Patients with major depressive disorder who have not responded to first-line antidepressants may experience short-term benefits from nitrous oxide, a recent systematic review and meta-analysis suggest.
Standard antidepressants often have a delayed onset of action and fail to benefit up to half of patients, especially those with treatment-resistant depression.
In response, antidepressant development has increasingly focused on the glutamatergic system, with ketamine showing rapid antidepressant effects and highlighting the potential of mechanisms beyond traditional monoaminergic pathways.
Ketamine’s success heightened interest in fast-acting treatments and prompted investigation into other N-methyl-D-aspartate (NMDA) receptor antagonists. Against this backdrop, researchers from the University of Birmingham, UK, have assessed the efficacy, safety and research landscape of the NMDA-receptor antagonist nitrous oxide for depressive disorders.
A systematic review and meta-analysis alongside evidence mapping of ongoing research was conducted. Seven completed clinical trials involving 247 participants with major depressive disorder, treatment-resistant depression, or bipolar depression, as well as four published protocol papers, were included.
Nitrous oxide was administered by inhalation at 25% or 50% concentration, either as a single or repeated session, and compared with air, oxygen or midazolam. Meta-analyses were performed when outcome data were available.
Strong evidence for nitrous oxide for depression
Pooled analyses from trials administering a single session of 50% nitrous oxide showed significant reductions in depressive symptoms at two hours (mean difference −2.74; 95% CI −4.72 to −0.76; p=0.007) and 24 hours (−3.32; 95% CI −5.09 to −1.55; p<0.001) compared with placebo. However, these effects were not sustained at one week.
Evidence mapping indicated that repeated-dosing regimens produced more durable symptom improvements than single-session protocols, although the data remained limited.
Nitrous oxide was generally well tolerated. Reported adverse events, including nausea, dizziness and headache, were mild and transient, with lower rates observed at the 25% concentration. No serious adverse events were reported across trials.
The researchers noted that most studies were small, early-phase trials with heterogeneous designs, dosing schedules and outcome measures. Limited sample sizes restricted the ability to assess long-term efficacy, dose–response relationships and subgroup effects, they added, and publication bias and incomplete blinding were also potential concerns.
Potential impact and future directions
Commenting on the findings, senior author of the study, Professor Steven Marwaha, an academic psychiatrist at the University of Birmingham, 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.’
He added that the findings highlight the urgent need for new treatments to complement existing care pathways, and acknowledged that ‘further evidence is needed to understand how this approach can best support people living with severe depression’.
Overall, the research showed both the potential and the current limitations of nitrous oxide and suggested that it could become a rapid-acting option for depression in the future, especially in acute settings.
Nonetheless, the researchers cautioned that its clinical usefulness depends on whether sustained benefits can be achieved through optimised and repeated dosing. They also called for larger, methodologically rigorous trials, better standardisation of outcomes and population diversity.
Reference
Gill K et al. Nitrous oxide for the treatment of depression: a systematic review and meta-analysis. eBioMedicine 2025;122:106023.
