In healthy volunteers, a single 1-hour inhalation of 50% nitrous oxide produced changes in brain connectivity that lasted at least 24 hours. Using resting-state functional MRI, the study found increased global connectivity in the occipital cortex at 2 and 24 hours after inhalation, particularly between the visual network and the dorsal attention network. Weaker connectivity changes were observed between the visual cortex and frontoparietal and default mode networks. No significant connectivity changes followed inhalation of air/oxygen. These persistent cortical effects suggest nitrous oxide induces neurophysiological changes beyond its acute psychotropic effects.
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.
NMDAR antagonists like ketamine and nitrous oxide are being studied as rapid-acting antidepressants. Intravenous ketamine rapidly reduces depressive and suicidal symptoms in treatment-resistant depression (TRD), as shown by several trials. The FDA has approved intranasal esketamine for TRD, with a REMS program to minimize misuse. Nitrous oxide, a gas used for anesthesia and analgesia, also acts as an NMDAR inhibitor. A recent double-blind, prospective, cross-over study found that nitrous oxide reduced depressive symptoms in severely ill TRD patients, though further research is needed.
In a small blinded, placebo-controlled crossover trial, 20 patients with treatment-resistant depression inhaled either 50% nitrous oxide or a placebo gas for about one hour. Depressive symptoms improved significantly more after nitrous oxide than after placebo, both at 2 hours and at 24 hours after treatment. Four patients (20%) showed a treatment response and three (15%) achieved full remission after nitrous oxide, compared with one response and no remission after placebo. All side effects were brief and mild to moderate; no serious adverse events occurred. The results suggest that nitrous oxide can produce rapid antidepressant effects in patients with treatment-resistant depression.