Angiotensin II is best known for its role in regulating fluid and electrolyte homeostasis. In addition, this system is now known to play a key role in the regulation of the hypothalamic-pituitary-adrenal axis and of the sympathetic nervous system. Because these systems are known to play critical roles in addiction, angiotensin II is likely to play a key role in addiction as well. Indeed, angiotensin II has recently been shown to enhance ethanol self-administration in rats. As yet, however, no published studies have evaluated the effects of medications affecting angiotensin II on behaviors related to other drugs of abuse, such as methamphetamine (MA). Supported by a grant from NIDA (R21 DA17182), we conducted a double-blind, placebo-controlled study to evaluate the effects of treatment with perindopril on the subjective and cardiovascular effects of MA in 30 MA-dependent human volunteers. Perindopril is an angiotensin converting enzyme inhibitor that inhibits the synthesis of angiotensin II from its inactive precursor. Perindopril treatment was associated with statistically significant reductions in ratings of `any drug effect'and `desire,'or craving, following administration of MA. Drug-induced craving is an obvious target for treatment, as higher levels of craving has been shown to be associated with greatly increased probability of drug use in studies of both MA and cocaine users. In this application, we propose to examine effects of treatment with perindopril on craving produced by experimental administration of MA in non-treatment-seeking volunteers. We then propose to examine the effects of perindopril treatment on MA use in these same participants in a 6-week outpatient clinical trial. Contingency management procedures will be used to reinforce clinic attendance and reductions in MA use, and manual- driven behavioral compliance enhancement and motivational interviewing techniques will be used to increase medication adherence and to enhance intrinsic motivation to reduce MA use. A separate human laboratory study will examine the dose-dependent effects of perindopril (8mg and 16mg, compared to placebo), on MA- induced craving, though these participants will not take part in the clinical trial. Pilot data suggests that that perindopril, an angiotensin converting enzyme inhibitor, was associated with reductions in methamphetamine-induced craving. Therefore, we propose to examine effects of perindopril treatment (4mg) on methamphetamine-induced craving in a larger human laboratory study enrolling only participants who demonstrate methamphetamine-induced craving in the laboratory. We then propose to examine the effects of perindopril treatment on MA use in these same participants in a 6-week outpatient clinical trial. A separate human laboratory study will examine the dose-dependent effects of perindopril on MA- induced craving, though these participants will not take part in the clinical trial.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023468-05
Application #
8266332
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Biswas, Jamie
Project Start
2008-08-01
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$368,515
Indirect Cost
$128,440
Name
Baylor College of Medicine
Department
Psychiatry
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Mahoney 3rd, James J; De La Garza 2nd, Richard; Jackson, Brian J et al. (2014) The relationship between sleep and drug use characteristics in participants with cocaine or methamphetamine use disorders. Psychiatry Res 219:367-71
Haile, Colin N; De La Garza 2nd, Richard; Mahoney 3rd, James J et al. (2013) Effects of methamphetamine on the noradrenergic activity biomarker salivary alpha-amylase. Drug Alcohol Depend 133:759-62
Mahoney, James J; Jackson, Brian J; Kalechstein, Ari D et al. (2012) Acute modafinil exposure reduces daytime sleepiness in abstinent methamphetamine-dependent volunteers. Int J Neuropsychopharmacol 15:1241-9