Noradrenergic α1 Receptor Antagonist Treatment Attenuates Positive Subjective Effects of Cocaine in Humans: A Randomized Trial

Background: Preclinical research implicates dopaminergic and noradrenergic mechanisms in mediating the reinforcing effects of drugs of abuse, including cocaine. The objective of this study was to evaluate the impact of treatment with the noradrenergic alpha(1) receptor antagonist doxazosin on the positive subjective effects of cocaine. Methods: Thirteen non-treatment seeking, cocaine-dependent volunteers completed this single-site, randomized, placebo-controlled, within-subjects study. In one study phase volunteers received placebo and in the other they received doxazosin, with the order counterbalanced across participants. Study medication was masked by over-encapsulating doxazosin tablets and matched placebo lactose served as the control. Study medication treatment was initiated at 1 mg doxazosin or equivalent number of placebo capsules PO/day and increased every three days by 1 mg. After receiving 4 mg doxazosin or equivalent number of placebo capsules participants received masked doses of 20 and 40 mg cocaine IV in that order with placebo saline randomly interspersed to maintain the blind. Results: Doxazosin treatment was well tolerated and doxazosin alone produced minimal changes in heart rate and blood pressure. During treatment with placebo, cocaine produced dose-dependent increases in subjective effect ratings of "high'', "stimulated'', "like cocaine'', "desire cocaine'', "any drug effect'', and "likely to use cocaine if had access'' (p<.001). Doxazosin treatment significantly attenuated the effects of 20 mg cocaine on ratings of "stimulated'', "like cocaine'', and "likely to use cocaine if had access'' (p<.05). There were trends for doxazosin to reduce ratings of "stimulated'', "desire cocaine'', and "likely to use cocaine if had access'' (p<.10). Conclusions: Medications that block noradrenergic alpha(1) receptors, such as doxazosin, may be useful as treatments for cocaine dependence, and should be evaluated further.