For years, ketamine has reshaped conversations around treatment resistant depression by demonstrating that meaningful symptom relief can occur much faster than with traditional antidepressants. Yet one important challenge remains. Existing ketamine treatments often require administration in specialized clinics because of temporary dissociative symptoms and cardiovascular monitoring requirements. New research exploring oral ketamine for treatment resistant depression may point toward a different path.
A pair of randomized clinical trials recently evaluated a prolonged-release oral ketamine tablet known as KET01. While the studies did not meet every predefined efficacy goal, they demonstrated encouraging antidepressant signals alongside an unusually favorable tolerability profile. Together, the findings suggest that researchers may be moving closer to a formulation suitable for outpatient or even future at-home use.
Why Current Ketamine Treatments Still Have Limitations
Intravenous ketamine and intranasal esketamine have become valuable options for individuals whose depression has not responded to multiple antidepressant medications. Their rapid onset distinguishes them from conventional treatments.
However, both approaches frequently produce short-lived dissociative experiences and temporary increases in blood pressure. Because of these effects, patients must typically receive treatment under clinical supervision and remain under observation after dosing. These logistical barriers can limit accessibility, increase healthcare costs, and reduce convenience for many patients.
Researchers have therefore continued searching for formulations that preserve ketamine’s antidepressant properties while minimizing adverse effects.
How Oral Ketamine For Treatment Resistant Depression Was Evaluated
Investigators conducted two complementary randomized clinical trials.
The first enrolled healthy volunteers and directly compared a single dose of prolonged-release oral ketamine with intranasal esketamine. Researchers closely monitored dissociative symptoms, cardiovascular responses, and drug metabolism.
The second trial enrolled adults with treatment resistant depression across multiple European centers. Participants continued their existing antidepressant medications while receiving either placebo or daily oral ketamine for three weeks.
This combination of early safety testing and patient-based efficacy evaluation allowed investigators to assess both biological effects and clinical outcomes.
Rapid Improvements Emerged Early
Although the primary endpoint at three weeks was not achieved, several encouraging trends appeared during treatment.
Patients receiving the higher oral ketamine dose experienced measurable reductions in depression severity within hours after their first dose. Improvements remained statistically significant during the first week compared with placebo, particularly on days four and seven.
By the end of three weeks, symptom improvement remained numerically greater than placebo but no longer reached statistical significance for the primary endpoint. Researchers noted that the relatively strong placebo response may have reduced the ability to detect treatment differences later in the study.
Importantly, nearly half of patients receiving the higher dose achieved a clinical response, while approximately 40 percent reached remission during treatment.
Minimal Dissociation May Change The Equation
Perhaps the most striking observation involved tolerability.
Participants receiving intranasal esketamine frequently experienced clinically meaningful dissociation, which aligns with previous research. In contrast, prolonged-release oral ketamine produced almost no dissociative symptoms in healthy volunteers, and patients with depression showed dissociation rates similar to those receiving placebo.
Blood pressure and pulse also remained comparatively stable during oral treatment.
These findings raise an important possibility. If future studies confirm that antidepressant benefits can occur without substantial dissociation, clinicians may eventually have greater flexibility when delivering ketamine-based therapies.
Why The Formulation Matters
The prolonged-release tablet appears to alter how ketamine enters and moves through the body.
Instead of producing a rapid spike in blood ketamine concentrations, the formulation generates a slower rise and greater exposure to downstream metabolites such as norketamine and hydroxynorketamine. Some preclinical research suggests these metabolites may contribute to antidepressant activity while producing fewer psychoactive effects.
Although the precise mechanisms remain under investigation, the pharmacokinetic profile offers one potential explanation for the combination of antidepressant signals and reduced dissociation observed in these studies.
What Makes These Findings Noteworthy
Many ketamine studies focus primarily on intravenous or intranasal delivery. This research instead examined whether modifying the drug’s release profile could fundamentally change the treatment experience.
The investigators also demonstrated that participants completed treatment in an outpatient setting, providing an early indication that prolonged-release oral ketamine could eventually support more accessible care if larger studies confirm safety and effectiveness.
The authors emphasized that longer follow-up and larger phase 3 trials will be necessary before any changes to clinical practice can be recommended.
Looking Ahead
The development of oral ketamine for treatment resistant depression represents more than a new formulation. It reflects a broader effort to make rapid-acting antidepressant therapies safer, simpler, and more accessible.
While important questions remain regarding long-term outcomes and durability of benefit, these early findings suggest that reducing dissociation does not necessarily eliminate antidepressant potential. If confirmed in future trials, prolonged-release oral ketamine could expand treatment options for patients who currently face significant barriers to receiving ketamine therapy.
Citations
Walter M, et al. Oral Prolonged-Release Ketamine for Treatment-Resistant Depression. JAMA Network Open. 2026. https://jamanetwork.com/journals/jamanetworkopen/fullarticle/10.1001/jamanetworkopen.2026.19121
McIntyre RS, et al. Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression. American Journal of Psychiatry. 2021. https://psychiatryonline.org/doi/10.1176/appi.ajp.2020.20081251
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