Pharmacogenetic Trial of Doxazosin for Treatment of Cocaine Abuse

The noradrenergic system, especially the alpha 1-adrenergic receptor, may play an important
role in cocaine addiction in humans. Doxazosin is a long-acting and selective alpha
1-adrenergic receptor blocker, which inhibits the binding of norepinephrine to alpha
receptors in the autonomic nervous system. This study will evaluate the efficacy of doxazosin
in reducing cocaine-using behavior in treatment seeking cocaine-dependent individuals, and
will guide future pharmacotherapy trials using Doxazosin or related alpha 1 receptor
antagonists for treatment of cocaine addiction. Additionally, this study will identify
genetic subpopulations of participants for whom doxazosin is preferentially effective,
specifically examining the R492C functional polymorphism of the ADRA1A gene.

This 15-week double-blind, placebo controlled clinical trial will provide treatment for 100
cocaine-dependent patients and includes a 13 week medication trial (weeks 1-13) and up to 2
week washout period (weeks 14-15). Qualifying subjects will be randomized to receive
Doxazosin 8 mg/day, or placebo during the study participation.

Subjects will be receiving 2 mg study medication/placebo capsules at week 1, with 2mg/week
induction rate for 3 weeks, according to their randomized assignments, and are maintained on
these agents through week 13. During the course of the trial, all participants will receive
manual-guided cognitive behavioral therapy. At the end of the study (weeks 14-15),
participants will undergo discontinuation from active/placebo medication over a 2-week
period. Subjects who wish to be transferred to an appropriate treatment program or
treatment-research program will be helped with referral during the 2 week period (weeks
14-15).

Inclusion Criteria:

1. Signed informed consent form and HIPAA authorization form

2. Subject is cooperative, understands the risks and benefits, and is willing and able to
adhere to study requirements

3. Any race or ethnic origin

4. Diagnosis of cocaine-dependence according to DSM-IV criteria

5. Between the ages of 18 and 64

6. Must be current users of cocaine with self-reported use of cocaine within the last 90
days, or at least one cocaine-positive urine during screening.

7. Women of childbearing age are eligible to be included in the study if they have a
negative pregnancy test at screening, agree to adequate contraception to prevent
pregnancy, to have monthly pregnancy tests, and they understand the risk of fetal
toxicity due to medication.

8. Must be in good general health as determined by self-report and/or CPRS-based medical
history, general clinical examination conducted by a study physician, and lab tests.
HIV testing will be recommended but is not required for participation in this study.

9. Motivated to discontinue or reduce cocaine use during the period of the study, as
evidenced both by the judgment of the Investigator or designee and by the subject's
compliance level with the requirement for attendance at clinic visits, such that
weekly urine sample requirements for inclusion criteria are fully met.

Exclusion Criteria:

1. Current diagnosis of other drug dependence, especially alcohol or benzodiazepine
dependence, or abuse (other than cocaine, tobacco, or cannabis)

2. Significant medical conditions (e.g., major cardiovascular, renal, endocrine, hepatic
disorders) such as abnormal liver function (with laboratory findings of SGOT or SGPT
greater than three times normal), hypotension, a current cardiac condition that in the
opinion of the investigator would contraindicate Doxasozin treatment, and those having
a high risk of cardiovascular disease, seizure disorders, or another significant
underlying medical condition which would contraindicate Doxazosin treatment

3. Lifetime schizophrenia, bipolar disorder, or other psychotic disorders (excluding
substance-induced psychotic disorders)

4. Actively considering plans of suicidality or homicidality

5. Women planning to become pregnant or breastfeed during the study, refusal to use a
reliable form of birth control, or refusal of monthly pregnancy testing

6. Subjects who are prescribed certain anti-hypertension drugs (i.e. doxasozin) will be
excluded because these medications may interact with Doxazosin's brain effects in
reducing cocaine abuse

7. Subject has participated in another clinical trial or received any other
investigational compound within 7 days prior to being randomized into this study