A recent research study has raised intriguing questions about the efficacy of ketamine as a therapy for depression. This comprehensive investigation revealed that patients diagnosed with depression, who received either saline or ketamine prior to undergoing anesthesia for surgical procedures, exhibited similar improvements in their depressive symptoms afterward. These findings suggest that a portion of the therapeutic effects attributed to ketamine may indeed stem from the placebo effect. However, further research will be necessary to substantiate these claims and explore the underlying mechanisms involved.

Numerous studies have indicated that low doses of ketamine—known for its use as a dissociative anesthetic and recreational substance—might also play a pivotal role in addressing depression and various other mental health challenges, in a manner distinct from traditional antidepressants. Some of these studies implemented a placebo-controlled design, widely regarded as the gold standard in evaluating the true efficacy of a drug or treatment (ideally, both patients and the healthcare professionals providing care are unaware of whether they belong to the treatment or control group).

However, the challenge lies in the fact that even low doses of ketamine can induce temporary physical effects such as dissociation or a “trip,” making it relatively easy for participants to discern whether they are receiving the treatment. This realization can undermine the effectiveness of creating a proper placebo for comparison. To address this issue, a team of researchers from Stanford University embarked on an innovative experiment aimed at minimizing the possibility of participants recognizing their treatment assignment.

In their study, 40 participants diagnosed with severe depressive disorder were scheduled for routine surgery requiring general anesthesia. Half of the participants were randomly assigned to receive a single dose of saline solution, acting as the placebo, just prior to surgery, while the other half received a single dose of intravenous ketamine. The researchers hypothesized that the experience of undergoing anesthesia would mitigate the potential for participants to experience a typical “trip.” They monitored the participants for up to three days following the procedure.

By the conclusion of the study, both groups reported similar average levels of improvement in their depressive symptoms. Interestingly, participants were only able to accurately guess whether they had received ketamine or the placebo less than half the time, indicating that the blinding process was indeed effective.

The authors concluded, “A single dose of intravenous ketamine delivered during surgical anesthesia had no greater effect than placebo in acutely reducing the severity of depressive symptoms in adults with major depressive disorder,” as documented in their publication in Nature Mental Health this month.

It is important to note that the findings of this study are based on a relatively small sample size and a short follow-up period, which means that any interpretations of the results should be approached with caution until further data is collected. Additionally, other researchers have already suggested that the outcomes might imply that surgical procedures and anesthesia in general (including ketamine) could provide rapid relief from depression, rather than asserting that ketamine lacks any therapeutic benefits beyond the placebo.

The authors of the study caution that this hypothesis is unlikely to fully explain their results, as previous research has not consistently established a connection between surgery and an improvement in depression (in fact, some individuals may even experience an exacerbation or new onset of depression following surgical interventions). They emphasize that they are not claiming ketamine should be regarded merely as a placebo for treating depression, nor are they suggesting that patients with depression are somehow fabricating their ailments.

“Saying ‘it’s just a placebo’ is really a disservice to what placebo is,” remarked research author Boris Heifets, an assistant professor of anesthesiology, in a statement released by Stanford. “It isn’t ‘I’ll feel better if I say it enough times,’ and it does not mean that there was nothing wrong with the patient.”

They do theorize that patient expectations could contribute significantly to the observed rapid benefits of ketamine for some individuals. However, even if this holds true, it does not negate the fact that patients are experiencing genuine and positive physiological changes when they receive treatment.

“There is definitely a physiological mechanism, something that happens between your ears, when you instill hope,” Heifets asserted.