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Nitrous Oxide for Treatment-Resistant Depression, Potential Advantages Over (Es)ketamine

Mascot / Mnemonic:

"Night dress Ox"

Water is H2O. Nitrous oxide is “N2O, not H2O”.   Is it nitric oxide? "NO" (see below)

N2O nitrous oxide, not nitric oxide, for depression. Comparisons with ketamine and esketamine. Mnemonic

What is N2O?

Nitrous oxide, a.k.a. “laughing gas”, is a dissociative anesthetic used since 1844. It is colorless, non-flammable, and has a slightly sweet odor. It is not a controlled substance in the U.S. Medical uses include procedural sedation and pain management, e.g., for labor contractions.  NO2 devices with a demand valve are available for self-administration.

Treatment of depression with N2O:

Yan & Liu et al (2022) found that nitrous oxide was effective for treatment-resistant depression. Subjects received a one-hour inhalation of 50/50 N2O/O2. Depression scores were lower than placebo at 2 hours and 24 hours post-treatment, but no different from placebo at 1 week. Two of the 22 patients in the N2O group withdrew due to nausea during the inhalation. Other side effects included sedation and dissociation. No serious adverse events were reported. Side effects did not persist beyond a few hours.   Nagele & Palanca et al (2021) found the efficacy of 25% nitrous oxide to be similar to 50% nitrous oxide with fourfold fewer side effects. 

Comparison of Nitrous Oxide to Ketamine / Esketamine for depression.

All are NMDA receptor antagonists. Ketamine / esketamine is a controlled substance while nitrous oxide is not. Esketamine is FDA-approved for depression, while N2O is investigational. Potential for addiction with N2O appears to be lower than with (es)ketamine. Treatment with (es)ketamine can cause significant hypertension, while N2O does not. Esketamine side effects peak at 40 minutes and wear off within two hours of treatment. N2O quickly exits the body with exhalation. If N2O is approved for depression, monitoring requirements post-treatment will likely be much less stringent than with esketamine.


Onset is rapid, with peak effect in 30 seconds. It exits the body unmetabolized by exhalation, with rapid offset of around 60 seconds.


Antidepressant effect is believed to be due to NMDA receptor antagonism, the same mechanism as ketamine. The analgesic effect of N2O is strong, similar to morphine. N2O increases respiratory rate but decreases tidal volume, so the net effect is lower ventilation. It increases cerebral blood flow and intracranial pressure. 


N2O is used as a propellant for whipped cream and to enhance engine performance in motor vehicles. Recreational users inhale N2O from whipped cream chargers—“whippets”— to produce euphoria and dissociation.  The nitrous cartridges are typically discharged in a balloon or inhaled directly. "Glue-sniffer's rash" may be seen in the perioral area extending to the midface.

nitrous oxide whippets

Risks / side effects of nitrous oxide:

Nausea/vomiting and dissociation. N2O can precipitate a functional vitamin B12 deficiency when used on a chronic basis or acutely in patients with marginal stores of vitamin B12 such as the elderly or malnourished. With long-term use it can cause anemia and nerve damage secondary to interference with metabolism of vitamin B12, folate, and methionine. In a case of severe neurological damage (Stockton et al, 2017) vitamin B12 levels were in the low normal range but homocysteine and methylmalonic acid levels were elevated.


Bowel obstruction, pneumothorax, recent scuba diving, early pregnancy, middle ear or sinus disease, inhalant abuse 

Not to be confused with Nitric Oxide (NO):

Nitric oxide (not to be confused with today's mascot, nitrous oxide) is an endogenous signaling molecule in humans, also generated by lightning in thunderstorms. It is a gas that in some instances serves as a neurotransmitter. Nitric oxide is a vasodilator, necessary for erections. Supplemental L-citrulline and L-arginine, which purportedly increase levels of nitric oxide, are taken as supplements to treat erectile dysfunction. NO is produced by bacteria in the mouth and killing these bacteria with mouth wash or fluoride may have adverse health consequences. Inhaled NO is approved for treatment of persistent pulmonary hypertension of the newborn. That's nitric, not nitrous, oxide.

Copyright 2024, CaferMed LLC

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