The effect of ketamine on mitochondrial bioenergetics, viability, and function: A systematic review

Extant literature indicates mitochondrial dysfunction may contribute to the pathophysiology of depressive disorders. Preclinical data indicate that anesthetic doses of ketamine are associated with deficits in mitochondrial viability and function. Ketamine and esketamine have demonstrated rapid antidepressant effects in persons with difficult-to-treat depressive disorders. Herein, we aim to synthesize literature reporting on the effect of antidepressant doses of ketamine and esketamine in vivo versus in vitro on mitochondrial viability and function.

We performed a systematic review of previous studies on PubMed, Ovid, and Scopus databases from inception to November 30, 2025. Preclinical studies reporting on the effect of antidepressant doses of ketamine and/or esketamine in mitochondrial viability, structure/morphology, bioenergetics, and metabolic function were sought for inclusion.

Thirteen studies were included. Lower ketamine/esketamine concentrations generally did not adversely affect membrane potential, oxidative phosphorylation, respiration, or bioenergetics, whereas higher concentrations or prolonged exposure induced mitochondrial dysfunction in some models. Additional evaluation of the safety of ketamine/esketamine on mitochondria in humans is required.

Preliminary research suggests that ketamine at lower concentrations may not adversely affect brain mitochondrial viability or bioenergetic function, but requires further validation. The reported effects on mitochondrial viability and function are preclinical, model- and dose-dependent and derived from limited heterogeneous literature. This study generates the hypothesis that ketamine's antidepressant mechanism of action may be partially mediated by insulin-sensitive metabolic pathways, energetically supporting synaptic remodeling and neurogenesis. Incorporation of mitochondrial and metabolic biomarkers into ketamine clinical trials is a current research imperative.