Ketamine has received a bad rap as an opioid, according to John Hopkins experts, and that when there’s plenty of evidence suggesting it isn’t one. They believe this reputation may hamper patients from getting necessary treatment for the kinds of depression that don’t respond to typical antidepressants. In hopes of restoring the therapy’s standing among healthcare professionals and the public, the researchers clarify the mechanism behind ketamine’s mechanism in a new paper. In March the US Food and Drug Administration approved esketamine, a version of the ketamine molecule, as a nasal spray to treat depression that hasn’t responded to other treatments.

When ketamine is taken, it turns on the master switch mTOR to enable antidepressant effects, but if naltrexone is given on top of that, naltrexone obstructs and shuts off the mTOR again.

“A study done late last year delivered a black eye to ketamine, and as a result of the coverage, there was a wholesale acceptance by both potential patients and physicians that ketamine is an opioid,” said Dr Adam Kaplin, assistant professor of Psychiatry and Behavioural Sciences at the Johns Hopkins University School of Medicine. “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.”

Naltrexone (the drug used to reverse accidental opioid overdoses) binds to opioid receptors on the surface of brain cells and prevents opioids like morphine or heroin from sticking to them and acting on the brain, preventing the high. In late 2018, researchers at Stanford University and Palo Alto University showed that naltrexone also blocks the antidepressant effects of ketamine, which led them to propose that ketamine must also bind to the same opioid receptors and thus concluded that ketamine must be an opioid.

Dr Kaplin said there’s plenty of contrary evidence demonstrating that ketamine sticks to an entirely different receptor on brain cells: the NMDA receptors – involved in learning and memory – instead of the opioid receptors. According to Dr Kaplin it works as follows: Normally, NMDA receptors get turned on when the chemical messenger glutamate binds to them. Turning on the NMDA receptors turns off a master control switch in the cell called mTOR, which ultimately results in learning a behaviour or forming a new memory. Ketamine can also bind to the NMDA receptors, but it has the opposite effect of glutamate, in that it turns these receptors off.

Turning off the NMDA receptors turns on the master control switch mTOR, which is required for ketamine’s antidepressant properties. Separately opioid receptors are normally turned on at low-levels all the time, even without opioids to turn them on all the way, said Dr Kaplin. This low activity of the opioid receptors normally suppresses the level of another chemical messenger called cyclic AMP (cAMP). When the overdose drug naltrexone is administered, it sticks to the opioid receptors, turning them completely off, which releases the brakes on cAMP.

This increase in cAMP is what then interferes with the master switch mTOR, shutting it down. When ketamine is taken, it turns on the master switch mTOR to enable antidepressant effects, but if naltrexone is given on top of that, naltrexone obstructs and shuts off the mTOR again. It is through cAMP that naltrexone overrides and extinguishes the antidepressant effects of ketamine. These NMDA receptors are found together with the opioid receptors on brain cells, and Dr Kaplin said it’s no surprise their components can meddle with one another, like interference picked up on a phone call or on the radio.

“This interference and cross-talk does not mean ketamine is an opioid, and to wrongly label it as such could eventually keep patients from essential antidepressant medications that could make a huge difference in their quality of life,” said Dr Kaplin. The FDA specified that ketamine is to be administered under the watch of physicians in small doses and in a healthcare setting to minimise any chance of abuse. The drug works much faster than other traditional antidepressants on the market, sometimes even after one or two uses. Chief psychiatrist at Yale Medicine and one of the pioneers of ketamine research in the US, Dr John Krystal has called esketamine ‘a game changer’.

“With most medications, like Valium, the anti-anxiety effect you get only lasts when it is in your system. When the Valium goes away, you can get rebound anxiety. When you take ketamine, it triggers reactions in your cortex that enable brain connections to regrow. It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects,” he explained. “And this is exactly what makes ketamine unique as an antidepressant, Dr Krystal said. Dr Kaplin and his team are in the process of setting up their own ketamine clinic at Johns Hopkins, which they anticipate will be opening within the next year.