Pharmacogenetics of Doxazosin for Cocaine Dependence

The NE system, especially the alpha 1-adrenergic receptor, may play an important role in
cocaine addiction in humans. The results of this study will provide medical safety data on
the duration of the induction schedule that will be optimal for attaining our target dose of
8 mg doxazosin daily and will guide future pharmacotherapy trials using Doxazosin or related
alpha 1 receptor antagonists for cocaine addiction.

This 16-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 1 mg study medication/placebo capsules at week 1, with 4mg/week
induction rate for weeks, according to their randomized assignments, and are maintained on
these agents through week 13. 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 (2) Subject understands the risk and
benefits and agrees to visit frequency and procedures (3) Male or female (4) Any race or
ethnic origin (5)Diagnosis of cocaine-dependence according to DSM-IV criteria (6) between
the ages of 18 and 64 (7)Must be current users of cocaine with self-reported use of
cocaine at least once weekly for at least one month preceding study entry,
cocaine-positive urine screen and score over 3 which is the cut-off for diagnosis of
cocaine dependence as assessed with the Severity of Dependence Scale (Kaye & Darke 2002;
Gossop, et al 1995; Gossop, et al. 1997) (8)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.

Exclusion Criteria: (1)Current diagnosis of other drug , especially alcohol or
benzodiazepine dependence or abuse (other than cocaine or tobacco) (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 or hypertension, a current cardiac condition, 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 (4) Actively considering
plans of suicidality or homicidality (5) Current use of a prescribed psychotropic
medication that cannot be discontinued (6) Women planning to become pregnant or breastfeed
during the study, or refuse to use a reliable form of birth control or refuse monthly
pregnancy testing (7) Subjects who are prescribed any anti-hypertension drugs, except
thiazides, will be excluded because these medications may interact with Doxazosin's brain
effects in reducing cocaine abuse.