Twenty-six years ago, researchers at Yale University made a surprising discovery when a small group of patients with major depressive disorder (MDD) showed improved symptoms after a single dose of intravenous (IV) ketamine.
Since then, other studies have added weight to the potential psychiatric benefits of the drug, which the FDA approved a half century ago as an anesthetic.
So in 2018 when a team of researchers at Trinity College Dublin in Dublin, Ireland, set out to investigate racemic ketamine infusions as a treatment for depression, they expected to find similar positive effects.
Instead, they found that adding ketamine to usual inpatient care offered no additional benefit compared to a psychoactive placebo, leaving the researchers to wonder if assertions of ketamine’s efficacy for depression have been overstated, lead investigator Declan McLoughlin, PhD, research professor of psychiatry at Trinity College Dublin, said.
“The evidence base for giving people with depression serial infusions of ketamine is very limited, and our findings are negative,” he told Medscape Medical News.
This study is the latest to explore — and in this case, question — the use of ketamine for depression, leading some researchers to ask: Is ketamine for depression moving too fast on weak data?
The Ketamine Landscape
While the nasal spray formulation of ketamine, esketamine, is FDA-approved for treatment-resistant depression (TRD) and strictly regulated, racemic ketamine is not.
Following comprehensive screening, the current recommendation is that for psychiatric illness, ketamine be administered in a controlled setting under appropriate medical supervision. However, the anesthetic is increasingly prescribed off-label for depression and other psychiatric illnesses in settings with little oversight, generating safety concerns among experts. With US ketamine industry revenues projected to reach more than $6 billion by 2030, the hype shows no sign of slowing.
Some of the interest is fueled by the absence of better treatment options for TRD, said Caleb Alexander, MD, MS, professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health, Baltimore.
“What you have with treatment-resistant depression is a condition that is not uncommon and that by definition is a setting where the typical sort of off-the-shelf approaches that clinicians and patients typically reach for aren’t working,” he told Medscape Medical News. “There remains a very large unmet need. So this is sort of the perfect storm.”
Without a national ketamine registry, tracking off-label use is difficult. Since the pandemic, telemedicine platforms have begun offering ketamine for at-home use for various psychiatric conditions, raising concern among experts. Access is also available through any of the estimated 1500 private ketamine clinics currently operating in the US.
“Many clinics promote ketamine for not only off-label uses but uses where there is a glaring paucity of evidence,” such as restless leg syndrome, social phobia, or opioid withdrawal, Alexander said.
In addition, clinics don’t always clearly communicate the risks of ketamine treatment to patients — a study of off-label ketamine prescribing in Maryland showed that 41% of ketamine advertisers did not disclose adverse effects or risk for addiction.
“Part of the problem that we have in the United States is that ketamine clinics have sprung up all over the country and the clinics are more than happy to keep giving patients ketamine as long as they keep coming back. That is just not good practice,” Charles Nemeroff, MD, PhD, professor and chair of psychiatry and behavioral sciences at The University of Texas at Austin, told Medscape Medical News.
“The state medical boards have not stepped up to regulate the use of ketamine,” he said. “It’s sort of like Dodge City out there.”
What’s the Evidence?
Studies point to ketamine’s mechanism of action as an N-methyl-D-aspartate antagonist that boosts neuroplasticity, jumpstarting the formation of new neural connections and restoring synapses affected by depression.
Randomized controlled trials have shown that both racemic ketamine and esketamine are associated with reduced depressive symptoms and less suicidal ideation among various patient populations.
A meta-analysis of 20 trials in unipolar and bipolar depression showed that both single and repeated doses of ketamine were associated with significant antidepressant effects compared with placebo.
Single-dose ketamine effectively reduced depressive symptoms for up to 7 days, whereas 3 weeks of serial infusions was associated with a significant reduction in depression severity. A larger meta-analysis showed that on average, those treated with the drug reported significant improvement in TRD (P < .0001), with an estimated mean 45% of patients achieving a response and 30% achieving remission.
But an equally consistent finding across studies is that ketamine efficacy varies significantly among different clinical populations. Compared with the more rigorous esketamine trials, ketamine studies are also smaller and not sufficiently powered to inform clinical guidelines, experts contended. And most have a short follow-up period.
“There’s a stark gap between the duration and chronicity of depression and the duration of the trials that have been performed assessing whether ketamine may be efficacious,” Alexander said.
The Trinity trial is one of the largest to date to show no superior effect of serial ketamine infusions compared with an active placebo, in this case, midazolam.
The double-blind, randomized controlled trial sought to uncover whether adding serial ketamine administration to standard care would improve depressive symptoms. The final analysis included 62 patients hospitalized for major depression who received eight twice-weekly infusions of ketamine (0.5 mg/kg) or midazolam (0.045 mg/kg) in addition to usual inpatient psychiatric care.
At 6-months follow up, there were no significant differences between groups in improvement in scores on the Montgomery-Åsberg Depression Rating Scale (MADRS) (P = .25) or the Quick Inventory of Depressive Symptoms, Self-Report (P > .99). Self-reported quality of life, depression severity, or healthcare costs were also similar between groups.
Based on the current literature and the trial’s negative findings, McLoughlin believes the rollout of IV ketamine for depression in the US is moving too fast.
“The randomized controlled trial data to date on serial ketamine infusions for depression is not supportive of its use. Others may be more optimistic,” he said.
In their trial, the Trinity researchers used midazolam as a psychoactive comparator in an effort to overcome functional unblinding — a well-known limitation of psychedelic studies. However, the majority of participants still accurately guessed which drug they received.
“The Trinity study clearly demonstrated that the addition of ketamine repeated injections was no better in reducing depressive symptoms than repeated placebo injections, both added to standard antidepressant treatment. It’s hard to ignore these findings especially because the patients clearly knew who received ketamine and who received placebo,” Nemeroff said.
But Gerard Sanacora, PhD, MD, professor of psychiatry and director of the Depression Research Program at Yale University in New Haven, Connecticut, said the new findings are underpowered and should be interpreted cautiously.
Specifically, the study estimated a clinically significant difference in MADRS scores between groups to be 8 or more points. But that range is typically only seen within groups, and clinically significant between-group differences are usually 2-3 points, Sanacora said.
“It addresses a very important question in the field. Unfortunately, a major flaw in the study is that it is just grossly underpowered,” he told Medscape Medical News.
The response and remission rates were around 14% higher in the ketamine group. “Those are pretty meaningful findings. And then the relapse rate was also very different. So I mean I think it’s a biased interpretation of this data,” he added.
McLoughlin contends that this scoring is in line with previous serial ketamine infusion trial data and highlighted the lack of difference between groups on the patient self-report depression scale.
Ketamine vs Electroconvulsive Therapy (ECT)
A growing body of research suggests that ketamine may be as effective as ECT, which is considered the gold standard treatment for TRD.
In a 2021 study, researchers compared ECT with racemic ketamine for unipolar depression. Although response rates were higher with ECT (63% vs 46%), researchers said the fact that nearly half of the patients achieved remission with ketamine is still clinically meaningful.
A 2023 multicenter open-label randomized trial co-authored by Sanacora showed ketamine was noninferior to ECT for TRD, with response rates of 55% in the ketamine group vs 41% in the ECT group (P < .001).
Researchers followed up the findings with a secondary analysis published in 2024 to determine if ketamine might be more beneficial in specific patient populations. They found that ketamine outperformed ECT most strongly among outpatients with nonpsychotic TRD with moderately severe or severe depression.
But some of these comparison studies and meta-analyses are based on methodologically flawed research, the Trinity researchers argued in a recent commentary. In all but one of the six randomized trials comparing the two treatments, researchers used what McLoughlin and his colleagues called “suboptimal” ECT and short treatment periods that don’t reflect how the therapy is used in real-world clinical practice.
“Our concern was that it’s been creeping into clinical guidelines in this past year that ketamine is as good as ECT,” McLoughlin said, referencing guidance published in 2025 in Australia and New Zealand.
“There is thus a real risk of patients and clinicians being steered towards a less effective treatment, particularly for patients with severe, sometimes life-threatening, depression,” he added.
Nemeroff agreed with the Trinity researchers’ outlook, noting that it’s an unfair comparison between the two if ECT treatment is suboptimal. “Put it this way, from a clinical point of view, if I had a patient with treatment refractory depression, I would absolutely recommend ECT before I recommended ketamine,” he said.
While ketamine may not be the best option for everyone, it could be an option for those who need a rapid intervention or patients who can’t access other treatments like ECT, said Benjamin Brody, MD, associate professor of clinical psychiatry at Weill Cornell Medicine in New York City.
“The real question here is in which patients should ketamine be used first and in which patients should ECT be used first,” Brody told Medscape Medical News.
In 2019, Brody set up a ketamine treatment program for hospitalized patients with nonpsychotic MDD. A retrospective review of 41 of those patients showed that twice weekly ketamine infusions were associated with quick improvement in depressive symptoms in about half of the sample, 15 of whom achieved remission. Nonresponders were switched to ECT. That should address concerns raised in the commentary by McLoughlin and others, Brody said.
“In the commentary, they’re saying ‘Well, you didn’t give ECT enough time.’ My response is, ‘Fine. So give patients four treatments with ketamine. If they don’t get better, switch them over to ECT,’” he said.
Ketamine’s Safety Profile
Ketamine’s dissociative effects don’t just pose a problem for studying the drug, they can also lead to negative experiences for patients, ranging from altered perceptions of reality to suicidal ideation.
Known as “dysphoric dissociation,” these experiences are understudied and likely underreported, due to exclusion from current clinical symptom scales and metrics, Brody and colleagues wrote in a recent commentary in The Journal of Clinical Psychiatry (JCP).
They called for increased psychotherapeutic interventions like cognitive behavioral therapy before and after ketamine treatment to increase patient awareness about adverse experiences.
Ketamine’s potential for misuse and addiction is another concern, given the fact that substance-use disorders (SUDs) are highly comorbid with TRD. The American Psychiatric Association’s (APA’s) 2017 consensus statement recommends that patients be evaluated before treatment for a history of SUDs and followed closely with urine toxicology screening for drugs of abuse if ketamine abuse is suspected.
The APA statement also noted ketamine’s potential adverse effects on blood pressure and heart rate, and suggested that the safest course would be for a licensed clinician with cardiac life support training to administer the drug.
When Brody and colleagues launched their ketamine treatment program at Weill Cornell Medicine, they thought that this recommendation may go too far. Now, they wonder if it goes far enough.
“Now, we have grave concerns that the racemic ketamine world has swung too far in the opposite direction and that too many providers and for-profit clinics are prescribing compounded ketamine to patients at home, who self-administer with little or no supervision,” they wrote in their JCP commentary.
What’s Next?
McLoughlin and others have called for a head-to-head comparison of ketamine vs esketamine. Sanacora is currently leading just such a study, a project that aims to assess the relative effectiveness, safety, and patient satisfaction of the two medications.
Further research should include double-blinded, well-controlled studies with active comparators and include comprehensive assessments of safety, Alexander said.
Meanwhile, the APA consensus statement recommends that patient history of antidepressant treatment should be thoroughly assessed to confirm they have had adequate trials of these medications before initiating a trial of ketamine.
