Comparative EEG analysis of the effects of ketamine enantiomers and metabolites in rhesus macaques.
Yoshihiro Iwamura, Kantaro Nishigori, Masataka Yamaguchi, Yuji Ogi, Atsushi Kobayashi, Tsuyoshi Iwasaki, Hidetaka Nagata, Kazuhito Ikeda
Journal of Neurophysiology April 1, 2026 DOI: 10.1152/jn.00203.2025 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort Peer reviewed |
|---|---|
| Population | Rhesus macaques |
| Interventions | (R)-ketamine (S)-ketamine (R S)-ketamine ketamine metabolites MK-801 |
| Topics | Ketamine Esketamine |
| Keywords | Electroencephalography Ketamine enantiomers Ketamine metabolites Rhesus monkey |
| Key findings | (R)-ketamine produced a comparable increase in gamma power to (S)-ketamine but had weaker effects on EEG features thought to be associated with adverse effects. |
Abstract
(R,S)-Ketamine, a dissociative anesthetic, has shown rapid and sustained antidepressant effects at lower doses than those required for anesthetic effects in patients with treatment-resistant depression. However, its use is limited because it causes side effects, including psychotomimetic symptoms and dependence. The enantiomer (R)-ketamine was reported to promote antidepressant-like effects in rodents with a potentially lower risk for adverse effects compared with (S)-ketamine. This study compared the effects of (R)-ketamine, (S)-ketamine, their metabolites, and another N-methyl-d-aspartate antagonist, MK-801, on the electroencephalograms (EEGs) of rhesus macaques across a wide range of doses. The results showed that the dose level of (R,S)-ketamine, corresponding to the clinically effective antidepressant concentration in humans, produced an increase in gamma power as reported in clinical trials. Compared with (S)-ketamine, (R)-ketamine produced a comparable increase in gamma power but had weaker effects on EEG features thought to be associated with adverse effects. The EEG changes induced by the ketamine metabolites were relatively mild, indicating a minimal contribution to the EEG effects of ketamine. This comprehensive EEG evaluation in a nonhuman primate, together with measurements of plasma drug concentrations, when interpreted in comparison with existing clinical data, provide increased translational insight into the dose-dependent neurophysiological characteristics of (R,S)-ketamine, its enantiomers, and metabolites. EEG-based comparisons of (R)-ketamine with (R,S)-ketamine and (S)-ketamine suggest that (R)-ketamine exhibits neurophysiological features consistent with a potentially broader therapeutic range for antidepressant effects.NEW & NOTEWORTHY (R,S)-Ketamine, used to treat depression, induces side effects. This study investigated the effects of (R,S)-ketamine, its enantiomers, and metabolites on EEG metrics which may be related to the antidepressant effects and side effects of (R,S)-ketamine. Findings suggest that (R)-ketamine may have a lower risk of adverse effects and a broader effective dose range compared with (R,S)-ketamine.
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |
Citations in the library
Cites 34
- A Randomized Trial of an N-methyl-D-aspartate Antagonist in Treatment-Resistant Major Depression Archives of General Psychiatry August 1, 2006
- mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Science August 19, 2010
- NMDAR inhibition-independent antidepressant actions of ketamine metabolites Nature April 24, 2016
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- The effect of a single dose of intravenous ketamine on suicidal ideation: a systematic review and individual participant data meta-analysis American Journal of Psychiatry October 3, 2017
and 29 more in the library