Mirtazapine for methamphetamine use disorder: drug-drug interaction study

项目概要/摘要 甲基苯丙胺的使用是毒品相关发病率和死亡率的一个主要驱动因素， 国家阿片类药物危机。甲基苯丙胺比许多其他药物更普遍，包括 阿片类药物，全世界有3，700万甲基苯丙胺和苯丙胺使用者，去年有140万人 2016年仅美国用户。使用甲基苯丙胺的年经济成本估计为23.4美元 亿在美国。没有FDA批准的药物治疗甲基苯丙胺的使用 疾病，加成医学领域的一大空白。有前途的药物，如安非他酮，缓释剂 纳洛酮、阿立哌唑和选定的苯丙胺类兴奋剂，都显示出混合或阴性 2期临床试验的结果。相反，在两个独立的2期临床试验中， 在增加甲基苯丙胺的戒断时间和减少 在患有甲基苯丙胺使用障碍的成年人中， 和男人做爱。在普通人群中测试本产品时，样本量更大， 需要密集的依从性干预，FDA要求的第一步现在是药物-药物 相互作用研究，以评价甲基苯丙胺在米氮平存在下的药代动力学， 评估不良事件，如QT间期延长和血清素综合征，并确保安全性 在可能使用非法阿片类药物的合并阿片类药物使用障碍患者中使用这些联合用药，或 维持激动剂治疗。我们建议进行这项1期人体实验室试验，同时探索 米氮平的作用机制与一系列心理测试，36名受试者（第1组， 无阿片类药物使用，第2组为非法阿片类药物使用，第3组为维持美沙酮的阿片类药物使用障碍）， 受试者内交叉研究。筛选后，受试者将住院16天， 随机分配至米氮平组或安慰剂组，随后达到稳态，并给予安慰剂和 甲基苯丙胺输液与相关的电池的心理测试，然后他们将被跟踪5 在对侧治疗组中开始。结果将有助于进一步评价 用于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.