Healthcare (Commonwealth Union) – A major meta-analysis led by the University of Birmingham suggests that people with major depressive disorder — including those who haven’t improved with standard first-line antidepressants — could benefit from short-term treatment with nitrous oxide.
The study, published in eBioMedicine, reviewed the strongest available clinical evidence and found that medically supervised nitrous oxide (N₂O) may provide rapid relief from depressive symptoms in adults with major depressive disorder (MDD) and treatment-resistant depression (TRD).
TRD refers to cases of depression that do not respond adequately even after a patient has tried two different antidepressant medications. Earlier work by the same research team indicates that about 48% of patients in the UK fall into this category and gain only limited improvement from conventional therapies.
The research group — involving experts from the University of Birmingham, the University of Oxford, and the Birmingham and Solihull Mental Health NHS Foundation Trust — reviewed seven clinical trials and four protocol papers from international investigators. These studies explored the use of nitrous oxide, commonly used as a pain management gas in various medical settings, as a potential treatment for depressive conditions including MDD, TRD, and bipolar depression.
The researchers discovered that a single session of inhaled medical nitrous oxide at a 50% concentration (across three studies) resulted in a quick and notable drop in depressive symptoms within 24 hours. However, these benefits did not last beyond a week. In comparison, multiple treatments given over several weeks produced longer-lasting effects, indicating that ongoing sessions—rather than a one-time dose—may be necessary to sustain improvement. The gas is believed to act on glutamate receptors, much like ketamine, another fast-acting antidepressant, which could explain why mood changes occur shortly after inhalation.
Kiranpreet Gill, a PhD student at the University of Birmingham funded by the Medical Research Council and the study’s lead author, highlighted the fact that depression is an extremely disabling condition, made worse by the fact that nearly half of patients see little to no benefit from standard antidepressants and there is increasing interest in adapting treatments from other areas of medicine to help improve mood. Gill further indicated that their analysis brings together the strongest available evidence showing that nitrous oxide may offer rapid and clinically meaningful short-term relief for people with severe depression.
“Our analyses show that nitrous oxide could form part of a new generation of rapid-acting treatments for depression. Importantly, it provides a foundation for future trials to investigate repeated and carefully managed dosing strategies that can further determine how best to use this treatment in clinical practice for patients who don’t respond to conventional interventions.”
The analysis of multiple studies showed clear evidence that nitrous oxide can bring short-term improvements in mood. However, because only a small number of trials have been conducted so far, there were noticeable differences in how researchers measured and reported depressive symptoms, as well as in when those measurements were taken. More research is required to identify the most effective dosage, to evaluate the long-term safety of nitrous oxide, and to understand how it might be incorporated into current treatment approaches.
The researchers also reviewed safety data and possible side effects. Some participants reported issues such as nausea, light-headedness, and headaches, but these symptoms were brief and cleared without medical treatment. Although higher concentrations (around 50%) made these effects more likely, no immediate safety risks were identified in the existing studies. The authors stressed that long-term safety still needs to be explored in future trials that follow patients for longer periods.
Professor Steven Marwaha of the University of Birmingham, who is also an Honorary Consultant Psychiatrist with the Birmingham and Solihull Mental Health Foundation Trust and the senior author of the paper, indicated that this represents an important step forward in understanding whether nitrous oxide could offer an additional treatment choice for people with depression who have not been helped by current therapies. Professor Marwaha further pointed out that many individuals in this group feel discouraged about their recovery, so these results are especially encouraging and the findings underline the urgent need for new treatment options that can work alongside existing care, and further research is essential to determine how this method can best support people living with severe depression.
