(66) Recognizing Nitrous Oxide Toxicity: Key Neuropsychiatric Symptoms and Diagnostic Clues

Background & Introduction: Nitrous oxide (N₂O), known as laughing gas, is used in medicine for its anesthetic and analgesic properties. Its euphoria-inducing effects stem from its influence on dopamine transmission in the nucleus accumbens, which also makes N₂O prone to misuse and addiction.

The availability of N₂O through whippits (8 g), canisters (~640 g), or cylinders (2000 g) sold at smoke shops and online has fueled recreational use. The lifetime prevalence of nitrous oxide use in the U.S. is estimated at 4–5%, affecting millions. Chronic misuse disrupts vitamin B12 metabolism, leading to deficiency, which can cause neuropathy, ataxia, weakness, cognitive decline, and perceptual distortions.

Prolonged use may result in anoxic brain injury, worsening neurocognitive symptoms. Clinicians should suspect N₂O use when evaluating unexplained neurological symptoms, as N₂O is not detectable on routine drug screens and may be used to avoid detection. Diagnostic clues, such as megaloblastic anemia, vitamin B12 deficiency, and changes in homocysteine and methylmalonic levels, can assist in identifying chronic N₂O toxicity.

This case series examines three patients with cognitive impairments due to prolonged nitrous oxide abuse. These cases highlight neuropsychiatric manifestations of chronic N₂O toxicity, diagnostic markers, and the challenges in recognizing N₂O misuse and outcomes following treatment.

Case Description: Case One:
A 48-year-old male was hospitalized in May 2020 after being found unconscious, surrounded by hundreds of N₂O canisters. He presented with excessive drowsiness, confusion, bilateral lower extremity numbness, weakness, ataxia, and delusions. He dismissed concerns from clinicians, attributing the entirety of his symptoms to gout. He was noted to be reaching into the air, attempting to grasp imaginary objects.

Laboratory tests revealed: elevated vitamin B12 levels (due to self-supplementation), elevated homocysteine levels, normal methylmalonic acid.

An MRI of the brain exhibited cortical atrophy markedly greater than expected for his age. The patient admitted to using up to 1200 whippits daily. Despite B12 supplementation and reported abstinence from N₂O, his condition worsened. Three months post-hospitalization, he experienced persistent ataxia and significant short-term memory deficits. By September 2022, he remained unable to return to work.

Case Two:
A 40-year-old male was hospitalized in February 2024 with ataxia, recurrent falls, confusion, bilateral numbness and weakness in the lower extremities and hands, and memory loss. On arrival, he exhibited disorientation to situation and poor insight, insisting he was healthy enough to leave the hospital and resume normal activities.

Laboratory tests revealed: Low vitamin B12 levels, elevated homocysteine, elevated methylmalonic acid.

The patient reported escalating to 12–18 canisters daily since starting to use N₂O the summer of 2023. Notably, he had been hospitalized in December 2023 for a pulmonary embolism, likely related to elevated homocysteine levels, which is a risk factor for thrombosis development, from N₂O use. Treatment included intramuscular B12 injections followed by oral supplementation. By May 2024, his lower extremity weakness showed minimal improvement, but he was able to return to his job.

Case Three:
A 49-year-old male presented in September 2024 with three weeks of confusion, difficulty completing sentences, and visual hallucinations, including objects appearing to pulsate or crawl up walls. He reported extreme anxiety accompanied by auditory hallucinations of indecipherable whispers.

Medical history included heavy tianeptine use, recent buprenorphine/naloxone taper, and kratom use. Initial tests revealed: cortical volume loss greater than expected for his age, low vitamin B12, elevated homocysteine and methylmalonic acid.

Despite initial denial, he later admitted to heavy N₂O use over six months. Treatment involved B12 supplementation, thiamine, sertraline for mood, and gabapentin. He declined methionine supplementation. By October 2024, he experienced significant motor and cognitive improvements and was able to return to work.

Conclusion & Discussion: Chronic N₂O use disrupts vitamin B12 function through oxidation and inactivation, leading to neurological symptoms from B12 deficiency. Other neuropsychiatric manifestations, such as hallucinations and delusions, may arise from N₂O’s effects on dopamine transmission and B12-dependent neurotrophic functions. Vitamin B12 serves as a cofactor in reactions required for neurotransmitter synthesis and in the repair and maintenance of myelin sheaths.

Cases one and two highlight the profound neurological and functional consequences of prolonged N₂O misuse. Case three underscores the diagnostic challenges posed by undisclosed N₂O use, which necessitated multiple physician consultations and an extensive medical evaluation before the underlying cause was identified.

Key diagnostic markers include vitamin B12, methylmalonic acid, and homocysteine levels. However, these markers may appear normal with self-supplementation, and there is no direct test for N₂O. While vitamin B12 supplementation can improve symptoms, continued N₂O use leads to further decline.

Limitations of this series include small sample size and reliance on retrospective data.

Early detection and increased awareness among clinicians and the public are essential to mitigating long-term effects of N₂O toxicity. While peripheral symptoms, such as weakness and neuropathy, may improve following cessation of N₂O use, ataxia and neurocognitive issues appear to exhibit greater resistance to recovery.

References: 1. Gernez E, Lee GR, Niguet JP, Zerimech F, Bennis A, Grzych G. Nitrous Oxide Abuse: Clinical Outcomes, Pharmacology, Pharmacokinetics, Toxicity and Impact on Metabolism. Toxics. 2023 Nov 28;11(12):962. doi: 10.3390/toxics11120962. PMID: 38133363; PMCID: PMC10747624.

2. Oulkadi S, Peters B, Vliegen AS. Thromboembolic complications of recreational nitrous oxide (ab)use: a systematic review. J Thromb Thrombolysis. 2022 Nov;54(4):686-695. doi: 10.1007/s11239-022-02673-x. Epub 2022 Jun 27. PMID: 35759070.

3. Garakani A, Jaffe RJ, Savla D, Welch AK, Protin CA, Bryson EO, McDowell DM. Neurologic, psychiatric, and other medical manifestations of nitrous oxide abuse: A systematic review of the case literature. Am J Addict. 2016 Aug;25(5):358-69. doi: 10.1111/ajad.12372. Epub 2016 Apr 1. PMID: 27037733.

4. Green R, Miller JW. Vitamin B12 deficiency. Vitam Horm. 2022;119:405-439. doi: 10.1016/bs.vh.2022.02.003. Epub 2022 Mar 11. PMID: 35337628.

5. Xiang Y, Li L, Ma X, Li S, Xue Y, Yan P, Chen M, Wu J. Recreational Nitrous Oxide Abuse: Prevalence, Neurotoxicity, and Treatment. Neurotox Res. 2021 Jun;39(3):975-985. doi: 10.1007/s12640-021-00352-y. Epub 2021 Mar 26. PMID: 33770366.