Yes, nitrous oxide addiction undeniably exists!

In their article, Back et al. endeavour to evaluate the ‘symptoms’ of substance use disorder (SUD) associated with nitrous oxide (N2O) use in the literature [1]. While presenting an engaging narrative review, a primary concern arises from the absence of a methodology paragraph, leaving uncertainties regarding their article selection process and eligibility criteria. The authors amalgamate animal studies, recreational clinical cases and pain management situations, blending acute and chronic exposures leading to the non-integration of SUD criteria into a clinical assessment necessitating a specific context (e.g. repeated use in the last year). Extracting each item from its overall clinical context is prone to bias, and does not align with the definition proposed by the American Psychiatric Association (APA) [2]. Interpreting literature data entails the risk of errors and biases, particularly, for example, when evaluating factors such as ‘persistent desire or unsuccessful efforts to cut down or control use of the substance’ using, relapse rates and ‘craving’ through reinforcement studies. Consequently, the authors’ conclusion mirrors their introduction: addiction seems plausible, but substantiating evidence requires more extensive studies.

However, the reality of N2O addiction is undeniable, and we should have anticipated SUDs. First, there is the history of Horace Wells [3]: as a dentist, he was obsessed with finding a way to alleviate the pain of dental surgery. In 1844, at a public road show exhibition of nitrous oxide, Wells realized its anaesthetic and analgesic potential, witnessing the fall of a man intoxicated with N2O who lacerated his leg to the bone with no pain response. He successfully subjected himself to an extraction of a troublesome third molar under N2O, but continued using it, as well as chloroform, ultimately becoming addicted. As early as 1850, falls and euphoric, analgesic and addictive properties were described. Secondly, there is N2O specific pharmacology; as partially described by Back et al., N2O influences not only the opioid and glutamatergic systems, but also the noradrenergic and GABAergic systems [4], neurotransmissions implicated in addictive mechanisms. All substances that act upon the opioid or GABA system are known to have an addictive potential. Thirdly, there is the evolution of N2O consumption: since 2018, consumption has surged, far surpassing the balloons and ‘five shots’ mentioned by Back et al., reaching levels equivalent to several hundred cartridges daily [5]. N2O has become a public health problem in many countries during the last few years [6].

While a dedicated clinical study evaluating N2O SUDs may not be possible for ethical reasons, systems exist for this purpose. For instance, France has a health monitoring system coordinated by the French National Agency for the Safety of Medicines and Health Products [7] focusing upon the abuse, dependence and consequences of psychoactive substances. The Addictovigilance network relies upon medical notifications of SUD, a regulatory obligation for health professionals. A total of 525 cases of N20 use were published [5], with an exponential increase between 2019 and 2021. Changes in notification characteristics were observed, including increased quantities consumed (use of cylinders), a negative evolution of usage contexts with a search for self-therapeutic effects. The main consequences were SUD and/or associated criteria (daily consumption and/or high dose, i.e. more than 20 cartridges or equivalent/occasion) (82.5%), neurological disorders (75.4%), psychiatric symptoms (15.4%) and cardiovascular events (8.6%). Moreover, new serious effects, notably cardiovascular events, were reported. Between 2020 and 2021, there was a greater proportion of SUD notifications: 58% in 2020 and 85.8% in 2021. All items of the DSM definition of SUD were described through the reported cases. The occurrence of addiction care or referral for addiction care was reported for 66 cases, the first case in 2017 and the other cases from 2020. Another publication highlighted a significant increase in SUD between 2018 (four of 10 cases) and 2022 (246 of 345 cases) [8].

Consequently, while SUD diagnoses were previously scarce in the literature until 2022, recent articles—including, in addition to our papers, those by Nugteren [9] and Cohen [10]—now explicitly mention SUDs. The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) report [11], drawing upon situations in various countries, also underscores this aspect. The lack of consensus on SUDs associated with N2O mentioned by Back et al. stems from outdated references, with cited articles published in 2015.

Therefore, the current question is not whether N2O addiction exists, but rather how to inform the general population, identify users with negative consequences and establish guidelines for treatment. Stopping consumption should be a priority when a N20 use disorder has emerged; whatever complication arises, it is the logical recommendation to give, and in this context addiction assessment must be carried out and specific treatment proposed.

None.