Fast depression relief? Nitrous oxide shows remarkable potential

The paper, published in eBioMedicine on November 30, reviewed the strongest available clinical data to explore how clinically administered nitrous oxide (N₂O) might provide fast-acting relief from depressive symptoms in adults with major depressive disorder (MDD) and treatment-resistant depression (TRD).

What treatment-resistant depression is and how common it can be

TRD is defined as depression that remains insufficiently controlled after a person has tried two different antidepressant medications. A previous study led by the same research team found that around 48% of patients in the UK gain only limited benefit from standard antidepressant treatments, highlighting a substantial unmet need.

Researchers from the University of Birmingham, the University of Oxford, and Birmingham and Solihull Mental Health NHS Foundation Trust evaluated seven clinical trials and four protocol papers conducted by research groups across the world. These studies examined the use of nitrous oxide, which is also widely used as a pain relief option in medical procedures, as a treatment for depressive disorders including MDD, TRD and bipolar depression.

Single sessions, repeated doses and how nitrous oxide may act in the brain

The analysis showed that a single session of inhaled clinical nitrous oxide at 50% concentration (in three of the trials) led to rapid and meaningful reductions in depressive symptoms within 24 hours. However, these improvements did not generally persist after one week. When patients received repeated treatments over several weeks, the benefits lasted longer, indicating that a course of multiple sessions, rather than a one-off dose, may be necessary to sustain clinical improvement.

Nitrous oxide is believed to act on glutamate receptors in a manner similar to ketamine, another rapid-acting antidepressant. This action on glutamate pathways may account for the relatively swift improvements in mood that are seen shortly 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 short-term evidence, but more trials are needed

The meta-analysis reported robust evidence that nitrous oxide can improve mood over the short term after administration. At the same time, the relatively small number of clinical trials meant there were noticeable differences in how depressive symptoms were measured and reported, as well as in the timing of follow-up assessments. The authors note that further research is essential to identify the most effective dosing regimen, to fully understand the long-term safety of nitrous oxide, and to work out how best to incorporate it into existing treatment pathways.

Safety profile and side effects of nitrous oxide

The researchers also evaluated safety and side effects. Some participants experienced issues such as nausea, dizziness and headaches, but these problems were short lived and resolved without the need for medical treatment. Higher doses at 50% concentration were linked with a greater chance of these side effects occurring, yet none of the studies identified any immediate safety concerns. The team stressed that long-term safety must still be clarified through future studies that include longer 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."

Expanding options for treatment-resistant depression in diverse communities

The study was carried out by researchers at the Mental Health Mission Midlands Translational Centre, which is 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 is focused on improving treatment options for treatment-resistant depression in superdiverse and deprived communities. The Centre's goal is to speed up the development and rollout of innovative, evidence-based treatments that can both enhance outcomes and reduce inequalities in mental health care.

This work also connects with ongoing initiatives at the Birmingham Clinic for Advanced Mood Disorder Management (CALM), where advanced, evidence-based treatments such as ketamine and neuromodulation are already being provided for people living with severe or treatment-resistant depression.

Next steps: preparing the first NHS trial of nitrous oxide for depression

Building on this translational pathway that moves discoveries into real-world care, the team is now planning the first NHS trial in the UK to examine whether nitrous oxide can be offered safely and in an acceptable way as a treatment for major depression. The results of this upcoming trial will guide how nitrous oxide might be incorporated into NHS services and could broaden the range of innovative treatment choices available for patients who have not gained adequate relief from standard approaches.