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. 2025 Apr 15;5(4):100504.
doi: 10.1016/j.bpsgos.2025.100504. eCollection 2025 Jul.

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

Paul S Myles  1   2 , Jayashri Kulkarni  3 , Jessica Kasza  4 , Sophie Wallace  1   2 , Carolyn Deng  1 , Alisa Turbić  5 , Verna Aykanat  1 , Charles R Conway  6 , Frank Brown  7 , Royce Lee  8 , Robert D Gibbons  9 , Peter Nagele  7
Affiliations

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

Paul S Myles et al. Biol Psychiatry Glob Open Sci. .

Abstract

Background: 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).

Methods: 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).

Results: 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.

Conclusions: In this study, we confirmed that nitrous oxide has likely beneficial antidepressant effects in people with MDD.

Keywords: Glutamatergic system; Major depression; NMDA; Nitrous oxide; Suicidality; Treatment-resistant depression.

Plain language summary

Nitrous oxide (laughing gas) has beneficial activity in key brain pathways associated with severe depression. We enrolled people for whom repeated treatments had failed to adequately treat their depression and studied the effects of nitrous oxide across 4 supervised 1-hour weekly treatment sessions. We found some evidence that nitrous oxide had beneficial and persistent antidepressant effects in people with severe depression. Additional studies are warranted.

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Figures

Figure 1
Figure 1
Trial profile. HAM-D, Hamilton Depression Rating Scale.
Figure 2
Figure 2
(A–C) Mean (95% CI) depression and suicide severity scores at each time point in the control and nitrous oxide (N2O) groups, superimposed on the complete case data from the participants. Additional scoring was done by the participants at 24 hours after the first treatment (day 0) and at 24 hours after the 3-week treatment (day 21). CAT-DI, Computerized Adaptive Test-Depression Inventory; CAT-SS, Computerized Adaptive Test-Suicide Scale; HAM-D, 21-item Hamilton Depression Rating Scale.
See this image and copyright information in PMC

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