What is the recommended dose of nitrous oxide (N2O) for the relief of depression?

Nitrous Oxide Dosing for Treatment-Resistant Depression

For treatment-resistant depression, use inhaled nitrous oxide at 25% concentration for 1 hour, as this provides comparable antidepressant efficacy to 50% concentration but with substantially fewer adverse effects.

Recommended Dosing Protocol

The optimal dose is 25% nitrous oxide mixed with oxygen, administered via inhalation for 1 hour. 1

Single-Dose Administration

• 25% concentration is the preferred starting dose based on the most recent high-quality evidence 1
• Administered as a single 1-hour inhalation session 1
• Mixed with oxygen to maintain safety and prevent hypoxia 2
• Maximum antidepressant effects observed at 24 hours post-administration 3

Alternative Higher Dose (When 25% is Insufficient)

• 50% concentration can be used if 25% proves inadequate 1
• Also administered for 1 hour 1
• However, adverse events increase substantially with this higher dose (P < 0.001) 1

Repeated Administration Protocol (Investigational)

• Weekly administration for 4 consecutive weeks is being studied for sustained effects 4
• Each session consists of 1 hour at 50% concentration 4
• This repeated dosing approach remains investigational and requires further validation 4

Evidence Supporting 25% Concentration

The pivotal 2021 phase 2 trial directly compared both concentrations and found:

• No significant difference in efficacy between 25% and 50% nitrous oxide (P = 0.58) 1
• At 2 weeks post-treatment, 25% showed -5.19 point improvement versus placebo (P = 0.02) 1
• At 2 weeks post-treatment, 50% showed -7.00 point improvement versus placebo (P = 0.001) 1
• Adverse events declined substantially with the lower 25% dose (P < 0.001) 1

A 2024 meta-analysis confirmed rapid antidepressant action with standardized mean difference of -2.36 at 24 hours (95% CI: -3.37 to -1.34, P < 0.0001) 5

Safety Considerations and Monitoring

Critical Safety Requirements

• Always co-administer with 30-50% oxygen to prevent hypoxia, which is the major risk 2
• Continuous pulse oximetry monitoring throughout administration 2
• Never use in patients at risk for hypercapnic respiratory failure 2

Common Side Effects (Dose-Dependent)

• Dizziness occurs in approximately 39% of patients 2
• Headache is a troubling side effect across multiple studies 6, 2
• Drowsiness is common and self-limiting 2
• Nausea and vomiting may occur 2

Serious Risks to Monitor

• Hypoxia is the most serious adverse effect and can be fatal 2
• Hypertension and arrhythmias have been reported 2
• Hypotension (21%), bradycardia (10%), and vertigo (26%) when combined with other agents 6

Clinical Context and Pitfalls

Common Pitfall: Using 50% concentration as first-line when 25% provides equivalent efficacy with better tolerability. The 2021 trial definitively showed no therapeutic advantage to the higher dose 1.

Important Note: While guidelines exist for nitrous oxide use in procedural pain management, they actually recommend against its use in critically ill ICU patients (conditional recommendation, low quality evidence) 6. However, this recommendation pertains to procedural analgesia, not psychiatric treatment of depression, which represents an entirely different clinical context and patient population.

The antidepressant application of nitrous oxide represents a novel repurposing of this agent, with the mechanism likely related to NMDA receptor antagonism and cerebral vasodilation effects rather than analgesic properties 7.