A new study from Stanford sheds light on how ketamine works in the brain to alleviate depression.

The research suggests that the drug not only impacts a network of switches called the glutamate system, but also engages the opioid system — the same one that's activated by opioid painkillers.

The finding could have big implications for plans to turn ketamine into the next blockbuster antidepressant.

Ketamine's unique ability to staunch the symptoms of depression has earned it a new reputation in recent months. No longer seen solely as an illicit party drug, the compound is the focus of research into a novel class of antidepressants that could yield the first new depression drug in more than 30 years.

But the science of how ketamine stonewalls depression symptoms has remained murky. For years, researchers believed it worked by acting on a network of brain receptors called the glutamate system, which other popular antidepressants ignore. But a new study suggests that ketamine also influences the brain's opioid network — the same one engaged by opioid painkillers.

That could have implications for plans to turn the drug into a pharmaceutical. Drug companies including Allergan, Johnson & Johnson, and a San Francisco-based drug maker called VistaGen have all been looking to ketamine as inspiration for the next blockbuster antidepressant.

"When we say this is a new generation of drugs, we mean it. This drug is fundamentally different from all the other antidepressants that have been approved so far," Shawn Singh, VistaGen's CEO, told Business Insider in May.

The new paper, published Tuesday night in the American Journal of Psychiatry and funded by the National Institutes of Health, is the first to illuminate how ketamine exerts its effects in the brain.

Alan Schatzberg, a co-author on the paper and a professor of psychiatry at Stanford, told Business Insider that he hopes drug makers can use his team's discovery to streamline their efforts and avoid the pitfalls of antidepressant drug candidates that have failed.

"Before we did the study, I had some doubts about ketamine's use for treating depression," Schatzberg said. "Now I've seen the drug work, but I've also seen it doesn't work the way people originally thought."

How ketamine is distinct from existing depression drugs

Most existing antidepressants, from Abilify to Zoloft, work by plugging up the places where our brain takes up serotonin, a chemical messenger that plays a key role in mood. The result is more free-floating serotonin and, in some people, relief from a dark curtain of depressive symptoms.

But those effects don't occur in everyone who tries the drugs. In fact, up to 80% of the people who try existing antidepressants fail to see results. Plus, the drugs take four to six weeks to work. As a result, depression remains one of the world's leading causes of death.

Ketamine, on the other hand, affects key switches in the brain called NMDA receptors. Collectively, these switches are part of a larger network in the brain called the glutamate system. Like serotonin receptors, those for NMDA play an important role in our mood and help keep our emotions in check. But NMDA receptors also keep our brain's synapses — the delicate branches that serve as the ecosystem for our thoughts — flexible and resilient.

Depression appears to cause those synaptic branches to shrivel up and in some cases even die. Scientists think existing antidepressant drugs send help to those branches indirectly over time by way of serotonin. Ketamine, by contrast, delivers its aid directly by plugging up NMDA receptors like a cork and nipping depressive symptoms within hours.

This mechanism of action spurred some scientists to call ketamine "the most important discovery in half a century" in 2012.

The new study suggests that in addition to affecting the glutamate system, ketamine also impacts the same switches that are targeted by opioid painkillers.

For their work, the Stanford researchers gave 12 adults whose depression failed to respond to multiple treatments two infusions of ketamine. Before the first infusion, the participants took a drug that blocks the brain's opioid receptors. Before the second infusion, the participants got a placebo. (The participants and researchers were never told whether they were getting the drug or the placebo — a double-blind setup designed to minimize the chance that observed results were merely psychological.)

In more than half the cases in which the participants got the placebo, the ketamine appeared to reduce depressive symptoms by roughly 90%; the effects lasted about three days. Conversely, when the patients got the opioid-blocker before the ketamine, the ketamine had virtually no antidepressant effects.

This finding led the researchers to hypothesize that ketamine's activity takes place in different phases. In the first, the drug activates the brain's opioid receptors, quickly smothering depressive symptoms, one of the researchers suggested in the paper. In the second phase — which is thought to be key for ketamine's lasting antidepressant qualities — the drug appears to engage the brain's glutamate system.

What the next blockbuster antidepressant needs

Several drug companies have tried and failed to create a new depression drug that targets the NMDA receptors in the glutamate system. Pharmaceutical giant Roche pulled the plug on a drug called basimglurant in 2016 after it failed to show results in a Phase II study; AstraZeneca discontinued its work on a heavily-promoted candidate called lanicemine in 2013.

Yet ketamine's rapid-fire ability to stymie depressive symptoms has continued to baffle and inspire researchers looking for an alternative to current treatments.

Allergan, Johnson & Johnson, and VistaGen are all currently working to develop new ketamine-inspired drugs. In fact, two of the authors on the latest paper previously consulted for these companies: Schatzberg received a grant from Janssen, Johnson & Johnson's neuroscience partner, and study author Carolyn Rodriguez has consulted for Allergan.

None of the three drug candidates target the brain's opioid system, however.

Mark Smith, VistaGen's chief medical officer, said that although the results of the study are "intriguing," they would not directly impact the company's work on its new drug.

Similarly, a representative from Janssen, whose work with Johnson & Johnson has focused on a nasal-spray version of esketamine (the chemical mirror image of ketamine), told Business Insider in a statement that the Stanford study would not impact the direction of their work. They added that there were several issues with the study, including the fact that it was small and did not include "relevant control conditions."

But overall, the new study sheds light on important questions about why — and how — ketamine works to fight depression in the brain.

"I think this paper points us in the direction that the [opioid system] is an area for potential interest," Schatzberg said. "The question is, can we have a rational discussion about this in an era when there’s an opioid crisis?"