Abstract
Objective: Disulfiram is a one of the few pharmacotherapies for cocaine addiction that shows promise. Since disulfiram and cocaine both affect levels of global methylation we hypothesized the MTHFR gene, whose product is involved in supplying methyl groups for DNA and protein methylation, may be associated with responsiveness to disulfiram in cocaine-dependent individuals. Methods: Sixty-seven cocaine-dependent patients were stabilized on methadone for 2 weeks and then randomized into disulfiram (250 mg/day, N = 32) and placebo groups (N = 35) for 10 weeks. Patients were genotyped for the MTHFR (rs1801133, also known as C677T) polymorphism and the data was evaluated for association with cocaine-free urines in the disulfiram or placebo groups. Data from patients that completed all 10 weeks of the study (N = 56) were analyzed using repeated measures analysis of variance (ANOVA), corrected for population structure. Results: The CT or TT MTHFR genotype group (N = 32) dropped from 73 to 52% cocaine-positive urines on disulfiram (p = 0.0001), while the placebo group showed no treatment effect. The CC MTHFR genotype group (N = 24) showed a smaller, but still significant, reduction in cocaine-positive urines on disulfiram compared to placebo; 81–69% (p = 0.007). Conclusion: This study indicates that a patient’s MTHFR genotype may be used to identify individuals who might show improved response to disulfiram treatment for cocaine dependence. Clinical Trial: Pharmacogenetics of Disulfiram for Cocaine, clinicaltrials.gov/ct2/show/NCT00149630, NIDA-18197-2, NCT00149630.
Highlights
Substance abuse is a critical problem in the United States
In this study, we tested the hypothesis that the C677T variant in methylene tetrahydrofolate reductase (MTHFR) is associated with response to disulfiram treatment in cocaine dependency (CD) individuals
The SNP examined in this study, rs1801133 or C677T, is a non-synonymous transition known to alter the enzyme activity of MTHFR
Summary
Cocaine is one of the most common drugs of abuse and the effects of cocaine dependency (CD) lead to social and physiological morbidities. CD may lead to risky behaviors making HIV, illicit opioid use, and emergency care more common [Substance Abuse and Mental Health Services Administration (SAMHSA), 2011]. CD is currently without an FDA-approved pharmacotherapy, some drugs show promise in treatment of CD, an example of which is disulfiram (Carroll, 1993; Carroll et al, 1998, 2004; George et al, 2000; Petrakis et al, 2000). The exact mechanism by which disulfiram exerts its effect to reduce cocaine cravings and/or use is not exactly known. Studies have shown that genetic background may be important in determining responsiveness to disulfiram as a CD pharmacotherapy (Kosten et al, 2012)
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