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.
1. Zaloum SA, Mair D, Paris A, Smith LJ, Patyjewicz M, Onen BL, et al. Tackling the growing burden of nitrous oxide- induced public health harms. Lancet Public Health 2025;10:e257–e63.
2. Winstock AR, Maier LJ, Zhuparris A, Davies E, Puljevic C, Kupers KPC, Ferris JA, Barratt MJ. Global Drug Survey (GDS) 2021 Key Findings Report. 2021.
3. Gummin DD, Mowry JB, Beuhler MC, Spyker DA, Rivers LJ, Feldman R, et al. 2023 Annual Report of the National Poison Data System(R) (NPDS) from America's Poison Centers(R): 41st Annual Report. Clin Toxicol (Phila). 2024;62(12):793–1027.
4. De Halleux C, Juurlink DN. Diagnosis and management of toxicity associated with the recreational use of nitrous oxide. CMAJ 2023;195:E1075–E81.
5. Quax MLJ, Van Der Steenhoven TJ, Antonius Bronkhorst MWG, Emmink BL. Frostbite injury: an unknown risk when using nitrous oxide as a party drug. Acta Chir Belg 2020;122:140–3.
6. Mohan R, Asir VD, Shanmugapriyan , Ebenezr V, Dakir A, Balakrishnan, et al. Nitrous oxide as a conscious sedative in minor oral surgical procedure. J Pharm Bioallied Sci 2015;7(Suppl 1):S248–S50.
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8. Knuf K MC. Nitrous Oxide. In: StatPearls. Treasure Island, FL: StatPearls Publishing; 2026 Jan. Updated Aug 8, 2023.
9. Winstock AR, Ferris JA. Nitrous oxide causes peripheral neuropathy in a dose dependent manner among recreational users. J Psychopharmacol 2020;34:229–36.
10. Ekeberg D, Ogner G, Fongen M, Joner EJ, Wickstrøm T. Determination of CH4, CO2and N2O in air samples and soil atmosphere by gas chromatography mass spectrometry, GCMS. J Environ Monit 2004;6:621–3.
11. Drescher SR, Brown SD. Solid phase microextraction-gas chromatographic–mass spectrometric determination of nitrous oxide evolution to measure denitrification in estuarine soils and sediments. J Chromatogr A 2006;1133:300–4.
12. Yu M, Qiao Y, Li W, Fang X, Gao H, Zheng D, et al. Analysis of clinical characteristics and prognostic factors in 110 patients with nitrous oxide abuse. Brain Behav 2022;12: e2533.
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.
This molecule is an anesthetic commonly used in dentistry. Abusers are mainly found among healthcare workers and employees in the restaurant and catering business.
Discovered in 1772 by English scientist Joseph Priestley, N2O was made by heating ammonium nitrate in the presence of iron filings and then passing the gas that came off (NO) through water to remove toxic by-products. Following Priestley's discovery, Humphry Davy of the Pneumatic Institute in Bristol, England, experimented with the gas, even administering it to visitors to the institute. After watching the amusing effects on people who inhaled it, he coined the term “laughing gas.” Early on, N2O was primarily used for recreation at traveling public shows but eventually found a more scientific use as an anesthetic in clinical dentistry and medicine. As the story goes, in 1844 a medical school dropout named Gardner Quincy Colton put on a nitrous oxide exhibition in Hartford, Connecticut. In the audience was a local dentist named Horace Wells. Dr. Wells watched with interest as one of the volunteers inhaled the gas then injured his leg when he staggered into some nearby benches. When he went back to his seat, he appeared to be unaware of the injury until the effects of the gas wore off. Dr.Wells immediately realized that N2O might possess painkilling qualities. Wells approached Colton and invited him to participate in an experiment the next day. Colton agreed and administered nitrous oxide to Wells while another local dentist extracted one of Wells' molars. Dr. Wells experienced no pain during the procedure, and the birth of N2O as a dental and medical painkiller had arrived. Nitrous oxide is a very safe and popular agent still utilized by dentists today. It is much less toxic than alternatives such as chloroform, with far less risk of explosion than ether. The main use for N2O is usually as a mild sedative and analgesic. It helps to allay anxiety that many patients may have toward dental treatment, and it offers some degree of painkilling ability.
N2O is a nonflammable gas present in the atmosphere in a concentration of ~0.3 ppm (4). It is water soluble and colorless and has a slightly sweet smell. Bacteriostatic properties and the lack of influence on food flavor make it a useful agent in the food industry (3). An important property of N2O for medicinal purposes is its low oil:gas partition coefficient of 1.4 at atmospheric pressure. This low partition coefficient produces a minimal alveolar concentration (MAC) of 1.05 atmospheres for anesthesia. Its low blood:gas partition coefficient (0.47 at 37 °C), quickly increases its partial pressure in blood, and results in a rapid induction of anesthesia. The low blood:gas coefficient also causes N2O to diffuse readily into enclosed air-filled body cavities, replacing nitrogen. N2O enters the cavity 35 times as rapidly as nitrogen exits, thereby expanding the cavity or increasing pressure. Therefore, use of N2O is not recommended in patients with occlusion of the middle ear, pneumothorax, obstructed intestine, or air emboli in the bloodstream (5).
N2O interacts with opioid receptors of the m- and k-subtypes to produce analgesia. N2O can act both as an antagonist that reduces the effect of morphine in humans and as an agonist that acts synergistically with the opioid-receptor–mediated anesthetic effect of ketamine. Therefore, N2O is considered a partial agonist at these receptors (6). Tolerance occurs for the nociceptive effect of N2O, which develops between 45 and 150 min, possibly because of a decrease in opioid-receptor density (7). N2O may also interact with the d- and s-receptors (6, 8).
Besides these direct effects on opiate receptors, indirect effects of N2O have been reported. It can cause the release of endogenous opioids, such as met-enkephalin and b-endorphin, and thereby indirectly activate opioid receptors (6).
The mechanism of action for gaseous anesthetics is still poorly understood. Anesthetic potency is correlated to drug lipophilicity. Lipophilic molecules enter the lipid bilayer and expand and impede the opening of ion channels in the membrane and thereby the generation and propagation of action potentials. Another hypothesis is that anesthetic molecules bind to lipid portions of the ion channels and inhibit proper functioning (5).
N2O is not biotransformed. It enters and exits the body unchanged, almost entirely through the lungs (2).
Because N2O is a gas, effects depend on its partial pressure in the administered gas mixture, and the partial pressure is directly proportional to the percentage of N2O in the mixture. Concentrations are therefore expressed in percentages. Clinical responses to different concentrations of N2O are as follows (5):
The analgesic effect of 20 percent N2O is comparable to that of 15 mg subcutaneous morphine (2). In 1991, the gas was used in more than half (2) of U.S. dental offices in concentrations of less than 50 percent in combination with oxygen to provide conscious sedation. The average concentration of N2O used for dental procedures is 40 percent (9). In higher concentrations, N2O f unctions as an anesthetic. Because of its low potency (high MAC value), it is not used as a sole general anesthetic. However, it is often combined with more potent anesthetics to provide general anesthesia with analgesia, rapid recovery, and a limited complication incidence (9). To distinguish between analgesic and anesthetic use of N2O, the former is also called psychotropic analgesic nitrous oxide (PAN). PAN has been used successfully to reduce craving in people who are withdrawing from alcohol, cannabis, and nicotine and may therefore be able to prevent relapses in these patients (10).
Other contraindications for the use of N2O include respiratory infections and chronic obstructive pulmonary diseases (COPD). Patients with respiratory infections contaminate tubing and the breathing apparatus and place other patients at risk. N2O with oxygen should not be used in patients with COPD because these patients depend partly on a low blood oxygen concentration to initiate a breathing stimulus. Pregnancy is not a contraindication if sedation is required; N2O with oxygen may even be recommended (2).
Because N2O is a weak anesthetic agent, it is generally considered a safe drug. Although N2O may be safe for acute effects of exposure, including nausea, hypoxia, and claustrophobia (1), chronic, occupation-related, low-dose exposure to N2O can cause serious side effects. N2O oxidizes components of the vitamin B12 omplex. The result is a decreased availability of the vitamin, decreased activity of the vitamin B12-dependent enzyme methionine synthetase, and a subsequent decrease in protein and nucleic acid synthesis, megaloblastic anemia, and other symptoms of vitamin B12 deficiency (5).
Other side effects related to chronic exposure to N2O are (11):
Chronic abusers of high concentrations of N2O can develop central nervous system myeloneuropathy with symptoms of numbness, equilibrium and coordination problems, muscle weakness, and headaches (11). Neuropsychiatric symptoms such as depression, impaired memory, confusion, and delusions have also been described (14). Recovery from these side effects can occur once the exposure ends. Treatment with steroids and vitamin B12 is of questionable value (15).
With more than 200,000 healthcare workers potentially exposed to the drug (3), it is important to keep N2O concentrations low in the workplace. The American Conference of Governmental Industrial Hygienists recommends a threshold value for N2O of 50 ppm for an eight-hour average exposure. The National Institute for Occupational Safety and Health recommends a limit of 25 ppm per anesthetic operation (12, 13).
There are no reports of allergic reactions to the gas or of irritation of the bronchial mucosa (2).
Although abuse of and addiction to N2O can occur, it is generally thought to have a low abuse potential because of its partial agonism and fast-developing tolerance. Abusers are mainly found among healthcare workers and employees in the restaurant and catering business. It is estimated that as many as 20% of medical and dental students have tried N2O to get high, although very few have continued to use the drug. N2O is usually one element of a polydrug addiction. The effects of the recreational use of N2O are euphoria and a sense of well-being, sometimes combined with fantasies; dysphoria is produced in some individuals (16). These effects are short-lived (14).
One method of administering the gas is through a breathing apparatus attached to a commercially available tank of N2O. Another method is to re-breathe the gas from a plastic bag. Without supplemental oxygen, however, this method can lead to hypoxia, syncope, and death. Medical examiners report that recreational use of N2O is responsible for less than 0.1 percent of drug-abuse-related deaths in the United States (3). Postmortem blood concentrations of 46–180 mL/L have been documented. Concentrations during anesthesia are 170–220 mL/L (17).
N 2 O analysis can be accomplished with gas chromatography using a molecular sieve or Porapak Q column (17). Detection methods include electron capture (sensitivity increases with the detector temperature), flame ionization, infrared analysis (18), mass spectrometry, and thermal conductivity. Exposure to N 2 O can be determined by analysis of air samples collected with a pump-bag sampling system (4). Commercial passive dosimeters for N2O are also available (13).
Because of its high volatility and rapid elimination, N2O is difficult to detect with traditional screening procedures (1). Head-space analysis of urine provides the best method, although blood and breath may also be analyzed. Measurement of N2O in arterial blood accurately reflects N2O exposure, whereas venous blood concentrations are poorly correlated. However, measurement in repeated arterial blood samples is impractical (4). Biological effects of exposure to N2O can be tested with the deoxyuridine suppression test. This is a sensitive biochemical way to detect temporary inactivation of the enzyme methionine synthetase (11).
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