Antidepressant Effects of Nitrous Oxide in Major Depressive Disorder: A Phase 2b Randomized Clinical Trial.
Paul S Myles, Jayashri Kulkarni, Jessica Kasza, Sophie Wallace, Carolyn Deng, Alisa Turbić, Verna Aykanat, Charles R Conway, Frank Brown, Royce Lee, Robert D Gibbons, Peter Nagele
Biological psychiatry global open science July 1, 2025 DOI: 10.1016/j.bpsgos.2025.100504 via PubMed
Summary
AI-generated from the abstractIn a phase 2b randomized, double-blind trial, 81 adults with major depressive disorder received either nitrous oxide (at 25% or 50% inspired concentration) or an oxygen/air control across four weekly one-hour sessions, with four additional weeks of follow-up. The primary outcome, change in Hamilton Depression Rating Scale scores over the four treatment weeks, was lower with nitrous oxide than control (mean difference -1.9, 95% CI -3.9 to 0.0, p = .051), a result that did not reach conventional statistical significance. However, in the first week, 38% of the nitrous oxide group versus 13% of the control group achieved remission (p = .031). Secondary measures of depression and suicidality also favored nitrous oxide. The findings suggest nitrous oxide likely has beneficial antidepressant effects.
Study at a glance
| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 81 |
| Population | Adults with major depressive disorder |
| Intervention | Nitrous oxide |
| Dose | 25% or 50% inspired nitrous oxide |
| Duration | 4-week intervention, 4-week follow-up |
| Topics | Depression |
| Keywords | Glutamatergic system Major depression Nmda Nitrous oxide Suicidality |
| Key finding | Nitrous oxide showed likely beneficial antidepressant effects in adults with major depressive disorder, with a higher remission rate in the first week compared to control. |
Abstract
Nitrous oxide ("laughing gas") is an NMDA receptor antagonist. In the current study, our aim was to investigate the efficacy, safety, and likely optimal dose of nitrous oxide in adults with major depressive disorder (MDD). In this phase 2b randomized, double-blind trial, 81 patients with MDD were allocated on a 1:1 basis to receive nitrous oxide or oxygen/air (control); the nitrous group was further randomized to either 50% or 25% inspired nitrous oxide. All participants received four 1-hour-long treatment sessions at 1-week intervals and were followed for an additional 4 weeks. The primary outcome was the change in the 21-item Hamilton Depression Rating Scale (HAM-D) over the 4 treatment sessions. Secondary outcomes included remission (HAM-D ≤7 points), the Computerized Adaptive Test-Depression Inventory (CAT-DI) and Computerized Adaptive Test-Suicide Scale (CAT-SS). The mean averaged change in HAM-D scores over the 4 weeks of treatment was lower with nitrous oxide than with control (-1.9 [95% CI, -3.9 to 0.0], p = .051). In the first week, 15 of 39 (38%) in the nitrous oxide group and 5 of 39 (13%) in the control group were remitted (p = .031). The mean averaged change in CAT-DI scores was -7.7 (95% CI, -14.1 to -1.4), p = .017; the mean averaged change in CAT-SS scores was -8.3 (95% CI, -14.4 to -2.1), p = .008, both favoring nitrous oxide. In this study, we confirmed that nitrous oxide has likely beneficial antidepressant effects in people with MDD.