Although cortico-mesolimbic dopamine neurons mediate cocaine's reinforcing effects associated with its abuse liability, previous studies demonstrated inefficacy among dopamine receptor antagonists for treating cocaine dependence. Alternatively, the ability of indirect inhibitors of cortico-mesolimbic dopamine release (e.g., the 5-HT3 receptor antagonist ondansetron) to diminish cocaine's reinforcing effects could be investigated. We hypothesized that ondansetron might exhibit greater efficacy than placebo at decreasing cocaine use and enhancing abstinence in cocaine-dependent individuals. In a pilot randomized, controlled, double-blind, 10-week trial, 63 treatment-seeking, cocaine-dependent individuals received ondansetron (0.25, 1, or 4 mg b.i.d.) or placebo. Subjects were assessed on several measures of cocaine use, including urine benzoylecgonine, up to three times weekly. Cognitive behavioral therapy was provided weekly. Ondansetron was well tolerated, with no serious adverse events. The ondansetron 4.0 mg group had the lowest dropout rate of all treatment groups and a greater rate of improvement in percentage of participants with a cocaine-free week than placebo recipients (p=0.02), while the ondansetron 1.0 mg group showed less improvement in percentage of weekly mean non-use days than placebo recipients (p=0.04). Our results provide preliminary evidence of efficacy for ondansetron 4 mg b.i.d. We also will present comparative information on a preliminary, multi-site, randomized, double-blind, 8-week controlled trial testing the efficacy of ondansetron (0.25, 1, or 4 mg b.i.d.) versus placebo for treating methamphetamine dependence. Additionally, results of pharmacogenetic analyses will be presented.