A combination of ketamine and naltrexone may help treat those suffering from depression and substance abuse disorders, according to a new Yale study.

Published in the Journal of the American Medical Association Network scientific journal on Jan. 19, the study was inspired by the need for a simultaneous treatment of depression and substance abuse disorders. As many as 40 percent of all those suffering from depression have alcohol abuse problems, according to Gihyun Yoon, psychiatry professor at the Yale School of Medicine and lead author of the study.

“This study is unique in the field of ketamine research as it focuses on patients suffering from substance abuse problems. Other similar studies do not administer ketamine to patients suffering from addiction problems because of ketamine’s known abuse potential as a recreational drug,” Yoon said.

Several School of Medicine studies from the late 1990s and early 2000s have shown that ketamine possesses rapid-acting antidepressant properties. While regular antidepressants may take months to improve depression symptoms, Yale researchers have noted that ketamine starts to take effect hours after its first administration.

This study found that ketamine treats depression by blocking the activity of glutamate, a chemical in the brain, while naltrexone acts as an opiate blocker.

“By combining an opiate blocker with a glutamate blocker, we think it may be possible to effectively treat patients who have a combination of depression and addiction,” explained John Krystal, chair of the psychiatry department at the medical school and co-author of the study.

In the study, five individuals suffering from depression and alcohol abuse disorder were first given an injection of naltrexone. Krystal noted that this single injection was enough to maintain sufficient drug levels in the participants for the entire study. Next, they received four intravenous ketamine infusions.

Four out of the five individuals responded to the first ketamine infusion, while all five individuals showed improvement in depression symptoms after four infusions. In addition, 80 percent of the respondents reduced their alcohol cravings and consumption.

The results of the study disagree with ketamine research conducted at Stanford University, which suggests that the use of naltrexone alongside ketamine would counterintuitively block the antidepressant effects of ketamine. The Stanford study found that opioid-receptor simulation was necessary to produce the antidepressant effects of ketamine, thus rendering the ketamine-naltrexone drug combination futile.

“Contrary to the research conducted at Stanford, our study found that ketamine was still effective in treating depression, even after it was administered with naltrexone,” Yoon said.

Recognizing the limits of this preliminary study as a tiny pilot study comprising only five participants, Yoon underscored the need to recreate this study on a larger scale. Currently, he is in the process of conducting a large randomized clinical trial testing the combined effects of the two drugs, which he hopes to complete by 2021.

Among individuals with recurrent major depression, roughly 16.5 percent have an alcohol use disorder, and 18 percent have a drug use disorder, according to the National Institutes of Health.

Ishana Aggarwal | ishana.aggarwal@yale.edu