In March, the U.S. Food and Drug Administration approved ketamine nasal spray to treat depression. Ketamine has gotten a bad rap as an opioid - which it is not - despite solid scientific evidence suggesting that it isn't one.
According to Adam Kaplin, M.D., Ph.D., an assistant professor of psychiatry and behavioral sciences at Johns Hopkins School of Medicine, both patients and physicians tend to perceive ketamine as an opioid. "This is most worrisome if people continue to think this way, particularly in the wake of the opioid epidemic; clinicians won't refer patients for treatment, despite that it has been shown to be incredibly effective for many patients with treatment-resistant depression," says Kaplin.
Researchers published their viewpoint and explanation of the drug's mechanism as a Letter to the Editor in the American Journal of Psychiatry.
Naltrexone - a drug used to treat opioid addiction by preventing opioid effects (e.g. feelings of well-being, pain relief) - binds to opioid receptors on brain cells and prevents other opioids like heroin from binding. In 2018, a study showed that naltrexone also blocks the antidepressant effects of ketamine, which led researchers to conclude that ketamine may also bind to opioid receptors. But this is not true. According to Kaplin, ketamine actually binds primarily to an entirely different set of receptors: the NMDA receptors - important for learning and memory - rather than the opioid receptors.
Normally, NMDA receptors are activated by the chemical glutamate. Turning on these receptors turns off a master control switch in the cell called mTOR, which ultimately is in charge of creating new memories. Ketamine also binds to the NMDA receptors, but it has the opposite effect in that it turns these receptors off. Turning off NMDA receptors turns on the mTOR switch, which is required for the drug's antidepressant effects.
The "ketamine as an opioid" misconception is all about mTOR. Opioid receptors in the brain are actually always turned on at low-levels, even in the absence of a drug. This low activity suppresses a chemical called cyclic AMP (cAMP). When the drug naltrexone is administered, it binds to opioid receptors, thereby increasing cAMP. Remember, ketamine turns on mTOR, which enables antidepressant effects; but if naltrexone is given in addition to ketamine, mTOR is shut down again. This is why naltrexone overrides the antidepressant effects of ketamine.
Although NMDA receptors are found together with opioid receptors in the brain, and their components can meddle with each other, this does not mean that ketamine is an opioid, says Kaplin.
In a more psychological or behavioral sense, another reason ketamine should not be considered an opioid because it actually does not have the same addictive potential as opioids. The FDA specified that ketamine is to be administered under the watch of physicians in small doses and in a controlled clinical setting to minimize any chance of abuse. The drug works much faster than traditional antidepressants, sometimes even after just one or two uses, which also decreases the risk of abuse.