Advances in the pharmacotherapy of stimulant dependence: From alcohol antagonists to Xenova vaccines

Several widely varying pharmacotherapies, which help 're-normalize' documented stimulant-induced brain dysfunction in DA, GABA and glutamate receptors and metabolism, are promising for stimulant dependence. Disulfiram has significantly reduced cocaine abuse in six independent clinical trials. It inhibits dopamine beta hydroxylase (DBH), which converts dopamine (DA) to norepinephrine (NE), and thereby reduces NE, which may reduce cocaine withdrawal symptoms, and increases DA, which may 're-normalize' depleted DA and compensate for down-regulated DA receptors that are associated with chronic cocaine dependence. Low DBH activity, which is determined by a functional genetic polymorphism, appears critical to disulfiram's efficacy in cocaine dependence. Amantadine, which is also an indirect DA agonist, is only effective in patients with severe withdrawal symptoms, a subgroup of patients who also respond to the adrenergic blocker propranolol. The GABA enhancers including tiagabine, baclofen and topiramate have shown some efficacy in clinical trials and in reducing cue-induced cocaine craving. Glutamate enhancers like modafinil show efficacy, perhaps by enhancing learning of new relapse prevention behaviors. Finally, a cocaine vaccine, which prevents cocaine from getting out of the blood stream and into the brain, shows a dose-response in reducing cocaine use.