• Adverse events; measured throughout methamphetamine infusions and at Day 18 [ Time Frame: Inpt study phase and followup ] [ Designated as safety issue: Yes ]
• Cardiovascular responses; measured throughout methamphetamine infusions and at Day 18 [ Time Frame: Inpt phase and followup ] [ Designated as safety issue: Yes ]
• Reinforcing effects of methamphetamine; measured throughout methamphetamine infusions and at Day 18 [ Time Frame: day 1-18 ] [ Designated as safety issue: No ]

• Adverse events; measured throughout methamphetamine infusions and at Day 18
• Cardiovascular responses; measured throughout methamphetamine infusions and at Day 18
• Reinforcing effects of methamphetamine; measured throughout methamphetamine infusions and at Day 18

Due to its ease of synthesis and powerful psychostimulant effects, abuse of methamphetamine has increased rapidly over the last decade. No medications are currently approved for the treatment of methamphetamine dependence or withdrawal. The purpose of this study is to determine whether perindopril, an angiotensin converting enzyme (ACE) inhibitor, modifies cardiovascular responses and adverse events when taking methamphetamines.

Methamphetamine is a commonly abused drug associated with dopamine neurotoxicity. It damages brain cells that contain dopamine, which can result in Parkinson-like symptoms, such as muscle rigidity, tremors, and limited movement. Because ACE inhibitors have the potential to reverse methamphetamine's neurotoxicity effects, they may prove useful as treatment drugs. Perindopril is an antihypertensive medication that demonstrates greater activity in the central nervous system than other ACE inhibitors. The purpose of this study is to determine whether perindopril modifies cardiovascular responses and adverse events during methamphetamine administration. In addition, this study will determine whether perindopril alters methamphetamine pharmacokinetics and its reinforcing effects, thus making perindopril a possible treatment option.

Participants in this double-blind, placebo-controlled trial will initially receive baseline infusions of methamphetamine. Those that tolerate the baseline methamphetamine will be randomly assigned to receive either perindopril or placebo. Perindopril will be administered at a dose of either 2, 4, 8, or 16 mg per day over a 5-day inpatient period. On Days 3 and 5, participants will receive infusions of 15 and 30 mg of intravenous methamphetamine. Each methamphetamine infusion will be preceded or followed by an intravenous infusion of saline. Heart rate and electrocardiograms will be continuously monitored. Participants will be discharged 2 days after the final doses of methamphetamine and perindopril, and will return approximately 1 week later (Day 18) for an additional evaluation.

• Methamphetamine Dependence
• Substance-Related Disorders

• Drug: Perindopril
• Drug: Placebo
• Drug: perindopril

• Placebo Comparator: Placebo
• Experimental: perindopril 2mg
• Experimental: perindopril 4mg
• Experimental: perindopril 8mg
• Experimental: perindopril 16mg

Inclusion Criteria:

• Current and past history of methamphetamine use
• Not currently seeking treatment for methamphetamine dependence
• Meets DSM-IV criteria for methamphetamine abuse or dependence, as determined by the SCID
• At least one positive urine test for methamphetamines within the 4 weeks prior to study entry
• Speaks and writes English
• Females must agree to use an adequate form of contraception for the duration of the study and have a negative pregnancy test prior to study entry

Exclusion Criteria:

• History of an adverse medical reaction to methamphetamine or other psychostimulants, including loss of consciousness, chest pain, cardiac ischemia, or seizure
• Current psychiatric disorder, other than drug abuse or dependence, including major depression, bipolar disorder, schizoaffective disorder, schizophrenia, organic brain disease, or dementia
• Meets DSM-IV criteria for dependence on opiates, benzodiazepines, alcohol, or other sedative-hypnotics
• Currently taking opiate-substitution therapy (e.g., methadone, LAAM, or buprenorphine) within the 2 months prior to study entry
• Current or past history of a seizure disorder, including alcohol- or psychostimulant-related seizures, febrile seizures, or familial history of seizure disorders
• Diagnosed with adult asthma, including a history of acute asthma within the 2 years prior to study entry
• Diagnosed with chronic obstructive pulmonary disease within the 2 years prior to study entry
• Treatment with an inhaled or oral beta-adrenergic agonist within the 2 years prior to study entry
• Head trauma that resulted in neurological abnormalities (e.g., loss of memory for greater than 5 minutes or that required hospitalization)
• Any unstable medical condition that might make participation unsafe, including AIDS, acute hepatitis, active tuberculosis, unstable cardiac disease, unstable diabetes, kidney or liver insufficiency (defined as serum bilirubin or creatine levels exceeding 1.5 times the normal limit)
• Pregnant or breastfeeding
• Current suicidal ideation, as determined by a SCID interview
• Clinically significant electrocardiogram abnormalities
• Donated blood within 4 weeks prior to study entry
• Participated in another clinical trial within 4 weeks prior to study entry
• Unable to complete study procedures due to incarceration or relocation from the area
• Known or suspected hypersensitivity to perindopril, other ACE inhibitors, methamphetamine, or other psychostimulants
• Currently using perindopril, potassium supplements, potassium-sparing diuretics, other antihypertensive medication, or any medications that may interact with study drugs