In study after study, the psychoactive drug ketamine has given profound and fast relief to many people suffering from severe depression. But these studies have a critical shortcoming: Participants usually can tell whether they have been given ketamine or a placebo. Even in blinded trials in which participants are not told which they received, ketamine’s oftentimes trippy effects are a dead giveaway.
In a new study, Stanford Medicine researchers devised a clever workaround to hide the psychedelic — or dissociative — properties of the anesthetic first developed in 1962. They recruited 40 participants with moderate to severe depression who were also scheduled for routine surgery, then administered a dose of ketamine or placebo when the participants were in surgery and under general anesthesia.
All researchers and clinicians involved in the trial also were blinded to which treatment patients received. The treatments were revealed two weeks later.
The researchers were amazed to find that both groups experienced the large improvement in depression symptoms usually seen with ketamine.
Just one day after treatment, both the ketamine and placebo groups’ scores on the Montgomery-Åsberg depression rating scale — a standard measure of depression severity often referred to as the MADRS — dropped, on average, by half. Their scores stayed roughly the same throughout the two-week follow-up.
The researchers concede that their study, having taken an unexpected turn, raises more questions than it answers.
The researchers determined that it was unlikely the surgeries and general anesthesia account for the improvements because studies have found that depression generally does not change after surgery; sometimes, it worsens.
A more likely interpretation, the researchers said, is that participants’ positive expectations may play a key role in ketamine’s effectiveness.
At their last follow-up visit, participants were asked to guess which intervention they had received. About a quarter said they didn’t know. Of those who ventured a guess, more than 60% guessed ketamine.
Their guesses did not correlate with their treatment — confirmation of effective blinding — but rather with how much better they
Those who had improved more in their depression scores were more likely to think they received ketamine, even when they didn’t, implying some preexisting positive expectations for ketamine.
Call it expectancy bias, call it placebo effect or call it hope. Whatever the label, the psychological factors involved in treatment can be powerful.
These factors might include how a study is described; interactions with health care professionals; and, in this case, the unavoidable media hype around ketamine.
The take-away should not be that ketamine “is just a placebo,” Heifets emphasized.
In fact, there may be physiological resonance between the placebo effect — in other words, hope — and how ketamine works. Studies suggest that both may be mediated in part by the brain’s μ-opioid receptors, which process pain.
The results also suggest that the psychedelic experience may not be crucial to ketamine’s benefits, though it likely encourages more positive expectations.
The study was supported by funding from the Society for Neuroscience in Anesthesiology and Critical Care, the National Institutes of Health (grants 3T32DA035165-02S1, UL1TR003142 and UL1TR001085), and the Stanford School of Medicine Research Office.