Laughing Gas May Provide Relief for Treatment-Resistant Depression, Trial Shows

Most of us are familiar with nitrous oxide in the context of the dentist's office as the mild sedative that makes us feel giggly. But a recent clinical trial revealed that the substance commonly known as "laughing gas" could, perhaps unsurprisingly, serve as an effective treatment for depression.

The Research

Researchers from the Washington University School of Medicine in St. Louis and the University of Chicago conducted a phase two clinical trial that included 24 individuals with severe treatment-resistant depression. This means the depression symptoms these participants had been experiencing hadn't improve after multiple standard antidepressant treatments.

Each participant was randomly assigned one of three treatments: a single one-hour inhalation with 50% nitrous oxide, 25% nitrous oxide or an oxygen placebo. Each participants received three treatments roughly one month apart. During the first treatment, individuals inhaled the 50% solution, in the second, the 25%, and in the third, the placebo.

The findings, published in Science Translational Medicine, revealed that a single one-hour treatment rapidly improved symptoms of depression for 55% or participants, and that these benefits can last for weeks. Forty percent of participants even considered themselves in remission. While the 50% dosage had greater antidepressant effects post-treatment, the 25% dosage resulted in fewer unpleasant side effects—nausea being the most common.

Nitrous oxide interacts with different receptors in the brain than traditional antidepressant treatments, and it works more quickly. This could explain some of its success.

"It's very important to find therapies to help these patients," said one of the study's senior investigators, Charles R. Conway, MD, 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."

This isn't the first time laughing gas has been studied as a treatment for depression. A previous proof-of-principle study showed that inhaling nitrous oxide produced immediate antidepressant effects for individuals with treatment-resistant depression, but it did not determine its effectiveness after 24 hours. The dosage of nitrous oxide tested was also high enough to increase the risk of nausea and other unwanted side effects.

“Our primary goals in this study were twofold: to determine whether a lower dose of nitrous oxide might be just as effective as doses we’d tested previously—and it was for most patients—and we also wanted to see how long the relief lasted,” said the study's co-senior investigator Peter Nagele, MD, in a statement. “In a proof-of-concept study several years ago, we assessed patients for 24 hours. In this study, we continued to assess them for two weeks, and most continued to feel better.”

The Stigma of 'Party Drugs'

As with any drug, there runs a risk of misuse. In a recreational context, nitrous oxide, commonly known as whippits, is often sold in canisters and inhaled using a balloon or whipped cream dispenser. This inhalant affects the central nervous system, producing mind- or mood-altering effects.

Inhaling nitrous oxide recreationally can have dangerous effects, but when taken as prescribed by a medical professional, it's completely safe. Laughing gas is used beyond the dentist's office—it's often used to treat traumatic injuries, as well as women in labor.

But this can be confusing for patients, which sows doubt as to the legitimacy and effectiveness of the drug.

"The bias is more in the public because it defies their own logic to have something that officials say 'This is harmful, don’t use this,' and then people say use it because it is good," says psychiatrist Tiago Reis Marques, PhD, CEO of Pasithea Therapeutics.

Marques assures that he is unbiased toward "party drugs" when they are carefully monitored and prescribed by professionals.

“The majority of drugs that are now currently used recreationally, they have been deviated from the lab to the party," he says. "As scientists, we look to substances not as recreational, we look at everything as drugs, which can have, then, a misuse. Of course, when you are trying to fix a problem, you are creating others. That’s always a risk. It’s all about knowing how to balance risk and benefit."

Nitrous oxide is just one among a plethora of drugs, including ketamine, being tested to treat severe depression. And while this particular study does have limitations, such as its small sample size, it is a step toward more accessible and effective treatments.