Ketamine for Depression: How the Promising Antidepressant Drug Appears to Work like an Opioid

Ketamine—the anesthetic co-opted as a party drug—appears to ease the symptoms of depression because it taps into the brain's opioid system, according to a small study.

In recent years, evidence suggesting ketamine could fight depression even in patients unresponsive to existing treatments has been piling up. While it has not yet been approved by the FDA for the condition, some doctors have prescribed it "off-label". Scientists at Stanford University School of Medicine set out to investigate what appears to make it so powerful.

Past studies have indicated ketamine works on the part of the brain in charge of glutamate: A neurotransmitter released by nerve cells in the brain. The cause of depression is unknown, but some evidence suggests a problem with the glutamatergic system could play a role. As a result, drugs that block the glutamate receptor NDMA to treat the mental illness have been explored.

But the team at Stanford University looked at ketamine from another angle and were surprised by what they found. Dr. Boris Heifets, co-author of the study published in the American Journal of Psychiatry and clinical assistant professor of anesthesiology, perioperative and pain medicine at Stanford University, told Newsweek: "Most scientists and clinicians have thought that ketamine belongs in a class of drugs called 'NMDA receptor antagonists'. We challenged that assumption, and found that ketamine's antidepressant effect actually requires opioid receptors."

To test their hypothesis, the researchers recruited 14 people with treatment-resistant depression for a small study. Of the total, 12 were given ketamine infusions on separate occasions. In one instance, they were dosed with naltrexone, a drug that blocks opioid receptors and is commonly used to reverse overdoses. The ketamine was preceded with a placebo in the other instance. The participants didn't know whether they were receiving a placebo or naltrexone.

Read more: FDA approves psychedelic magic mushrooms ingredient psilocybin for depression trial

When ketamine was administered with a placebo, more than half of participants reported a 90 percent reduction in their depressive symptoms for three days. But when they were given naltrexone, their symptoms largely remained.

The authors of the study deduced ketamine cuts away at depressive symptoms because it lights up the brain's opioid receptors. And the glutamate system likely plays a role in keeping these effects rolling after the body has metabolized the drug.

Selective serotonin reuptake inhibitors, among the most commonly prescribed antidepressant medication, can take up to six weeks to kick in and don't help two thirds of patients. Off the back of studies suggesting ketamine could treat depression, clinics offering drips of the drug have popped up. But experts have warned more research is needed to uncover the side effects of such treatments. The drug is also used to treat chronic pain, which is relatively common among depression patients.

Heifets said he was surprised to find ketamine's antidepressant effect seemed to be blocked by naltrexone. "We use ketamine quite a lot in the operating room and even the textbooks say ketamine is primarily an NMDA receptor antagonist."

Dr. Alan Schatzberg, co-author of the study and professor of psychiatry and behavioral sciences, said in a statement: "Before we did the study, I wasn't sure that ketamine really worked to treat depression. Now I know the drug works, but it doesn't work like everyone thought it was working."

The team hopes its research can help tackle some of the biggest public health crises facing the U.S.: mental health, pain and opioid addiction.

"Our findings add to a body of research showing that depression, pain and the brain's opioid system are tightly related; we have an epidemic of all three in the USA, and I believe we have to address them together," said Heifets.