RCT · 2026
Why oral (S)-ketamine feels different: a metabolite may drive the subjective effects
- Original title
- Pharmacokinetics and pharmacodynamics of intravenous and oral (S)-ketamine: Investigating metabolite contribution to subjective effects.
- Authors
- Otto ME, Jacobs GE, van Mechelen JC, et al.
- Journal
- British journal of clinical pharmacology, 2026
- Molecules
- Esketamine
- Conditions
- Healthy volunteers
- Participants
- 17
- Evidence grade
- Very low
- Source
- Read the original paper
The question
When (S)-ketamine is swallowed rather than injected, is the drug itself or one of the substances the body turns it into responsible for the altered mental state people feel?
What they did
The researchers reused data from an earlier randomized, placebo-controlled crossover trial in which 17 healthy volunteers received (S)-ketamine by mouth (0.20 and 0.45 mg/kg) and into a vein (0.4 mg/kg over 40 minutes). Blood levels of (S)-ketamine and its breakdown products, (S)-norketamine and (S)-hydroxynorketamine, were measured. They built computer models linking those blood levels to how ‘high’ participants said they felt on a simple rating scale.
What they found
Swallowed (S)-ketamine is heavily broken down by the liver before reaching the bloodstream, so blood levels of the parent drug are low while levels of its breakdown products are high. The models found a statistically significant link between (S)-norketamine levels and the ‘Feeling High’ ratings, in addition to (S)-ketamine itself. The authors concluded that after oral dosing the metabolite, rather than (S)-ketamine, appears to be the main driver of subjective effects. They also noted the model’s estimated variability was high, so the finding needs further testing.
The fine print
This was a re-analysis of an existing small trial with just 17 healthy volunteers, not people with depression, and no antidepressant outcomes were measured. The main outcome was a subjective ‘feeling high’ rating, which is a stand-in measure and not a clinical benefit. The authors themselves flag high uncertainty in the model. This summary is based on the abstract only.
What it means
In healthy volunteers, the mind-altering effects of swallowed (S)-ketamine seem to be driven largely by a breakdown product rather than the drug itself, which may matter for how oral versions are studied in depression, but this remains an early, uncertain modelling result.
Evidence grade: Very low. A modelling analysis of data from a small randomized crossover trial in only 17 healthy volunteers, with high estimated variability in the model.
This summary is based on the study’s published abstract.