Depression affects over 300 million people globally and includes complex neural dysregulation in psychological, biological, and environmental systems. Standard therapy, including serotonin-noradrenaline reuptake inhibitors (SNRIs) and selective serotonin reuptake inhibitors (SSRIs), acts slowly. They are also ineffective in up to half of the depressive patients. This led to increased interest in fast-acting treatment options for treatment-resistant depression (TRD). Ketamine’s rapid effects have highlighted the glutamatergic system as a key target. Nitrous oxide (N2O) is an N-methyl-D-aspartate (NMDA) receptor antagonist with anaesthetic properties. N2O also modulates the default mode network and influences dopamine as well as opioid pathways. A systematic review and meta-analysis published in eBioMedicine aimed to evaluate N2O safety, efficacy, and the current evidence landscape, including ongoing trials and protocols.
This review followed guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and a preregistered study protocol. The review was conducted using various databases like Embase, ClinicalTrials.gov, PsycINFO, reference lists, PubMed, and Google Scholar. These databases were used to identify the ongoing and completed interventional studies. Studies were eligible if they assessed N2O for depression, included protocols or clinical trials, and reported safety or efficacy outcomes. Data were extracted on adverse events (AEs), dosing, design, demographic characteristics, and outcomes. Quantitative data were analyzed through meta-analysis techniques. Risk of bias was determined by the Cochrane Risk of Bias 2 (RoB 2) tool. Publication bias was estimated using the funnel plot and standardized mean differences (SMDs).
A total of 11 studies and eight trials were included in this review, involving approximately 247 patients with treatment-resistant depression, bipolar disorder, or major depressive disorder. N2O was administered at concentrations of 25% or 50% to the patients through inhalation as single or repeated sessions with controls such as midazolam, air, or oxygen. Meta-analysis showed significant antidepressant effects of N2O at 2 hours with MD of −2.74 (95% confidence interval [CI]: −4.72 to −0.76), p = 0.007, and heterogeneity (I2) = 0% across three studies and at 24 hours with MD of −1.52 (95% CI: −4.07 to 1.03) and p = 0.24 across four studies. Effects were not significant in one week with MD of −1.52 (95% CI: −4.07 to 1.03) and p = 0.24. Funnel plots demonstrated moderate asymmetry, suggesting possible publication bias. Across six clinical trials, AEs were transient and mild with no serious AEs reported. In three trials, 25% N2O showed higher risks of vomiting and nausea (RR = 8.01; 95% CI: 1.61 to 39.77; p = 0.01; I2 = 0%) as well as dizziness (RR = 2.79; 95% CI: 1.35 to 5.78; p = 0.006; I2 = 0%) compared to placebo. Whereas 50% N2O produced higher rates of risk of dizziness (RR 3.55; 95% CI: 1.92 to 6.56; p < 0.001; I2 = 42%), nausea-vomiting (RR 12.69; 95% CI: 3.26 to 49.35; p < 0.001; I2 = 0%), and headache (RR = 2.26; 95% CI: 1.08 to 4.72; p = 0.03; I2 = 38%). 25% N2O had significantly lower vomiting/nausea risk compared to 50% N2O with RR of 0.42 (95% CI: 0.18 to 0.97), p = 0.04, and I2 = 35%. Risk of bias assessment rated two studies low risk, three with concerns, and one high risk.
This study was limited by small samples, variable quality, subgroup variability, short-term focus, dose-response analysis, restricted meta-analysis power, inconsistent outcomes, and partial blinding.
In conclusion, this study highlights that N2O showed reproducible and rapid antidepressant effects in early studies. Repeated use, diverse populations, standardized outcomes, optimized dosing, and sustained efficacy are needed to determine its full clinical potential for depression.
Reference: Gill K, de Cates AN, Wiseman C, et al. Nitrous oxide for the treatment of depression: a systematic review and meta-analysis. eBioMedicine. 2025:106023. Nitrous oxide for the treatment of depression: a systematic review and meta-analysis
