Differential effects of ketamine enantiomers on EEG parameters including the gamma-delta shift phenomenon.
Szabolcs Koncz, Dóra Pothorszki, Noémi Papp, Donát Pál, György Bagdy
British journal of pharmacology June 1, 2026 Peer reviewed DOI: 10.1111/bph.70399 via PubMed
Summary
(S)-ketamine shows significantly stronger effects than (R)-ketamine in enhancing wakefulness and reducing non-rapid eye movement (NREM) sleep in Wistar rats. Specifically, the wake-inducing and NREM sleep-reducing effects of (S)-ketamine were fourfold stronger, and its gamma power increase during wakefulness was twice that of (R)-ketamine. Furthermore, only (S)-ketamine enhanced delta power during NREM sleep and induced the gamma-delta shift phenomenon, suggesting this shift is specific to (S)-ketamine.
Study at a glance
| Population | Wistar rats |
|---|---|
| Key finding | (S)-ketamine has fourfold stronger wake-inducing effects and twice the gamma power increase compared to (R)-ketamine. |
Abstract
Ketamine consists of two enantiomers, (R)-ketamine and (S)-ketamine, which exhibit distinct pharmacological properties. Currently, only the (S)-enantiomer has been approved for the treatment of major depressive disorder, whereas recent clinical studies have failed to demonstrate an antidepressant effect for (R)-ketamine. The quantitative electroencephalography (qEEG) gamma-enhancing effect of racemic ketamine has been reported before; moreover, a previous study has described a phenomenon that shows a temporal shift between the elevation of qEEG gamma and qEEG delta power, which we named as gamma-delta shift. It has been proposed as a marker of the antidepressant activity of racemic ketamine. To determine which enantiomer is responsible for these effects and in which sleep-wake states these changes occur, we compared the effects of the two enantiomers together with the separation of the different sleep-wake stages and examining dose dependency across a broad frequency spectrum. In Wistar rats, frontoparietal EEG and muscle activity were recorded following intraperitoneal administration of (S)-ketamine (7.5, 15 and 30 mg kg-1) or (R)-ketamine (7.5, 15, 30 and 60 mg kg-1) or vehicle at the beginning of the passive phase. Wake-inducing and NREM sleep-reducing effects of (S)-ketamine were fourfold stronger compared to (R)-ketamine. The gamma power increase induced by (S)-ketamine during wakefulness was twice as strong as that of (R)-ketamine. Additionally, once gamma activity normalized, only (S)-ketamine enhanced delta power during non-rapid eye movement (NREM) sleep and induced the gamma-delta shift. These findings indicate that the gamma-delta shift phenomenon is specific to (S)-ketamine.