Short-Term Nitrous Oxide for Depression: Findings from a Recent Meta-Analysis

A recent meta-analysis found that short-term nitrous oxide produces rapid antidepressant effects in adults with major depressive disorder—including many with treatment-resistant presentations—and highlights a potential option for patients unresponsive to standard pharmacotherapy.

The analysis aggregated seven clinical trials and four protocol papers across international centers, using randomized and crossover designs and a modest pooled sample that included sizable representation of treatment-resistant patients in several cohorts. Primary endpoints emphasized acute change at 24 hours and short-term durability at one week; heterogeneity existed in rating scales and timing, but the consistent signal was rapid reduction in depressive scores after nitrous oxide inhalation.

Benefit appeared in both general MDD cohorts and those defined as treatment-resistant. Response and remission used standard rating scales with prespecified thresholds. Studies reported outcomes after single-dose and repeated-session regimens; single doses produced clear early improvement, while repeated sessions tended to yield more durable symptom reduction, making patients with established treatment resistance among the most likely to show early gains.

Short-term safety signals were described as generally reassuring at the study protocol’s 50% concentration, with transient effects (nausea, dizziness, headache) more common at higher exposures but resolving quickly without major acute events in the pooled analysis. Trial sessions were short and clinic-delivered—commonly under an hour—and required continuous monitoring of consciousness and oxygenation, brief recovery observation after cessation, and staffing competent in airway and sedation safety.