A Randomized Double-Blind Controlled Trial of Creatine in Female Methamphetamine Users

项目摘要 甲基苯丙胺（MA）对个人造成毁灭性的伤害，但没有批准的治疗方法， MA使用障碍。女性MA使用者的抑郁率增加， 症状比男性。抑郁症可能会导致复发的风险，因为消极情绪与 MA渴望。我们之前的神经影像学研究发现，女性MA使用者的额叶减少， 磷酸肌酸（PCr）水平，与男性MA用户和女性健康对照组相比。后续行动 关于这一关键的翻译发现，我们网站收集的初步数据表明，当给予 女性MA使用者，补充肌酸一水合物与脑PCr、N-乙酰 天冬氨酸（NAA，神经元健康的标志物）和γ-氨基丁酸（GABA，主要的抑制性 大脑的神经递质）。PCr是肌酸激酶反应的底物库， 将PCr转化为三磷酸腺苷（ATP），这是大脑的主要能量供应和肌酸。临床上， 肌酸的服用与抑郁和焦虑症状的减轻有关。这还可以减少 MA使用，通过尿液药物筛查测量。该提案遵循专家建议， 增强和神经元修复，在开发兴奋剂成瘾的药物疗法。长期 本研究项目的目标是确定MA使用障碍的脑化学变化， 利用平移MRS神经成像来确定合理的基于脑的治疗靶点。曾经的假设- 当确定了驱动干预时，MRS可以进一步用于治疗研究，以验证"目标 实现了“参与”。 在MA使用障碍的女性中，肌酸是一种假设产生的干预措施，旨在恢复 神经化学，减少抑郁和焦虑症状，改善认知功能。超过5年 在此期间，该项目将招募76名年龄在18岁至55岁之间患有MA使用障碍的女性，并随机 他们8周的治疗与肌酸或安慰剂。MA使用者的神经成像和认知测试 将在基线时进行，并在治疗8周后重复。作为结果指标，多层次 将对脑化学、认知功能和临床症状进行评估。将 在女性MA使用者中确定肌酸补充剂与安慰剂相比是否1）修复MA- 在额叶脑区引起神经化学毒性，将使用磷-31和 质子-1多核磁共振波谱（MRS），2）改善抑郁和焦虑，这将 使用汉密尔顿抑郁评定量表和贝克焦虑量表测试进行评估，以及3）恢复 与MA毒性相关的认知缺陷，将使用威斯康星州卡片分类任务进行评估， Stroop颜色词测试和韦氏记忆量表。此外，尿液药物检测结果将 探索以确定肌酸补充后MA使用减少的可能性。

PROJECT SUMMARY Methamphetamine (MA) causes devastating harm to individuals, yet there are no approved treatments for MA use disorders. Female MA users have increased rates of depression, and more severe depressive symptoms than males. Depression may contribute to the risk of relapse because negative mood is associated MA craving. Our previous neuroimaging study found that female MA users have decreased frontal lobe phosphocreatine (PCr) levels, compared with both male MA users and female healthy controls. Following up on this key translational finding, preliminary data collected at our site suggests that when administered to female MA users, creatine monohydrate supplementation is associated with increased brain PCr, N-acetyl aspartate (NAA, a marker for neuronal health) and gamma-aminobutyric acid (GABA, the major inhibitory neurotransmitter of the brain). PCr is the substrate reservoir for the creatine kinase reaction, which reversibly converts PCr into adenosine triphosphate (ATP), the brain's major energy supply, and creatine. Clinically, creatine administration was associated with decreased depression and anxiety symptoms. It may also reduce MA use, measured by urine drug screens. This proposal follows expert recommendations to target cognitive enhancement, and neuronal repair, in developing pharmacotherapies for stimulant addiction. The long-term goal of this research program is to define the alterations in brain chemistry that underlie MA use disorders, and to utilize translational MRS neuroimaging to identify rational brain-based treatment targets. Once a hypothesis- driven intervention is identified, MRS can then be further employed in treatment studies, to verify that "target engagement" is achieved. In women with MA use disorders, creatine is a hypothesis-generated intervention aimed at restoring neurochemistry, reducing depression and anxiety symptoms, and improving cognitive function. Over a 5-year period, the project will enroll 76 women between the ages of 18 and 55 with MA use disorders and randomize them to 8 weeks of treatment with either creatine or placebo. Neuroimaging and cognitive testing of MA users will be performed at baseline, and repeated after 8 weeks of treatment. As outcome measures, multi-level assessments will be performed for brain chemistry, cognitive function, and clinical symptoms. It will be determined in female MA users whether creatine supplementation, compared to placebo, will 1) repair MA- induced neurochemical toxicity in the frontal brain regions, which will be assessed using phosphorus-31 and proton-1 multinuclear magnetic resonance spectroscopy (MRS), 2) improve depression and anxiety, which will be assessed using Hamilton Depression Rating Scale and Beck Anxiety Inventory tests, and 3) restore cognitive deficits associated with MA toxicity, which will be assessed using Wisconsin Card Sorting Task, the Stroop Color-Word Test, and the Wechsler Memory Scale. Additionally, urine drug testing results will be explored to determine the likelihood of reduced MA use following creatine supplementation.