Nitrous oxide for the treatment of depression: a systematic review and meta-analysis.

BACKGROUND: Depression remains a global public health challenge, prompting interest in translational targets which allow for more effective and rapidly acting interventions. Nitrous oxide (N2O), an N-methyl-d-aspartate receptor antagonist, has demonstrated potential as a rapid-acting antidepressant. This study synthesised existing data on the efficacy and safety of N2O in depressive disorders. METHODS: We systematically reviewed clinical trials, exploratory studies, and protocol papers evaluating N2O for the treatment of depression, including major depressive disorder (MDD), treatment-resistant depression (TRD), and bipolar depression, following PRISMA guidelines. Meta-analysis was completed where possible. Primary outcomes were change in depressive symptoms and adverse events (AEs). Pooled mean differences (MD) and relative risk ratios were calculated using random- or fixed-effects models. Evidence mapping described trial characteristics across completed and ongoing studies. FINDINGS: Seven clinical trials involving 247 participants with depressive disorders, and four protocol papers were reviewed. N2O was administered via inhalation at 25% or 50%, as single or repeated sessions, with comparators including air, oxygen, or midazolam. Pooled results from three trials administering 50% N2O in a single session showed significant reductions in depressive symptoms at 2 h (pooled MD -2.74, 95% Confidence Interval (CI): -4.72 to -0.76; p = 0.007) and 24 h (MD -3.32, 95% CI: -5.09 to -1.55; p < 0.0001), but not at 1 week post-inhalation (MD -1.52; 95% CI: -4.07 to 1.03; p = 0.24). AEs were mild and transient, with 25% N2O generally being better tolerated. Evidence mapping showed that most trials are early-phase and focused on short-term outcomes in adults with MDD and TRD. INTERPRETATION: N2O demonstrates rapid, reproducible antidepressant effects in early-phase trials. Its future clinical value depends on whether these effects can be sustained over time through optimised dosing and extended/repeated use. Improved trial design, outcome standardisation, and population diversity is required to clarify its full potential for the treatment of depression. FUNDING: The funder had no role in study design, data collection, analysis, interpretation, or writing.