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 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Double-blind Peer reviewed |
|---|---|
| Sample size | 81 |
| Population | Adults with major depressive disorder |
| Interventions | Nitrous oxide Oxygen/air (control) |
| Dose | 50% or 25% inspired nitrous oxide |
| Duration | 4-week intervention, 4-week follow-up |
| Measures | 21-item Hamilton Depression Rating Scale (HAM-D), Computerized Adaptive Test-Depression Inventory (CAT-DI), Computerized Adaptive Test-Suicide Scale (CAT-SS) |
| Topics | Depression |
| Keywords | Glutamatergic system Major depression Nmda Nitrous oxide Suicidality |
| Key findings | 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.
Comparable studies
Other randomized controlled trials on depression, most cited first.
Citations in the library
Cited by 3
- Rapid antidepressant potential of nitrous oxide: current state and major questions. Molecular Psychiatry June 1, 2026
- All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants. Pharmacological Research October 1, 2025
- Novel and emerging anesthetic drugs for the treatments of major depression: a comprehensive review of efficacy, mechanism, and outlook. Frontiers in Psychiatry 2025
Cites 10
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and 5 more in the library