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

The recreational use of nitrous oxide (N(2)O) has increased over the years. At the same time, more N(2)O intoxications are presented to hospitals. The incidental use of N(2)O is relatively harmless, but heavy, frequent and chronic use comes with considerable health risks. Most importantly, N(2)O 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 N(2)O can cause harmful effects. Because these effects mostly occur after prolonged use, it raises the question of whether N(2)O has addictive properties, explaining its prolonged and frequent use at high dose. Several lines of evidence for N(2)O’s dependence liability can be found in the literature, but the underlying mechanism of action remains controversial. N(2)O interacts with the opioid system, but N(2)O 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 N(2)O-induced abuse/dependence and for N(2)O-induced neurotoxicity.