Nitrous oxide for the treatment of depression: a systematic review and meta-analysis.
Kiranpreet Gill, Angharad N De Cates, Chantelle Wiseman, Susannah E Murphy, Ella Williams, Catherine J Harmer, Isabel Morales-Muñoz, Steven Marwaha
EBioMedicine December 1, 2025 DOI: 10.1016/j.ebiom.2025.106023 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Systematic review and meta-analysis Peer reviewed |
|---|---|
| Sample size | 247 |
| Population | Adults with depressive disorders (major depressive disorder, treatment-resistant depression, or bipolar depression) |
| Intervention | Nitrous oxide |
| Dose | 25% or 50% inhalation, single or repeated sessions |
| Duration | Single session; outcomes measured at 2 hours, 24 hours, and 1 week |
| Topics | Depression |
| Keywords | Antidepressant N-methyl-d-aspartate receptor Nitrous oxide |
| Key findings | A single 50% nitrous oxide inhalation significantly reduces depressive symptoms at 2 and 24 hours, but not at one week. |
Abstract
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. 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. 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. 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. The funder had no role in study design, data collection, analysis, interpretation, or writing.
Comparable studies
Other systematic reviews and meta-analyses on depression, most cited first.
Citations in the library
Cited by 3
- Propofol for depression: mechanisms and therapeutic potential Frontiers in Physiology August 10, 2026
- A conceptual framework based on current and emerging treatments for treatment-resistant depression: mechanistic evolution, clinical evidence, and future directions. Expert Review of Neurotherapeutics July 1, 2026
- Nitrous oxide for late-life depression with inadequate antidepressant response: a randomised controlled trial. EClinicalMedicine April 2, 2026
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