Laughing gas touted as rapid-acting antidepressant in meta-analysis

Administration of nitrous oxide (N2O) appears to alleviate depressive symptoms as quickly as 2 h, according to a meta-analysis.

Pooled data from clinical trials administering N2O via inhalation at 50-percent concentration in a single session showed significant reductions in depressive symptoms at 2 h (mean difference [MD], −2.74, 95 percent confidence interval [CI], −4.72 to −0.76; p=0.007; I²=0 percent) and 24 h (MD, −3.32, 95 percent CI, −5.09 to −1.55; p<0.0001; I²=0 percent) compared with placebo. This antidepressant benefit disappeared at 1-week postinhalation (MD, −1.52, 95 percent CI, −4.07 to 1.03; p=0.24). [EBioMedicine 2025;doi:10.1016/j.ebiom.2025.106023]

Adverse events (AEs) were mostly mild and transient. Common AEs included nausea, dizziness, headache, and transient dissociation, all of which resolved spontaneously.

Notably, the lower N2O concentration was better tolerated than the higher concentration. Relative to placebo, 50-percent NO2 was associated with a higher risk of dizziness or light headedness (relative risk [RR], 3.55, 95 percent CI, 1.92–6.56; p<0.001; I²=42 percent) and nausea and vomiting (RR, 12.69, 95 percent CI, 3.26–49.35; p<0.001; I²=0 percent) than 25-percent NO2 (dizziness or light headedness: RR, 2.79, 95 percent CI, 1.35–5.78; p=0.006; I²=0 percent; nausea and vomiting: RR 8.01, 95 percent CI, 1.61–39.77; p=0.01; I²=0 percent). Additionally, 50-percent NO2 was associated with an increased risk of headache compared with placebo (RR, 2.26, 95 percent CI, 1.08–4.72; p=0.03; I²=38 percent).

Taken together, the present data demonstrate the promise of N2O  as a rapid-acting intervention to alleviate depressive symptoms, especially in major depressive disorder (MDD) and treatment-resistant depression (TRD), the investigators said.

“Although 25-percent N2O was associated with fewer AEs and may be more tolerable for maintenance treatment, its clinical utility could be constrained by lower response and remission rates observed in some studies compared to the 50-percent concentration,” they noted.

Two trials evaluating N2O at both 25-percent and 50-percent concentrations indicated a possible dose–response effect. Furthermore, repeated administration of N2O was associated with more durable reductions in depressive symptoms compared with single-session protocols, suggesting a potential cumulative benefit.

“Evidence mapping of completed and ongoing trials showed that research is generally concentrated around early-phase studies in adults with MDD or TRD, using single-dose protocols. In contrast, trials investigating repeated or maintenance dosing, longer-term outcomes, adolescent and bipolar populations, and consistent outcome frameworks remain limited,” according to the investigators.

They called for additional research to address the mentioned uncertainties, clarify underlying mechanisms, systematically evaluate N2O’s feasibility across diverse and real-world populations, and establish its role within the evolving landscape of antidepressant therapies.

“[The meta-analysis] is a significant milestone in understanding the potential of NO2 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 … particularly exciting,” said senior investigator Prof Steven Marwaha from the University of Birmingham in Birmingham, UK.

For the meta-analysis, Marwaha and colleagues reviewed seven clinical trials—which involved 247 participants with MDD, TRD, or bipolar disorder—and four protocol papers. The trials evaluated the efficacy of N2O at 25-percent and/or 50-percent concentration against that of placebo (air, oxygen, or midazolam). Treatment was delivered via inhalation for 20–60 min, typically in early-phase designs. Most trials employed single-session protocols, with a subset investigating repeated administration.