3 papers and 1 clinical trial exploring nitrous oxide as a treatment for treatment-resistant depression (trd).
Nitrous oxide (N₂O) is a rapid-acting NMDA receptor antagonist with emerging evidence for antidepressant efficacy in treatment-resistant depression. Delivered as a 50% N₂O/50% O₂ inhalation mixture over one-hour sessions, it produces rapid mood improvements that can persist for days to weeks. Its established safety record in anesthesia, short session duration, minimal recovery time, and low cost position it as a potentially scalable alternative to IV ketamine and esketamine, though the psychiatric evidence base remains early-stage and no formal psychiatric indication exists. Key open questions include optimal dosing frequency, long-term durability, and the mechanism by which NMDA antagonism without intense psychedelic phenomenology produces antidepressant effects.
Full Nitrous Oxide profileTreatment-resistant depression, depression that has not responded to at least two adequate antidepressant trials, is where psychedelic and rapid-acting therapies are furthest along. Esketamine is FDA-approved, and in 2025 a synthetic psilocybin became the first classic psychedelic to meet a Phase 3 endpoint for depression. The progress is real, but so are the caveats: modest effect sizes, short-lived benefits, and unresolved questions about how well these trials are blinded.
Full Treatment-Resistant Depression (TRD) profile