Doxazosin treatment in cocaine use disorder: pharmacogenetic response based on an alpha-1 adrenoreceptor subtype D genetic variant

ABSTRACT

Background: The α₁ antagonist doxazosin reduces cocaine use in individuals with cocaine use disorder (CUD) through a functional polymorphism of the α₁ adrenoreceptor. The regulatory role of the α₁ adrenoreceptor subtype D (ADRA1D) gene polymorphism in CUD is uncharacterized.

Objectives: To study how the genetic variant of ADRA1D gene (T1848A, rs2236554) may affect the treatment efficacy of doxazosin in reducing cocaine use.

Methods: This 12-week pilot trial included 76 participants with CUD with ADRA1D (T1848A, rs2236554) AA (N = 40) or AT/TT genotype (N = 36). Participants were randomized to doxazosin (8 mg/day, N = 47) or placebo (N = 29), and followed with thrice weekly urine toxicology and once weekly cognitive behavioral psychotherapy.

Results: The AA and the AT/TT groups had comparable baseline rates of cocaine positive urines at weeks 1–2 (~ 76%). In the placebo group, an increase of cocaine positive urines in the AT/TT group was found as compared to the AA group (24% vs. 9%). In the doxazosin group, a greater decrease in cocaine positive urines was found in the AT/TT group relative to the AA group. The difference between the doxazosin and placebo groups in cocaine negative urines became evident at weeks 5–6 and peaked at weeks 9–10 (~35% difference). The AT/TT group demonstrated a significant medication and time by medication effect (p < .001), whereas the AA group did not.

Conclusion: The T-allele carriers showed a greater reduction of cocaine use after treatment with doxazosin in participants with the ADRA1D gene polymorphism (T1848A), suggesting that this SNP may serve as a pharmacogenetic marker in pharmacotherapy of CUD.

KEYWORDS:

• Α₁ adrenoreceptor subtype D
• single gene polymorphism
• cocaine use disorder
• doxazosin
• urine toxicology

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

Authors Contribution

Daryl Shorter, Xuefeng Zhang, David Nielsen, Coreen Domingo, and Thomas Kosten were responsible for the study concept and design. David Nielsen contributed to genotyping. David Nielsen and Ellen Nielsen contributed to the data analysis. Daryl Shorter and Coreen Domingo contributed to the acquisition of clinical data. Daryl Shorter and Xuefeng Zhang drafted the manuscript. David Nielsen, Coreen Domingo and Thomas Kosten provided critical revision of the manuscript. All authors critically reviewed content and approved final version for publication.

Additional information

Funding

This study was supported in part by Career Development Award I01BX007080 from the United States Department of Veterans Affairs Clinical Sciences Research and Development Service..