BACKGROUND Recent clinical studies support the use of 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct treatment for posttraumatic stress disorder (PTSD). Despite these promising findings, MDMA administration in controlled settings can increase blood pressure, heart rate, and body temperature. Previous studies indicate thatO-demethylated metabolites of MDMA contribute to its adverse effects. As such, limiting the conversion of MDMA to reactive metabolites may mitigate some of its adverse effects and potentially improve its safety profile for therapeutic use. METHODS We compared the interoceptive and hyperthermic effects of a deuterium-substituted form of MDMA (d2-MDMA) to MDMA using rodent drug discrimination and biotelemetry procedures, respectively. RESULTS Compared to MDMA, d2-MDMA produced full substitution for a 1.5 mg/kg MDMA training stimulus with equal potency and effectiveness in the drug discrimination experiment. In addition, d2-MDMA produced increases in body temperature that were shorter-lasting and of lower magnitude compared to equivalent doses of MDMA. Last, d2-MDMA and MDMA were equally effective in reversing the hypothermic effects of the selective 5-HT2A/2C antagonist ketanserin. CONCLUSION These findings indicate that deuterium substitution of hydrogen at the methylenedioxy ring moiety does not impact MDMA's interoceptive effects, and compared to MDMA, d2-MDMA has less potential for producing hyperthermic effects and likely has similar pharmacodynamic properties. Given that d2-MDMA produces less adverse effects than MDMA, but retains similar desirable effects that are thought to relate to the effective treatment of PTSD, additional investigations into its effects on cardiovascular functioning and pharmacokinetic properties are warranted.

中文翻译：

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3,4-亚甲二氧基甲基苯丙胺（MDMA）及其氘代形式在啮齿动物中的体内作用：药物区分和温度调节。

背景技术最近的临床研究支持使用3，4-亚甲二氧基甲基苯丙胺（MDMA）作为创伤后应激障碍（PTSD）的辅助治疗。尽管有这些令人鼓舞的发现，但在可控的环境中使用MDMA可以增加血压，心率和体温。先前的研究表明，MDMA的O-去甲基化代谢产物对其不利影响有所贡献。这样，限制MDMA向反应性代谢物的转化可以减轻其一些不利影响并潜在地改善其用于治疗用途的安全性。方法我们分别使用啮齿动物药物鉴别法和生物遥测法，比较了氘代形式的MDMA（d2-MDMA）与MDMA的互感和热疗作用。结果与MDMA相比，d2-MDMA完全替代了1。5 mg / kg MDMA训练刺激在药物鉴别实验中具有同等效力和效​​力。此外，与等效剂量的MDMA相比，d2-MDMA产生的体温升高持续时间较短且幅度较小。最后，d2-MDMA和MDMA在逆转选择性5-HT2A / 2C拮抗剂酮色林的低温效应方面同样有效。结论这些发现表明，氢在亚甲基二氧基环上的氘取代不会影响MDMA的互感作用，并且与MDMA相比，d2-MDMA具有较小的产生高热作用的潜力，并且可能具有相似的药效学性质。鉴于d2-MDMA产生的副作用比MDMA少，但保留了与有效治疗PTSD有关的相似理想效果，