Theoretical considerations as well as pre-clinical data suggest a potential role for glutamate-inhibiting agents in the treatment of cocaine addiction. At present, however, there is little clinical data to inform the use of these agents for this application. In this preliminary study eighteen HIV-seropositive cocaine dependent, opiate-agonist maintained patients received lamotrigine (300 mg/day), an indirect glutamate release inhibitor, on either a standard (n = 8) or accelerated (n = 10) induction schedule for 12 weeks. Results showed a significant decrease in percentage of cocaine-positive urine screens in the standard induction lamotrigine group but not in the accelerated induction group. There were fewer reports of side-effects and fewer dropouts in the standard-induction lamotrigine group compared to the accelerated induction group. Neuropsychological assessments suggested a decrement in the Trail Making Tests, but no other decreases in cognitive functioning. We conclude that standard-induction lamotrigine warrants further investigation for the treatment of cocaine abuse in this patient population.