KET 01: less dissociation, but depression primary endpoint not met

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 separate 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 lower dissociation in the healthy-volunteer trial but did not meet the depression efficacy primary endpoint. Sponsor Ketabon actively participated in design, data and publication; several authors disclose HMNC financial ties.

Two trials, two different questions

The compound, called KET01, is a slow-absorption racemic ketamine under investigation for potential home administration, whose safety requires risk mitigation and further study. 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 and exploratory efficacy signals

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—whose possible antidepressant role the authors discuss as a contested hypothesis, not demonstrated mediation. 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), without statistically significant separation from placebo at the primary endpoint.

What this implies

The phase 2 primary endpoint was not met, and early signals are exploratory with nominal p values. Lower dissociation in a small healthy sample does not establish equivalent efficacy, zero dissociation for every participant or causal independence of dissociation and response. These findings about ketaminemust be weighed against safety: phase 2 included serious events of suicidal depression requiring hospitalization and suicidal ideation, and withdrawals for hypertension, elevated liver enzymes or enteritis. No suicide attempts were documented during the trial, which does not establish absence of risk. Short follow-up cannot establish long-term or safe home use; the authors call for risk mitigation and larger, diverse trials.

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.