Depression is one of the most common and disabling mental health conditions in the world. For many people, standard antidepressant medicines help improve mood and daily functioning.
But for a large number of patients, these treatments do not work well or do not work at all.
Now, a new large review of clinical studies suggests that nitrous oxide, often known as “laughing gas,” may offer fast relief for people living with major depressive disorder, including those whose depression has not improved with usual medications.
The research was led by scientists at the University of Birmingham and published in the journal eBioMedicine.
The team reviewed the strongest available clinical evidence to understand whether medically supervised nitrous oxide treatment could reduce depressive symptoms in adults with major depressive disorder and treatment-resistant depression.
Treatment-resistant depression is usually defined as depression that does not improve after a person has tried at least two different antidepressant medications at proper doses. This is more common than many people realize.
Earlier research by the same group found that nearly half of patients in the UK get little or no benefit from standard antidepressants. This means millions of people are left struggling with ongoing symptoms, often for years, with limited treatment options.
To better understand whether nitrous oxide could help, researchers from the University of Birmingham, the University of Oxford, and Birmingham and Solihull Mental Health NHS Foundation Trust examined seven completed clinical trials and four trial protocols from research teams around the world.
These studies tested nitrous oxide as a treatment for different depressive conditions, including major depressive disorder, treatment-resistant depression, and bipolar depression. Nitrous oxide is already widely used in hospitals and clinics as a pain relief and sedation tool during medical and dental procedures.
The analysis showed that a single session of inhaled nitrous oxide, usually given at a concentration of 50 percent under clinical supervision, led to clear improvements in mood within 24 hours for many patients.
This rapid effect is very different from traditional antidepressants, which often take weeks to show benefits. However, the review also found that when nitrous oxide was given only once, the improvement often faded within a week.
More promising results were seen when patients received repeated nitrous oxide treatments over several weeks. In these cases, the benefits lasted longer, suggesting that a short course of multiple sessions may be necessary to maintain improvement. This finding is important because it helps guide how the treatment might be used in real clinical settings.
Scientists believe nitrous oxide works in the brain by affecting glutamate, a key chemical messenger involved in mood, learning, and memory.
This is similar to how ketamine works, another fast-acting antidepressant that has gained attention in recent years. By acting on these brain pathways, nitrous oxide may help reset abnormal activity linked to depression, leading to quicker relief from symptoms.
Kiranpreet Gill, a PhD researcher at the University of Birmingham and the first author of the study, explained that depression can be especially devastating when treatments fail. Many patients lose hope after trying multiple medications without success.
She noted that there is growing interest in using existing medical treatments in new ways to help people with severe depression. This review brings together the best available evidence showing that nitrous oxide has real potential to provide fast and meaningful short-term improvements for patients who have not responded to standard care.
The researchers emphasized that the current evidence strongly supports short-term benefits, but more research is still needed. Because the number of clinical trials is relatively small, there were differences between studies in how depression was measured and how long patients were followed.
Larger trials are needed to find the best dose, treatment schedule, and long-term safety profile.
Safety was also carefully examined in the review. Some patients experienced side effects such as nausea, dizziness, or headaches, especially at higher doses. However, these effects were temporary and resolved on their own without medical treatment.
Importantly, none of the studies reported serious immediate safety concerns when nitrous oxide was used in a controlled medical setting. Still, researchers stress that long-term safety must be studied further, especially if repeated treatments are used.
Professor Steven Marwaha, a psychiatrist at the University of Birmingham and senior author of the study, said the findings are especially important for patients who feel they have run out of options.
For people living with long-term, severe depression, even short-term relief can be life-changing. He added that these results highlight the urgent need for new treatments that can work alongside existing therapies.
This research is part of a wider effort by the Mental Health Mission Midlands Translational Centre, which focuses on improving care for treatment-resistant depression, particularly in diverse and disadvantaged communities.
The team is now preparing the first NHS clinical trial in the UK to test whether nitrous oxide can be delivered safely and acceptably as a treatment for major depression. The results of this trial could help determine whether laughing gas becomes a new option for patients who have not found relief through current treatments.
If you care about mental health, please read studies about how dairy foods may influence depression risk, and 6 foods you can eat to improve mental health.
For more mental health information, please see recent studies about top foods to tame your stress, and Omega-3 fats may help reduce depression.
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