Pharmacokinetics and pharmacodynamics of orally administered S-ketamine in healthy participants.
Joost C Van Mechelen, Tobias A Wieles, Laura Borghans, Marije E. Otto, Maria J Juachon, Amy L Gillespie, Martijn S. van Noorden, Catherine J Harmer, Albert M Van Hemert, Joop van Gerven, Gabriël E. Jacobs
Journal of psychopharmacology (Oxford, England) June 25, 2026 DOI: 10.1177/02698811261456187 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, double-blind, placebo-controlled, double-dummy, four-way cross-over study Peer reviewed |
|---|---|
| Sample size | 16 |
| Population | Healthy participants |
| Intervention | S-ketamine |
| Dose | 0.20 mg/kg oral, 0.45 mg/kg oral, 0.40 mg/kg intravenous |
| Duration | Single dose, assessments up to 24 hours post-dose for safety and up to 6 hours for central nervous system effects |
| Measures | quantitative electroencephalography (qEEG) |
| Topics | Depression Esketamine Ketamine |
| Keywords | Pharmacodynamics Pharmacokinetics Rapidly acting antidepressants Safety |
| Key points | Oral S-ketamine has poor bioavailability and produces limited central nervous system effects compared to intravenous administration, with the lower oral dose lacking any effects. |
Abstract
Oral S-ketamine (S-KETPO) is being explored as an alternative to intravenous maintenance treatment (S-KETIV) in treatment-resistant depression (TRD). However, the first-pass effect with S-KETPO significantly alters S-ketamine's bioavailability and the systemic exposure of its active metabolites, raising potential safety and efficacy concerns. This study characterized the pharmacodynamic and safety profiles of S-KETPO related to its pharmacokinetics in healthy participants, compared head-to-head with an S-KETIV dose that had previously demonstrated antidepressant effects in TRD . In a randomized, double-blind, placebo-controlled, double-dummy, four-way cross-over study, 16 healthy participants received a single dose of S-KETPO 0.20 and 0.45 mg/kg, S-KETIV 0.40 mg/kg and placebo. Plasma concentrations of S-KET and its active metabolites norketamine (S-NOR) and S-hydroxynorketamine (S-HNK) were measured, safety assessments were conducted up to 24 hours post-dose, and central nervous system (CNS) effects were evaluated up to 6 hours post-dose. Absolute bioavailability of S-KETPO was poor (9-12%). Peak plasma concentrations for S-KETPO 0.20 mg/kg, 0.45 mg/kg and S-KETIV were 9.81, 22.7 and 146 ng/mL (S-KET); 62.0, 127 and 55.2 ng/mL (S-NOR); and 29.5, 62.1 and 32.2 ng/mL (S-HNK), respectively. S-KET and S-HNK:S-KET metabolite-to-parent compound ratios were 7.52, 6.98 and 0.42, and 3.78, 3.71 and 0.23, for KETPO 0.20 mg/kg, S-KETPO 0.45 mg/kg, and S-KETIV, respectively. S-KETIV produced sedative, psychomotor and psychotomimetic effects coinciding with reductions in quantitative electroencephalography (qEEG) alpha, beta and delta power, whereas S-KETPO 0.45 mg/kg demonstrated inconsistent effects on vigilance and arousal but clear albeit relatively smaller reductions in qEEG alpha, beta and delta power coinciding with limited psychotomimetic effects, and finally, KETPO 0.20 mg/kg lacked effects altogether. Safety was comparable across treatments. Oral administration of S-ketamine alters pharmacokinetic and pharmacodynamic profiles, resulting in poor bioavailability, increased pharmacologically active metabolite exposures, and limited CNS effects relative to intravenous administration. The current findings have implications for S-KETPO dose selection, which may impact safety and/or therapeutic outcomes in future TRD studies. The study was registered in the 'Overview of Medical Research in the Netherlands' (OMON) under NL-OMON55261.
Comparable studies
Other randomized controlled trials on esketamine for depression, most cited first.