Researchers Discover That Fast-Acting Antidepressant Ketamine Engages the Body’s Opioid System

Researchers Discover That Fast-Acting Antidepressant Ketamine Engages the Body’s Opioid System

Posted: October 2, 2018
Researchers Discover That Fast-Acting Antidepressant Ketamine Engages the Body’s Opioid System

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In a small clinical trial, researchers demonstrated that the experimental rapid-acting antidepressant ketamine cannot exert its therapeutic effects without engaging the body’s opioid system. This result will likely intensify efforts to determine the drug’s mechanism of action, and should inform the way the drug is used, even experimentally, in patients with chronic major depression.



Alan F. Schatzberg, M.D.

Stanford University School of Medicine

Scientific Council Member (Joined 2005)

2005 Falcone Prizewinner for Outstanding Achievement in

Affective Disorders Research (Colvin Prize)


Ketamine has been used for decades as an anesthetic and occasionally as a pain reliever. In recent years the drug has been used experimentally as a rapid-acting antidepressant for patients who have failed to respond to FDA-approved antidepressant treatments. In many instances, seriously depressed individuals, including some who have been on the verge of suicide, have responded to the drug within minutes or hours, their symptoms dissipating for periods typically ranging from days to a week.

Yet ketamine remains an experimental treatment. One reason is that it has serious side effects that would argue against its repeated use over long periods of time in chronically depressed people. It can be abused and has been misused for many years as a “party drug.” It can also cause dissociation, a feeling of detachment that can verge on a loss of connection with the surrounding environment.

In research published in September 2018 in the American Journal of Psychiatry, a team led by Alan F. Schatzberg, M.D., a Foundation Scientific Council member and 2005 Falcone Prize winner, and Nolan Williams, M.D., a BBRF 2018 and 2016 Young Investigator, both of Stanford University, has now discovered that ketamine cannot exert its acute antidepressant effect without engaging the body’s opioid system. Other senior investigators included Carolyn Rodriguez, M.D., Ph.D., a 2014 and 2009 BBRF Young Investigator.

The team gave 14 patients with treatment-resistant depression two courses of treatment. In both courses, they were treated with ketamine, administered intravenously. In both courses, the subjects also took a pill prior to receiving ketamine. In one treatment, the pill was a placebo. In the other treatment, the pill contained naltrexone, a drug that blocks the body’s opioid receptors.

Twelve of the patients completed both courses of treatment. When they were pretreated with placebo and then received ketamine, 7 of the 12 had a dramatic reduction of their depression symptoms. None of those 7 patients responded when they were pretreated with naltrexone, the opioid receptor blocker.

This study, supported in part by Dr. Williams’ 2016 BBRF Young Investigator award, leads the team to recommend replicating the experiment in a larger patient group and learning more about how ketamine engages the opioid system, perhaps via functional neuroimaging studies.

Efforts have been under way for several years to modify the ketamine molecule or to synthesize alternative molecules that act like it but which have better side-effect profiles. For the moment, as BBRF Scientific Council member Mark S. George, M.D., noted in an editorial published in concert with the paper in the American Journal of Psychiatry, “we should be cautious about widespread and repeated use of ketamine” until its mechanism of action is more fully understood. “While almost anything that resolves suicidality is helpful, it is important to remember that treatment-resistant depression is a chronic and recurring illness, and ketamine may or may not become a chronic treatment,” Dr. George wrote.

If you found this article interesting, you may find this Meet the Scientist Webinar interesting: Ketamine: Why Now? How? Where Do We Go from Here?