Ketamine is not an opioid and treats depression in a unique way

Ketamine has a reputation for being an opioid when there is ample evidence to suggest that this is not one, say the Johns Hopkins experts. They believe that this reputation may prevent patients from receiving the treatment needed to treat types of depression that do not respond to conventional antidepressants. In a new article, researchers clarify the mechanism underlying the mechanism of action of ketamine in the hope of restoring the status of therapy to health professionals and the public.

In March of this year, the US Food and Drug Administration approved ketamine nasal spray for treating depression.

"A study at the end of last year found that ketamine had black eyes and thanks to this coverage, potential patients and doctors have widely accepted that ketamine is an opioid," says Adam Kaplin. MD, Ph.D., Assistant Professor of Psychiatry and Behavioral Sciences at the Johns Hopkins University School of Medicine. "It's worrying if people continue to think that way, especially as a result of the opioid epidemic; clinicians will not refer patients to treatment even though it has been shown to be incredibly effective for many patients with treatment-resistant depression. "

The researchers published their point of view and an explanation of the alternative mechanism in the form of a letter to the editor in the May 1 issue of American Journal of Psychiatry.

Naltrexone, a medication used to treat accidental overdoses of opioids, binds to the opioid receptors on the surface of brain cells and prevents opioids such as morphine or heroin from sticking to them and acting on the brain. .

At the end of 2018, researchers at Stanford and Palo Alto Universities showed that naltrexone also blocked the antidepressant effects of ketamine, which led them to suggest that ketamine also had to bind to the same opioid receptors and concluded that so that ketamine should be an opioid. Kaplin says that there is much contrary evidence showing that ketamine sticks on a receptor totally different from brain cells: NMDA receptors – involved in learning and memory – instead of opioid receptors.

He proposes how it works:

Normally, NMDA receptors are activated when chemical messenger glutamate binds to them. The activation of NMDA receptors disables a master control switch in the cell called mTOR, which results in the learning of behavior or the formation of a new memory. Ketamine can also bind to NMDA receptors, but it has the opposite effect of glutamate, ie it deactivates these receptors. The deactivation of the NMDA receptors activates the main mTOR control switch, essential for the antidepressant properties of ketamine.

Kaplin explains that opioid receptors are normally activated at low levels all the time, even without an opioid to fully activate them. This low opioid receptor activity normally suppresses the level of another chemical messenger called cyclic AMP (cAMP). When Naltrexone overdose is administered, it sticks to the opioid receptors, completely extinguishing them, which releases the cAMP brakes. This increase in cAMP is what then interferes with the main mTOR switch, which turns it off. When ketamine is taken, it activates the main mTOR switch to activate antidepressant effects, but if naltrexone is administered on top of that, naltrexone clogs and closes the mTOR again. It is through cAMP that naltrexone reverses and extinguishes the antidepressant effects of ketamine.

These NMDA receptors are found at the same time as the opioid receptors on the brain cells and Kaplin explains that it is no wonder that their components can mingle with each other, such as interference picked up by a phone call or on the radio. "This interference and cross-talk does not mean that ketamine is an opioid, and the wrong label as such could possibly prevent patients from taking essential antidepressants that could make a huge difference in their quality of life." Kaplin said.

The FDA has specified that ketamine should be administered in small doses and in a health care facility under medical supervision to minimize the risk of abuse. The drug works much faster than other traditional antidepressants on the market, sometimes even after one or two uses.

Kaplin and his team are setting up their own ketamine treatment clinic at Johns Hopkins, which should open in the next year.