Mechanisms Involved in the Neurotoxicity and Abuse Liability of Nitrous Oxide: A Narrative Review

Abstract

The recreational use of nitrous oxide (N2O) has increased over the years. At the same time, more N2O intoxications are presented to hospitals. The incidental use of N2O is relatively harmless, but heavy, frequent and chronic use comes with considerable health risks. Most importantly, N2O can inactivate the co-factor cobalamin, which, in turn, leads to paresthesia’s, partial paralysis and generalized demyelinating polyneuropathy. In some patients, these disorders are irreversible. Several metabolic cascades have been identified by which N2O can cause harmful effects. Because these effects mostly occur after prolonged use, it raises the question of whether N2O has addictive properties, explaining its prolonged and frequent use at high dose. Several lines of evidence for N2O’s dependence liability can be found in the literature, but the underlying mechanism of action remains controversial. N2O interacts with the opioid system, but N2O also acts as an N-methyl-D-aspartate (NMDA) receptor antagonist, by which it can cause dopamine disinhibition. In this narrative review, we provide a detailed description of animal and human evidence for N2O-induced abuse/dependence and for N2O-induced neurotoxicity.

Does nitrous oxide addiction exist? An evaluation of the evidence for the presence and prevalence of substance use disorder symptoms in recreational nitrous oxide users

“…Self‐administration paradigms are frequently used to study craving in animals [46] as craving often signifies an intention to use [47]. However, self‐administration studies provide limited evidence for self‐administration [48] and animal studies seem to collectively point toward a low reinforcing value of N 2 O [9].…”

“…The rising use of recreational N 2 O use has caused concern because of its negative health effects, including the potential development of addictive behaviors. However, there is little to no consensus regarding the addictive potential of N 2 O and research on the matter is scarce [7][8][9]. In a recent report, the European Monitoring Center for Drugs and Drug Addiction (EMCDDA) highlighted the lack of understanding of the addictive potential of N 2 O and called for better classification and coding systems as well as standardized case definitions to improve diagnosis, treatment, quantification and understanding of the issue [10].…”

A case of functional vitamin B12 deficiency after recreational nitrous oxide use

“…The chronic toxicity is mainly neurological, with symptoms of peripheral neuropathy (most commonly), myelopathy, and encephalopathy ( 3 , 4 ). The precise mechanisms of these effects are not fully understood, but the alteration of vitamin B12 functions plays an important role ( 5 ). The present case report points out the challenges in diagnosing vitamin B12 deficiency in the context of N 2 O abuse due to normal concentrations of serum vitamin B12.…”

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

“…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.…”