A Few ‘Laughing Gas’ Breaths May Rapidly Lift Depression, Major Study Finds

Nitrous oxide is emerging as a surprisingly fast-acting option for people with major or treatment-resistant depression.

New research shows that even a single inhaled dose can ease symptoms within a day, while repeated sessions may create longer-lasting improvements.

Nitrous Oxide Shows Potential for Fast Depression Relief

Patients diagnosed with major depressive disorder, including many who have not improved with first-line antidepressants, may benefit from short-term treatment with nitrous oxide. This conclusion comes from a large meta-analysis led by the University of Birmingham.

A new paper published in eBioMedicine on November 30 reviewed the most reliable clinical data available to examine how medically administered nitrous oxide (N2O) may offer rapid relief from depressive symptoms in adults with major depressive disorder (MDD) and treatment-resistant depression (TRD).

Understanding TRD and Why New Options Are Needed

TRD refers to depression that remains insufficiently controlled after a person has tried two different antidepressants. According to a previous study* by the same research team, about 48% of UK patients see limited benefit from current treatments, making the search for alternative approaches increasingly important.

To explore this further, researchers from the University of Birmingham, University of Oxford, and Birmingham and Solihull Mental Health NHS Foundation Trust examined seven clinical trials and four protocol papers produced by scientists around the world. These studies focused on how nitrous oxide, a gas commonly used as pain relief in medical settings, might help treat depressive disorders such as MDD, TRD, and bipolar depression.

How Nitrous Oxide Performed in Clinical Trials

The analysis found that a single inhaled dose of nitrous oxide at 50% concentration (reported in three of the trials) led to notable and rapid reductions in depressive symptoms within 24 hours. However, these improvements usually faded by the one-week mark. Repeated dosing over several weeks produced longer-lasting benefits, suggesting that multiple sessions, rather than a single treatment, may be necessary to maintain improvement.

Researchers believe the gas influences glutamate receptors in a way that resembles ketamine, another fast-acting antidepressant. This action could help explain why some patients experience mood improvement 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.”

Early Evidence Is Strong, but More Research Is Essential

The meta-analysis revealed consistent short-term mood improvements following nitrous oxide treatment, although the small number of available trials led to variation in how depressive symptoms were measured and when follow-up assessments took place. Larger studies will be needed to determine the most effective dosage, long-term safety, and how nitrous oxide could be incorporated into existing treatment options.

Safety and side effects were also evaluated. Some patients experienced nausea, dizziness, or headaches, but these effects resolved quickly without medical intervention. Higher dosing (at 50% concentration) increased the likelihood of such side effects, yet none of the studies identified short-term safety concerns. The researchers emphasised that longer follow-up periods are necessary to fully assess long-term safety.

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.”

Toward New Treatment Options in Diverse Communities

The research was carried out through 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 is focused on expanding treatment choices for people with treatment-resistant depression in superdiverse and deprived communities. The Centre aims to speed up the development and introduction of innovative, evidence-based mental health interventions to improve outcomes and reduce inequalities.

This work is also connected to ongoing efforts at the Birmingham Clinic for Advanced Mood Disorder Management (CALM), where treatments such as ketamine and neuromodulation are already being used to support patients with severe or treatment-resistant depression.

Preparing for the First NHS Trial of Nitrous Oxide for Depression

Following this research pathway from early discovery to practical clinical use, the team is now preparing the UK’s first NHS trial to determine whether nitrous oxide can be delivered safely and acceptably as a treatment for major depression. The results will help clarify how this approach could be integrated into NHS services and may broaden the range of innovative options available to patients who have not responded to standard treatments.

Reference: “Nitrous oxide for the treatment of depression: a systematic review and meta-analysis” by Kiranpreet Gill, Angharad N. de Cates, Chantelle Wiseman, Susannah E. Murphy, Ella Williams, Catherine J. Harmer, Isabel Morales-Muñoz and Steven Marwaha, 30 November 2025, eBioMedicine.
DOI: 10.1016/j.ebiom.2025.106023

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