Ketamine for Depression, but at What Cost? A Review of Ketamine’s Neurotoxic Effects From Preclinical and Human Studies
American Journal of Psychiatry September 10, 2025 Songze Li, Kristina T. Kumpf, Julian Urrutia et al. 13 citations
Repeated or high-dose subanesthetic ketamine causes excitotoxic neuronal damage and lasting cognitive deficits in animals, especially perinates. Infrequent low-to-moderate doses (<1 mg/kg human intravenous equivalent) do not produce overt brain damage in rats and nonhuman primates. In humans, frequent high-dose (>1 g/day) recreational users show memory and executive function impairments. However, a large clinical trial found that intranasal esketamine at up to 84 mg weekly or every other week for several years is associated with maintained or slightly improved cognition in adults with major depression, though some elderly patients showed potential worsening in attention and processing speed. Direct comparisons of esketamine and off-label racemic ketamine at higher doses are lacking.