Nitrous oxide, the stuff dentists use, might actually help people with treatment-resistant depression. A new meta-analysis in eBioMedicine pulled together seven clinical trials covering 247 adults and found that inhaling the gas produced rapid drops in depressive symptoms, sometimes within two hours.
The catch? The effect usually fades within a week.
Researchers at the University of Birmingham led the review, looking at studies where patients breathed nitrous oxide at concentrations between 25 and 50 percent for anywhere from 20 to 60 minutes. They were compared against people breathing regular air, oxygen, or a sedative control. Depression scores dropped fast and stayed lower at 24 hours, but by the one-week mark, most of that benefit was gone unless patients got repeated doses.
Treatment-resistant patients responded best
The strongest results came from people who’d already tried at least two antidepressants without relief. That’s a huge group—earlier work from the same Birmingham team suggests nearly half of depression patients in UK primary care fall into this category.
“Depression is a debilitating illness, made even more so by the fact that antidepressants make no meaningful difference for almost half of all patients diagnosed with it. There is a growing body of research on repurposing treatments from other clinical domains to alleviate low mood. This study brings together the best possible evidence indicating that nitrous oxide has the potential to provide swift and clinically significant short term improvements in patients with severe depression.”
When researchers pooled data from trials using a single 50 percent dose, nitrous oxide beat placebo at two hours and 24 hours. But not at one week. That tracks with what’s known about nitrous oxide—it’s fast in, fast out.
Repeated dosing changed things. In studies where patients got multiple sessions over several weeks, improvements lasted longer and more people went into remission. One trial gave people with major depression eight sessions of 50 percent nitrous oxide over four weeks. More than 90 percent responded. Three out of four went into remission. Compare that to the oxygen placebo group, where response rates were far lower.
Side effects were mild
Nitrous oxide caused more side effects than placebo—nausea, dizziness, headaches—but they were mostly short-lived and resolved once the gas stopped. Lower doses at 25 percent were better tolerated than 50 percent.
None of the trials reported serious safety problems in medical settings. What’s not clear is whether using nitrous oxide repeatedly over months or years would introduce different risks. The studies were small and early-phase, with lots of variation in how outcomes were measured.
“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. This population has often lost hope of recovery, making the results of this study particularly exciting. These findings highlight the urgent need for new treatments that can complement existing care pathways, and further evidence is needed to understand how this approach can best support people living with severe depression.”
The Birmingham group is working with the Mental Health Mission Midlands Translational Centre, focusing on treatment-resistant depression in underserved populations. They’re already using other rapid-acting treatments like ketamine and neuromodulation at the Birmingham Clinic for Advanced Mood Disorder Management.
Next: an NHS trial
The team is planning the first UK National Health Service trial to test whether nitrous oxide can be delivered safely in specialist mood disorder clinics. The idea is to use it as a rapid-acting add-on for patients who haven’t responded to standard care, then learn who responds, how often it can be used, and whether the effects can be sustained.
For now, nitrous oxide isn’t a cure. It’s not even close. The evidence says it can lift mood briefly for some of the people who need it most, with tolerable short-term risks. Whether that brief lift can become something durable—something that fits into regular clinic schedules and tight budgets—will take bigger trials and probably a rethink of how depression care works in the first place.
Journal: eBioMedicine
DOI: 10.1016/j.ebiom.2025.106023
