Merck, MiCure, Navitor Pharmaceuticals, Neurocrine, Novartis, Noven Pharmaceuticals, Otsuka, Perception Neuroscience, Praxis Therapeutics, Relmada Therapeutics, Sage Pharmaceuticals, Seelos Pharmaceuticals, Supernus, Taisho Pharmaceuticals, Tetricus, Transcend Therapeutics, the Usona Institute, Valeant, Vistagen Therapeutics, and XW Labs; he has received research contracts from Johnson & Johnson/Janssen, Merck, and the Usona Institute; he holds equity in Biohaven Pharmaceuticals, Freedom Biosciences, Gilead, Relmada, and Tetricus; he has a U.S. patent licensed to Biohaven and a U.S. provisional patent licensed to Freedom and is a co-inventor on U.S. patents held by Yale University; Yale University has a financial relationship with Janssen Pharmaceuticals and may receive financial benefits from this relationship. Dr. Wilkinson has received contract research funding (administered through Yale University) from Oui Therapeutics and has served as a consultant or provided data safety and monitoring board services for Joyous, LivaNova, Mind Medicine, Neumora, Sooma Medical, and Sage Therapeutics. The other authors report no financial relationships with commercial interests.

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