‘Laughing Gas’ May Help Tough-to-Treat Depression

By Alan Mozes
Health Day reporter

THURSDAY, June 10, 2021 (HealthDay News) – When antidepressants fail to control difficult-to-treat depression, the common anesthetic best known as ‘laughing gas’ could be a safe and effective alternative, new research finds .

The discovery follows work on 28 patients with “treatment-resistant major depression,” a serious illness that researchers say affects about one-third of all patients – about 17 million American adults – who develop major depressive disorder.

For these patients, antidepressants often fail to provide relief. But after three one-hour laughing gas inhalation sessions over three months, 85% of patients had significant relief from depression that lasted for weeks after treatment.

“Laughing gas is nitrous oxide, one of the oldest and most commonly used anesthetics,” said study author Peter Nagele, president of anesthesia and intensive care at the University of Chicago.

“And we’ve found that laughing gas, at a much lower concentration than that used, for example, during dental procedures, can help patients with difficult-to-treat depression,” Nagele said.


Between 2016 and 2019, Nagele’s team tested two formulations of laughing gas: one at 50% nitrous oxide and the other at 25%.

Previous investigations had already demonstrated an antidepressant benefit to the next level. But these efforts only evaluated a 24-hour post-treatment benefit. And patients exposed to the highest dose often experienced side effects, including nausea, sedation, and / or “mild dissociation,” a kind of daydreaming.

In the last study, the patients were between 18 and 75 years old. Everyone was told to continue with their usual depression care and to maintain their existing antidepressant regimen.

About a third were exposed to three sessions of 50% nitrous oxide inhalation therapy, one third received 25% nitrous oxide inhalation therapy, and one third received oxygen inhalation therapy without laughing gas.

Treatment was administered via a standard anesthetic face mask, and all were monitored for up to one hour after treatment.

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


The researchers found that both formulations offered significant depression control. In fact, just one session (at either dosage) brought depression in patients “quickly”, the team noted.

Control of depression also appeared to increase in effect over time, persisting for up to a month after treatment in some of the patients. After three months, the team found that 85% of patients had improvement in symptoms and 40% were in remission from depression.

Perhaps equally important, the team also found that “using a lower concentration of nitrous oxide also reduced the risk of side effects by four times.”

So how exactly does laughing gas alleviate depression?

“The mechanism by which nitrous oxide exerts antidepressant effects is unknown and is likely different from how it induces sedation and unconsciousness as well as pain relief,” Nagele said. “That said, the most widely accepted theory is that nitrous oxide blocks a specific receptor in the brain called the NMDA receptor, which is also believed to be the primary mechanism of [the medication] ketamine. “


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

According to Steven Hollon, professor of psychology at Vanderbilt University in Brentwood, Tennessee, “ketamine is the hottest thing” in the world of alternative depression treatment research.

Hollon was not involved in the new study and admitted that he was unfamiliar with the specifics of research into the treatment of depression with nitrous oxide. Still, he stressed that the finding “suggests a common mechanism” with ketamine. And he described Nagele’s work as “a most impressive ‘proof of concept’ study that would make me want to see the question pursued.”

The depression control seen in patients exposed to low doses of laughing gas was “as good or better than what you expect in a placebo-controlled trial of antidepressants, and these are treatment-resistant patients.” [It’s] pretty impressive, ”Hollon noted.

“If they presented this as pilot data, I would fund them for a major test,” he added. “These are very promising findings.”


Nagele and colleagues’ report appeared in the June 9 issue of Science Translational Medicine.

More information

There is more information on treatment-resistant depression at the Mayo Clinic.

SOURCES: Peter Nagele, chair, Anesthesia and Critical Care, Department of Anesthesia and Critical Care, University of Chicago; Steven Hollon, PhD, professor of psychology, Vanderbilt University, Brentwood, Tenn .; Science Translational Medicine, June 9, 2021

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