Recreational N2 O Use: Just Laughing or Really Bad News?

There is evidence of a global increase in N2O use among young people, along with a low level of awareness about the risks of prolonged/heavy use and late presentation to treatment after experiencing side effects. We advocate a combined effort of legislation and better education about side effects to limit problems associated with excessive N2O use. Nitrous oxide (N2O; laughing gas) has been inhaled by hundreds of millions of patients in medical settings for acute pain control mainly in surgery and dentistry since 1844. N2O also has a long history of recreational use, but recently, there has been an increase in recreational N2O use in many countries, including Australia, United Kingdom, United States, the Netherlands, and China [1-3]. The highest rate of last year N2O use was found in the United Kingdom in 2019/2020 with 8.7% of youngsters age 16 to 24 years [4] using N2O in the past year, although it has stabilized over the past few years. In the United Kingdom, N2O use is the second most popular drug among 16- to 24-year-olds, following cannabis [5]. In Australia, an increase of 8% in 2003 to 67% in 2020 was reported among recreational drug users in New South Wales [6]. The apparent upsurge of N2O use and the related public nuisance (empty balloons, canisters and bulbs) have led to an increased coverage in the media demanding legislative measures aiming to take N2O out of legal circulation in some countries [7], although some experts are warning that criminal drug runners will then control the market and young minors will be exposed to a myriad of more harmful controlled drugs. They propose instead that youngsters should be approached with credible information to limit their use, raise awareness of early symptoms (persistent numbness and tingling in feet, mouth, tongue and fingers) and seek help [8]. Although general prevalence data are lacking for most countries and N2O use is usually not included in general population surveys, there are some indications that problematic N2O use is on the rise [1, 2, 9]. In the United States, the number of N2O related cases reported to the Food and Drug Administration (FDA) (FDA Adverse Event Reporting [FAERS] data) increased from 25 in 2012 to 2015 to 99 in 2016 to 2019 [10], which referred in 70% of cases to subjects age 13 to 29 years. The FAERS cases (n = 128) comprised hospitalization (34%), disabling events (7%), life threatening events (7%) and fatalities (25%). Improved registration of the N2O-related events (e.g. coding) may partly explain the increasing trends in N2O related adverse events, but several studies from other countries have shown a similar gradual increase in clinical cases [2, 9, 11, 12]. It has been noted that some patients wait too long before seeking medical assistance [1, 11]. One of the reasons is shame. This became specifically apparent in a small subgroup of young Muslim heavy N2O users [13]. Moreover, their use of N2O in high quantities for prolonged periods suggests that N2O may have some dependence liability. In addition, a shift was noted in the Netherlands from using standard cartridges (8 g) to using 2-kg tanks. A specific harm, observed in the Netherlands, was the increased number of N2O related traffic accidents (from 130 in 2017 to 960 mid-2019) [14]. However, no distinction was made between accidents because of N2O intoxication and accidents because of filling balloons while driving. Based on hospital data, it was concluded that the COVID-19 lockdown may have generated a further increase in the abuse of N2O and more neurological hospital admissions [2, 3]. The pandemic may have disturbed drug trafficking and shifted national drug consumption trends, because of shortage of drugs, like cocaine and heroin, may have facilitated the increased consumption of locally produced or more accessible and cheaper substances, like N2O and cannabis. For example, the use of ecstasy, a typical party drug, decreased during the lockdown [15]. However, a report from the Netherland noted a decrease in ecstasy and N2O use during the COVID-19 lockdown because of a lack of social opportunities [16]. The typical recreational N2O user takes ≤5 hits (whippets) in a single session [8] and is unaware of its side-effects [17]. Although incidental N2O use is indeed associated with little or no harm, prolonged use of high doses may lead to neurological damage [8], including generalized demyelinating polyneuropathy, resulting in paraesthesia, unsteady gait, weakness and even paralysis because of spinal cord injury [1, 2, 8, 11]. In almost all clinical cases, N2O-related neurological symptoms were accompanied by vitamin B12 (cyanocobalamin) deficiency [1, 8, 9, 18]. In the absence of timely supplement with vitamin B12, excessive N2O use causes increases in homocysteine and methylmalonic acid, which attributes to demyelination of the spinal cord. Some reports explicitly stated that patients presented too late to hospital for adequate treatment [1, 11]. In conclusion, there is evidence of a global increase in N2O use and N2O-related harm and concerns are raised about the specific popularity of N2O use among young subjects (16–24 years.), the low level of awareness about the risks to prolonged and/or heavy N2O use, and the late presentation to treatment after experiencing side-effects. Therefore, we advocate a combined effort of legislation (reducing availability of N2O) and better education of potential users (including N2O information in existing prevention strategies) and medical professionals about side-effects to limit problems associated with (excessive) N2O use. In addition, hospital doctors and neurologists should take into account homocysteine, methylmalonic and vitamin B12 levels when dealing with young, otherwise heathy, patients with neurological symptoms. None.