A large analysis led by the University of Birmingham has found that patients with major depressive disorder, including people who have not improved with standard antidepressants, may benefit from short-term treatment with nitrous oxide (often called “laughing gas”). The research suggests that, when given in a controlled medical setting, nitrous oxide can provide fast relief from depressive symptoms for adults with major depressive disorder and treatment-resistant depression.
Treatment-resistant depression (TRD) is usually defined as depression that does not improve after trying at least two different antidepressants. Previous work from the same team suggests that this affects almost half of people with depression in the UK, who gain only limited benefit from usual treatments. This makes it important to explore other options that might work more quickly or for people who have not responded to current medicines.
Researchers from the University of Birmingham, the University of Oxford and Birmingham and Solihull Mental Health NHS Foundation Trust reviewed seven clinical trials and four protocol papers from teams around the world. These studies looked at using nitrous oxide, a gas already used for pain relief in many medical procedures, to treat different depressive disorders, including major depression, treatment-resistant depression and bipolar depression.
In three of the trials, a single inhaled treatment of 50% nitrous oxide led to a rapid and meaningful drop in depressive symptoms within 24 hours. However, these benefits did not usually last beyond one week. In contrast, when patients received repeated treatments over several weeks, the improvements in mood tended to last longer, which suggests that more than one session may be needed to maintain benefit. Nitrous oxide is thought to act on glutamate receptors in the brain in a similar way to ketamine, another fast-acting antidepressant, and this may help explain why mood can improve soon after inhalation.
The authors emphasise that depression remains a disabling illness, and that standard antidepressants do not help a large proportion of patients enough. There is growing interest in “repurposing” treatments already used in other areas of medicine to help with low mood. This new analysis brings together the best available evidence to date and suggests that nitrous oxide has the potential to offer rapid and clinically meaningful short-term improvements for people with severe depression, especially when other treatments have failed.
At the same time, the paper highlights that only a relatively small number of trials have been completed so far. The studies used different ways of measuring depression and assessed patients at different time points, which makes it hard to say exactly what the best dose and schedule should be. More research is needed to confirm the best way to give nitrous oxide, to understand its long-term safety, and to see how it might fit into current treatment pathways.
Safety was also carefully reviewed. Some patients experienced short-lived side effects such as nausea, dizziness and headaches, but these generally settled quickly on their own and did not require extra medical treatment. Higher doses, such as 50% nitrous oxide, were more likely to cause these side effects, but the trials did not report any serious short-term safety problems. The researchers stress that longer-term safety still needs to be studied with larger trials and longer follow-up.
The study team describe these results as an important step in understanding how nitrous oxide might become an additional treatment choice for people whose depression has not improved with current options. Their work sits within the Mental Health Mission Midlands Translational Centre, led by the University of Birmingham and funded by the National Institute for Health and Care Research, which aims to improve care for people with treatment-resistant depression, particularly in diverse and disadvantaged communities. It also links with work at the Birmingham Clinic for Advanced Mood Disorder Management (CALM), where innovative treatments such as ketamine and neuromodulation are already being offered to patients with severe or hard-to-treat depression.
Building on this pathway from research to real-world care, the team is now planning the first NHS trial in the UK to test whether nitrous oxide can be given safely and acceptably as a treatment for major depression. The results of that trial will help show how nitrous oxide could be woven into NHS services in future and may increase the range of options available for people who have not benefited from standard treatments.
