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 Borghans, Johan G C Van Hasselt, Linda B S Aulin
British Journal of Clinical Pharmacology July 1, 2026 DOI: 10.1002/bcp.70503 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized, placebo-controlled, crossover clinical trial Peer reviewed |
|---|---|
| Sample size | 17 |
| Population | Healthy participants |
| Intervention | (S)-ketamine |
| Dose | 0.20 and 0.45 mg/kg orally; 0.4 mg/kg intravenously over 40 min |
| Topics | Ketamine Esketamine |
| Keywords | Pkpd model Norketamine Pharmacodynamics Pharmacokinetics Subjective effects |
| Key findings | (S)-norketamine, not (S)-ketamine, appears to be 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.
Comparable studies
Other randomized controlled trials on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Subanesthetic Effects of the Noncompetitive NMDA Antagonist, Ketamine, in Humans Healthy human subjects recruited from the community | 1994 | Randomized controlled trial | n = 19 |
| Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode | 2013 | Randomized controlled trial | n = 73 |
| Remifentanil-induced Postoperative Hyperalgesia and Its Prevention with Small-dose Ketamine Patients undergoing major abdominal surgery | 2005 | Randomized controlled trial | n = 75 |
| Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder Patients with chronic PTSD related to a range of trauma exposures | 2014 | Randomized controlled trial | n = 41 |
| Ketamine-Induced Deficits in Auditory and Visual Context-Dependent Processing in Healthy Volunteers Healthy volunteers | 2000 | Single-blind placebo-controlled study | n = 20 |