'Laughing Gas' Shows Promise Against Tough-to-Treat Depression

When antidepressants fail to rein in hard-to-treat depression, the common anesthetic most know as "laughing gas" might be a safe and effective alternative, new research suggests.

The finding follows work with 28 patients struggling with "treatment-resistant major depression," a severe condition that investigators say affects about one-third of all patients — an estimated 17 million American adults — who develop major depressive disorder.

For such patients, antidepressants often fail to provide relief. But following three one-hour laughing gas inhalation sessions spread across three months, 85% of patients had significant depression relief that endured weeks post-treatment.

"Laughing gas is nitrous oxide, one of the oldest and most commonly used anesthetics," explained study author Peter Nagele, chair of anesthesia and critical care at the University of Chicago.

"And we found that laughing gas, at a much lower concentration than is used, for instance, during dental procedures, can help patients with difficult-to-treat depression," Nagele said.

Between 2016 and 2019, Nagele's team tried out two laughing gas formulations: one at a level of 50% nitrous oxide and one at a level of 25%.

Previous investigations had already demonstrated an antidepressant benefit at the higher level. But those efforts only assessed a post-treatment benefit of 24 hours. And patients exposed to the higher dose commonly experienced side effects, including nausea, sedation and or "mild dissociation," a kind of daydreaming experience.

In the latest study, patients were between the ages of 18 and 75. All were told to continue their usual depression care and maintain their existing antidepressant regimen.

About one-third were exposed to three sessions of 50% nitrous oxide inhalation treatment, one-third were given a 25% nitrous oxide inhalation treatment and one-third were given an oxygen inhalation treatment that contained no laughing gas.

Treatment was delivered via a standard anesthesia face mask, and all were monitored for up to one hour post-treatment.

After four patients withdrew from the study, results were drawn from 20 patients who completed all three inhalation sessions and four patients who completed at least one treatment.

The investigators found that both formulations offered significant depression control. In fact, just a single session (at either dosage) provided "rapid" depression control among patients, the team noted.

Depression control also appeared to grow in effect over time, enduring up to a month post-treatment among some of the patients. At the three-month mark, the team found that 85% of patients had symptom improvement and 40% were found to be in depression remission.

Perhaps just as importantly, the team also found that "using a lower concentration of nitrous oxide also reduced the risk of side effects fourfold."

So, how exactly does laughing gas tamp down depression?

"The mechanism of how nitrous oxide exerts antidepressant effects is unknown, and is likely different from how it induces sedation and unconsciousness and also pain relief," Nagele said. "Having said this, the most widely accepted theory is that nitrous oxide blocks a specific receptor in the brain called NMDA-receptor, which is also considered the main mechanism for [the medication] ketamine."

Ketamine is a class III scheduled drug. While hospitals traditionally deploy the drug as an anesthetic, it's also been explored for its potential as an "off-label" treatment for depression.

According to Steven Hollon, a professor of psychology at Vanderbilt University in Brentwood, Tenn., "Ketamine is the hottest thing going" in the world of alternative depression treatment research.

Hollon was not involved in the new study, and acknowledged that he is not well-versed in the specifics of nitrous oxide depression treatment research. Still, he stressed that the finding "suggests a common mechanism" with ketamine. And he characterized Nagele's work as "a most impressive 'proof-of-concept' study that would make me want to see the matter pursued."

The depression control seen among those patients exposed to low-dose laughing gas was "as good or better than you would hope to get in a placebo-controlled trial with antidepressant medications, and these are treatment-resistant patients. [It's] quite impressive," Hollon noted.

"If they came forward with this as pilot data, I would fund them for a major trial," he added. "These are very promising findings."

The report by Nagele and his colleagues was published in the June 9 issue of Science Translational Medicine.