Cocaine produces its psychoactive effects primarily by blocking presynaptic transporters for biogenic amine neurotransmitters, especially dopamine and serotonin. This has the effect of increasing activity in the brain's mesocorticolimbic dopaminergic reward circuit. There is no proven medication to treat cocaine dependence. The difficulty in developing an effective medication may derive from cocaine's direct activation of the reward circuit, its ability to generate sensitization with repeated use, and its rapid access to the brain when smoked or injected. Attempts to directly affect the reward circuit, e.g., by blocking the dopamine transporter or dopamine receptors, have not been successful. Attempts to indirectly influence the reward circuit by affecting other neurotransmitters that modulate it have been more promising. These include increasing activity of GABA (an inhibitory neurotransmitter) with baclofen, vigabatrin, or topiramate (which also decreases glutamate activity); and increasing the activity of glutamate (an excitatory neurotransmitter) with N-acetylcysteine. Also somewhat promising are agonist substitution approaches using long-acting amphetamine preparations. Medications that are promising in animal studies, but not yet tested in humans, include dopamine D3 receptor partial agonists and cannabinoid CB1 receptor antagonists. In addition to these pharmacodynamic approaches, pharmacokinetic approaches, which reduce cocaine's access to the brain or enhance its metabolism, are being studied. An anti-cocaine vaccine, which binds cocaine and keeps it from crossing the blood-brain barrier, has been safe and effective in early clinical trials. Administration of cocaine-metabolizing enzymes, e.g., butyrylcholinesterase, has been effective in animal studies, but not yet studied in humans.