Nitrous oxide (“laughing gas”) is used as an adjuvant for general anesthesia, an anesthetic and analgesic agent for minor procedures, and a propellant in many commercial products, such as whipped cream and cooking oil spray. (“Whippets” are small cartridges of nitrous oxide that can be purchased at restaurant supply stores, grocery convenience stores, and “head shops.”) Nitrous oxide is used by many US dentists, in some cases without adequate scavenging equipment. Abuse of nitrous oxide is not uncommon in the medical and dental professions.

1. Acute toxicity after exposure to nitrous oxide is caused mainly by asphyxia if adequate oxygen is not supplied with the gas.
2. Chronic toxicity to the hematologic and nervous systems results from the effects of nitrous oxide on vitamin B₁₂. Nitrous oxide exposure causes a functional B₁₂ deficiency by irreversibly oxidizing the cobalt atom in vitamin B₁₂. Vitamin B₁₂ is an essential cofactor for the enzymes methionine synthase and methylmalonyl CoA mutase. Inhibition of methionine synthase prevents the conversion of homocysteine to methionine and also the production of tetrahydrofolate. Methionine is essential for myelin synthesis and tetrahydrofolate for DNA synthesis. Inhibition of methylmalonyl-CoA mutase impairs lipid synthesis, necessary for myelin sheath creation and maintenance. Absolute vitamin B₁₂ deficiency may also occur from the formation of vitamin B₁₂ analogues that are more likely to be excreted. Brief exposure to nitrous oxide can precipitate neurologic symptoms in patients with subclinical B₁₂ or folic acid deficiency.
3. Adverse reproductive outcomes have been reported in workers chronically exposed to nitrous oxide.

The toxic dose is not established. Chronic occupational exposure to 2,000 ppm nitrous oxide produced asymptomatic but measurable depression of vitamin B₁₂ in dentists. The ACGIH-recommended workplace exposure limit (TLV-TWA) is 50 ppm (90 mg/m³) as an 8-hour time-weighted average.

1. Signs of acute toxicity are related to asphyxia, and include headache, dizziness, confusion, syncope, seizures, and cardiac dysrhythmias. Interstitial emphysema and pneumomediastinum have been reported after forceful inhalation from a pressurized whipped cream dispenser.
2. Chronic nitrous oxide abuse primarily manifests with neurological symptoms, including numbness, paresthesias, and weakness. Coordination and gait difficulties may be prominent due to difficulties with proprioception. Less commonly described symptoms include bowel and bladder dysfunction, mental status changes, and sexual dysfunction. Prominent psychiatric symptoms are also described. Clinical manifestations can occur from demyelination localized to peripheral nerves, the spinal cord (myelopathy), or the combination of both (myeloneuropathy). Subacute combined degeneration refers to demyelination predominantly in the posterior columns of the spinal cord, and is a classic finding. Hematological findings include megaloblastic anemia, leukopenia, and thrombocytopenia. Rarely skin hyperpigmentation has been described.

Is based on a history of exposure and clinical presentation. It also should be considered in any patient with clinical manifestations of vitamin B₁₂ deficiency.

1. Specific levels. Specific levels are not generally available and are unreliable owing to off-gassing.
2. Useful laboratory studies include CBC with manual differential, vitamin B₁₂, folate (serum or red cell), nerve conduction studies, and MRI if the patient has neuropathy. Homocysteine and methylmalonic acid levels are usually elevated.

1. Emergency and supportive measures
   1. Maintain an open airway and assist ventilation if necessary (see airway). Administer high-flow supplemental oxygen.
   2. After significant asphyxia, anticipate and treat coma (see coma), seizures, and cardiac arrhythmias.
2. Specific drugs and antidotes. Discontinue nitrous oxide use, as treatment with vitamin B₁₂ is futile if there is ongoing exposure. Chronic effects may resolve over 2-3 months. Give vitamin B₁₂ 1,000 mcg intramuscularly daily or every other day for a week followed by weekly administration until symptom resolution. Folinic acid supplementation is indicated to correct any underlying deficiency Increasing methionine intake via the diet or supplementation has been described.
3. Decontamination. Remove victims from exposure and give supplemental oxygen if available.
4. Enhanced elimination. These procedures are not effective.