# Non-medical nitrous oxide misuse: From identifying a signal to unprecedented addictovigilance network communication

Marylène Guerlais, Sylvie Deheul, Reynald Le Boisselier, Caroline

Victorri-Vigneau

► To cite this version:

Marylène Guerlais, Sylvie Deheul, Reynald Le Boisselier, Caroline Victorri-Vigneau. Non-medical nitrous oxide misuse: From identifying a signal to unprecedented addictovigilance network communication. Therapies, 2024, 910, pp.7. 10.1016/j.therap.2024.10.057. hal-04902210

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ADDICTOVIGILANCE

# Non-medical nitrous oxide misuse: From identifying a signal to unprecedented addictovigilance network communication

Marylène Guerlais<sup>a</sup>, Sylvie Deheul<sup>b</sup>, FAN<sup>c1</sup>, Reynald Le Boisselier<sup>d</sup>, Caroline Victorri-Vigneau<sup>e,*</sup>

Received 28 June 2024; accepted 8 July 2024

KEYWORDS

Addictovigilance;
Communication;
Signal;
Alert;
Psychoactive
substance;
Nitrous oxide

**Summary** Addictovigilance is a French health monitoring system, composed of 13 centres distributed across the national territory, that aims to monitor cases of abuse, misuse, or use disorders related to psychoactive substances. Fulfilling these missions requires a regional network that ensures efficient information flow, dissemination to health authorities, and subsequent downward communication to prevent risks. This was illustrated through the example of nitrous oxide misuse. The Nantes Addictovigilance Centre, which is responsible for nitrous oxide monitoring, has highlighted the emergence of a signal from the very first cases. Since 2018, 6 national addictovigilance reports have subsequently been produced highlighting the increase in this signal in quantitative terms and in qualitative terms, with a diversification and worsening of complications (use disorders, neurological, psychiatric, cardiac and more recently thromboembolic). At the local and regional level, each addictovigilance centre has relayed information to

<footnote><sup>a</sup> Service de pharmacologie clinique – centre d’évaluation et d’information sur la pharmacodépendance – addictovigilance, Nantes université, CHU de Nantes, 44000 Nantes, France</footnote>

<footnote><sup>b</sup> Service de pharmacologie – centre d’évaluation et d’information sur la pharmacodépendance – addictovigilance des Hauts-de-France, Lille université, CHU de Lille, 59037 Lille, France</footnote>

<footnote><sup>c</sup> FAN (French Addictovigilance Network)</footnote>

<footnote><sup>d</sup> Service de pharmacologie – centre d’évaluation et d’information sur la pharmacodépendance-addictovigilance Bretagne-Normandie, Caen université, CHU Nantes, 14033 Caen, France</footnote>

<footnote><sup>e</sup> INSERM, methodS in Patient-centered outcomes & Health ResEarch, Nantes université, CHU Nantes, 44000 Nantes, France</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail address: caroline.vigneau@chu-nantes.fr (C. Victorri-Vigneau).</footnote>

<footnote n="1">¹ Célian Bertin, Emilie Bouquet, Leila Chouachi, Amélie Daveluy, Céline Eiden, Valérie Gibaja, Emilie Jouanjus, Joëlle Micallef, Bruno Revol.</footnote>
its network, in a variety of ways, but also to the general public, particularly through the media. Studies have also been carried out to better quantify and qualify nitrous oxide consumption. These signals from addictovigilance data have been the subject of numerous national and international communications (health authorities, addictovigilance network, international scientific articles). They have also contributed to the promulgation of the French law of June 2021 aimed to prevent dangerous uses of nitrous oxide, and international reporting. The addictovigilance centres have made it possible to obtain an early, rapid and accurate signal with pharmacological and medical data. Nitrous oxide is an example of the wide potential of action of the French addictovigilance network, in all its fields of competence: training, specific collection, research and information.

© 2024 Published by Elsevier Masson SAS on behalf of Société française de pharmacologie et de thérapeutique.

## Abbreviations

**ANSES** French National Agency for Food, Environmental and Occupational Health and Safety

**ANSM** French National Agency for the Safety of Medicines and Health Products (Agence nationale de sécurité des médicaments et des produits de santé)

**CASAR** support centre for emergency situations, health alerts, and risk management

**CEIP-A** Centre for Evaluation and Information on Drug Dependence and Addictovigilance

**DRAMES** deaths related to drug and substance abuse (décès en relation avec l'abus de médicaments et de substances)

**EMCDDA** European Monitoring Centre for Drugs and Drug Addiction

**N₂O** non-medical nitrous oxide

## Introduction

The national addictovigilance network is composed of 13 centres distributed across the national territory. Addictovigilance aims to monitor cases of abuse, misuse, or use disorders related to psychoactive substances. It seeks to identify these situations and their associated consequences as early as possible, quantify and characterize the signal, alert health authorities and inform healthcare professionals, and in some cases, target populations to minimize public health risks [1,2]. Fulfilling these missions requires a regional network that ensures efficient information flow, dissemination to health authorities, and subsequent downward communication to prevent risks. This article aims to illustrate these information exchanges through the example of nitrous oxide misuse.

## Birth and evaluation of a signal

The Nantes Centre for Evaluation and Information on Drug Dependence and Addictovigilance (CEIP-A) is responsible for the national monitoring of nitrous oxide. In this context, it

analyses all notifications received by the national network of the 13 addictovigilance centres, as well as all relevant data, to produce national addictovigilance reports.

It was in the context of monitoring medical nitrous oxide mixed with oxygen that the cases of misuse of this gas in its non-medical form, culinary cartridges, were highlighted. In the period from November 2011 to September 2013, 5 notifications of non-medical nitrous oxide were reported to the addictovigilance network. They all concerned young adults, with festive or recreational use of nitrous oxide in the form of whipped cream cartridges and balloons. In the October 2013 to August 2016 period, 9 notifications concerning non-medical nitrous oxide (N₂O) were reported. Dependence was reported in 2 cases, including one where consumption was initially festive and then gradually increased. Consequences on health, linked to the consumption of nitrous oxide, were also reported. Nitrous oxide was implicated in a death in 2016 in a subject who developed massive pulmonary oedema following inhalation of very cold nitrous oxide in a festive context [3]. At the end of 2017, the notification of a 24-year-old man who developed acute cervical myelitis after consuming nitrous oxide alone, initially for recreational purposes and then on a daily basis, was reported to Bretagne-Normandie area centre [3], then was presented as a significant case, and the support centre for emergency situations, health alerts, and risk management (CASAR) of the Agence nationale de sécurité du médicament et des produits de santé (ANSM - French National Agency for the Safety of Medicines and Health Products) made this a priority alert leading to the opening of a specific national addictovigilance report on non-medical nitrous oxide.

The Nantes CEIP-A has since produced six national addictovigilance reports on nitrous oxide.

As soon as the data was analyzed in May 2018, a signal was sent out by the reporting centre, with national and international data highlighting the start of a phenomenon. The following national addictovigilance reports highlighted new signals: a steady increase in the number of cases reported, both nationally (notifications received by addictovigilance network) and internationally. The number of cases received in addictovigilance reached 350 notifications/year in 2021 and 2022 and around 100 cases reported
<figure><img src="image_4.png" /><figcaption>**Figure 1.** Chronological quantitative and qualitative evolution of the nitrous oxide misuse signal and the resulting national and international communication actions. ANSM: French National Agency for the Safety of Medicines and Health Products; ANSES: French National Agency for Food, Environmental and Occupational Health and Safety; DGS: French General Directorate of Health (French Ministry of Health); MILDECA: French Interministerial Mission for Combating Drugs and Addictive Behaviours; SUD: substance use disorder. *Presentation of national addictovigilance reports.</figcaption></figure>

in the literature in 2020 and 2022. In total, between 2018 and 2022, the number of notifications will increase 35-fold, with a new increase observed in 2023. What's more, clinical complications have diversified and worsened, not only in terms of neurological disorders but also use disorders, psychiatric or cardiac manifestations and, more recently, thromboembolic complications. The effects sought have also evolved, in particular with the search for auto therapeutic effects as anxiolysis or 'high', and consumption in negative contexts (prostitution, assault...). This French signal has been the subject of international publications [4,5]. Fig. 1 illustrates these signal evolutions.

Specific national data collection was carried out for the monitoring of nitrous oxide misuse: all cases from poison control centres were analyzed in order to enhance monitoring. In addition, the calls received by 'Drogue info service', an anonymous telephone dialogue structure intended for subjects directly or indirectly concerned by drug use, were also collected and analyzed.

At the local and regional level, most of the centres contacted certain hospital departments in their regions to receive and report on complications induced by nitrous oxide misuse. These were most often neurology, emergency, physical medicine and rehabilitation, vascular medicine and addiction departments. The data collected is consistent with addictovigilance notifications on nitrous oxide misuse, contributing to the confirmation of signals.

The network has conducted several studies among students to better quantify and qualify nitrous oxide consumption among students, especially health students.

In some regions, multidisciplinary working groups have been set up to encourage the collection of lesser-known complications.

The other addictovigilance tools have contributed little to this evaluation, notably 'décès en relation avec l'abus de médicaments et de substances' (deaths related to drug and substance abuse — DRAMES) and chemical submission. Indeed, nitrous oxide is a gas that cannot be routinely identified in biological fluids, and therefore, even in cases of suspicion, the instances cannot be included in these collections. This is the reason why, additionally, a specific study was conducted among analytical toxicologists to quantify the instances where nitrous oxide was mentioned in the case files.

By the end of 2023, the addictovigilance network has the largest collection of cases, with 1334 reports detailing effects associated with the use of nitrous oxide since 2012.

## Informations and communications

### Regional communication

Globally, at the moment the signal is generated, that is between 2019 and March 2022, the centres have relayed the national documents to a large audience, between 10,000 and 20,000 recipients according to the documents. Regional and territorial targets of the actions are presented on Fig. 2.

Twenty-three specific information documents were produced by the centres.
<figure><img src="image_5.png" /><figcaption>**Figure 2.** Regional and territorial targets of the communication actions in the context of the misuse of N₂O.</figcaption></figure>

Fifty-six interviews or press articles were published.

Forty-five specific training courses on nitrous oxide have been carried out, and the subject of nitrous oxide misuse has been added to 135 training courses.

Finally, 51 meetings with regional health agencies or other institutions regarding nitrous oxide were held.

Furthermore, it is important to underline the wide diversity of health practitioners who were informed; some addictovigilance centres systematically send information to very large distribution lists including all hospital doctors or very large networks of general practitioners, whatever their medical speciality. Thus, almost systematically, neurologists, algologists and emergency physicians, for example, were informed.

Finally, extensive communication to the general public has been implemented by the addictovigilance centres through various communication channels: email and mail to disseminate national publications, in-person communications (conferences, various meetings including on a YouTube channel), the general press through national and regional print media (at least 20 different media outlets), and audio-visual press on the main national channels as well as some regional channels (at least 12 different channels).

## International and national communication

Numerous communication actions have been carried out by the French health authorities, French National Agency for the Safety of Medicines and health products (ANSM), French National Agency for Food, Environmental and Occupational Health and Safety (ANSES) and French Ministry of health, French association of addictovigilance centres,

to inform and/or to warn about the risks related to the recreational consumption of N₂O. French association of addictovigilance centres published two newsletter [6,7] and two press releases [8,9] National and international targets are presented on Fig. 3.

In 2019, without waiting for the 2020 report assessing the 2018–2019 period, which will give rise to new signals, national communications have been drafted to warn of the clinical complications, particularly neurological, associated with recreational drug use. Then, new communications actions have been taken in response to the new highlighted signals targeting numerous structures at both national and international levels (Figs. 1 and 3): health authority press releases, publications of addictovigilance reports, communications from the addictovigilance network including press releases, dedicated newsletters, international scientific articles specifically concerning addictovigilance cases [4,5,10–16] as well as many papers at national or international conferences, drawing up diagnostic and management aid document.

In addition, regulatory measures had been taken: the law of 1 June 2021 to prevent dangerous uses of nitrous oxide, particularly among minors (Table 1) [17]. Prior to the promulgation of this law, the addictovigilance centres most concerned were audited on the subject of nitrous oxide by member of parliament.

## Discussion

The widespread media coverage of the subject of nitrous oxide misuse, and the extensive involvement in all regions
<figure><img src="image_6.png" /><figcaption>**Figure 3.** National and international targets of the communication actions in the context of the misuse of N₂O. ANSM: French National Agency for the Safety of Medicines and Health Products; ANSES: French National Agency for Food, Environmental and Occupational Health and Safety; DGS: French General Directorate of Health (French Ministry of Health); MILDECA: French Interministerial Mission for Combating Drugs and Addictive Behaviors; OFDT: French Observatory of Drugs and Addictive Trends.</figcaption></figure>

<table><caption>**Table 1** French regulatory measures concerning nitrous oxide.</caption><thead><tr><td>Laws and regulations</td><td>Application date</td><td>Actions taken</td></tr></thead><tbody><tr><td>Law no. 2021-695</td><td>June 2nd, 2021</td><td>Prohibition of the sale of nitrous oxide to minors<br>Prohibition of the sale in drinking establishments and tobacco shops<br>Prohibition of the sale of products intended to facilitate the use of nitrous oxide (crackers, balloons, etc.)</td></tr><tr><td>Order of July 19, 2023<br>Decree no. 2023-1224 of December 20, 2023</td><td>January 1st, 2024<br>July 21st, 2024</td><td>Sales limited to 10 cartridges of 8.6g maximum<br>Apposition of the statement "Risk of serious effects on the nervous system through repeated or prolonged exposure by inhalation" on products containing only nitrous oxide</td></tr><tr><td>Proposed law of April 5, 2019</td><td>?</td><td>Prohibition on inciting a minor to consume nitrous oxide for non-medical purposes<br>Provision of information on the risks of nitrous oxide in schools<br>Display of a pictogram and the words "not for sale to minors" on packaging</td></tr></tbody></table>

of the addictovigilance centres, lead us to discuss several points.

First of all, the early warning that enabled the addictovigilance centres to react quickly to this problematic. Indeed, if they were able to react by disseminating information and setting up collections and care networks, it is because the signal was reported very early by addictovigilance network. Since then, nitrous oxide has been closely monitored, and

many successive reports [18-21] have made it possible, thanks to the pharmacological and medical analysis of the cases carried out by the medical pharmacologists working in the addictovigilance centres, to highlight and characterize the complications, in particular addictological, neurological, psychiatric and vascular complications of its use. This has enabled early communication from the addictovigilance centres.
The second major characteristic of the addictovigilance signal is its accuracy. As shown in this work, the network has demonstrated its ability to set up specific collection circuits, which have allowed for the precise characterization of complications and communication. In particular, the network has made it possible to describe doses, consumption patterns and their evolution, contexts of use and finally the potential for abuse and dependence of nitrous oxide thanks to characterization/collection of use disorders, which until now had been poorly described in France. Other data available in France are data on the prevalence of use, measured in a heterogeneous way in different populations, particularly students [22–24].

The third strength of this addictovigilance system is its broad regional and national information capacity. The addictovigilance network, coordinated by the ANSM, works with all national institutions and political actors involved in addictology. This network is widely adapted at regional level by each addictovigilance centre, with the added benefit of working with professionals in the field on a regular basis (which is necessary in addictovigilance in order to collect data from specific surveys) [25], which allows for wide-ranging communication, both quantitatively (number of recipients) and qualitatively (variety of people who receive information).

This capacity of the addictovigilance network to detect the becoming of a substance and its use in a population is close to the concept of social pharmacology. The World Health Organization defines clinical pharmacology as all activities related to the becoming and effects of drugs in humans and their use. Social pharmacology characterizes the multi-directional interactions between the drug, the partners involved from its discovery to its final use and society. Discovered in 1776 by Joseph Priestley, experimented with by the British chemist Humphry Davy in 1800 where he described the euphoric and hilarious effects, it was in 1844 that Horace Wells, an American dentist, observed a demonstration of the anesthetic effect of nitrous oxide, then used as 'laughing gas', at a fair. At the end of the demonstration, the subject staggered to his feet and fell off the stage; a nail that was sticking out stuck in his calf but he did not seem to feel any pain. Horace Wells immediately thought of the use of nitrous oxide in dental treatment. He was a pioneer in the use of anesthetic techniques. It should be noted that he committed suicide in prison after abusing several psychoactive substances, the first of which was nitrous oxide.

This anecdote contextualizes the problematic of nitrous oxide misuse, and as early as 1844 it was already described as having hilarious properties (today this search for euphoria is still at the forefront of misuse), rapid reversibility of effects, risks of falling and analgesic properties. The story does not end there, and today the panorama of complications linked to the misuse of nitrous oxide is much broader.

## Conclusion

Nitrous oxide is an example of the wide potential of action of the addictovigilance network, in all its fields of competence: alert, training, specific collection, information and research. In 2022, the addictovigilance network continued

its communication actions, bringing them to a European level. The example of French monitoring is described in the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) report on nitrous oxide misuse [26] and a dedicated session at the addictovigilance congress in Biarritz provided an opportunity to communicate widely on the situation in Europe and in France.

A French law was implemented in 2021 to protect minors, limit the quantities sold and inform about the dangerousness of administration in humans [17, 26, 22, 27]. A new law has been proposed in 2022 [29].

## Disclosure of interest

The authors declare that they have no competing interest.

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