• Posted October 28, 2025

Clinical Trial Finds Ketamine Not Effective For Depression

Ketamine might not be effective in treating depression, new clinical trial results reveal.

Ketamine infusions added to standard depression care did nothing for people hospitalized with the mood disorder, researchers reported Oct. 22 in JAMA Psychiatry.

“Our initial hypothesis was that repeated ketamine infusions for people hospitalized with depression would improve mood outcomes. However, we found this not to be the case,” senior researcher Declan McLoughlin, a research professor of psychiatry at Trinity College Dublin, said in a news release.

Earlier studies that found ketamine effective in treating depression might have been flawed, in that patients might have guessed they were getting the drug and experienced improvement due to a placebo effect, researchers said. This trial also found many patients were able to guess which treatment they were getting.

“Our trial highlights the importance of reporting the success, or lack thereof, of blinding in clinical trials, especially in clinical trials of therapies where maintaining the blind is difficult, e.g. ketamine, psychedelics, brain stimulation therapies,” lead researcher Ana Jelovac of Trinity College Dublin said in a news release.

“Such problems can lead to enhanced placebo effects and skewed trial results that can over-inflate real treatment effects,” Jelovac said.

About 30% of people with depression don’t respond well to conventional antidepressants that target brain chemicals like serotonin, dopamine and adrenaline, researchers said in background notes.

That’s why such hope has been placed on ketamine, which is increasingly being used as an off-label treatment for depression, researchers said.

A nasal spray version of ketamine called Spravato was even approved in 2019 by the U.S. Food and Drug Administration for hard-to-treat depression, according to Harvard Medical School.

For the new trial, more than 60 people with depression were randomly assigned to receive up to eight twice-weekly IV infusions of either ketamine or midazolam, a benzodiazepine.

Midazolam produces sedation and psychoactive effects, so researchers have used it as the placebo alternative in ketamine trials. That way, patients are less likely to guess they haven’t gotten ketamine, so the thinking goes.

Results showed no significant difference in depression symptoms between the ketamine and midazolam groups by the end of the four weeks of treatment.

No differences were found between the groups in other measures such as cognitive function, finances or quality of life.

“Under rigorous clinical trial conditions, adjunctive ketamine provided no additional benefit to routine inpatient care during the initial treatment phase or the six-month follow-up period,” McLoughlin said. “Previous estimates of ketamine’s antidepressant efficacy may have been overstated, highlighting the need for recalibrated expectations in clinical practice.”

However, most of the patients were able to successfully guess whether they’d gotten ketamine or midazolam, researchers noted. Between 78% to 85% of ketamine patients knew they’d gotten the anesthetic, while 46% to 62% of midazolam patients guessed correctly.

“While midazolam was selected to mitigate unblinding, this was not successful, raising the possibility that even the small observed effect reflects expectancy rather than a specific treatment effect,” researchers wrote.

More information

Harvard Medical School has more on ketamine therapy for depression.

SOURCES: Trinity College Dublin, news release, Oct. 22, 2025; JAMA Psychiatry, Oct. 22, 2025