Ketamine is an NMDA receptor antagonist that can lift depression within hours. The randomized evidence is for intravenous infusion given in clinic, not for tablets taken at home. This article covers the main trials and what they do and do not show.
The first placebo-controlled trial
Murrough and colleagues ran a two-site randomized trial in 73 patients with treatment-resistant major depression. One IV ketamine infusion was compared with midazolam, an anaesthetic used as an active placebo. At 24 hours, the ketamine group's MADRS scores were 7.95 points lower, and response was higher with ketamine (Am J Psychiatry 2013).
Against electroconvulsive therapy
Anand and colleagues randomized 403 patients with nonpsychotic treatment-resistant depression to IV ketamine, or to electroconvulsive therapy (ECT). Response was 55.4% with ketamine and 41.2% with ECT, a difference of 14.2 points (95% CI 3.9 to 24.2). Ketamine was not inferior. The trial was open-label, so participants and clinicians knew which treatment they had (NEJM 2023).
Bipolar depression
Orsini and colleagues randomized 68 patients with treatment-resistant bipolar depression to serial IV ketamine or midazolam. At day 14, the ketamine group's MADRS score was 7.3 points lower (95% CI 12.0 to 2.5 lower). Five participants withdrew before the primary endpoint (JAMA Psychiatry 2026).
Tablets
We found no published trial of orally disintegrating ketamine tablets for depression. The trials above used IV infusion, and tablet bioavailability is different, so the infusion results cannot be transferred to tablets.
What this does not say
- Murrough and colleagues concluded that more information on how long the response lasts and on safety was needed before clinical use, and that statement still applies.
- The trials excluded people with psychosis and many other conditions. Averages describe groups who met criteria, not one person.
- Ketamine is a controlled substance. Blood pressure rises during and after dosing, and dissociative effects are part of each treatment session.
How we use this
Ketamine is used in clinic under supervision. We discuss it when other treatments have not worked, and we explain that the tablet form has no trial behind it.
We do not present ketamine as a fast cure. The trials show a faster effect in selected patients; they do not show that the effect lasts without follow-up.
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- 1.Murrough JW et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry 2013. American Journal of Psychiatry
- 2.Anand A et al. Ketamine versus ECT for nonpsychotic treatment-resistant major depression. N Engl J Med 2023. NEJM
- 3.Orsini DK et al. Serial ketamine infusions for treatment-resistant bipolar depression: a randomized clinical trial. JAMA Psychiatry 2026. JAMA Psychiatry
- 4.Diazgranados N et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry 2010. Archives of General Psychiatry