Pharmacotherapies have not proven to be clinically useful in the treatment of cocaine dependence. Two lines of research indicate that calcium channel antagonists are promising in the treatment of cocaine dependence. 1) Clinical studies of chronic cocaine use have demonstrated multiple neurovascular changes on PET, SPECT and MRI scans of the brain. These studies demonstrate functional abnormalities in energy utilization and reductions in regional cerebral blood flow. Some improvement in these deficits have been noted with lengthening abstinence from cocaine; however, recent work indicates that some regional blood flow changes are persistent over many months. It is possible that these neurovascular abnormalities decrease cognitive abilities and thus reduce the benefits of rehabilitative treatment for cocaine dependence such as cognitive-behavioral therapy (CBT). Calcium channel antagonists antagonize cerebral vasoconstriction, enhance regional cerebral blood flow and possibly could lead to cognitive improvement. 2) Preclinical studies indicate that dihydropyridine type channel antagonists have specific binding sites in rat brains and play a role in modulating dopaminergic reinforcement. Calcium channel antagonists reduce cocaine- related behaviors. One human trial demonstrated that a calcium channel antagonist decreased the subjective rush of cocaine and reduced euphoric properties of cocaine. Thus, there is animal and human evidence that calcium channel antagonists may improve cerebral circulation, enhancing cognitive functioning, and alter the subjective rewarding experience of cocaine. This protocol proposes to evaluate amlodipine, a marketed dihydropyridine calcium channel antagonist which has a well-established safety profile and has known effects of enhancing regional cerebral blood flow. In conjunction with CBT, amlodipine versus placebo will be tested for efficacy in 160 males and females, Caucasians and African-Americans. After screening and informed consent, cocaine dependent individuals will enter a two week placebo period followed by randomization to 12 weeks of amlodipine plus CBT or placebo plus CBT. Follow-up will occur three months after treatment ends. Treatment outcome will be measured with twice weekly quantitative urine drug screens for cocaine and cocaine metabolites, retention in treatment,subjective cocaine craving, and psychometric testing of cognitive functions. Evaluation of this agent for effectiveness and safety provides the opportunity to examine the rationale that improvements in regional cerebral blood flow or modulation of dopamine mechanisms through calcium channel antagonism will enhance recovery from cocaine dependence.
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| McRae, Aimee L; Hedden, Sarra L; Malcolm, Robert J et al. (2007) Characteristics of cocaine- and marijuana-dependent subjects presenting for medication treatment trials. Addict Behav 32:1433-40 |
| Malcolm, Robert; LaRowe, Steven; Cochran, Kristi et al. (2005) A controlled trial of amlodipine for cocaine dependence: a negative report. J Subst Abuse Treat 28:197-204 |
| Malcolm, Robert; Liao, Jason; Michel, Melissa et al. (2002) Amlodipine reduces blood pressure and headache frequency in cocaine-dependent outpatients. J Psychoactive Drugs 34:415-9 |
