Can Laughing Gas Lift Chronic Depression?


Nitrous oxide may be a way to treat people with severe depression who have not responded to standard therapies, a small study suggests.

In 20 patients who had treatment-resistant clinical depression, two-thirds experienced an improvement in symptoms after receiving nitrous oxide, also known as laughing gas.

In comparison, one-third of the same patients reported improved symptoms after treatment with a placebo. The patients were evaluated on the day of and day after each treatment.

Researchers say the results, published in the journal Biological Psychiatry and presented at the annual meeting of the American College of Neuropsychopharmacology, are encouraging, even though the effects of the treatment were evaluated only twice over a 24-hour period.

“Our findings need to be replicated, but we think this is a good starting point, and we believe therapy with nitrous oxide eventually could help many people with depression,”

says principal investigator Peter Nagele, assistant professor of anesthesiology at Washington University in St. Louis.

As many as one-third of patients with clinical depression don’t respond to existing treatments, which points to the need to develop more effective therapies. Laughing gas is attractive because its side effects are limited— the most common are nausea and vomiting— and it leaves the body very quickly after people stop breathing the gas.

That’s why the researchers believe the improvement in symptoms a day later is real and not a side effect of the nitrous oxide. Further, in some patients, the improvements lasted for at least a week.

The Next Day

As part of the study, patients received two treatments, but neither the subjects nor the researchers knew the order in which those treatments were given. In one session, patients were given a gas mixture that was half oxygen and half nitrous oxide—the same mixture dentists give to patients undergoing dental procedures.

In a second session, the patients received a placebo mixture of oxygen and nitrogen, the two main gases in the air we breathe.

Two hours after each treatment, and again the next day, the study subjects were surveyed about the severity of their symptoms, such as sadness, feelings of guilt, suicidal thoughts, anxiety, and insomnia.

One day after nitrous oxide treatment, seven patients reported mild improvement in their symptoms, while another seven reported significant improvement. Three patients reported that their symptoms had disappeared almost completely. No patients said their symptoms worsened after treatment with nitrous oxide.

Meanwhile, after receiving the placebo, one patient reported worse symptoms the next day, five reported mild improvements, and two reported that they felt significantly better.

Risk for Suicide

“When they received nitrous oxide, many of the patients reported a rapid and significant improvement,”

says co-investigator Charles R. Conway, associate professor of psychiatry.

“Although some patients also reported feeling better after breathing the placebo gas, it was clear that the overall pattern observed was that nitrous oxide improved depression above and beyond the placebo. Most patients who improved reported that they felt better only two hours after treatment with nitrous oxide. That compares with at least two weeks for typical oral antidepressants to exert their beneficial, antidepressant effects.”

With standard antidepressants, such as Prozac, Zoloft, Lexapro, and other selective serotonin reuptake inhibitors (SSRIs), patients and their doctors often wait several days or weeks before they know whether treatments are working. The effects of treatments such as cognitive behavior therapy also often aren’t obvious for weeks.

“If our findings can be replicated, a fast-acting drug like this might be particularly useful in patients with severe depression who may be at risk for suicide and who need help right away,” says co-investigator Charles F. Zorumski, professor of psychiatry. “Or perhaps the drug could be used to relieve symptoms temporarily until more conventional treatments begin to work.”

More Studies Planned

More studies are needed to learn whether nitrous oxide has the same benefits in other patients with depression. The researchers also plan to test various concentrations of laughing gas to see how each influences symptoms of depression. Those studies will begin soon.

“It’s kind of surprising that no one ever thought about using a drug that makes people laugh as a treatment for patients whose main symptom is that they’re so very sad,”

Nagele says.

  1. Nagele, Peter et al. Nitrous Oxide for Treatment-Resistant Major Depression: A Proof-of-Concept Trial. Biological Psychiatry , Volume 78 , Issue 1 , 10 – 18

Last Updated on November 11, 2023