Antidepressant Effects of Nitrous Oxide in Major Depressive Disorder: A Phase 2b Randomized Clinical Trial

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.