Oral Ketamine Achieves Antidepressant Effect Without Dissociation

Psiconáutica Editorial Team · August 24, 2026

A team of researchers based in Germany and Switzerland, with participation from the company Boehringer Ingelheim, has tested a new prolonged-release oral ketamine formulation in two independent clinical trials. The drug is designed to separate the antidepressant effect from the dissociation that typically accompanies this substance. The results, published on June 24, 2026, in the journal JAMA Network Open, show that this separation is possible, at least in part.

Two trials, two different questions

The compound, called KET01, is a slow-absorption racemic ketamine intended for at-home use without continuous clinical supervision. To test it, the team led by Martin Walter of Jena University Hospital and collaborators from HMNC Brain Health in Munich designed two studies. The first, KET01-03, was a phase 1 crossover trial with 26 healthy men who received a single 240 mg dose of KET01 and, in another session, 84 mg of esketamine intranasally, the formulation already marketed as Spravato. The second, KET01-02, was a phase 2 trial with 122 people with treatment-resistant depression, distributed across 29 centers in the Czech Republic, Germany, and Poland, who took 120 or 240 mg of KET01 daily or a placebo for three weeks, in addition to their usual medication.

Less dissociation, earlier antidepressant effect

In the trial with healthy volunteers, the difference was stark: nasal esketamine caused an average increase of 29.6 points on the CADSS scale, which measures dissociative symptoms, compared to only 0.7 points with KET01 (p < 0.001). Pulse and blood pressure also rose rapidly after esketamine, while they barely moved with KET01. Interestingly, KET01 reached a lower maximum plasma concentration than esketamine but generated higher levels of its active metabolites, norketamine and hydroxynorketamine—compounds that the authors link to the antidepressant effect itself. In the patient trial, the primary endpoint—the difference in the MADRS depression scale at 21 days between the 240 mg dose and the placebo—was not statistically significant: -1.82 points (95% CI: -6.21 to 2.57; p = 0.41). However, an earlier improvement with nominal significance was observed: -3.66 points on the fourth day (p = 0.02) and -3.95 points on the seventh (p = 0.04), an effect that diluted in the following weeks.

What this implies

The authors themselves are cautious: the primary objective of the phase 2 trial was not met, the sample size is small, and the clearest benefit is concentrated in the first days of treatment. But the most significant finding is not efficacy, but the avoided dissociation: it suggests that the antidepressant effect of ketamine does not depend on undergoing an intense dissociative state, something that until now was taken for granted in much of the clinical research on this drug. If this separation is confirmed in larger trials, it would open the door to ketamine treatments designed for at-home use, without the medical supervision currently required for both intravenous infusion and nasal spray. The researchers themselves note that the feasibility of having conducted the phase 2 trial in an outpatient setting already points in that direction, although they warn that larger phase 3 trials with longer follow-ups and more diverse populations are needed before drawing firm conclusions.

Source

• Walter M, zu Eulenburg C, Damyanova A, et al. Oral Prolonged-Release Ketamine for Treatment-Resistant Depression: Two Randomized Clinical Trials. JAMA Network Open, June 24, 2026.

Educational content written from a harm reduction perspective and with respect for individual freedom. It is not a substitute for advice from a healthcare professional and is not intended to encourage or condemn any drug use.