For those struggling with severe forms of depression, ketamine has emerged as a potential solution. Extensive research has shown that this dissociative anesthetic may offer treatment options where other medications have failed, providing the benefits of electroshock therapy with fewer risks.
However, the drug’s strong psychoactive effects have complicated efforts to separate hope from hype. How can researchers conduct a blind test for a drug that so clearly disconnects the mind from the body?
To address this challenge, a team of researchers from Stanford University School of Medicine in the US conducted a groundbreaking study. They took advantage of the unconscious state of patients under general anesthesia to subject ketamine to the ultimate gold standard test.
In their randomized, triple-masked study, they found that a single dose of ketamine is just as likely as a saline infusion to improve the mood of patients diagnosed with moderate-to-severe depression in the days following treatment.
“I was genuinely surprised by these results, especially after speaking to some of the patients who said, ‘My life has changed, I’ve never felt this way before,’ only to find out they were in the placebo group,” says Boris Heifets, the senior author of the study and an anesthesiologist at Stanford University School of Medicine.
Developed in the 1960s in the search for new anesthetics and analgesics, ketamine has a rich medical history. It continues to be used in emergency care as a fast and reliable method of relieving pain and distress. Over the years, its recreational use for its dreamy, dissociative effects has also increased.
In the past decade, ketamine’s potential as an antidepressant has garnered renewed interest in the pharmaceutical industry. Clinical studies have shown that even small amounts of this psychedelic substance can improve moods in rats after a single dose.
Researchers quickly identified potential explanations for these effects in various anatomical and animal model studies. They discovered links between ketamine’s impact and changes in functional connectivity and activity in brain regions associated with depression.
Subsequent studies involving patients diagnosed with severe depression have demonstrated significant reductions in suicidal thoughts and improvements in mood, leading to the FDA approval of ketamine as a nasal spray for treatment-resistant depression.
Despite the hope surrounding ketamine, it raises the question of whether the experience of taking a powerful psychoactive substance is crucial to its therapeutic benefits.
In order to examine this, Heifets and his team assigned 40 surgical patients to either the ketamine group or the saline group while they were under general anesthesia, effectively ‘masking’ the mind-altering effects of the drug. Neither the patients nor the investigators or care staff knew which group received which infusion. At the end of the trial, just over a third of the participants correctly guessed their group affiliation.
Interestingly, in the days following their infusion, both groups showed improvements in mood according to the Montgomery–Åsberg Depression Rating Scale. This suggests that ketamine’s benefits may be largely attributed to the psychology of medical treatment in general, rather than specific biochemical mechanisms.
However, this does not necessarily mean that ketamine is ineffective in treating depression. It implies that its influence may be more related to the overall treatment experience rather than precise biochemical adjustments.
“We also considered the possibility that surgery and general anesthesia without ketamine has an antidepressant effect,” write the researchers. “However, our review of previous studies measuring symptoms of depression in the perioperative period strongly suggests otherwise.”
The human brain is complex, and depression itself is a multifaceted phenomenon that cannot be easily explained by ‘chemical imbalances’ or maladjusted circuits.
Just as we have discovered that combining MDMA with therapy can provide healing experiences for patients with PTSD, controlled doses of ketamine in the right environment may help individuals with severe depression find a way forward.
“There is undoubtedly a physiological mechanism, something that happens between your ears when you instill hope,” says Heifets.
This research has been published in Nature Mental Health.
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