Pharmacogenetic randomized trial for cocaine abuse: Disulfiram and α1A-adrenoceptor gene variation

Disulfiram is a cocaine addiction pharmacotherapy that inhibits dopamine β-hydroxylase (DβH) and reduces norepinephrine production. We examined whether a functional variant of the ADRA1A gene (Cys to Arg at codon 347 in exon 2, Cys347Arg) may enhance treatment response through decreased stimulation of this α1A-adrenoceptor, since antagonists of this receptor show promise in reducing cocaine use. Sixty-nine cocaine and opioid co-dependent (DSM-IV) subjects were stabilized on methadone for two weeks and subsequently randomized into disulfiram (250 mg/day, N=32) and placebo groups (N=37) for 10 weeks. We genotyped the ADRA1A gene polymorphism (rs1048101) and evaluated its role for increasing cocaine free urines in those subjects treated with disulfiram using repeated measures analysis of variance, corrected for population structure. The 47 patients who carried at least one T allele of rs1048101 (TT or TC genotype) reduced their cocaine positive urines from 84% to 56% on disulfiram (p=0.0001), while the 22 patients with the major allele CC genotype showed no disulfiram effect. This study indicates that a patient's ADRA1A genotype could be used to identify a subset of individuals for which disulfiram and, perhaps, other α1-adrenoceptor blockers may be an effective pharmacotherapy for cocaine dependence.