Nitrous Oxide Shows Rapid Short-Term Relief for Severe Depression, Major Meta-Analysis Finds
UK Researchers Confirm Fast-Acting Benefits in Treatment-Resistant Depression
Study Overview and Key Findings
A major-analysis lead by the University of Birmingham has found that patients living with major depressive disorder — including those who do not respond to first-line antidepressants — may benefit from short-term treatment with nitrous oxide.
The study, published in eBioMedicine, reviewed the strongest available clinical evidence and concluded that medically supervised nitrous oxide (N₂O) can provide rapid relief of depressive symptoms in adults with major depressive disorder (MDD) and treatment-resistant depression (TRD).
TRD refers to depression that fails to improve after a patient has tried two different antidepressant medications. According to earlier research by the same team, it affects around 48% of patients in the UK who gain only limited benefit from standard therapies.
Researchers from the University of Birmingham, the University of Oxford, and the Birmingham and Solihull Mental Health NHS Foundation Trust reviewed seven clinical trials and four protocol papers produced by international teams.
Each study examined the use of nitrous oxide—commonly employed as a medical analgesic—for the treatment of depressive disorders, including MDD, TRD and bipolar depression.
Evidence from Clinical Trials
They found that a single 50% dose of inhaled clinical nitrous oxide, tested in three trials, triggered rapid and marked reductions in depressive symptoms within 24 hours.
However, these improvements had faded by the one-week mark. In contrast, repeated administration over several weeks delivered more lasting benefits, indicating that multiple sessions may be necessary to sustain therapeutic effects.
Nitrous oxide is believed to act on glutamate receptors in a manner similar to ketamine, another fast-acting antidepressant, which may account for the rapid mood improvements seen shortly after inhalation.
Kiranpreet Gill, a Ph.D. researchers at the University of Birmingham and the study's lead author, said, "Depression is a profoundly debilitating condition, made worse by the reality that nearly half of all patients see little meaningful benefit from existing antidepressants. There is increasing interest in repurposing treatments from other medical fields to lift symptoms of low mood.
"This analysis offers the strongest evidence yet that nitrous oxide may deliver swift and clinically significant short-term relief for people with severe depression."
"Our analysis indicates that nitrous oxide could play a role in a new generation of fast-acting depression treatments. Crucially, it lays the groundwork for future clinical studies to explore repeated and carefully controlled dosing regimes, helping determine how best this therapy might be used for patients who gain little benefit from standard antidepressants."
How Nitrous Oxide Works as a Rapid-Acting Antidepressant
Mechanism Linked to Glutamate Receptors
Strong evidence, but few trials so far
The meta-analysis revealed compelling evidence that nitrous oxide can deliver short-term improvements in mood. However, with only a small number of trials available, researchers noted considerable variation in how depressive symptoms were recorded, interpreted and timed across the studies.
More studies will be necessary to pinpoint the ideal dosage, confirm nitrous oxide's safety over longer periods, and understand how it could complement existing therapeutic approaches.
Safety Profile and Limitations of Current Studies
Reported Side Effects and Short-Term Safety
The researchers examined reported side effects and found that some participants experienced temporary nausea, light-headedness and headaches. These symptoms faded quickly and required no medical assistance.
While stronger doses (50%) made such side effects more common, no short-term safety problems were observed. The authors highlighted the need for further research to explore long-term safety.
Professor Steven Marwaha of the University of Birmingham, an Honorary Consultant Psychiatrist at Birmingham and Solihull Mental Health Foundation Trust and senior author of the study, said, "This marks an important milestone in exploring nitrous oxide as an additional treatment for patients whose depression has not responded to conventional therapies. Many in this group have lost confidence in the possibility of recovery, which these findings particularly encouraging.
"These results underscore the pressing need for new therapies to support existing care pathways, and further research is essential to determine how this approach can best assist those living with severe depression."
Future of Nitrous Oxide Treatment in the NHS
Upcoming NHS Trial and Clinical Implementation
The study was carried out by researchers at the Mental Health Mission Midlands Translational Centre, led by the University of Birmingham, who are working to improve treatment options for treatment-resistant depression among highly diverse and disadvantaged communities.
The Centre's mission is to speed up the development and delivery of innovative, evidence-based treatments designed to improve patient outcomes and reduce longstanding inequalities in mental health care.
This work complements ongoing initiatives at the Birmingham Clinic for Advanced Mood Disorder Management (CALM), where cutting-edge therapies— including ketamine and neuromodulation— are already being offered to individuals with severe or treatment-resistant depression.
Building on this pipeline from scientific discovery to clinical application, the team is now preparing to launch the UK's first NHS trial to evaluate whether nitrous oxide can be administered safely and effectively as a treatment for major depression.
Potential to Transform Mental Health Pathways
The results will guide how nitrous oxide might be incorporated into NHS treatment pathways and could widen the range of innovative therapies available to patients who have not responded to traditional methods.
