Sustained pharmacodynamic effects of S-ketamine on cortical excitability and resting-state brain activity: A randomized, placebo-controlled trial.
Catherine M K E De Cuba, Annika A De Goede, Joost C Van Mechelen, Laura G J M Borghans, Liam Van der Aa, Erik Olofsen, Maria J Juachon, Robert J Doll, Amy Gillespie, Catherine J Harmer, Gabriël E Jacobs, Jules A A C Heuberger
British journal of clinical pharmacology June 24, 2026 Peer reviewed DOI: 10.1002/bcp.70649 via PubMed
Summary
S-ketamine administration in healthy participants resulted in both acute and delayed central nervous system effects. Specifically, intravenous S-ketamine led to an immediate decrease in motor-evoked potential amplitude and sustained changes in long-interval intracortical inhibition, with effects lasting up to 7 days. High-dose oral S-ketamine also produced delayed effects. Additionally, changes in brain wave activity were observed, indicating the complexity of S-ketamine's pharmacodynamic profile.
Study at a glance
| Design | randomized controlled trial |
|---|---|
| Sample size | 16 |
| Population | healthy participants |
| Key finding | S-ketamine induced both acute and delayed pharmacodynamic effects, with significant changes sustained for up to 7 days post-dose. |
Abstract
This study aimed to investigate a set of pharmacodynamic biomarkers reflecting acute, delayed and sustained central nervous system effects of S-ketamine, used as a tool compound for rapid-acting antidepressant activity, with the goal of informing biomarker strategies for delayed antidepressant effects. In this randomized, double-blind, double-dummy, placebo-controlled, 4-way crossover study in 16 healthy participants, we administered S-ketamine in a therapeutic intravenous dose (IV), a low and high oral dose, versus placebo. Measurements were conducted from baseline up to 7 days post-dose using Transcranial Magnetic Stimulation combined with electromyography (TMS-EMG) and encephalography (TMS-EEG), pharmaco-electroencephalography (pEEG), alongside drug and metabolite plasma concentrations. Outcomes were analysed using mixed-effects ANCOVA and cluster-based permutation testing. Post-hoc concentration-effect relationships were explored. IV S-ketamine induced an acute reduction in motor-evoked potential (MEP) amplitude and sustained attenuation of long-interval intracortical inhibition (LICI50), the latter showing a linear concentration-effect relationship with the parent compound. Acute TEP modulation was observed across all treatments, whereas delayed effects occurred only after IV and high-dose oral. pEEG showed acute reductions in alpha, beta and delta power (eyes closed) and sustained increases in delta power (eyes open) following IV and high-dose oral S-ketamine; with delta power exhibiting a less analyte-specific linear concentration-effect relationship. We provide evidence suggestive of delayed pharmacodynamic effects of S-ketamine in healthy participants sustained up to 7 days post-dose, using TMS and pEEG derived measures, which are markedly distinct from its acute effects and may be relevant to understand its antidepressant efficacy.