Mirtazapine for methamphetamine use disorder: drug-drug interaction study

项目摘要/摘要 甲基苯丙胺的使用是与毒品有关的发病率和死亡率的主要驱动因素，与 国家阿片类药物危机也是如此。甲基苯丙胺比许多其他毒品更普遍，包括 类阿片，全世界有3700万甲基苯丙胺和苯丙胺使用者，过去一年有140万人 2016年，仅在美国就有用户。甲基苯丙胺的年经济成本估计为23.4美元 在美国有10亿美元。目前还没有FDA批准的甲基苯丙胺药物疗法 无序，是加药领域的一大空白。安非他酮、缓释剂等前景看好的药物 纳曲酮、阿立哌唑和部分苯丙胺类兴奋剂均呈混合或阴性。 2期临床试验结果。相比之下，在两个独立的2期临床试验中，米氮平 在延长甲基苯丙胺戒断期和减少戒断期方面有显著效果 男性和男性甲基苯丙胺使用障碍患者的HIV相关危险行为 和男人做爱。当在普通人群中测试此产品时，样本量更大， 需要密集的依从性干预，FDA要求的第一步是药物-药物 米氮平存在下评价甲基苯丙胺药代动力学的相互作用研究 评估不良事件，如QT延长和5-羟色胺综合征，并确保 这些组合用于可能使用非法阿片类药物或合并阿片类药物使用障碍的患者 维持使用激动剂治疗。我们建议进行这一阶段的人体实验室试验，也探索 米氮平的作用机制和一系列心理测试，36名受试者(第1组， 不使用阿片类药物，第2组非法使用阿片类药物，第3组使用美沙酮维持阿片类药物使用障碍) 受试者内交叉研究。经过筛查，参与者将获准住院16天， 随机分配米氮平或安慰剂，随后进入稳定状态，并给予安慰剂和 注射甲基苯丙胺和相关的心理测试；然后他们将被跟踪5次 洗脱的天数和开始在相反的治疗臂。结果将有助于进一步的评估 米氮平治疗甲基苯丙胺使用障碍。

Project Summary/Abstract Methamphetamine use is a major driver of drug-related morbidity and mortality, with intimate involvement in the national opioid crisis as well. Methamphetamine is more prevalent than many other drugs, including opioids, with 37 million users of methamphetamine and amphetamine worldwide and 1.4 million past-year users in the U.S. alone in 2016. The annual economic cost of methamphetamine use is estimated to be $23.4 billion in the United States. There are no FDA-approved pharmacotherapies for methamphetamine use disorder, a major gap in the field of addition medicine. Promising agents such as bupropion, extended-release naltrexone, aripiprazole, and selected amphetamine-based stimulants, have all shown mixed or negative results in phase 2 clinical trials. In contrast, in two separate phase 2 clinical trials mirtazapine has demonstrated a significant effect in increasing periods of abstinence from methamphetamine and decreasing related HIV risk behaviors among adults with methamphetamine use disorder who were born male and have sex with men. While testing this product in the general population, with larger samples sizes, and more intensive adherence interventions is demanded, the first step required by the FDA is now a drug-drug interaction study to evaluate pharmacokinetics of methamphetamine in the presence of mirtazapine, to evaluate for adverse events such as QT prolongation and serotonin syndrome, and to ensure the safety of these combinations in patients with co-morbid opioid use disorder who may be using illicit opioids or maintained on agonist therapy. We propose to conduct this Phase 1 human laboratory trial, also exploring mechanisms for the effect of mirtazapine with a battery of psychological testing, with 36 subjects (Group 1 with no opioid use, Group 2 with illicit opioid use, Group 3 with opioid use disorder maintained on methadone) in a within-subject crossover study. After screening, participants will be admitted to a 16-day inpatient stay, randomly assigned to mirtazapine or placebo, followed to steady state, and given placebo and a methamphetamine infusion with associated batteries of psychological testing; they will then be followed for 5 days for washout and initiated in the opposite treatment arm. Results will contribute toward further evaluation of mirtazapine for treatment of methamphetamine use disorder.