In brief
- The KARMA-Dep 2 clinical trial, published in October 2025 in JAMA Psychiatry, found no significant differences between intravenous ketamine and an active placebo (midazolam) in hospitalized patients with moderate-to-severe depression.
- With 62 patients analyzed at a university hospital in Dublin, it is one of the best-controlled active-placebo trials on ketamine for depression to date.
- The study identified a key issue: up to 90% of evaluators correctly guessed who had received ketamine, casting doubt on previous studies that used saline placebos.
A new clinical trial conducted in Ireland and published in the journal JAMA Psychiatry has found that repeated ketamine infusions did not outperform an active placebo in reducing depressive symptoms among patients hospitalized for moderate-to-severe depression. The finding, which the authors themselves describe as a call for “cautious interpretation” of previous studies, adds to a growing debate regarding the extent to which ketamine’s efficacy has been overestimated due to flawed trial designs.
A trial designed to plug a methodological hole
Ketamine, a dissociative anesthetic used for decades in medicine, gained popularity over the last decade as a treatment for treatment-resistant depression due to its ability to provide rapid mood relief, in contrast to the weeks required for conventional antidepressants. Its derivative, esketamine nasal spray (Spravato), has regulatory approval in several countries, including Spain, for treatment-resistant depression. However, many of the trials supporting the use of intravenous ketamine—which is much more widely used in private clinics off-label—compared the drug to a saline placebo. This design suffers from an obvious problem: patients almost immediately notice whether or not they have received a dissociative substance, which can inflate the observed effect through simple expectation.
The team led by Declan McLoughlin of St. Patrick’s University Hospital, affiliated with Trinity College Dublin, designed the KARMA-Dep 2 trial specifically to correct this bias. Instead of saline, they used midazolam, a sedative that also induces perceptible sensations, as an “active” placebo. The goal was to determine if ketamine still showed an advantage when the patient could not easily distinguish which substance they had received based solely on how they felt.
No differences against active placebo
The randomized, double-blind trial was conducted between 2021 and 2024 with 65 people hospitalized for a major depressive episode (62 were ultimately analyzed), all of whom met a minimum severity score on the MADRS scale. Participants received up to eight infusions, two per week, of either ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg), always as an adjunct to their usual psychiatric care in the hospital.
At the end of the treatment, the adjusted difference on the MADRS scale between the two groups was -3.16 points, a margin the authors consider clinically irrelevant and which did not reach statistical significance (95% CI: -8.54 to 2.22; p = 0.25). Remission rates were 43.8% for ketamine versus 30% for midazolam, a difference that was also inconclusive given the small sample size. No relevant differences were observed in self-reported symptoms, cognitive functions, quality of life, or cost-effectiveness. The study did note that ketamine caused more dissociation and midazolam caused more sedation, as expected, but both the patients and the evaluation team correctly guessed the assigned treatment in the vast majority of cases (over 90% accuracy among evaluators after the first infusion), which highlights how difficult it is to blind a trial with a substance so recognizable by its effects.
What this implies
The authors themselves emphasize that their results do not mean that ketamine “does not work,” but rather that they call into question the magnitude of the benefit attributed to it by previous trials with less rigorous designs, and they urge caution when interpreting that literature. This is a single trial, with a moderate sample size (62 patients) and conducted in a very specific context—patients hospitalized for severe depression who were already receiving intensive psychiatric care—so its conclusions cannot be automatically extrapolated to other profiles, such as outpatient treatments in private ketamine clinics, which are increasingly numerous and where supervision and protocols vary greatly from one center to another. The finding does not affect the regulatory approval of nasal esketamine, which is supported by its own program of trials, but it does reinforce the need to demand evidence with active placebos before accepting the efficacy of any therapy involving psychoactive substances with such perceptible effects.
Source
- McLoughlin D, et al. “Serial Ketamine Infusions as Adjunctive Therapy to Inpatient Care for Depression: The KARMA-Dep 2 Randomized Clinical Trial”. JAMA Psychiatry, October 22, 2025.
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. Treatments with psychedelics are experimental and are performed in controlled clinical settings.
