A randomized, double-blind, placebo-controlled trial of ondansetron for the treatment of cocaine use disorder with post hoc pharmacogenetic analysis

Abstract

Background: Cocaine use disorder (CUD) has significant consequences and there remain no FDA-approved pharmacotherapies. Ondansetron is an indirect dopaminergic modulator that has shown efficacy in alcohol use disorder, particularly in phenotypic and genotypic subgroups, and was found to be efficacious in a pilot dose-finding trial for CUD.

Methods: One-hundred eight (108) adults with CUD were randomized to ondansetron 4 mg twice daily or placebo for 9 weeks and assessed up to thrice weekly to evaluate self-reported cocaine use and urine benzoylecgonine. Participants received cognitive-behavioral therapy and brief behavioral compliance enhancement therapy. Consenting participants (N = 79) provided blood samples for exploratory pharmacogenetic analyses.

Results: Participants in both arms reduced cocaine use over time, but there was no statistically significant difference on percentage of cocaine-free days (PCFD; p = 0.972) or percentage of cocaine-free urine samples (PCFU; p = 0.909). Participants with early-onset CUD had greater improvement regardless of study arm (p = 0.002). Post hoc pharmacogenetic analyses demonstrated an interaction effect between treatment and rs1176713 SNP on PCFU in the total sample (p = 0.040) and African ancestry subset (p = 0.03). Constipation, fatigue, and somnolence were more common among ondansetron-treated participants (Fisher exact p < 0.05). Those who developed constipation were mostly rs1176713:GG carriers (Fisher exact p = 0.029).

Conclusions: Ondansetron did not demonstrate efficacy in the treatment of CUD. However, these preliminary results suggest a genotype-based variance in response to ondansetron in African ancestry individuals with CUD. Further studies are needed to validate findings for developing a personalized genomic approach for CUD treatment in racially and ethnically diverse populations.

Trial registration: ClinicalTrials.gov NCT00689572.

Keywords: Cocaine use disorder; Ondansetron; Pharmacogenetic.

Figure 1:

CONSORT Flow Diagram of the total sample of participants in a randomized trial of ondansetron for the treatment of cocaine use disorder

Figure 2:. Comparison of estimated means for percentages of cocaine-free urine samples (PCFU)

(A) Estimated mean PCFU in the total sample by treatment arm (B) Estimated mean PCFU in treatment-by-rs1176713 genotype groups in the total sample (C) Estimated mean PCFU in treatment-by-rs1176713 genotype in the African ancestry sample population. All bars indicate the estimated mean of PCFU across 9 weeks of treatment. The numbers of rs1176713:GG carriers in African ancestry population treated with ondansetron and placebo were 5 and 5, respectively. The numbers of rs1176713:AA/AG carriers were 22 and 27, respectively for the same treatment groups.