An ACE Inhibitor as a Treatment for Methamphetamine Dependence

血管紧张素II以其调节体液和电解质稳态的作用而闻名。此外，该系统 现在已知在调节下丘脑-垂体-肾上腺轴和下丘脑-垂体-肾上腺轴中起关键作用。 交感神经系统因为这些系统在成瘾中起着关键作用，血管紧张素 II也可能在成瘾中发挥关键作用。事实上，血管紧张素II最近被证明可以增强 乙醇在大鼠体内的自我给药。然而，到目前为止，还没有发表的研究评估了 影响血管紧张素II的药物对其他药物滥用相关行为的影响，如甲基苯丙胺 （MA）。在NIDA（R21 DA 17182）的资助下，我们进行了一项双盲、安慰剂对照的研究。 评价培哚普利治疗对MA主观和心血管效应的影响的研究 30名MA依赖性人类志愿者。培哚普利是一种血管紧张素转换酶抑制剂， 从其无活性前体合成血管紧张素II。培哚普利治疗与 在MA给药后，“任何药物作用”和“欲望"或渴望的评级显著降低。 药物诱导的渴望是一个明显的治疗目标，因为更高水平的渴望已被证明是 在对MA和可卡因使用者的研究中，这与药物使用的概率大大增加有关。在这 应用，我们建议检查治疗与培哚普利对渴望产生的实验性 在非寻求治疗的志愿者中施用MA。然后，我们建议检查的影响， 在一项为期6周的门诊临床试验中，在这些相同的参与者中使用培哚普利治疗MA。应急 管理程序将用于加强诊所出勤率和减少MA使用，并手动- 将使用行为驱动的合规性增强和激励性访谈技术来提高 药物依从性和增强内在动机，以减少MA的使用。一个独立的人体实验室 研究将检查培哚普利（8 mg和16 mg，与安慰剂相比）对MA的剂量依赖性作用， 诱导的渴望，尽管这些参与者不会参加临床试验。初步数据表明，培哚普利，一种血管紧张素转换酶抑制剂， 减少甲基苯丙胺引起的渴望。因此，我们建议检查培哚普利的作用， 在一项仅入组的大型人体实验室研究中，对甲基苯丙胺诱导的渴求进行治疗（4 mg） 在实验室中表现出甲基苯丙胺诱导的渴望的参与者。因此，我们建议 在为期6周的门诊研究中，检查培哚普利治疗对这些相同参与者使用MA的影响 临床试验一项单独的人体实验室研究将检查培哚普利对MA的剂量依赖性作用， 诱导的渴望，尽管这些参与者不会参加临床试验。

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.