Nitrous Oxide: Inhaling “Laughing Gas” Could Be Surprisingly Effective For Treating Severe Depression

Nitrous oxide (N₂O), also known as laughing gas, could be a game-changing treatment option for severe depression, according to a new meta-analysis. The study incorporated seven clinical trials and four protocol papers from teams across the globe, and found good reason to think that inhaling the gas at clinical concentrations could help where other treatments have had no effect.

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The research was conducted by a team from the University of Birmingham, the University of Oxford, and Birmingham and Solihull Mental Health NHS Foundation Trust, and was led by PhD researcher Kiranpreet Gill.

“Our group aims to develop and evaluate treatments for people with mood disorders such as severe and treatment-resistant depression, where current options often provide limited benefit,” Gill told IFLScience. 

A study published earlier this year, on which Gill was once again the first author, found that almost half of a group of patients with major depressive disorder could be classed as “treatment-resistant”, with over a third having already tried four or more different treatments. There’s clearly a big need for some new options.

The studies we reviewed showed similar short-term improvements in depressive symptoms, with early indications that repeated dosing might extend these effects.

Kiranpreet Gill

“Clinical nitrous oxide emerged as a candidate because early studies indicated rapid symptom change through mechanisms distinct from traditional antidepressants,” Gill told us. “We wanted to systematically assess the available evidence to determine whether these findings were reliable and clinically relevant.”

In three trials they looked at, the team found just one treatment with N₂O, inhaled at a 50 percent concentration, was enough to start significantly reducing depressive symptoms in as little as 2 hours. However, these benefits didn’t last long, so other dosing strategies were tested.

It looks as though multiple treatment sessions over several weeks will be needed for sustained benefits, but that’s still a very different prospect than taking daily antidepressant medications, for example.

“The studies we reviewed showed similar short-term improvements in depressive symptoms, with early indications that repeated dosing might extend these effects,” said Gill.

So how does it work? We asked Gill to explain.

“Evidence suggests that nitrous oxide affects the glutamate system in the brain, which is important for how mood-related circuits function. By briefly blocking specific receptors in this system, it appears to help rebalance activity in areas involved in mood and emotional processing. These changes may help explain why some people experience improvement in depressive symptoms shortly after treatment.”

It sounds promising, but it’s still very early days. The meta-analysis was limited by the small number of existing studies, and differences in how the data were collected.

There are also safety aspects to consider. When used recreationally, N₂O has been associated with serious health problems, but it has been safely used in clinical settings for well over 100 years – as you’ll know, if you’ve ever had “gas and air” at the dentist or in hospital. Its use in patients with depression would be similarly well-controlled, but that doesn’t mean there are no potential side effects.

Further research will be needed to fully understand the risks, but current data are encouraging, with none of the existing studies reporting short-term safety concerns.

“This is a significant milestone in understanding the potential of nitrous oxide as an added treatment option for patients with depression who have been failed by current treatments,” said senior author Professor Steven Marwaha in a statement. “This population has often lost hope of recovery, making the results of this study particularly exciting.”

Gill shared this optimism. “[T]hese findings suggest that nitrous oxide, when delivered clinically in controlled settings, warrants further evaluation for people who have not responded to standard treatments.”

“Our focus now is on building the evidence needed to understand how it could fit within clinical care.”

The study is published in the journal eBioMedicine.