Methamphetamine is a commonly abused psychostimulant associated with dopamine neurotoxicity in both preclinical models and patients who primarily abuse methamphetamine. Because angiotensin converting enzyme (ACE) inhibitors may attenuate reductions in dopamine transmission and neurotoxicity to the dopamine system, they may have a role in the management of substance abuse disorders. Perindopril is an FDA-approved antihypertensive medication that has greater activity in the central nervous system than other ACE inhibitors. In preclinical studies, perindopril has been shown to increase extracellular dopamine levels and attenuate neurotoxicity to the dopamine system. A double-blind clinical evaluation showed that chronic perindopril treatment can improve symptoms of motor dysfunction in Parkinson's disease. This is a human laboratory study to determine the potential for interactions between oral perindopril and intravenous methamphetamine, being conducted in preparation for an outpatient-based clinical trial to assess the ability of perindopril to prevent relapse in treatment-seeking patients. After establishing eligibility, non-treatment-seeking methamphetamine-experienced volunteers will receive baseline infusions of IV methamphetamine. Subjects that tolerate baseline infusions of 15 and 30 mg of methamphetamine will be randomized to receive either perindopril (2, 4, 8, or 16 mg daily over five days; six subjects for each dose level) or matching placebo (six subjects). On the third and fifth days of perindopril or placebo treatment, subjects will receive treatment infusions of 15 and 30 mg of intravenous methamphetamine. Each methamphetamine infusion will be preceded or followed by an intravenous infusion of saline in a random order. Heart rate (HR) and electrocardiograms (ECG) will be continuously monitored following intravenous methamphetamine treatment. Primary outcome measures are adverse events and cardiovascular responses, including effects of methamphetamine on BP, HR, and ECGs. Secondary outcome measures are methamphetamine pharmacokinetics and the subjective and reinforcing effects of methamphetamine. To assess safety, adverse events identified by clinical observations or laboratory measures will be compared in placebo- and perindopril- treated subjects. Cardiovascular responses and secondary outcome measures will be evaluated by repeated-measures analysis of variance (ANOVA).
