An Assessment of the Safety of Varenicline in Methamphetamine-dependent Volunteers

Study Procedures:

Study participants are those who meet criteria for MA dependence, who are not seeking
treatment, and who also meet criteria for nicotine dependence. Participants will be asked to
wear a telemetry device during screening and throughout the study that records heart rate and
body temperature. Participants will be required to refrain from smoking at certain times,
illicit and prescription drug use for the duration of the study and this will be confirmed
with daily urine testing.

The study consists of 30 days or less of outpatient screening. The 2-component inpatient
portion of the study lasts a total of 18 days. Participants will be admitted to the GCRC at
UCLA for Days 1-10. After the first study day, participants will be randomized to varenicline
or matched placebo for 9-days and then discharged from the GCRC. Then, after 2-4 weeks, the
same subjects return to the GCRC to be switched to the alternate condition (placebo or
varenicline) for the second component of the study, which lasts another 8-days. Each subject
is randomized to both varenicline and placebo, so total time commitment is 18 inpatient study
days. One follow-up visit is scheduled 2 weeks after completion of both study phases for
assessment of delayed adverse events and for final payment.

On the first day of the inpatient procedure, subjects received 10 3mg infusions of
methamphetamine over 2.5 hours for assessment of drug tolerability. On day 9 of the first
component and day 7 of the second component, subjects received either 10 3mg infusions of
saline OR methamphetamine over 2.5 hours. In the afternoon, the infusion was the opposite of
the morning condition.

Inclusion Criteria:

1. Be English-speaking volunteers who are not seeking treatment at the time of the study;

2. Be between 18-55 years of age;

3. Meet DSM-IV TR criteria for MA dependence;

4. Must be cigarette smokers, defined as smoking 10 or more cigarettes per day by
self-report;

5. Have a self-reported history of using MA by the smoked or IV route and provide at
least one MA-positive urine prior to admission;

6. Have vital signs as follows: resting pulse between 50 and 90 bpm, blood pressures
between 105-150 mm Hg systolic and 45-90 mm Hg diastolic; this criterion must be met
within 2 days of admission;

7. Have hematology and chemistry laboratory tests that are within normal (+/- 10%) limits
with the following exceptions: a) liver function tests (total bilirubin, ALT, AST, and
alkaline phosphatase) < 3 x the upper limit of normal, and b) kidney function tests
(creatinine and BUN) < 2 x the upper limit of normal;

8. Have a baseline EKG that demonstrates normal sinus rhythm, normal conduction
(including QTc), and no clinically significant arrhythmias;

9. Have a medical history and brief physical examination demonstrating no clinically
significant contraindications for study participation, in the judgment of the
admitting physician or nurse practitioner and the principal investigator.

Exclusion Criteria:

1. Have any history or evidence suggestive of seizure disorder or brain injury

2. Have any previous medically adverse reaction to MA, including loss of consciousness,
chest pain, or epileptic seizure

3. Have neurological or psychiatric disorders, such as

- psychosis, bipolar illness or major depression as assessed by SCID;

- organic brain disease or dementia assessed by clinical interview;

- history of any psychiatric disorder which would require ongoing treatment or
which would make study compliance difficult;

- history of suicide attempts within the past three months assessed by SCID and/or
current suicidal ideation/plan as assessed by SCID;

4. Have evidence of clinically significant heart disease or hypertension, as determined
by the PI;

5. Have a family history in first-degree relatives of early cardiovascular morbidity or
mortality, as determined by the PI;

6. Have evidence of untreated or unstable medical illness including: neuroendocrine,
autoimmune, renal, hepatic, or active infectious disease;

7. Have HIV and are currently symptomatic, have a diagnosis of AIDS, or are receiving
antiretroviral medication;

8. Be pregnant or nursing. Other females must either be unable to conceive (i.e.,
surgically sterilized, sterile, or post-menopausal) or be using a reliable form of
contraception (e.g., abstinence, birth control pills, intrauterine device, condoms, or
spermicide). All females must provide negative pregnancy urine tests before study
entry, upon hospital admission, and at the end of study participation;

9. Have asthma or currently use alpha or beta agonists, theophylline, or other
sympathomimetics;

10. Have any other illness, condition, or use of psychotropic medications, which in the
opinion of the PI and/or the admitting physician or nurse practitioner would preclude
safe and/or successful completion of the study.