Nitrous oxide, also known as laughing gas, could help patients with treatment-resistant depression, according to some researchers.

An estimated 15% of depression patients around the world don’t respond to treatment the way they should. Very often, alternative treatment options aren’t available to these individuals, and they’re left to handle their condition without any help from medication. We know from previous research that a single inhalation session using a relatively thin mix of (50%) nitrous oxide can help relieve the symptoms of treatment-resistant depression. However, it can also cause some unpleasant side effects.

New research reports that a similar clinical outcome can be achieved even with a much lower dose of laughing gas (a 25% mix). Participants who underwent this process saw improvements in their condition for upwards of two weeks while having fewer and less intense side effects.

Laughing it away

“This investigation was motivated by observations from research on ketamine and depression,” said Peter Nagele, MD, Chair of Anesthesia and Critical Care at UChicago Medicine. “Like nitrous oxide, ketamine is an anesthetic, and there has been promising work using ketamine at a sub-anesthetic dose for treating depression.”

“We wondered if our past concentration of 50% had been too high. Maybe by lowering the dose, we could find the ‘Goldilocks spot’ that would maximize clinical benefit and minimize negative side effects.”

Nitrous oxide is widely employed as a short-term anesthetic, mostly used in dentistry and surgery. But, as previous research has found, a one-hour inhalation session with 50% nitrous oxide gas led to rapid improvements in depressive symptoms for 20 patients. These improvements lasted for at least 24 hours and were compared to a placebo. However, several of the participants in that initial study experienced side effects such as nausea, vomiting, and headaches.

This study repeated the experiment, again with 20 patients, but this time the inhalation session used only 25% nitrous oxide — half of the original concentration. This produced similar clinical effects as the 50% concentration trial but reduced the incidence of reported negative side effects to only one-quarter.

Each participant’s clinical depression scores were monitored for over two weeks, while the initial study only followed their state for up to 24 hours after treatment. The authors report that, after a single inhaling session, some patients saw improvements in their symptoms for the entire evaluation period.

“The reduction in side effects was unexpected and quite drastic, but even more excitingly, the effects after a single administration lasted for a whole two weeks,” said Nagele. “This has never been shown before. It’s a very cool finding.”

Overall, the results are quite encouraging, suggesting that nitrous oxide could become a fast-acting treatment option for patients with severe depression that doesn’t respond to typical treatments such as SSRIs

“A significant percentage—we think around 15%—of people who suffer from depression don’t respond to standard antidepressant treatment,” said Charles Conway, MD, Professor of Psychiatry and Director of the Treatment Resistant Depression and Neurostimulation Clinic at Washington University School of Medicine.

“These ‘treatment-resistant depression’ patients often suffer for years, even decades, with life-debilitating depression. We don’t really know why standard treatments don’t work for them, though we suspect that they may have different brain network disruptions than non-resistant depressed patients. Identifying novel treatments, such as nitrous oxide, that target alternative pathways is critical to treating these individuals.”

For now, however, these are just very early studies. The authors hope that the data they provide will help the medical community accept nitrous oxide as a possible treatment avenue and spark further research into its use. Psychiatrists in particular, they explain, are not familiar with nitrous oxide or how it can be administered. Hopefully, the results will help spark their interest. Public acceptance is also an issue, the team adds, that could slow down the implementation of this procedure. Despite the name, Nagele says, patients who undergo treatment with laughing gas are “not getting high or euphoric”, but “sedated”.

If our estimates are correct, there are millions of individuals living with depression who cannot be helped using traditional methods. If nitrous oxide proves itself to be a reliable option for these individuals, it could end up saving a lot of lives.

The paper “A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression,” has been published in the journal Science Translational Medicine.