Ondansetron reduces naturalistic drinking in nontreatment-seeking alcohol-dependent individuals with the LL 5'-HTTLPR genotype: a laboratory study.

Background: One hypothesis suggests that the differential response to ondansetron- and serotonin-specific re-uptake inhibitors (SSRIs) may be due to a functional polymorphism of the 5'-HTTLPR promoter region in SLC6A4, the gene that codes for the serotonin transporter (5-HTT). The LL 5'-HTTLPR genotype is postulated to be specifically sensitive to the effects of ondansetron with SS/SL 5'-HTTLPR genotypes sensitive to SSRIs. This study tests this hypothesis by matching nontreatment-seeking alcohol-dependent (AD) individuals with LL genotype to ondansetron and SS/SL genotypes to the SSRI sertraline, and mismatching them assessing naturalistic and bar-laboratory alcohol drinking.

Methods: Seventy-seven AD individuals were randomized to 1 of 2 counterbalanced arms to receive sertraline 200 mg/d or ondansetron 0.5 mg/d for 3 weeks followed by an alcohol self-administration experiment (ASAE) and then received placebo for 3 weeks followed by a second ASAE. Individuals then received the alternate drug for 3 weeks followed by a third ASAE. Drinks per drinking day (DDD with drinks in standard drinking units) for 7 days prior to each ASAE and milliliters consumed during each ASAE were the primary outcomes.

Results: Fifty-five participants completed the study. The genotype × order interaction was significant, F(1, 47) = 8.42, p = 0.006, for DDD. Three analyses of covariance were conducted for DDD during the week before each ASAE. Ondansetron compared to sertraline resulted in a significant reduction in DDD during the week before the first, F(1, 47) = 7.64, p = 0.008, but not the third ASAE. There was no difference in milliliters consumed during each ASAE.

Conclusions: This study modestly supports the hypothesis that ondansetron may reduce DDD in AD individuals with the LL genotype as measured naturalistically. By contrast, there was no support that ondansetron reduces drinking during the ASAEs or that sertraline reduces alcohol use in individuals who have SS/SL genotypes. We provide limited support that ondansetron may reduce drinking in nontreatment-seeking individuals with the LL genotype.