Slow-Release Ketamine Pill Eases Depression: Study

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A new slow-release pill form of ketamine can quell hard-to-treat depression without producing psychedelic side effects normally associated with the drug, early research suggests.

Patients on the strongest dose of ketamine tablets saw significant improvement in their depression compared to a placebo, researchers found.

On a 30-point depression scale, people taking the ketamine pill improved by 14 points, while the placebo group had an average reduction of 8 points.

The tablet could provide an improvement over ketamine injections and nasal sprays, which already are used to treat depression, said researcher Colleen Loo, a clinical psychiatrist with the University of New South Wales in Australia.

A derivative of ketamine called esketamine (Spravato) is already approved in the United States for treatment-resistant depression in adults. It comes as a pill, nasal spray or injection, but these all work quickly and produce psychedelic effects.

“This is a way of administering ketamine to treat depression that’s much easier to give,” Loo said in a university news release. “Rather than having to come to the clinic and have an injection and have medical monitoring for two hours, once or twice a week, this is much more convenient and allows patients to have their treatment at home, making it as convenient as other antidepressant medications.”

Extended-release ketamine also doesn’t cause the hallucinations typically associated with the drug, Loo added.

It had been thought that the altered reality and perception caused by ketamine are part of the reason why the drug helps depression, Loo noted.

“That’s very similar to the psychedelic-assisted therapy model that says changing your brain circuit functioning in that very profound way gives you new insights that help you to break out of your way of thinking, and that this acute kind of dissociative, altered reality experience is necessary for you to improve,” Loo said.

But the results with the slow-release tablet call that theory into question, she said.

“With this tablet form you don’t experience that because only a tiny amount is released into the bloodstream at a time, with ongoing slow release over days, and you don’t experience the dissociation at all, and yet people are improving,” Loo said.

In this clinical trial, researchers gave 231 people with severe, hard-to-treat depression a moderate dose of the time-release ketamine tablet.

By day eight, 168 patients had received some benefit from the tablet and 132 had their depression lift to the point they could be considered in remission, results show.

Researchers then zeroed in on the people who had responded to extended-release ketamine, randomly assigning them into one of five groups. Four of the groups received different strengths of extended-release ketamine pills, and one received a placebo.

The strongest dose of slow-release ketamine had a significantly better effect than a placebo, researchers found.

All of the lower doses had slightly, but not significantly, better outcomes than a placebo, results show. However, researchers did see a dose response — the higher the dose, the more a person’s symptoms subsided.

“The results here, they look encouraging,” Dr. Brian Barnett, clinical director of the Psychiatric Treatment Resistance Program at the Cleveland Clinic, told CNN. Barnett was not involved in the study.

Barnett noted that a two-point drop in the depression rating scale used in this study is considered meaningful to patients.

A six-point drop is “similar to what we’ve seen in recent clinical trials of psilocybin for treatment-resistant depression,” Barnett said, referring to studies of “magic” mushrooms and depression.

This was the first trial to measure the effectiveness of a slow-release form of ketamine against depression, researchers said.

It will likely take years to fully test the tablet before it’s ready for approval as a clinical treatment, researchers said.

“Douglas Pharmaceuticals, which is the New Zealand company that has produced the drug, still needs to do further studies, and it’s important to note this is not yet approved by the FDA in the US or the [Therapeutic Goods Administration] here in Australia,” Loo said.

“But if it does get through all those hoops and becomes an approved treatment, it certainly makes it much more convenient, not to mention cheaper, to use ketamine to treat severe depression,” Loo added.

The next step is to run similar clinical trials in sites around the world, involving larger numbers of patients, Loo said.

The trials could also compare extended-release ketamine against injectable and nasal spray versions.

“It is also possible that some people may respond to one approach to treatment, such as the tablet, while others respond to another, such as the injection, so having more treatment approaches is very useful,” Loo noted.

Douglas Pharmaceuticals sponsored the trial, while lead researcher Paul Glue, with the University of Otago in New Zealand, is named on a patent for the extended-release ketamine formulation.

The new study was published June 24 in the journal Nature Medicine.

More information

The National Institute on Drug Abuse has more about ketamine.

SOURCE: University of New South Wales, news release, June 24, 2025

Source: HealthDay

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