Nitrous oxide: The label ‘potentially addictive’ may do more harm than good

Although more evidence is needed to characterize the addictive potential of nitrous oxide, the provision of evidence-based guidance to users and healthcare professionals does not require it. For most people, the greatest impact on reducing harm will be through smart education and evidence-based regulation, not reclassification in DSM. Back et al. [1] ask whether nitrous oxide addiction exists. It is an important question, whose provisional answer will no doubt be welcomed by United Kingdom legislators who will see it as supportive of nitrous oxide's recent inclusion as a schedule C drug under the Misuse of Drugs Act [2]. Recent surges in use, especially in the United Kingdom, France and the Netherlands, and more reported cases of neurological harm make the question timely as part of a wider discussion of how to reduce supply and demand [3]. Despite its widespread use, previous researchers seem to have ignored the question. There is little excuse for this given that most physical harms, such as peripheral neuropathy, are dose related and arise in users exhibiting what could be described as uncontrolled or heavy use [4, 5]. In addition, nitrous oxide has three characteristics that increase abuse liability, namely, rapid onset of action, a very short duration of effect and dose-related intense (dissociative) intoxicating effects [6]. The evidence for many of the operational criteria for dependence is weak, especially in the areas of tolerance and withdrawal, in part because of its muddled pharmacology. Partial opioid agonist activity [7] and antagonism at the N-methyl-d-aspartate-receptor [8] do not typically characterize drugs with high abuse liability and are usually associated with lower rates of dependence [9, 10]. Although tolerance to its analgesic effects can be seen, reinforcing effects are not [11]. Escalating use in the absence of reinforcement and withdrawal is atypical for drugs of dependence, but is consistent with the absence of a clearly defined mechanism underlying neuroadaptation to chronic nitrous oxide exposure [7, 12]. This analysis led to nitrous oxide being previously being classified, among other short-lived inhalants, as a drug that did not have dependence potential [13]. Substances associated with binge/frequent use may not necessarily require a defined neurobiological mechanism that commonly characterize drugs of dependence. When evaluating criteria relying on assessment of behaviors such as loss of control (criteria 1), primacy of use (criteria 7) and continued use despite knowledge of harm (criteria 9), the researchers are limited by the atypical nature of the cohorts they are examining. Often presenting with chronic dose-related health harms, generally following continued use despite experiencing serious health harms, the researched populations are often comprised of polydrug users who often share a range of psychosocial vulnerabilities, including social marginalization, limiting the ability to generalize the findings to the wider population from which they were taken [14, 15]. Epidemiological analysis that could allow the determination of risk factors and the link between heaviness of use and endorsement of individual dependence criteria are missing. Limited work into potential comorbidities and exploration of the risk profile for those developing compulsive use is required, especially where dissociation may be attractive to individuals seeking relief from the consequences of emotional trauma as seen with those seeking treatment for ketamine use disorders [16]. With craving such a central concept in addiction and one that is often poorly defined [17] the fact there is inconsistent data from human studies and the limited ability to extrapolate its existence in naïve or heavy users suggests this area is one that requires further research. Nitrous oxide is a comparatively safe drug that despite easy availability and widespread use does not cause significant harm in the overwhelming majority of users [5, 18, 19]. On a population basis there may be 1% to 2% of heavy users who are at risk of serious dose-related harm. Existing psychological approaches to helping people reduce use and risk are likely to be applicable as will assessment and treatment of underlying psychiatric comorbidities and other vulnerabilities. Defining a substance as having addictive potential, especially when clearly understood neurobiological mechanisms underlying neuroadaptation exist, may usefully inform pharmacological approaches to treatment. However, the label is not required to craft optimal public health responses, provide harm reduction and guide the management of health harms when their etiology and consequences are already well understood as they are for nitrous oxide. Adding the label of 'addiction', like criminalization, as in the case of nitrous oxide, is not helpful and may add to stigma and reduce treatment seeking [19]. In line with previous conclusions based on existing research on consumers and acknowledging its mechanisms of action, nitrous oxide does not appear to fulfil the necessary criteria to be labelled a substance of dependence, or if it does, a more accurate term would be as a substance with the potential to induce a mild use disorder, with a low potential for dependence in the general population. Adam R. Winstock: Conceptualization; writing—original draft. None.