British journal of clinical pharmacology
July 1, 2026
Marije E Otto, Gabriël E Jacobs, Joost C Van Mechelen et al.
Oral (S)-ketamine for treatment-resistant depression undergoes extensive first-pass metabolism, yielding low parent drug but high levels of active metabolites like (S)-norketamine. Using data from 17 healthy participants in a crossover trial, researchers developed a population PK model linking (S)-ketamine and (S)-norketamine concentrations to subjective 'Feeling High' scores. A significant relationship was found for (S)-norketamine alongside (S)-ketamine, though model variance was high. The analysis suggests that (S)-norketamine, not (S)-ketamine itself, primarily drives subjective effects after oral administration and may contribute to antidepressant effects in patients.
Journal of psychopharmacology (Oxford, England)
June 25, 2026
Joost C Van Mechelen, Tobias A Wieles, Laura G J M Borghans et al.
Oral S-ketamine (S-KETPO) has poor bioavailability (9-12%) and produces much lower peak concentrations of S-ketamine but higher levels of its active metabolites norketamine and hydroxynorketamine compared to intravenous S-ketamine (S-KETIV). In 16 healthy participants, S-KETIV caused sedative, psychomotor, and psychotomimetic effects along with reductions in brain electrical activity, while the higher oral dose (0.45 mg/kg) showed limited psychotomimetic effects and smaller brain activity reductions, and the lower oral dose (0.20 mg/kg) had no effects. Safety was similar across treatments. These pharmacokinetic and pharmacodynamic differences may affect dose selection and therapeutic outcomes in treatment-resistant depression.
British journal of clinical pharmacology
June 24, 2026
Catherine M K E De Cuba, Annika A De Goede, Joost C Van Mechelen et al.
A single intravenous dose of S-ketamine produced acute and delayed effects on brain activity and motor cortex excitability that lasted up to seven days in 16 healthy adults. Intravenous S-ketamine reduced motor-evoked potential amplitude acutely and caused a sustained weakening of long-interval intracortical inhibition, which followed a linear relationship with drug concentration. Transcranial magnetic stimulation combined with electroencephalography showed acute changes in brain electrical activity across all treatments, but delayed changes only after intravenous and high-dose oral S-ketamine. Electroencephalography revealed acute decreases in alpha, beta, and delta power with eyes closed, and sustained increases in delta power with eyes open, the latter also showing a linear concentration-effect relationship. These delayed pharmacodynamic effects are distinct from acute effects and may help explain S-ketamine's antidepressant action.