Arguments can be made for the efficacy of disulfiram in
Arguments can be made for the efficacy of disulfiram in cocaine dependence being enhanced in individuals who have the C-1021T allele that is associated with normal DβH or low levels. However, the potential importance of this functional variant in treatment outcome merits testing. Thus, we tested this hypothesis of its importance in a placebo controlled randomized clinical trial of disulfiram at 250 mg daily by comparing the efficacy of disulfiram at reducing cocaine abuse in methadone-maintained patients with the CC genotype and normal levels with those carrying the T allele and lower DβH levels.
Methods and Materials
Discussion We found a significant reduction in cocaine-positive urines with 250 mg of disulfiram compared with placebo, which is consistent with several other previous studies in cocaine abusers (17, 18, 19, 20, 21). This reduction in cocaine use was associated with a specific functional genetic polymorphism in the gene that codes for the enzyme dopamine β-hydroxylase (DβH) (rs1611115). We found that patients having two of the AMTB hydrochloride associated with normal levels of DβH (CC) responded to disulfiram, whereas those with the genotypes encoding lower levels (CT and TT) showed no difference from placebo. Genotype made no difference in the reduction in opioid use. The different treatment response to disulfiram between those patients with low and high DβH activity might reflect differences in brain dopamine receptors. Minimal DβH activity reduces norepinephrine but also reduces basal extracellular dopamine in the nucleus accumbens and caudate-putamen (34, 60). This reduction upregulates high-affinity postsynaptic dopamine receptors as much as sixfold and produces behavioral hypersensitivity to psychostimulants (61). Psychostimulant-induced locomotor, reinforcing, and aversive effects are enhanced in DBH knockout mice (34, 62). These findings suggest that modest reductions of norepinephrine and dopamine transmission from disulfiram might not attenuate the behavioral responses to psychostimulants in those individuals who have upregulated dopamine receptors because of their genetically low DβH levels. The number of DBH alleles affects dopamine and norepinephrine levels in the prefrontal cortex of mice when they are treated with disulfiram (33). Disulfiram increased dopamine and decreased norepinephrine levels in their prefrontal cortex of mice with two normal alleles, whereas disulfiram showed relatively little effect on these levels in mice with null alleles (33). Like these mice, our human study participants with low DβH seemed less affected by disulfiram-induced inhibition of DβH than those with high DβH activity. Lowering DβH activity through disulfiram might increase aversive symptoms from acute cocaine use, as one mechanism for its efficacy. Although none of these outpatients reported aversive symptoms from cocaine as an adverse event, disulfiram has increased cocaine-associated negative effects, including anxiety and paranoia, and reduced positive subjective effects during acute laboratory cocaine administration in humans (63, 64, 65, 66). Low DBH levels have been associated with psychotic symptoms in psychiatric disorders (see review ). For instance, schizophrenic or depressed patients who have low plasma or cerebrospinal fluid levels of DβH exhibit more positive psychotic symptoms compared with those with higher levels of DβH (68, 69, 70, 71, 72). Moreover, patients diagnosed with unipolar depression plus psychotic features have lower DβH levels than those without psychotic features (73). In addition, the genetic predisposition for lower levels of DβH protein is associated with cocaine-induced paranoia (39).