An ACE Inhibitor (Perindopril) or an Angiotensin Receptor Blocker (Candesartan) as a Treatment for Methamphetamine Dependence

Our preliminary data indicate that the ACE inhibitor perindopril can attenuate MA-induced
drug craving, suggesting that perindopril should be evaluated as a treatment for MA
dependence. Candesartan works similarly to perindopril but should lack the U-shaped dose
response. Like perindopril, candesartan is used for hypertension. Whereas perindopril reduces
the synthesis of angiotensin II, candesartan blocks angiotensin II receptors.

Inclusion Criteria:

- Be English-speaking non-treatment-seeking volunteers.

- Be between 18-55 years of age.

- Meet DSM-IV TR criteria for MA dependence.

- Have a self-reported history of using MA by the IV route.

- Have vital signs as follows: resting pulse between 50 and 90 bpm, blood pressures
between 85-150mm Hg systolic and 45-90mm Hg diastolic.

- Have a breathalyzer test indicating an undetectable blood alcohol level upon
admission.

- 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.

- Have a baseline ECG that demonstrates normal sinus rhythm, normal conduction, and no
clinically significant arrhythmias.

- Have a medical history and brief physical examination demonstrating no clinically
significant contraindications for study participation, in the judgment of the
admitting physician and the principal investigator. Adult ADHD is allowable, as long
as symptoms do not interfere with participation.

- Demonstrate MA-induced craving, evidenced by a change in "desire" greater than 20 on a
0 to 100mm VAS.

- Weigh between 60 and 100kg.

Exclusion Criteria:

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

- Have neurological or psychiatric disorders, such as: episode of major depression
within the past 2 years as assessed by MINI; lifetime history of schizophrenia, other
psychotic illness, or bipolar illness as assessed by MINI; current organic brain
disease or dementia assessed by clinical interview; history of or any current
psychiatric disorder which would require ongoing treatment or which would make study
compliance difficult; history of suicide attempts within the past three months and/or
current suicidal ideation/plan; history of psychosis occurring in the absence of
current MA use.

- Meet DSM-IV criteria for abuse or dependence on alcohol or other drugs, except for
nicotine or marijuana.

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

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

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

- 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, and weekly throughout the study.

- Have any history of asthma, chronic coughing and wheezing, or other chronic
respiratory illnesses.

- Currently use alpha or beta agonists, theophylline, or other sympathomimetics.

- Have any other illness, condition, or use of medications, which in the opinion of the
P.I. and/or the admitting physician would preclude safe and/or successful completion
of the study.

Rationale for Other Exclusion Criteria:

Participants with asthma or who take medications for asthma are excluded due to potential
adverse interactions between treatment medications and MA. Participants who use alcohol
heavily are excluded due to the potential of withdrawal symptoms in the hospital.
Participants with active HIV disease are excluded to avoid potentially exacerbating their
underlying illness and because of potential drug interactions. Reliable methods of birth
are required to prevent pregnancy, and the use of frequent urine pregnancy tests will
exclude women who become pregnant. This is important because perindopril can produce
significant birth defects.

Criteria for Discontinuation Following Initiation:

Participants will be discharged if they have a positive breath test indicating use of
alcohol or a urine test indicating use of illicit use of drugs while on the study, if they
do not comply with study procedures, or if they do not tolerate MA.