Anaesthetic-turned-recreational drug ketamine has become the subject of intense research in recent years, as scientists hunt for new and improved treatments for depression. This line of investigation has produced many promising results, but a new study has highlighted some parallels between ketamine and opioids, raising red flags for scientists concerned about the potentially addictive qualities of the drug.

Evidence uncovered by scientists in recent years has pointed to a protein receptor in the brain called N-methyl-D-aspartate (NMDA) as being pivotal to the antidepressant effects of ketamine. Recent research has shown that by blocking this receptor, the drug is suppressing the brain's anti-reward center, which plays the unsavoury role of blocking pleasure-giving neurotransmitters like dopamine and serotonin.

And ketamine does this with remarkable swiftness and longevity compared to traditional antidepressant medications. So much so that, although ketamine is not approved by the FDA as a treatment for depression, a number of ketamine clinics have popped up in the US offering off-label experimental treatments for the condition at exorbitant prices.

But one team of Stanford scientists had a sense that something else was at play beyond the mere NMDA-blocking capacity of ketamine. These suspicions were aroused by an earlier study at the university examining how ketamine can also reduce the symptoms of obsessive compulsive disorder (OCD), which appeared eerily similar to another study exploring the use of the opioid morphine.

So the scientists designed a study to explore a possible relationship between the antidepressant effects of ketamine and the body's opioid receptors. In it, 12 subjects with treatment-resistant depression were given randomized ketamine infusions, after either receiving an opioid receptor blocker called naltrexone, or after receiving a placebo.

In this randomized double-blind crossover trial, the scientists found that more than half the subjects who received a placebo experienced a 90 percent reduction in depressive symptoms for three days, while virtually no effect was observed in those who received naltrexone.

The study may be small but its findings are significant, largely because they are unexpected and mark the first time that an opioid receptor site has been shown as necessary to the antidepressant effects of ketamine. For so long, ketamine had been classed as a non-opioid drug, yet this new evidence points to the contrary.

"Everything that I was taught, and everything that I've always taught my students – all of the evidence supports the fact that ketamine is not an opioid," says study co-author Boris Heifets, assistant professor of anesthesiology, perioperative and pain medicine a Stanford. "I was really surprised at the results."

These results may also help explain how ketamine works so quickly as an antidepressant. Scientists think it might be switching on these opioid receptors during initial stages for fast-acting relief, while the NMDA-blocking function may be the cause for the long-lasting effects once the ketamine has been metabolized.

"I wasn't sure that ketamine really worked to treat depression," says Alan Schatzberg, MD, professor of psychiatry and a senior author of the study. "Now I know the drug works, but it doesn't work like everyone thought it was working."

Given this small but disconcerting link with the opioid system, scientists are urging a rethink of the widespread use of ketamine as a depression treatment, and with good reason. Opioid use and addiction has now skyrocketed to the point where it was declared a public health emergency by the US Department of Health and Human Services last year, following 42,000 deaths from opioid overdose in 2016.

"We would hate to treat the depression and suicide epidemics by overusing ketamine, which might perhaps unintentionally grow the third head of opioid dependence," writes neuroscientist Mark George, from the Medical University of South Carolina in an editorial accompanying the study. "With these new findings, we should be cautious about widespread and repeated use of ketamine before further mechanistic testing has been performed to determine whether ketamine is merely another opioid in a novel form."

The research was published in the journal The American Journal of Psychiatry.