An ACE Inhibitor as a Treatment for Methamphetamine Dependence

说明(申请人提供)：血管紧张素II因其调节液体和电解质稳态的作用而广为人知。此外，该系统现在已知在调节下丘脑-垂体-肾上腺轴和交感神经系统中起关键作用。因为已知这些系统在成瘾中起关键作用，血管紧张素II可能也在成瘾中起关键作用。事实上，血管紧张素II最近被证明可以增强大鼠的乙醇自我给药。然而，到目前为止，还没有发表的研究评估影响血管紧张素II的药物对其他滥用药物相关行为的影响，如甲基苯丙胺(MA)。在NIDA(R21 DA17182)的资助下，我们进行了一项双盲、安慰剂对照研究，以评估培哚普利对30名MA依赖者的主观和心血管效应的影响。培哚普利是一种血管紧张素转换酶抑制剂，可抑制其非活性前体合成血管紧张素II。在服用MA后，培哚普利治疗与“任何药物效果”和“欲望”或渴望的评分在统计学上显著降低有关。药物诱导的渴望是一个明显的治疗目标，因为在对MA和可卡因使用者的研究中，已经表明渴望程度越高，使用药物的可能性就越大。在这项申请中，我们建议检查培哚普利对非寻求治疗的志愿者实验中服用MA所产生的渴求的影响。然后，我们建议在为期6周的门诊临床试验中检查培哚普利治疗对这些参与者MA使用的影响。将使用应急管理程序来加强临床就诊和减少MA使用，并将使用手动驱动的行为遵从性增强和动机访谈技术来增加用药依从性和增强减少MA使用的内在动机。另一项单独的人体实验室研究将检验培哚普利(与安慰剂相比，分别为8毫克和16毫克)对MA诱导的渴求的剂量依赖效应，尽管这些参与者不会参加临床试验。试点数据表明，血管紧张素转换酶抑制剂培哚普利与减少甲基苯丙胺诱导的渴求有关。因此，我们建议在一项更大的人体实验室研究中检验培哚普利治疗(4 Mg)对甲基苯丙胺诱导的渴望的影响，该研究只招募在实验室中表现出甲基苯丙胺诱导渴望的参与者。然后，我们建议在为期6周的门诊临床试验中检查培哚普利治疗对这些参与者MA使用的影响。另一项单独的人体实验室研究将检验培哚普利对MA诱导的渴求的剂量依赖效应，尽管这些参与者不会参加临床试验。

DESCRIPTION (provided by applicant): 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.