A randomized, double‐blind, placebo‐controlled, pharmacogenetic study of ondansetron for treating alcohol use disorder.

Background: In a previous study, ondansetron, a serotonin 5‐HT3 receptor antagonist, reduced drinking intensity (drinks/drinking day [DPDD]) among European‐ancestry (EA) participants with moderate‐to‐severe alcohol use disorder (AUD) and variants in genes encoding the serotonin transporter (SLC6A4) and 5‐HT3A (HTR3A), and 5‐HT3B (HTR3B) receptors. We tested whether (1) ondansetron reduces DPDD among individuals of either European or African ancestry (AA), and (2) that reductions in DPDD are greatest among ondansetron‐treated individuals with population‐specific combinations of genotypes at SLC6A4, HTR3A, and HTR3B. Methods: In this 16‐week, double‐blind, placebo‐controlled, parallel‐group clinical trial, adults with AUD were randomized to receive low‐dose oral ondansetron (0.33 mg twice daily) or placebo stratified by "responsive" versus "nonresponsive" genotype defined using population‐specific genotypes at the three genetic loci. Generalized estimating equation regression models and a modified intent‐to‐treat analysis were used to compare the treatment groups on the primary outcome—DPDD—and two secondary outcomes—heavy drinking days per week [HDD] and drinks per day [DPD] across the 16 weeks of treatment. Results: Of 296 prospective participants screened, 95 (58 EA and 37 AA) were randomized and received at least one dose of study medication. In the modified intent‐to‐treat analysis, the ondansetron group averaged 0.40 more DPDD (p = 0.51), 1.35 times as many HDD (p = 0.16), and 1.06 times as many DPD (p = 0.59) as the placebo group. There were no significant interactions with genotype. There were no study‐related serious adverse events (AEs) and similar proportions of participants in the two treatment groups experienced AEs across organ systems. Conclusions: We found no evidence that low‐dose oral ondansetron is beneficial in the treatment of AUD, irrespective of genotype, thus failing to confirm prior study findings. However, the study was underpowered to identify medication by genotype interactions. [ABSTRACT FROM AUTHOR]