The effect of ketamine on mitochondrial bioenergetics, viability, and function: A systematic review.
Sabrina Wong, Gia Han Le, Simryn Selby, Stavroula Bargiota, Diana Orsini, Sara Di Luch, Shreya Vasudeva, Gabrielle F. M. Lovell, Joshua D. Rosenblat, Roger S McIntyre
Journal of Psychopharmacology September 7, 2026 DOI: 10.1177/02698811261481085 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review Peer reviewed |
|---|---|
| Population | Preclinical studies reporting on ketamine or esketamine effects on mitochondria |
| Interventions | Ketamine Esketamine |
| Topics | Esketamine Ketamine |
| Keywords | Bioenergetics Mitochondria |
| Key findings | In preclinical models, lower ketamine/esketamine concentrations generally did not adversely affect mitochondrial membrane potential, oxidative phosphorylation, respiration, or bioenergetics, while higher concentrations or prolonged exposure induced dysfunction in some models. The authors argue that ketamine's antidepressant mechanism may be partially mediated by insulin-sensitive metabolic pathways, but human validation is needed. |
Abstract
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.
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 19
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation American Journal of Psychiatry March 17, 2021
- GABA interneurons are the cellular trigger for ketamine's rapid antidepressant actions. Journal of Clinical Investigation November 19, 2019
- Ketamine and rapid antidepressant action: new treatments and novel synaptic signaling mechanisms Neuropsychopharmacology July 24, 2023
and 14 more in the library