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

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.