Pharmacokinetics and pharmacodynamics of intravenous and oral (S)-ketamine: Investigating metabolite contribution to subjective effects.
Marije E Otto, Gabriël E Jacobs, Joost C Van Mechelen, Laura G J M Borghans, Johan G C Van Hasselt, Linda B S Aulin
British journal of clinical pharmacology July 1, 2026 Peer reviewed DOI: 10.1002/bcp.70503 via PubMed
Summary
The study indicates that after oral administration of (S)-ketamine for treatment-resistant depression, its metabolite (S)-norketamine is the primary contributor to subjective effects, as measured by the visual analogue scale 'Feeling High'. The analysis utilized data from 17 healthy participants who received varying doses of (S)-ketamine both orally and intravenously. A significant pharmacokinetic/pharmacodynamic relationship was found between (S)-norketamine and subjective effects, although there was high variance in the model estimates.
Study at a glance
| Design | randomized controlled trial |
|---|---|
| Sample size | 17 |
| Population | healthy participants |
| Key finding | (S)-norketamine, rather than (S)-ketamine, is the main driver of subjective effects after oral administration. |
Abstract
Oral administration of (S)-ketamine for treatment-resistant depression (TRD), as alternative to the registered intranasal or off-label intravenous administrations, has high potential. However, it is characterized by an extensive first-pass metabolism, resulting in low (S)-ketamine exposure and high levels of active metabolites, including (S)-norketamine and (S)-hydroxynorketamine. The relative contribution of the parent and metabolites to the resulting antidepressant effects remains unclear. Therefore, this study aimed to first characterize the pharmacokinetics (PK) of (S)-ketamine and its metabolites after oral and intravenous administration in healthy participants and secondly quantify the pharmacokinetic/pharmacodynamic (PKPD) relationship of (S)-ketamine and (S)-norketamine to the subjective effects measured on the visual analogue scale (VAS) 'Feeling High'. Data from a previously conducted clinical study was used, where 17 healthy participants received oral (0.20 and 0.45 mg/kg) and intravenous (0.4 mg/kg over 40 min) (S)-ketamine in a randomized, placebo-controlled, crossover clinical trial. A semi-physiological population PK model was developed to describe the first-pass metabolism and (S)-ketamine and subsequently (S)-norketamine concentrations were linked to the VAS 'Feeling High' using a bounded integer modelling approach. A significant (S)-norketamine PKPD relationship was determined alongside (S)-ketamine, but estimated variance of the bounded integer model was high warranting further investigation. Our analysis suggests that not (S)-ketamine, but its metabolite, is the main driver of subjective effects after oral administration, and as such may also contribute to antidepressant effects in TRD patients receiving oral (S)-ketamine.