Biological psychiatry global open science
July 1, 2025
Paul S Myles, Jayashri Kulkarni, Jessica Kasza et al.
In 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.
medRxiv : the preprint server for health sciences
August 17, 2024
Charles R Conway, Ben Julian A Palanca, Thomas Zeffiro et al.
preprint
Nitrous oxide (N2O) reduces functional connectivity in mood-related brain networks in people with treatment-resistant major depression (TRD) but increases connectivity in healthy controls. In a crossover trial, 14 TRD patients and 16 healthy controls received one-hour inhalations of 50% N2O or placebo. Resting-state fMRI scans before, 2 hours, and 24 hours after inhalation showed that N2O progressively decreased connectivity in TRD patients across five brain networks (salience, default mode, reward, cingulo-opercular, and the dorsal nexus), while increasing connectivity in controls. The findings suggest N2O's antidepressant effects involve specific alterations in depressed brains.
Science translational medicine
June 9, 2021
Peter Nagele, Ben J Palanca, Britt Gott et al.
A single 1-hour inhalation of 25% nitrous oxide improves depressive symptoms in patients with severe treatment-resistant major depression as effectively as 50% nitrous oxide, but with substantially fewer adverse effects. In a phase 2 crossover trial with 24 patients, both concentrations significantly reduced depression scores on the Hamilton Depression Rating Scale compared to placebo over two weeks. The 25% dose showed significant improvements at week 1 and week 2, while the 50% dose showed significant improvement at week 2. Adverse events declined substantially with the lower dose.
Frontiers in Psychiatry
July 17, 2020
P. Nagele, Frank Brown, Victoria Bass et al.
A patient with severe recurrent treatment-resistant major depression experienced full remission lasting more than one month after a single nitrous oxide (laughing gas) inhalation treatment. Previous studies had shown antidepressant effects starting within two hours and lasting up to one week, but it was unknown whether effects could persist longer. This case provides evidence that remission can extend beyond one month.