Nitrous Oxide May Offer Rapid-Acting Depression Relief
Key Clinical Summary:
- A systematic review and meta-analysis (n=247) found that nitrous oxide (N2O) may offer rapid-acting benefit for the treatment of major depressive disorder (MDD), treatment-resistant depression (TRD), and bipolar depression (BD).
- Pooled results found that a single dose of 50% N2O significantly reduced depressive symptoms at 2 hours (MD −2.74; 95% CI: −4.72 to −0.76; p = 0.007) and 24 hours (MD −3.32, 95% CI: −5.09 to −1.55; p < 0.0001) post-inhalation, but effect was not sustained at 1 week.
- Additional adequately powered trials are needed to establish long-term efficacy.
A systematic review and meta-analysis of 7 clinical trials and 4 published protocol papers found that nitrous oxide (N2O) may offer rapid-acting benefit for the treatment of depression, including major depressive disorder (MDD), treatment-resistant depression (TRD), and bipolar depression (BD). Researchers shared their findings in eBioMedicine.
Main Findings
In the 7 included trials (n=247), N2O was administered via inhalation for 20-60 minutes at concentrations of 25% or 50% in single or repeated sessions with comparators including air, oxygen, or midazolam. Depressive symptoms were evaluated at timepoints ranging from 2 hours to 1-week post-inhalation. The authors also noted that most trials were early-phase and focused on short-term outcomes in adults with MDD or TRD.
Pooled results from 3 trials that administered 50% N2O in a single session saw a significant reduction in depressive symptoms at 2 hours (MD −2.74; 95% CI: −4.72 to −0.76; p = 0.007) and 24 hours (MD −3.32, 95% CI: −5.09 to −1.55; p < 0.0001) post-inhalation. This benefit was not sustained at 1 week after inhalation (MD −1.52; 95% CI: −4.07 to 1.03; p = 0.24). Repeated dosing regimens were associated with more durable antidepressant effects compared to single-session dosing.
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While N2O was generally well tolerated across all trials, common adverse effects included nausea, dizziness, headache, and transient dissociation. These were more common in the 50% dose than the 25% dose.
Clinical Implications
The review suggests that N2O may offer a rapid, short-term antidepressant effect in patients with depression. This may be especially useful for individuals who do not respond to first-line interventions. However, the transient nature of symptom relief early-phase nature of the studies underscore the need for additional research to confirm optimal dosing regimens, long-term efficacy, and safety.
Expert Commentary
“N2O shows promise as a rapid-acting intervention for depression, addressing an urgent need for faster-acting antidepressant treatments,” wrote Kiranpreet Gill, Institute for Mental Health, University of Birmingham, Birmingham, UK, and study coauthors. “Future research must address methodological inconsistencies, clarify underlying mechanisms, and systematically evaluate N2O's feasibility across diverse, real-world populations,” they concluded.
