In Episode 56, we explore a fascinating 2026 pharmacokinetics study by Otto and colleagues that completely changes how we view oral ketamine for Treatment-Resistant Depression (TRD). When taken orally, ketamine hits a massive biological roadblock: the liver’s “first-pass effect”. The liver acts as an aggressive tollbooth, metabolizing almost all of the parent drug and transforming it into a high volume of a metabolite called (S)-norketamine before it reaches the wider bloodstream.

Using advanced Pharmacokinetic-Pharmacodynamic (PKPD) modeling, researchers discovered a mind-bending reality. While intravenous ketamine drips rely on the original parent drug to drive the therapeutic high, the subjective experience of an oral pill is almost entirely driven by its metabolite, (S)-norketamine. Because this metabolite is a “clunkier key” with a low ...