New Study Raises Questions About Ketamine for Depression

An important study published in JAMA Psychiatry (2025) challenges some of the most popular narratives about ketamine’s effectiveness as a rapid antidepressant, underscoring the crucial role of context and methodology in the evolving story of this treatment.

Given how common depression is, and how difficult it has been to treat, it's understandable that promising treatments are met with great enthusiasm. However, great enthusiasm often is incompatible with critical thinking.

Precision interventional psychiatry is in its infancy

As an interventional psychiatrist offering transcranial magnetic stimulation (NeuroStar TMS) since 2010, I take hype with a grain of salt. I also did not buy into the TMS hype.

I've also worked with people receiving ketamine, seemingly with good benefit. Individuals should not be deterred from getting proper evaluation with psychiatrists experienced in the growing range of alternatives available in order to pursue greatest relief and recovery. The one thing in shortest supply is a comprehensive evaluation and treatment plan—seeking fragmented individual treatment modalities sometimes works well but often doesn't work as well as they would given better oversight. Medicine used to be more patient-centered but now it has become increasingly specialized and divided.

Unlike ketamine, which like psychedelic treatments and medication, has a generalized effect on the brain, targeted TMS has continued to develop as we gain a more refined understanding of mechanisms of action and ways to enhance outcomes. We begin to approach true precision Interventional psychiatry.

With ketamine, there's often an initial improvement that tapers off and almost always requires regular maintenance. I've also seen innumerable ketamine clinics pop up, often with a strong profit motive and sometimes dubious clinical oversight.

Much of the ketamine treatment approach is based on idiosyncratic and not well researched approaches. We sometimes refer to it as the "wild, wild west". There are even mail order ketamine clinics which ship this potentially dangerous and addictive substance to your home, with brief video consultations.

At the end of the proverbial day, it is critical to highlight that good clinical oversight and a comprehensive treatment plan makes all the difference. Patient safety and ethical and responsible care ought always come first.

Psychotherapy, actually

Of particular and understated importance is the psychotherapeutic context. Positive changes and improvements in the brain's capacity to change, known as neuroplasticity, must be leveraged.

I've referred to this as TMS-Assisted Psychotherapy, and my experience is that patients may have dramatic improvements particularly with newer accelerated TMS protocols, but they do even better with ongoing psychotherapeutic follow-up. It's a little bit like doing rehabilitation after a surgical repair of the shoulder.

Treatments like ketamine, which require an ongoing engagement in the process, have an aura therapeutic effect which is distinct from the direct medication effect, producing an ongoing motivational state.

What is the verdict on ketamine?

The recent randomized controlled trial compared intravenous ketamine to midazolam (an active placebo) in patients hospitalized for moderate to severe depression. At first glance, the results may disappoint: when added to intensive inpatient psychiatric care, repeated optimal-dose ketamine infusions (0.5 mg/kg, the “gold standard”) showed no significant benefit over placebo on measures of depression, cognition, quality of life, or even cost-effectiveness.

For years, debates around ketamine studies have centered on dosing. This trial carefully avoided the common pitfalls: neither underdosed nor pushing into higher doses that increase risk of dissociation and unwanted side effects without added benefit.

By using the 0.5 mg/kg standard, researchers chose an appropriate benchmark, at the risk of underdosing some participants. Critics of the study note that in clinical practice they often give higher doses. According to them, getting into the dissociative range may be required for treatment efficacy. But this runs significant risks of worsening other conditions, is intolerable for some, and has not been definitively shown to be effective (Fava et al., 2020).

Common problems with study design

Perhaps the biggest challenge facing ketamine research is the issue of "blinding". Ketamine’s distinctive psychoactive effects make it easy to tell who is getting the drug and who is getting the placebo, even with an active placebo like midazolam. In this study, most patients and clinicians correctly guessed their group assignment, raising real concerns about expectancy effects and placebo responses influencing outcomes.

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Furthermore, the study population in this research included both unipolar and bipolar depression, two groups known to respond differently to interventions, further complicating interpretation. It would be important to see whether outcomes were different between these two groups.

Good science begets better questions, when sure answers are elusive

Despite these limitations, the trial deserves attention. It’s among the largest and most rigorous randomized ketamine studies to date, and it was published in a top journal because well-conducted trials with negative results are vital to medical progress as breakthrough findings.

This study suggests ketamine is not the universal solution its reputation sometimes touts. The lack of benefit in a complex, hospitalized population — where patients are actively receiving intensive care and monitoring — hints that ketamine’s advantages may depend way more from treatment context, patient selection, and real-world variables than enthusiasts acknowledge.

To add to the confusion, treatments that are labeled "psychedelic" have a deep, arguably atavistic cultural significance, which can obscure clinical use. These are powerful, often shamanistic fantasies used to boost treatment. To that point, emerging research suggests that molecules which act similar to psilocybin have antidepressant effects in animals without the "trip" (Moliner et al., 2023).

These findings are not a death knell of ketamine for depression. Instead, they’re a call for deeper research: larger trials, more nuanced patient selection, better blinding techniques, and a more critical look at real-world clinical settings.

For clinicians, patients, and policymakers, this trial is an invitation to pause and reflect. Rigorous science doesn’t always deliver the answers we want, but it reliably moves mental health care closer to the truth — even if we don't like what we find.