A single 60-minute inhalation of 50% nitrous oxide (N2O) significantly reduced depressive symptoms in older adults (aged 60–90) with late-life depression who had not responded to at least one adequate antidepressant trial. In a double-blind, randomized, placebo-controlled trial with 60 participants, those receiving N2O showed a greater reduction in Montgomery-Åsberg Depression Rating Scale (MADRS) scores at two weeks compared to placebo (−6.2 points; 95% CI: −9.1 to −3.4). Improvements were rapid, appearing within 24 hours and persisting at one week. All adverse events were mild and transient. The findings suggest N2O may be a safe and effective rapid-acting treatment for this difficult-to-treat population, though further studies are needed to confirm long-term efficacy and safety.
A single one-hour session of a 50:50 nitrous oxide/oxygen mixture (EMONO) rapidly alters functional connectivity in the default mode network and increases brain tissue pulsations in depressed women who respond to the treatment. Among 20 women with treatment-resistant depression, 45% showed at least a 50% reduction in depression scores one week after exposure. Responders exhibited decreased connectivity between the subgenual anterior cingulate cortex and the precuneus, and a larger early increase in brain tissue pulsations, which may enhance drug delivery. Non-responders and healthy controls showed different connectivity changes. The findings suggest potential cerebral mechanisms and markers for antidepressant response to nitrous oxide.