Patients with major depressive disorder, including those resistant to first-line antidepressants, may find relief in short-term nitrous oxide treatment, according to a major meta-analysis led by the University of Birmingham. The study, published in eBioMedicine, highlights how clinically administered nitrous oxide (N2O) can offer rapid symptom relief for adults with major depressive disorder (MDD) and treatment-resistant depression (TRD).
The announcement comes as 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 from global investigators. The studies evaluated the use of nitrous oxide, commonly used for pain relief, in treating depressive disorders, including MDD, TRD, and bipolar depression.
Understanding Treatment-Resistant Depression
TRD is characterized by depression that remains unmanaged after a patient tries two different antidepressants. It affects approximately 48% of UK patients who experience limited benefit from standard treatments, according to previous research led by the same team.
The study found that a single treatment of inhaled clinical nitrous oxide at 50% concentration produced rapid and significant reductions in depressive symptoms within 24 hours. However, 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 may be necessary to maintain clinical benefit. Nitrous oxide is thought to target glutamate receptors similarly to ketamine, another rapid-acting antidepressant, explaining the swift mood improvements observed post-inhalation.
Expert Insights and Future Directions
Kiranpreet Gill, a PhD researcher funded by the Medical Research Council at the University of Birmingham and first author of the study, emphasized the potential of nitrous oxide: “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. 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,” Gill added. “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.”
Challenges and Considerations
Despite strong evidence for short-term mood improvements following nitrous oxide administration, the limited number of existing trials resulted in notable variability in how depressive symptoms were measured and reported. 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.
Safety and potential side effects were also examined. Some patients experienced side effects such as nausea, dizziness, and headaches, which resolved quickly without medical intervention. While higher dosing increased the likelihood of these side effects, none of the studies reported any short-term safety concerns. However, researchers emphasized that longer-term safety must be assessed through future studies with extended follow-up periods.
Implications for Mental Health Treatment
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, remarked: “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.”
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 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 aligns with ongoing efforts within the Birmingham Clinic for Advanced Mood Disorder Management (CALM), where innovative treatments such as ketamine and neuromodulation are being delivered to individuals with severe or treatment-resistant depression.
Looking Ahead
Building on this translational pathway from discovery to clinical practice, the team is 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.
