Nitrous oxide may produce rapid reductions in depressive symptoms, although current evidence suggests these effects are short-lived and based primarily on early-phase clinical trials, according to a new systematic review and meta-analysis published in The Lancet.
The review synthesized data from 7 completed clinical trials involving 247 participants with major depressive disorder (MDD), treatment-resistant depression (TRD), or bipolar depression, along with 4 published protocol papers. Nitrous oxide, an N-methyl-d-aspartate (NMDA) receptor antagonist, was administered via inhalation at concentrations of 25% or 50%, typically in single-session protocols lasting 20 to 60 minutes.
Pooled analyses of randomized trials evaluating a single session of 50% nitrous oxide demonstrated significant reductions in depressive symptom scores compared with placebo at 2 hours and 24 hours following inhalation. However, symptom improvement was not sustained at 1 week posttreatment. Most trials assessed outcomes using standardized depression rating scales, including the Hamilton Depression Rating Scale and the Montgomery–Åsberg Depression Rating Scale.
Repeated dosing regimens were evaluated in a small number of studies and were associated with more durable symptom improvement over several weeks, particularly in patients with MDD. Evidence also suggested a possible dose–response relationship, with 50% nitrous oxide producing greater symptom reductions than 25%, though higher concentrations were associated with more adverse events.
Across studies, adverse events were generally mild and transient. The most commonly reported effects included nausea, dizziness, headache, and brief dissociative symptoms. No serious adverse events were reported. Lower-dose nitrous oxide (25%) was better tolerated than 50%, particularly with respect to nausea and vomiting, the review said.
Most trials were small, early-phase, and focused on short-term outcomes in adults with MDD or TRD. Evidence mapping identified substantial gaps in the literature, including limited data on long-term efficacy, maintenance strategies, adolescent populations, and bipolar depression, as well as variability in dosing protocols and outcome measures.
The authors concluded that nitrous oxide demonstrates reproducible, rapid antidepressant effects in early trials, but its clinical utility remains uncertain. Larger, well-designed randomized trials are needed to determine whether symptom improvements can be sustained through optimized dosing strategies and repeated administration, according to the review, and to better define its safety profile and role in the treatment of depressive disorders.
Disclosures can be found in the published review.
Source: eBioMedicine
