The Subjective Response to Nitrous Oxide is a Potential Pharmaco-Endophenotype for Alcohol Use Disorder: A Preliminary Study with Heavy Drinkers.

Heavy drinkers with a family history of alcohol-use disorders show a distinct subjective response to nitrous oxide (N2O) inhalation compared to those without such familial risk. During 50% N2O inhalation, the 23 participants with an ostensible family history reported a higher ratio of stimulant to sedative effects than the 37 without that risk. This pattern closely resembles that previously observed with ketamine, suggesting a common mechanism involving N-methyl-D-aspartate receptors (NMDARs). N2O may offer a safer, more accessible alternative to ketamine for studying heritable NMDAR dysregulation in neuropsychiatric disorders.

Study at a glance

Abstract

Healthy people with a family history of alcohol problems show a pattern of subjective responses to alcohol that resemble those of affected probands. Studies on ketamine suggest that up-regulation of N-methyl-D-aspartate receptors (NMDARs) underlies these effects, and point to a pharmacologically-responsive endophenotype reflecting enhanced risk for alcohol-use disorders. Subjective stimulant and sedative effects were assessed before and during nitrous oxide (N2O; 50%) inhalation in heavy drinkers who were otherwise healthy. Participants with an ostensible family history of alcohol-use disorders (n = 23) were distinguishable from those without such familial risk (n = 37) by an enhanced stimulation-to-sedation ratio during N2O inhalation. The pattern of subjective effects of N2O according to familial risk is remarkably similar to that previously seen with ketamine, supporting the idea of a common, NMDAR-mediated mechanism of action. N2O may prove to be a safe and accessible alternative to ketamine for probing heritable NMDAR dysregulation in neuropsychiatric disorders.