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

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 α1adrenoreceptor 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.