Hold the advertisements. We’re gonna need more trials.
It doesn’t cause much dissociation, but is it effective?
STUDY: Walter M et al, JAMA Network Open 2026
STUDY TYPE: Two randomized clinical trials (phase 1 crossover; phase 2 placebo-controlled)
FUNDING: Ketabon GmbH (industry)
Background
Intravenous ketamine and intranasal esketamine (Spravato) work fast in treatment-resistant depression, but both cause dissociation and blood pressure elevation that require supervised clinic administration. KET01 is a prolonged-release oral ketamine tablet designed to blunt these effects by slowing absorption, delaying peak plasma levels until about 6.5 hours after the dose (provisionally branded as Ketabon).
Oral ketamine often fails because only 15-30% is absorbed, but this trial tried to adjust for that by using a high dose.
The Study
- Trial 1 (KET01-03): 26 healthy male volunteers received a single dose of oral KET01 240 mg vs. intranasal esketamine 84 mg in a crossover design; primary endpoint was dissociation measured by the Dissociation scale (CADSS).
- Trial 2 (KET01-02): 122 outpatients with treatment-resistant depression took KET01 120 mg/day, 240 mg/day, or placebo for 3 weeks as an add-on to existing antidepressants; primary endpoint was change in Depression scale (MADRS) at day 21.
Results
The oral version dampened dissociation, with rates of 4% compared to 95% with intranasal esketamine in healthy volunteers. Blood pressure didn’t rise with KET01, in contrast to the rapid spike seen with esketamine.
But whether oral ketamine treats depression is less certain. It started out positive, beating placebo on days 4 and 7 at 240 mg/day by about 4 points (p < 0.05). But these benefits faded by day 21, the primary endpoint (1.8-point difference, p=0.41).
Side Effects
The most common adverse events with KET01 240 mg/day were headache (10%), dizziness (17.5%), and elevated liver enzymes (10%, yes it’s a new risk with ketamine).
Limitations
These are small phase I and II trials. But we already know that oral ketamine has poor bioavailability, and prior studies also had mixed results. Functional unblinding may have also skewed the results in favor of ketamine.
Practice Implications
- With growing concerns about the risks of oral ketamine, this trial doesn’t bring any new hope.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
