PDF(Pubmed)
Abstract：
3,4-Methylenedioxymethamphetamine (MDMA) is being investigated in controlled clinical trials for use as an adjunct medication treatment for post-traumatic stress disorder. MDMA is metabolized by N-demethylation, primarily by CYP2D6, to its main inactive metabolite, 4-hydroxy-3-methoxymethamphetamine. It is also metabolized to a lesser extent by CYP1A2, CYP2B6, and CYP3A4 to its active metabolite, 3,4-methylenedioxyamphetamine. Considering the extensive hepatic metabolism and excretion, MDMA use in psychiatry raises concerns over drug-induced liver injury (DILI), a rare but dangerous event. Majority of the drugs withdrawn from the market for liver injury caused death or transplantation at frequencies under 0.01%. Unfortunately, markers for liver injury were not measured in most published clinical trials. At the same time, no visible DILI-related symptoms and adverse events were observed. Idiosyncratic DILI cases are rarely registered during clinical trials due to their rare nature. In this study, we surveyed a larger, over 1,500, and a more diverse set of reports from the FDA Adverse Event Reporting System and found 23 cases of hepatic injury and hepatic failure, in which MDMA was reported to be taken in addition to one or more substances. Interestingly, 22 out of 23 cases had one or more listed drugs with a known DILI concern based on the FDA\'s DILIrank dataset. Furthermore, only one report had MDMA listed as the primary suspect. Considering the nearly 20 million doses of MDMA used annually, this single report is insufficient for establishing a significant association with DILI.
摘要：
3,4-亚甲二氧基甲基苯丙胺（MDMA）正在对照临床试验中进行研究，用作创伤后应激障碍的辅助药物治疗。MDMA通过N-去甲基化代谢，主要由CYP2D6，其主要的非活性代谢物，4-羟基-3-甲氧基甲基苯丙胺。它也被CYP1A2，CYP2B6和CYP3A4代谢为其活性代谢物，3,4-亚甲二氧基苯丙胺。考虑到广泛的肝脏代谢和排泄，MDMA在精神病学中的使用引起了人们对药物性肝损伤（DILI）的担忧，罕见但危险的事件.大多数因肝脏损伤而退出市场的药物导致死亡或移植的频率低于0.01％。不幸的是,在大多数已发表的临床试验中,肝损伤标志物均未测定.同时,未观察到明显的DILI相关症状和不良事件.特殊的DILI病例由于其罕见性质，在临床试验中很少登记。在这项研究中,我们调查了一个更大的，超过1500例，以及来自FDA不良事件报告系统的更多样化的报告，发现23例肝损伤和肝功能衰竭，据报道，除了一种或多种物质外，还服用了摇头丸。有趣的是,根据FDA的DILIrank数据集，23例病例中有22例具有已知DILI关注的一种或多种上市药物。此外，只有一份报告将MDMA列为主要嫌疑人.考虑到每年使用近2000万剂摇头丸，此单一报告不足以与DILI建立重要关联。
