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.
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.