Laughing gas may treat depression, small study suggests

Laughing gas doesn't just make people giggle, it can also induce a feeling of euphoria. Now, a new study suggests that laughing gas, or nitrous oxide, may relieve depression in patients who are resistant to other treatments.

Two weeks after inhaling a mixture of laughing gas and oxygen for an hour, participants in an early stage clinical trial had less severe symptoms of depression than they did two weeks after a placebo treatment, according to research published June 9 in the journal Science Translational Medicine. 

"A large percentage of patients don't respond to standard antidepressant therapies," Dr. Charles R. Conway, a professor of psychiatry at Washington University in St. Louis and one of the study's senior investigators, said in a statement. "That we saw rapid improvements in many such patients in the study suggests nitrous oxide may help people with really severe, resistant depression." 

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As many as one-third of patients with depression, or up to 17 million people in the United States, do not respond to standard treatments, most of which stimulate serotonin and norepinephrine receptors in the brain, the statement said. 

The patients in this study had tried an average of 4.5 different antidepressants and had had depression for 17.5 years on average, according to the study. 

"Even with the best medication algorithms that we have, we have a number of people still left with significant symptoms that affect their quality of life, sometimes very severely. So there are a range of treatments available [for treatment-resistant major depression], but none of them are easy," said Dr. Timothy Sullivan, chair of psychiatry and behavioral sciences at Staten Island University Hospital in New York City, who was not involved in the new study. Those alternatives include deep brain stimulation, which involves implanting an electrode in the brain, and vagal nerve stimulation, which involves implanting a pacemaker-like device that stimulates the vagus nerve, Sullivan told Live Science. "We certainly need more, and more accessible, treatments for the treatment of this condition. Any treatment that's promising to kind of address this issue is certainly worth taking note of." 

Another such alternative, Sullivan said, is esketamine, a form of anesthetic ketamine, which the Food and Drug Administration approved for treatment-resistant major depression in 2019 and has successfully treated some patients with depression who don't respond to other treatments, as Live Science previously reported. Ketamine and esketamine both work, at least in part, by binding to N-methyl-D-aspartate (NMDA) glutamate receptors, a type of receptor on neurons, or brain cells. 

Like ketamine and esketamine, nitrous oxide also binds to NMDA glutamate receptors. This similarity led Conway and Dr. Peter Nagele, professor and chair of the Department of Anesthesia and Critical Care at the University of Chicago, to hypothesize that laughing gas might help patients with treatment-resistant major depression, they wrote in a 2015 study published in the journal Biological Psychiatry.

In that study, Conway, Nagele and colleagues reported that a one-hour administration of nitrous oxide had "rapid and marked antidepressant effects" in patients with treatment-resistant major depression. In that study, the antidepressant effects of inhaling nitrous oxide gas at a concentration of 50% were statistically meaningful at two and 24 hours following the treatment, the authors wrote at the time. The researchers were curious whether a lower dose of laughing gas, which might come with a lower risk of nausea and other side effects, would be as effective, the authors wrote in their new study. They also wanted to test whether the effects would last longer than the 24 hours they'd followed patients in their previous study.

To that end, in three sessions about a month apart, 24 study participants with treatment-resistant depression inhaled either 25% nitrous oxide, 50% nitrous oxide, or an oxygen-only placebo for one hour. The team then periodically measured the patients' depressive symptoms using the Hamilton Depression Rating Scale, a 21-point assessment conducted by a health care professional, for two weeks following the treatment. All 20 patients that completed the experiment received all three treatments to serve as his or her own control in the experiment, and all had follow-up exams. 

Two weeks after the laughing gas treatment, patients had fewer depressive symptoms according to the rating scale. This was true at both concentrations of laughing gas, the authors wrote in their paper. However, at 50% concentration, some patients experienced nausea as a side effect of the treatment.

"When they received 25% nitrous oxide, no one developed nausea," Conway said in the statement. "And that lower dose was just about as effective as the higher dose at relieving depression."

Following all three treatments, 55% (11 of 20) of participants who completed the study had a statistically meaningful improvement in at least half of their depressive symptoms, and 40% (eight out of 20) experienced short-term remission, according to the statement.  

Of the patients who completed the study, 85% (17 of 20) improved so much that their depression moved from one category to another, such as from severe to moderate depression, according to the press release.

As a next step, the researchers would like to study nitrous oxide, esketamine and a placebo in a larger, multicenter trial, according to the statement.

Sullivan said that he'd like to see the trial repeated by other investigators with larger numbers of patients. "If these initial results are certainly validated, it could well be offered as a treatment," he said. 

Originally published on Live Science.