Pharmacogenetic Randomized Trial for Cocaine Abuse: Disulfiram and Dopamine β-Hydroxylase

Abstract

Background Disulfiram has been an effective cocaine addiction pharmacotherapy, and one of its possible mechanisms of efficacy is through copper chelation and inhibition of an enzyme involved in catecholamine metabolism, dopamine β-hydroxylase (DβH), which converts dopamine to norepinephrine. A variant in the gene encoding DβH leads to reduced DβH activity and as such, disulfiram may not be an effective treatment of cocaine dependence for individuals with this variant. This study explored that potential matching. Methods Seventy-four cocaine and opioid co-dependent (DSM-V) subjects were stabilized on methadone for two weeks and subsequently randomized into disulfiram (250 mg/day, N =34) and placebo groups (N =40) for 10 weeks. We genotyped the DBH gene polymorphism, −1021C/T (rs1611115), that reduces DβH enzyme levels and evaluated its role for increasing cocaine free urines with disulfiram. Results Using repeated measures analysis of variance, corrected for population structure, disulfiram pharmacotherapy reduced cocaine positive urines from 80% to 62% (p = .0001), and this disulfiram efficacy differed by DBH genotype group. Patients with the normal DβH level genotype dropped from 84% to 56% on disulfiram (p = .0001), while those with the low DBH level genotype showed no disulfiram effect. Conclusions This study indicates that a patient’s DBH genotype could be used to identify a subset of individuals for which disulfiram treatment may be an effective pharmacotherapy for cocaine dependence.

Efficacy of Medications Approved for the Treatment of Alcohol Dependence and Alcohol Withdrawal Syndrome in Female Patients: A Descriptive Review

“…Accordingly, in women, the inhibition of DβH activity due to disulfiram administration may be attenuated by the stimulating effect of DβH activity induced by oestrogens and/or oral contraceptives. Another study, not included in the meta-analysis we selected, recently found an inverse relationship between the efficacy of disulfiram and DβH activity in patients with cocaine dependence [86] .…”

Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy

“…In a study of 74 cocaine-and opioid-dependent individuals stabilized on methadone, Kosten et al found that patients with the DbH genotype conferring normal levels of the enzyme responded preferably to disulfiram (reduction in cocaine positive urines from 84 to 56%, p = 0.0001), while those patients with the DbH-genotype conferring low levels of the enzyme did not show a medication effect [95]. Other pharmacogenetic targets examined as potential genotypes by which to identify individuals for whom disulfiram may be effective include ANKK1, DRD2 and ADRA1A [96,97].…”

Effects of Pharmacologic Dopamine β-Hydroxylase Inhibition on Cocaine-Induced Reinstatement and Dopamine Neurochemistry in Squirrel Monkeys

“…In a follow-up study by Carroll et al (2012), the disulfiram treatment group with no 12-step program support had the highest rate of cocaine use. The results of all of these trials must be interpreted with caution because the latest reports indicate that the ability of disulfiram to reduce cocaine use is dependent on both dose and pharmacogenetic considerations (Haile et al, 2012;Kosten et al, 2013;Shorter et al, 2013). Thus, despite these conflicting outcomes, there does appear to be sufficient evidence to continue the evaluation of DBH inhibitors as cocaine pharmacotherapies.…”