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

BACKGROUND: 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. METHODS: Subjective stimulant and sedative effects were assessed before and during nitrous oxide (N(2)O; 50%) inhalation in heavy drinkers who were otherwise healthy. RESULTS: 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 N(2)O inhalation. CONCLUSION: The pattern of subjective effects of N(2)O according to familial risk is remarkably similar to that previously seen with ketamine, supporting the idea of a common, NMDAR-mediated mechanism of action. N(2)O may prove to be a safe and accessible alternative to ketamine for probing heritable NMDAR dysregulation in neuropsychiatric disorders.