Ondansetron Reduces Naturalistic Drinking in Nontreatment-Seeking Alcohol-Dependent Individuals with the LL 5′-HTTLPR Genotype: A Laboratory Study

Abstract

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 non-treatment seeking alcohol dependent (AD) individuals with LL genotype to ondansetron and SS/SL genotypes to the SSRI sertraline, and mis-matching them assessing naturalistic and bar-laboratory alcohol drinking. Methods Seventy-seven AD individuals were randomized to one of two counterbalanced arms to receive sertraline 200mg/day or ondansetron 0.5 mg/day for three weeks followed by an alcohol self-administration experiment (ASAE), then received placebo for three weeks followed by a second ASAE. Individuals then received the alternate drug for three weeks followed by a third ASAE. Drinks per drinking day (DDD with drinks in SDUs) 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 x order interaction was significant [F(1,47) = 8.42, p = .006] for DDD. Three ANCOVAs 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 = .008] but not the third ASAE. There was no difference in milliliters consumed during each ASAE. Conclusion 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 non-treatment seeking individuals with the LL genotype.

Ondansetron and sertraline may interact with 5-HTTLPR and DRD4 polymorphisms to reduce drinking in non-treatment seeking alcohol-dependent women: Exploratory findings

“…The order of the active medications was controlled through urn randomization with gender and baseline DDD as the two urn variables, so that half the subjects received 100 mg twice a day of sertraline for the first active medication phase, and the other half received 0.25 mg twice a day of ondansetron for the first medication phase. The main results of this study are published in Kenna et al (2014).…”

“…As for sertraline we examined if sertraline had any efficacy based on the interaction of these polymorphisms, but consistent with the “subtype” hypothesis proposed by Johnson (2000) one might expect that sertraline would demonstrate the most efficacy to reduce drinking in participants with the SS/SL 5-HTTLPR genotypes. Though exploratory, this analysis was performed before the data for the main trial were analyzed (Kenna et al, in press) based on our interest and above hypothesis from several studies published after the main study was initiated.…”

Medications for substance use disorders (SUD): emerging approaches

“…Also, ondansetron, a 5HT3-antagonist which is approved as an antiemetic, may be studied for its effects on smoking. Ondansetron has also been studied in alcohol use disorders, and potential pharmacogenetic associations to its effectiveness have been reported [42,129]. …”

Alcohol abuse and related disorders treatment of alcohol dependence

“…Ондансетрон блокирует серотониновые 5-HT3-рецеп-торы и обладает способностью снижать потребление алко-голя у зависимых лиц, причем его эффективность определя-ется генетическими способностями индивида; отмечено, в частности, снижение дозы потребляемого алкоголя у лиц, являющихся носителями LL-аллели гена, контролирующе-го синтез переносчика серотонина [21].…”