Clinical use of nitrous oxide could help treat depression, major study shows

Patients with major depressive disorder, including those who have not responded to first-line antidepressants, may benefit from short-term nitrous oxide treatment, a major meta-analysis led by the University of Birmingham has found.

The new paper published in eBioMedicine has assessed the best available clinical information to show how clinically administered nitrous oxide (N2O) can offer fast-acting depressive symptom relief for adults with major depressive disorder (MDD) and treatment-resistant depression (TRD).

TRD is characterised as depression that isn’t effectively managed after a patient tries two different antidepressants. It affects approximately 48% of UK patients who experience limited benefit from standard treatments, according to a previous study led by the research team.

Researchers from the University of Birmingham, University of Oxford, and Birmingham and Solihull Mental Health NHS Foundation Trust assessed seven clinical trials and four protocol papers published by investigators from around the world. Each research study looked at the use of nitrous oxide, also used as pain relief in a range of medical situations, for treating depressive disorders, including MDD, TRD and bipolar depression.

The team found that a single treatment of inhaled clinical nitrous oxide at 50% concentration (in three trials), produced rapid and significant reductions in depressive symptoms within 24 hours, although these effects were not sustained at one week. In contrast, repeated dosing over several weeks led to more durable improvements, suggesting that multiple treatment sessions (compared to a single dose) may be required to maintain clinical benefit. It is thought to target glutamate receptors in a similar way to ketamine, another rapid-acting antidepressant, and this may help explain why improvements in mood can be observed soon after inhalation.

Kiranpreet Gill, a PhD researcher funded by the Medical Research Council at the University of Birmingham and first author of the study, said: “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.

“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.”

Strong evidence, but limited numbers of trials currently

The meta-analysis of studies found strong evidence for short-term improvements in mood following nitrous oxide administration. Due to the limited number of existing trials, there was notable variability in how depressive symptoms were measured and reported, as well as in the timing of these assessments. Further studies are needed to determine the optimal dose, nitrous oxide’s long-term safety, and the best way to integrate it into existing treatment pathways.

The team also examined the safety and potential side effects of nitrous oxide. Some patients experienced side effects such as nausea, dizziness and headaches, all of which passed quickly and resolved without medical intervention. While higher dosing (at 50% concentration) increased the likelihood of these side effects, none of the studies reported any short-term safety concerns. The researchers emphasised that longer-term safety must be assessed through future studies with extended follow-up periods.

Professor Steven Marwaha from the University of Birmingham, Honorary Consultant Psychiatrist at Birmingham and Solihull Mental Health Foundation Trust, and senior author of the study said: "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 study was conducted by researchers at the Mental Health Mission Midlands Translational Centre, led by the University of Birmingham and funded by the National Institute for Health and Care Research through the NIHR Oxford Biomedical Research Centre. The team are working on improving treatment options for treatment-resistant depression in superdiverse and deprived populations. The Centre aims to accelerate the development and delivery of innovative, evidence-based interventions to improve outcomes and reduce disparities in mental health care.

This work also aligns with ongoing efforts within the Birmingham Clinic for Advanced Mood Disorder Management (CALM), where innovative, evidence-based treatments such as ketamine and neuromodulation are being delivered to people with severe or treatment-resistant depression.

Building on this translational pathway from discovery to clinical practice, the team is now preparing the first NHS trial in the UK to assess whether nitrous oxide can be delivered safely and acceptably as a treatment for major depression. The findings will help determine how nitrous oxide could be integrated into NHS care and may expand the range of innovative options available for patients who have not benefited from standard approaches.