Ketamine no better than placebo at alleviating depression, unusual trial finds

Ketamine is a powerful anesthetic and sometimes recreational drug that causes people to feel dissociated from their own bodies. Recent studies suggest the drug may help treat people with depression who have tried more conventional treatments without success. But there are major questions about what makes it work. Is it the weird dissociative experience? Some molecular effect on the brain? Or just the experience of being in a clinical trial?

In a new study that is yet to be peer reviewed, researchers attempted to find the answer in a unique way: They gave volunteers ketamine while they were under general anesthesia, theoretically preventing the participants from going on a trip. The approach alleviated the subjects’ depression, but not any better than a placebo did.

The authors interpret this as evidence that ketamine’s effects on depression are strongly tied to a patient’s experience of being seen by medical professionals. But other experts say the study’s implications may be more complicated.

Ketamine causes “dissociative” effects such as out-of-body experiences. Patients sometimes also report visual and auditory hallucinations—the voices of friends and family members who aren’t there, for example. The dissociative effects of ketamine have been linked to a stronger antidepressant response, possibly by helping patients reframe their experience from an outside perspective. But it’s a problem for researchers running double-blinded clinical trials, as participants can usually tell whether they have received ketamine or a placebo.

To disentangle the subjective experience of ketamine from the biochemical effects of the drug, researchers at Stanford University recruited 40 participants who were preparing to undergo general surgery and who also had mild to moderate depression. The scientists gave the volunteers ketamine or saline as placebo right after they were put under anesthesia, but before their surgery, essentially blinding them to any psychedelic or dissociative effects. Then, for the next 3 days, the researchers surveyed the participants on their depression symptoms, scoring them on such factors as sadness, loss of appetite, and lack of sleep.

After the procedures, about 40% of the participants guessed correctly whether they had received a placebo or ketamine—no better than chance, that is—indicating that the anesthesia had done its job in masking the drug’s dissociative effects. Both groups experienced a 15-point drop in their depression scores, and about 40% of patients in both groups still had more than a 12-point decrease 3 days after infusion, meaning they were in remission for their depression.

That improvement is similar to the antidepressant effects reported when participants take ketamine and have a dissociative experience, says Eduardo Schenberg, a neuroscientist at the Phaneros Institute who was not involved with the study.

One possible interpretation is that the anesthesia itself alleviated depression. Anesthesia has been shown to help depression in other studies. However, the doses of anesthesia used in this study were much lower than those that have been used in other antidepression studies, the authors note.

All of this suggests that neither ketamine nor the anesthesia by themselves may do much to alleviate depression, says Theresa Lii, an anesthesiologist at Stanford and co-author of the study. Instead, simply going through the complex, orderly treatment procedure itself—during which participants receive attention and one-on-one interactions with doctors and psychiatrists—benefits people. By merely participating in this trial, she says, participants in both the ketamine and placebo groups may have created an expectation that they were going to get better—and they did.

The study suggests the effects of ketamine on depression don’t rely on “just the pharmacological agent,” says Matthew Butler, a neuropsychiatrist at King’s College London who was not involved with the work. “These results sort of shock the narrative a little bit.”

The work complicates an already fraught field, says Boris Heifets, an anesthesiologist at Stanford and author of the study . At the same time that studies are delving into the biological workings of ketamine, clinics that provide the drug to patients are closing across the United States .

It’s still possible, however, that the volunteers had a subjective experience, like a psychedelic or dissociative trip, that could be influencing the findings, Schenberg says, but the authors didn’t check for that. “It makes it very difficult to interpret the results beyond the fact that the general anesthesia had an antidepressant effect.” Schenberg points out that people often report dreamlike and visual, auditory, and affective experiences under anesthesia. “Maybe people who had dreamlike experiences during the anesthesia had more improvement than the people who didn’t,” he says.

Even if it’s just the placebo effect at play, the study highlights just how powerful this effect can be, says David Mathai, a psychiatrist at Johns Hopkins University who was not involved. “[These effects] reflect a sense of hope and belief that someone can get better,” Mathai says. “And I think that’s an incredibly important part of the clinical process.”

“We went into the study, definitely having the question of ‘Does the trip matter?’” Lii says. “And we came out of the study with a different question: ‘Does the entire experience before and after the trip matter more?’”