Aripiprazole to Reduce Cocaine Relapse

Cocaine addiction is a serious health problem with no available medical treatment for
preventing relapse. Cocaine abusers often report that upon attempting to demonstrate control
over the drug by only "sampling" it following a period of abstinence, they are more likely
to relapse. These small "sampling" amounts of cocaine are thought to function as priming
doses. Priming doses act as a stimulus in the brain to signal that there is more cocaine
available, which in turn may lead to further cocaine use. Medications that reduce the
stimulating effect of the cocaine priming dose may be useful in preventing cocaine relapse.
Aripiprazole, a medication that is currently used to treat schizophrenia, may be effective
at reducing relapse in individuals addicted to cocaine. By enhancing activity of the brain
chemicals dopamine and serotonin, aripiprazole may counter the effects of cocaine and also
reduce cocaine cravings.

This study will involve three sequential experiments. Experiment 1 will evaluate the
physiological and behavioral effects of various combinations of cocaine and aripiprazole.
Experiment 2 will evaluate the capability of aripiprazole at reducing the stimulating
effects of cocaine. Lastly, Experiment 3 will evaluate the role of cocaine priming doses on
subsequent cocaine use and how aripiprazole might alter the effect of the priming dose. In
turn, these findings may lead to future clinical trials using aripiprazole to treat cocaine
addiction and prevent relapse.

All three experiments will involve inpatient hospital stays. Participants will be required
to refrain from using any non-study drugs, other than nicotine, and will undergo daily urine
and breathalyzer tests. Questionnaires will be used to assess drug effects and cocaine
cravings, and a computerized test will measure motor function and performance. Heart rate
and blood pressure will be monitored periodically; an electrocardiogram (ECG) will record
continuously to monitor heart electrical activity. Following the end of each experiment, all
participants will be offered a referral to a drug abuse treatment program.

The first experiment will last 9 weeks and will enroll 8 individuals addicted to cocaine.
Participants will take part in daily sessions in which they will receive varying doses of
cocaine and aripiprazole, alone and in combination. This will provide important information
regarding the safety and tolerability of cocaine-aripiprazole combinations.

The second experiment will last 10 weeks and will enroll 12 individuals addicted to cocaine.
Participants will take part in various phases, which will each last several days. The phases
will include a cocaine sampling phase; a cocaine acquisition phase in which participants
will receive monetary rewards for distinguishing between cocaine and placebo; a placebo
phase; an aripiprazole maintenance phase; a cocaine dose response phase in which the ability
of aripiprazole to reduce cocaine's stimulating effects will be examined; and a washout
phase in which no drugs will be given. Cocaine and aripiprazole doses will be determined by
the results of the first experiment.

The third experiment will last 8 weeks and will enroll 12 individuals addicted to cocaine. A
self-administration procedure designed to model relapse will be used to assess the effects
of priming doses of cocaine on subsequent cocaine-taking behavior, alone and following
aripiprazole treatment. Participants will be assigned to receive placebo for the first part
of the study followed by aripiprazole for the remainder of the study or vice versa. During
experimental sessions, participants will receive a specified amount of cocaine, which will
act as the priming dose. Next, participants will choose between receiving either another
similar dose of cocaine or money. This will be followed by a washout phase and then several
more sampling-choice sessions with differing amounts of cocaine. Cocaine and aripiprazole
doses will be determined by the results of the first experiment.

Inclusion Criteria:

- Meets DSM-IV diagnostic criteria for cocaine dependence

- Current cocaine use at study entry, as determined by a urine screen

- Body Mass Index of less than 30

- ECG results within normal limits

- If female, willing to use contraception throughout the study

Exclusion Criteria:

- Meets DSM-IV diagnostic criteria for dependence on any drugs other than cocaine or
nicotine

- Currently seeking treatment for substance abuse

- Current or past serious illness, including impaired heart function, seizures, head
trauma, or central nervous system tumors

- A family history of heart disease or seizures

- Current or past psychiatric disorder, other than substance abuse

- Pregnant