In brief
- An international team has published two clinical trials in JAMA Network Open regarding KET01, an extended-release oral ketamine capsule designed for at-home use.
- The primary endpoint at 21 days was not met compared to placebo, but significant early improvements were observed at 4 and 7 days of treatment.
- Compared to intranasal esketamine, the oral capsule caused significantly less dissociation (3.8% versus 96% of participants) and barely affected blood pressure or pulse.
A consortium led by psychiatrist Martin Walter has presented the results of two randomized clinical trials on KET01, an extended-release oral ketamine formulation designed to treat treatment-resistant depression. The study, published on June 24, 2026, in JAMA Network Open, is one of the first to directly compare this oral route with the well-known intranasal esketamine, providing concrete data on efficacy and, above all, the side-effect profile associated with each formulation.
Two trials, one goal: reducing dissociation
The first study (KET01-03) was a phase 1 trial in 26 healthy men who received, in separate sessions, either oral KET01 or a single 84 mg dose of intranasal esketamine, allowing for a direct comparison of their acute effects. The second (KET01-02) was a placebo-controlled phase 2 trial involving 122 people with treatment-resistant depression, who received either 120 mg or 240 mg of KET01 daily, or a placebo, for three weeks. The logic behind an extended-release capsule is simple: release the drug gradually to maintain the antidepressant effect without the concentration spikes associated with more intense dissociative experiences.
The data: modest efficacy, notable safety
Regarding the primary endpoint, measured at 21 days using the MADRS scale, the difference between the 240 mg dose and the placebo was 1.82 points, which was not statistically significant (p=0.41). However, significant differences did appear at 4 and 7 days (3.66 and 3.95 points respectively, p=0.02 and p=0.04), suggesting an early effect that later wanes. Response rates (at least 50% improvement) were 47.5% with 240 mg, 34.1% with 120 mg, and 37.5% with placebo; remission rates were 40.0%, 24.4%, and 25.0% respectively. Where the study makes a clearer difference is in safety: only 3.8% of those who took KET01 exceeded the clinical threshold for dissociation, compared to 96% of those who received intranasal esketamine. Furthermore, the oral formula barely modified blood pressure or pulse, unlike the rapid spikes observed with esketamine. Conversely, transient elevations in liver enzymes were detected, with 10% of the highest dose group exceeding three times the normal limit, although values normalized after treatment ended.
What this implies
The authors themselves are clear: the phase 2 trial did not meet its primary statistical objective, so calling this a validated alternative would be premature. What it does provide is a solid signal that the route of administration significantly influences the subjective experience and cardiovascular effects of ketamine—a relevant finding for those who value these treatments and for those researching more manageable formulations outside of supervised clinical settings. The researchers emphasize that the tolerability profile supports further development of this oral capsule, with larger samples and longer follow-ups to clarify whether the early effect observed at 4–7 days can be sustained over time. As always with these types of early-phase trials, percentages should be read with caution: the samples are small and the results are preliminary.
Source
- Walter M, 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.
