Topiramate to Reduce Cocaine Dependence

GABA is an inhibitory neurotransmitter that is found primarily in the brain. High GABA
levels result in low levels of dopamine, another neurotransmitter that is the brain's "feel
good" chemical and which plays a primary role in cocaine drug addiction. Cravings for
cocaine can be reduced by lowering dopamine levels. This makes topiramate, a GABA-altering
medication, a potential treatment for cocaine addiction. This study will involve two
sequential experiments and will evaluate the subjective, behavioral, and physiological
effects of topiramate in individuals addicted to cocaine. The purpose of the first
experiment is to evaluate the effectiveness of various doses of topiramate at reducing
cocaine-mediated mood changes. The purpose of the second experiment is to evaluate whether
the most effective topiramate dose from the first experiment reduces cocaine-induced mood
changes over a period of several days. In turn, these findings may guide future cocaine
pharmacotherapy trials.

Potential participants will initially attend a 4- to 6-hour screening session. This will
include review of medical and drug histories, standardized psychological questionnaires, a
physical exam, and blood collection. Eligible participants will then be admitted to the
inpatient clinic. During the first day of both experiments, participants will receive
instructions and information about the study procedures. They will also undergo a physical
exam, an electrocardiogram, standardized psychological questionnaires, and blood and urine
collection. A single test dose of cocaine will be administered intravenously to all
participants to ensure safety with continuation in the study. Vital signs will be monitored
hourly throughout the day.

The first experiment will last 29 days and will enroll 18 individuals addicted to cocaine.
Participants will take part in nine testing sessions, each separated by 2 to 4 days.
Participants will receive varying combinations of topiramate, cocaine, and placebo during
the testing sessions. They will be monitored by the study physician throughout the sessions.
Blood will be drawn frequently to assess levels of cocaine and topiramate. Participants will
complete standardized questionnaires to evaluate mood changes and cognitive function.

The second experiment will last 25 days and will enroll 24 individuals addicted to cocaine.
In this three-part experiment, participants will be admitted to the inpatient clinic for an
8-day study session. Following this session, they will be discharged from the clinic for a
1-week washout phase. Participants will then return to the inpatient clinic for another
8-day study session. The two study sessions will be identical. During both sessions,
participants will first receive topiramate or placebo for 4 consecutive days. While
continuing to receive topiramate or placebo, participants will then also receive intravenous
cocaine or placebo for 3 consecutive days. Topiramate doses will be determined by the
results of the first experiment. Participants will be monitored by the study physician.
Electrocardiograms will be used to monitor heart activity, and blood will be drawn
frequently to monitor levels of cocaine and topiramate. Participants will complete
standardized questionnaires several times each day to assess mood changes and cognitive
function.