The Evolving Recreational Use of Nitrous Oxide
By Chinonye Udechukwu, PhD, and Kamisha L. Johnson-Davis, PhD, MBA, DABCC (CC, TC), FADLM
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Published in the June 2026 issue of Clinical & Forensic Toxicology News
When Joseph Priestley synthesized nitrous oxide (N2O) in 1772, he could not have anticipated that this colorless, non-flammable, and faintly sweet-smelling gas would evolve from an experimental curiosity into legitimate, useful applications as an anesthetic and analgesic in medical and dental surgeries, a propellant in whipped cream dispensers, and a fuel oxidant in some automotive engines. On the other hand, he also could not have foreseen its misuse as a recreational inhalant— thanks to the euphoric effects of the gas, so striking that Humphry Davy nicknamed it a “laughing gas” after observing how much inhaling the gas made him laugh. Even before its debut as an anesthetic in 1844, N2O had attracted public recreational interest as early as 1799. The gas was inhaled for its euphoric and dissociative effects at so-called “laughing gas frolics,” which were popular public entertainment among members of the British upper class and Americans in the early 19th century. Today, N2O has gained greater global recreational appeal, particularly among adolescents and young adults, driven by easy and largely unregulated access, low cost, and a false perception of safety among users (1).
According to the Global Drug Survey 2021, N2O ranks among the most used recreational substances, with misuse doubling from 10% in 2015 to 20% in 2021 (2). In the United States (US), reports of N2O misuse have risen steadily since 2014, reaching approximately 96% increase by 2023 (3). Similar trends have been observed in the United Kingdom (UK), where N2O was reported as the 3rd most abused drug after cannabis and cocaine in England and Wales. Recreational N2O is commonly obtained from commercial whipped cream chargers (“whippets”), which are small 8-g pressurized cartridges intended for culinary use (4). Larger canisters (typically 600-2000 g), sometimes marketed with flavors such as pineapple or coconut, have become increasingly available and allow for repeated or prolonged inhalation. Popular brands of the larger canisters include “Galaxy Gas,” “Baking Bad,” and “Miami Magic.” Recreational N2O products may be purchased online or in grocery stores, gas stations, and smoke or vape shops, often at a low cost (approximately $1) per 8 g cartridge. The gas is typically inhaled by releasing it from pressurized containers into a balloon, with users inhaling hundreds of cartridges daily (4). Alternative methods include direct inhalation from larger cylinders via tubing or masks, which increases the risk of frostbite, as well as inhalation in enclosed spaces, which can result in hypoxia (5).
Contrary to users’ misconceptions of safety, N2O misuse can cause pneumothorax, unconsciousness, seizures, and potentially death from asphyxiation in severe acute exposures. Chronic use often results in serious neurological complications, most notably myelopathy, as well as anemia and increased thrombotic risk (4). Road traffic accidents and fatalities have also been reported (1). Public health regulations to curb N2O misuse and associated harms vary widely across jurisdictions and are often complicated by the legal use of the drug in healthcare, food production, and the automobile industry. The UK classified N2O as a Class C drug (like benzodiazepines), whereas it is not federally scheduled as a controlled substance in the US, although the FDA regulates its manufacturing, labeling, and distribution for use in medical and food sectors, and some states (e.g., California, Illinois, and Florida) restrict or criminalize its sale, distribution, and possession with recreational intent, particularly among minors (1).
Given that N2O misuse is less commonly recognized than other substances of abuse, such as opioids, patients presenting with N2O toxicity may be overlooked or misdiagnosed, contributing to the underestimation of the true prevalence of misuse. Therefore, understanding the pharmacological effects of N2O, its mechanisms of toxicity and clinical manifestations, and current diagnostic modalities and their limitations is crucial for timely clinical detection and patient management.
Although considered a weaker anesthetic and analgesic, N2O is clinically used to manage pain during surgical procedures in dentistry, emergency medicine, labor and delivery, reduce anxiety, and promote conscious and unconscious sedation (6). The drug is currently included on the World Health Organization’s List of Essential Medicines as a general inhalation anesthetic for its sedative and pain-relieving properties. The pharmacological effects of N2O are concentration-dependent, where concentrations of 25% can reduce pain sensation, 60% induces drowsiness, and sedation or unconsciousness can occur at 70%. Notably, concentrations of 50- 70% do not promote respiratory depression. The drug is thought to relieve pain by stimulating the release of endogenous opioids (dynorphins and enkephalins) and neurotransmitters in the brain. The anesthetic effect is attributed to decreased glutamate neurotransmission via inhibition of NMDA glutamate receptors and antagonism of the kappa opioid receptor (7). Its sedative and anxiolytic effects result from stimulating GABA-A receptor activity, which promotes the inhibitory effects of GABA on the central nervous system (8). Furthermore, N2O can stimulate cardiac output, blood flow, and intracranial pressure (8).
N2O is absorbed through the lungs into the bloodstream after inhalation, the main route of administration. It has low blood solubility, with a blood-gas partition coefficient of 0.47, and can diffuse rapidly across the alveolar-capillary membrane to produce an onset of effects within 1 minute in highly perfused organs. The “second gas effect” can occur when rapid N2O absorption into the blood causes the immediate onset of the anesthetic effects (8). In addition, N2O can cross the placenta when administered during labor and delivery; however, it does not cause teratogenic effects in the neonate. The drug undergoes negligible metabolism and is mainly excreted intact from the body through the lungs (8).
Chronic N2O use is associated with significant neurological toxicity, notably myelopathy in the form of subacute combined degeneration of the cervical spine, as well as peripheral neuropathy, characterized by numbness, loss of motor function, nerve damage, and muscle weakness in the lower extremities (4). These effects arise from N2O-induced irreversible oxidation of the cobalt ion in vitamin B12, leading to vitamin B12 inactivation (9). Vitamin B12 is a critical cofactor for methionine synthase, which catalyzes the transfer of a methyl group from 5-methyltetrahydrofolate to homocysteine, generating methionine and tetrahydrofolate. Methionine is subsequently converted to S-adenosylmethionine, a key methyl donor required for DNA methylation and myelin sheath synthesis, whereas tetrahydrofolate is essential for thymidine and purines synthesis during DNA replication. Thus, functional vitamin B12 deficiency disrupts methylation and DNA synthesis pathways, impairing myelin sheath formation and leading to neurologic dysfunction as well as hematologic abnormalities, such as megaloblastic anemia. Also, hyperhomocysteinemia resulting from methionine synthase inhibition can contribute to oxidative stress, vascular damage, and protein dysfunction. Chronic N2O exposure also inhibits methylmalonyl- CoA mutase, another vitamin B12-dependent enzyme that converts methylmalonyl-CoA to succinyl- CoA, resulting in methylmalonic acid accumulation.
Other adverse effects of N2O misuse include respiratory depression, hypoxia, psychiatric symptoms, nausea, and vomiting (8). Consequently, N2O is contraindicated in patients with cardiovascular disease, critical illness, pulmonary hypertension, psychiatric disorders, and pregnant individuals during the first trimester, due to the impact on vitamin B12 and folate metabolism (8). Treatment of N2O-induced toxicity involves discontinuing exposure and supplementing with intramuscular vitamin B12 (e.g., hydroxocobalamin).
Clinical diagnosis of N2O toxicity is often challenging due to nonspecific presentations, limited clinical awareness, and the absence of direct, specific biomarkers. However, given the increasing prevalence of recreational misuse, N2O exposure should be considered in the differential diagnosis of adolescents and young adults presenting with myelopathy or peripheral neuropathy, especially without an obvious cause. A detailed substance use history is essential for identifying potential N2O exposure. Direct N2O detection has limited clinical utility due to its rapid elimination and very short half-life of 5 minutes, leading to undetectable blood or breath concentrations by the time of clinical presentation. Although N2O measurement using gas chromatography-mass spectrometry (including headspace GC-MS) is feasible and has been described in environmental and forensic settings (10, 11), it is rarely performed in routine clinical practice, and available methods have low sensitivity and lack standardized/suitable internal standards. Therefore, laboratory evaluation of N2O toxicity primarily relies on indirect biochemical assessments of altered vitamin B12 metabolism.
Given that N2O inactivates cobalamin, reducing functional vitamin B12 concentrations, patients may present with low serum vitamin B12, commonly measured using automated immunoassays, with fast turnaround time (12). However, 25-50% of patients with neurological manifestations of N2O exposure have normal serum vitamin B12, especially given that some users take vitamin B12 supplements to prevent neurotoxicity. In contrast, up to 90% of affected patients demonstrate elevated serum/ plasma homocysteine and methylmalonic acid (MMA), making these metabolites more sensitive indicators of toxicity (12). Analytical methods include enzymatic assays for homocysteine and liquid chromatography tandem mass spectrometry (LC-MS/MS) for MMA. Homocysteine is a more sensitive but less specific marker compared to MMA, as homocysteine concentrations may rise rapidly after exposure but decline within days. The timing of specimen collection relative to the last exposure should be considered in result interpretation. Homocysteine elevations may also occur in conditions unrelated to N2O toxicity, including vitamin B12, B6, or folate deficiency, hypothyroidism, renal dysfunction, and inherited metabolic disorders. Additionally, delayed separation of serum or plasma from cells may falsely increase results. Assessments of renal, liver, and thyroid functions, as well as folate and vitamin B6 status, are useful in excluding alternative causes of vitamin B12 abnormalities to avoid misinterpretations of elevated homocysteine results. Besides diagnosis of N2O toxicity, homocysteine and MMA may also be useful in monitoring the response to intramuscular hydroxocobalamin treatment. Other relevant tests include a complete blood count, which may reveal macrocytosis or megaloblastic anemia in 5-20% of patients with chronic N2O exposure.
Neuroimaging of the central and peripheral nervous systems plays a key role in evaluating patients presenting with N2O-induced neurotoxicity. Magnetic resonance imaging (MRI) of the cervical and thoracic spine is preferred for assessing myelopathy, with characteristic findings of T2 hyperintensities in the dorsal columns, consistent with subacute combined degeneration of mainly the cervical cord but also the thoracic cord in extreme cases (12). Brain MRI is often normal but may reveal frontal lobe demyelination in patients with neuropsychiatric symptoms (12). Although not necessary, nerve conduction studies usually demonstrate abnormalities in most symptomatic patients, particularly axonal degeneration, sometimes with demyelination, and marked motor dysfunction, supporting the diagnosis (4).
The growing recreational use of N2O and related toxicity and deaths spurred global public health concerns that require concerted efforts to mitigate risks. Diagnosing N2O toxicity is challenging for emergency departments due to its short half-life and elimination, as well as the lack of analytical methods for N2O detection. However, clinical laboratories can perform testing for homocysteine and methylmalonic acid to evaluate functional vitamin B12 deficiency. Effective prevention and harm reduction strategies require public health education campaigns (TV, radio, and social media) to warn teens and young adults about the dangers of N2O. Poison control centers and emergency departments are essential for continuous data collection on occurrences and demographics to support surveillance monitoring of N2O misuse and toxicity. Furthermore, to reduce the incidence of N2O toxicity, legislation is needed to control the sale and distribution of N2O or undergo DEA classification as a controlled substance to restrict access.
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Chinonye Udechukwu, PhD, is a second-year Clinical Chemistry Fellow in the Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, Utah.
Kamisha L. Johnson-Davis, PhD, MBA, DABCC (CC, TC), FADLM, is a Professor of Clinical Pathology in the Department of Pathology, University of Utah and a Medical Director of Clinical Toxicology at ARUP Laboratories, Salt Lake City, Utah.
The authors have nothing to disclose.
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