Several clinical trials have shown that modafinil treatment can reduce cocaine use. In recent studies we found that treatment with doxazosin can reduce the positive subjective effects of cocaine and that doxazosin treatment can also reduce cocaine use. Modafinil impacts histamine, glutamate, and dopaminergic systems (among others) whereas doxazosin specifically attenuates noradrenergic signalling. Because modafinil and doxazosin act by different mechanisms, a combination of modafinil and doxazosin may prove particularly effective for reducing cocaine's effects and reducing cocaine use. As a first step towards evaluating this, we propose this Specific Aim: To conduct human laboratory research evaluating the impact of treatment with modafinil and doxazosin, individually and in combination, on the subjective and reinforcing effects produced by cocaine. We will evaluate two dose levels of modafinil (200 and 400 mg/d), two dose levels of doxazosin (4 and 8 mg/d), and placebo. The resulting nine treatment groups will be: (1) placebo, (2 and 3) modafinil 200 or 400 mg/d, (4 and 5) doxazosin 4 or 8 mg/d, (6 and 7) doxazosin 4 or 8 mg/d combined with modafinil 200 mg/d, and (8 and 9) doxazosin 4 or 8 mg/d combined with modafinil 400 mg/d. The primary outcome measure will be: self-reported ratings of High following administration of cocaine. The secondary outcome measure will be proportion of available doses of cocaine participants choose to take when given a series of choices between cocaine and money. We hypothesize that, compared to treatment with placebo or treatment with either modafinil or doxazosin alone, treatment with 400 mg/d modafinil combined with 8 mg/d doxazosin will be associated with reductions in ratings of High following administration of cocaine and with reductions in the proportion of available doses of cocaine taken.

R01DA035513

2015-05-01

2018-03-31