Tiagabine, Sertraline, or Donepezil for the Treatment of Cocaine Dependence - 9

Considerable progress in preclinical research has provided a basis for hypothesis driven
clinical trials in cocaine dependence. A greater mechanistic understanding of both cocaine
and many clinically approved medications has led to the identification of many promising
medications for the treatment of cocaine dependence.

For this reason NIDA has developed a CREST (Clinical Rapid Evaluation Screening Trial)
protocol to provide a needed incremental medication screening step between preclinical
research and full blown expensive Phase III pivotal trials. While patients receive manual
based psychotherapy, three medications are screened compared to unmatched placebo in an
eight-week, 80-subject, four cell design trial. Other important features of the CREST
protocol include collecting baseline measurements over a two week period and analyzing
primary outcome measures (quantitative urine toxicology and clinical global improvement
scales) in terms of a composite score of overall individual patient improvement.

The three medications being evaluated in this trial include tiagabine, sertraline, and
donepzil. Tiagabine is hypothesized to interfere with glutamatergic cocaine mechanisms
relevant to addiction. Sertraline is a potent and selective inhibitor of neuronal 5-HT
reuptake, which may modulate the reinforcing and cueing effects of cocaine. Donepezil is
hypothesized to interfere with cholinergic cocaine mechanisms relevant to addiction.

Inclusion Criteria:

1. Males and females, 18 to 60 years of age.

2. DSM-IV diagnosis of cocaine dependence as determined by a semi-structured psychiatric
evaluation.

3. Use of at least $100 worth of cocaine within the past 30 days.

4. Substantiated current cocaine use demonstrated by six urine toxicology specimens, two
of which are positive for BE, in a consecutive two week period during the 30 days
prior to study entry. No more than 4 specimens within seven days will be collected.

5. Additional baseline measures must be completed in conjunction with urine specimens
described in #4, which include: once weekly craving measure (BSCS), Self and Observer
Global ratings, semiquantitative urine specimen for toxicology of six substances
(amphetamines, barbiturates, benzodiazepines, cocaine, methadone, opiates); and three
times weekly alcohol breathalyzer and Self Report of Drug Use (SUR).

6. Ability to provide written informed consent and to comply with all study procedures.

7. Women of child-bearing capacity must be using one of the following acceptable methods
of birth-control: a. oral contraceptives, b. barrier (diaphragm or condom) with
spermicide, c. intrauterine progesterone contraceptive system, d. levonorgestrel
implant, e. medroxyprogesterone acetate contraceptive injection, f.complete
abstinence

Exclusion Criteria:

1. Dependence on psychoactive substance other than cocaine, alcohol, or nicotine.
Physiological dependence on alcohol requiring medical detox.

2. Neurological or psychiatric disorders which require treatment or which would make
medication compliance difficult.

3. Serious medical illnesses that may compromise patient safety or study conduct.

4. Receiving a drug with known potential for toxicity to a major organ system within the
month prior to entering treatment or being on any experimental medication within the
past 60 days.

5. Women who are pregnant, lactating, have had three or more days of amenorrhea beyond
the time of expected menses at the time of the first dose of study medication.

6. Women of childbearing capacity who are not on a medically accepted method of birth
control.

7. Clinically significant abnormal laboratory values.

8. Any disease of the gastrointestinal system, liver, or kidneys which could result in
altered metabolism or excretion of the study medication or history or diagnosis of
chronic disease of the gastrointestinal tract.

9. Receiving chronic therapy with any medication which could interact adversely with one
of the study medications.In particular patients must not have used MAO inhibitors
within 60 days of dosing.

10. Receiving therapy with any of the opiate-substitutes within 60 days of enrollment in
this study.

11. The diagnosis of adult asthma, including those with a history of acute asthma within
the past two years, and those with current or recent (past 2 years) treatment with
inhaled or oral beta-agonists or steroid therapy.

12. Using albuterol or other beta agonist medications, regardless of whether they are
diagnosed with asthma.

13. For individuals who may be suspect for asthma but carry no diagnosis (exclude if on
beta agonists). Patients with FEV1 <70 should be excluded.

14. History of rashes or other sensitivity reactions to study meds.

15. Plans to receive psychosocial treatment external to that designated in the protocol.