Can Ketamine Use Trigger Opioid-Like Dependency?

Researchers investigated whether ketamine works on depression by acting like an opioid in the brain.

Though ketamine has gained the support of some mental health professionals as a possible therapy for depression, a new study suggests that the drug’s anti-depressive qualities may also have a hidden and potentially dangerous side effect: ketamine may offer relief from depressive symptoms by activating the body’s opioid system, which in turn may make some users dependent upon it, like an opioid.

In an editorial that accompanied the study, Dr. Mark George, professor of psychiatry, radiology and neuroscience at the Medical University of South Carolina, wrote, “We would hate to treat the depression and suicide epidemics by overusing ketamine, which might unintentionally grow the third head of opioid dependence.”

The study, conducted by researchers from Stanford University and published in the August 2018 edition of the American Journal of Psychiatry, was comprised of a double-blind crossover of 30 adults with treatment-resistant depression, which was defined as having tried at least four antidepressants and receiving no benefit from them.

The authors looked at 14 of the patients—of which 12 had received, in randomized order, two doses of 0.5 mg of ketamine—once after receiving 50 mg of naltrexone (or Vivitrol) which blocks the brain’s opiate receptors and diminishes cravings for opioids; and once after receiving a placebo instead of the naltrexone—with the injections occurring about a month apart. 

The goal of the study was to determine whether the naltrexone and ketamine combination would reduce the latter drug’s antidepressant qualities, or its dissociative or opioid-like response.

The authors’ analysis found that when patients received the placebo/ketamine combination, they experienced what Live Science called a “dramatic reduction” of their depressive symptoms. But the naltrexone/ketamine combination appeared to have no effect on their symptoms.

Additionally, those participants who received naltrexone experienced the dissociative effects of ketamine, which include hallucinations, which prompted the authors to cut the study short to avoid exposing more participants to a “clearly ineffective and noxious combination treatment,” as the study noted.

The scope of the study was small, and as George (who was not involved in the study) noted, additional research is required in order to determine if the ketamine’s antidepressant qualities are caused by its impact on opioid receptors or another receptor. He ultimately expressed caution in regard to using ketamine for the treatment of depression.

“Ketamine clinics that do not focus on accurate diagnosis, use proper symptom rating instruments and discuss long-term treatment options are likely not in patients’ best interests,” he wrote in the editorial. “We need to better understand ketamine’s mode of action and how it should be used and administered.”

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