Deux cents ans d’histoire des usages et mésusages du protoxyde d’azote

Nitrous oxide (N₂O) was discovered by chance at the end of the 18th century. While working on nitric acid, the English chemist Joseph Priestley forgot a gas he called “nitrous air” for two months in contact with mercury and iron nails. He thus discovered a new gas which supports combustion, but which is fatal for animals. At that time, few instruments existed, and scientists tasted and inhaled their discoveries to study them. Writers were called upon to test Priestley's air and find the most accurate words to describe its extraordinary effects on the human mind. Humphry Davy, a young English chemist, was passionate about nitrous oxide. He synthesized it late in the evening at the Pneumatic Institute and inhaled it regularly, sometimes with other substances, including wine. In his book Researches, Chemical and Philosophical, chiefly concerning Nitrous Oxide and its Respiration, he specified that his health had deteriorated with the repetition of these experiments from April 1799 to June 1800, evoking disorders similar to what we observe today with the recreational use of N₂O cartridges. This gas will subsequently inspire poets and philosophers and become popular in circuses and fairs, where it was used to entertain crowds. In the 19th century, in France, a first wave of concern about the use of Nitrous oxide appeared following cases of death and madness among users. In the 20th century, recreational use remained scattered until the 1990s. It circulated at this time, mainly on the party and techno scene where it was inhaled from whipped cream siphon cartridges, using balloons, alone or in combination, to enhance the effect of other substances such as ecstasy for example. Its ability to block NMDA receptor activity makes it a product that modifies perceptions and the coherence of thought: an effect similar to that caused by ketamine. Its medical potential first came to light in dentistry. Horace Wells, an American dentist, attended a public “laughing gas” demonstration. A man who had just inhaled it fell and injured his calf. He showed no pain. The dentist then had the idea of testing it on himself by inhaling nitrous oxide and having his assistant pull out a tooth, with success. Then he used it on his patients for pain-free care. In France, it was Apolloni Pierre Préterre who developed the use of nitrous oxide for dental care. In 1866, he filed a patent for his invention, which synthesized and administered N₂O for anesthetic purposes. He developed a mask that allowed for the inhalation through the mouth and nose: the use of anesthesia was quickly adopted. However, during the Franco-Prussian War in the 1870s and the subsequent great demand for anesthesia, nitrous oxide was abandoned in favor of chloroform, which was easier to use. Today, its place is essential and unique among the therapeutic options against pain. Its action is rapid, with few side effects. The patient does not need to fast and can quickly return to their usual activities. It is used during painful treatments or in obstetrics instead of or while waiting for an epidural injection to take effect. Currently, several targets have been identified in the body. Nitrous oxide is an agonist of opioid receptors and gabaergic receptors, and an antagonist of glutamate receptors (NMDA receptors). It is therefore both anxiolytic, analgesic and disrupts memory. It is an essential tool for the prevention of pain induced by medical procedures (dental but also sutures, mobilizations, painful washing of children as well as adults and the elderly). Its use in anesthesia makes it possible to limit the use of opioids. However, its effect on climate change is considerable (300 times greater than CO²), and that fact is currently taken into account and it is used less and less in the operating room out of concern for the environment. If Humphry Davy appears to be the first to have used N₂O to relieve withdrawal symptoms (from alcohol), there is a detailed case in 1972 of a woman suffering from chronic pain and dependent on pentazocine (a powerful synthetic opioid) who was weaned from taking it thanks to N₂O. From the 1980s on, it was used in alcohol withdrawal by Gillman, but also for cannabis and cocaine addiction. In 2006, the American dentist Alan Blanton described his relationship with nitrous oxide as an addiction. He details in his testimony the phenomenon of tolerance, i.e. the need to increase the dosage to obtain the same effect, and the schemes he put in place to hide his consumption for thirteen years. Contemporary recreational use eventually became part of many students’ lives. In 2015, in Lyon, a 22 years old medical student was treated in a Center for Care and Support and Prevention in Addictology. He presented the eleven criteria of the DSM 5 defining substance use disorder. The beginning of its consumption was festive, then for analgesic purposes in the context of an irritable bowel syndrome. His medical history includes several depressive episodes: a vulnerability, which probably favored his addiction to nitrous oxide. This antidepressant effect of N₂O has been particularly studied by Peter Nagele, in the USA. In 2018, Bourbon estimates that 49% of medical students had experimented with N₂O. In a study published in April 2021, 77% of the medical students surveyed said they had already inhaled it. In recent years, new modes of delivery have appeared: canisters of around 600 grams of liquefied gas is the most common model. The complications linked to the inhalation of this pure gas in large quantities are increasing. They are neurological, psychiatric but also vascular with thromboses and cases of substance use disorders appearing. Tolerance to this gas develops quickly, as early as 30 minutes, and signs of withdrawal may appear as soon as inhalation stops. Among users who present a first episode of neurological complications, some resume consuming with ensuing cravings, thus demonstrating the addictive power of this substance. Finally, in France and in many other countries, a paradox exists regarding the sale of nitrous oxide. In its pure form used for whipped cream, it is accessible over the counter while the medical form, mixed with oxygen, was included on list 1 of toxic substances and treated similarly to the legislation on narcotics. Legislation on toxic substances therefore had to be adapted. Since 2019, several mayors in France have issued municipal decrees to try to regulate the sale of nitrous oxide to minors and its use on public roads. Then in 2021, under law No. 2021-695 of June 1, its sale is prohibited to minors, and the incitation of a minor to misuse the product to obtain a psychoactive effect is punishable with a fine of €15,000. Finally, since January 2024, sales to individuals are limited to 8.6 g cartridges in packaging not to exceed a total of ten cartridges. On the health front, new recommendations from the ANSM (National Medicines Safety Agency) were disseminated at the beginning of 2023, to improve detection of the use of N₂O and to manage serious complications arising from its use, and to insist on an assessment of an addictive disorder.