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

女性甲基苯丙胺使用者肌酸的随机双盲对照试验

• 批准号: 10227185
• 负责人: PERRY FRANKLIN RENSHAW
• 金额: $ 48.9万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227185
• 关键词: Abstinence; Adenosine Triphosphate; Adult; Age; Animals; Anti-Anxiety Agents; Antidepressive Agents; Anxiety; Apoptosis; Base of the Brain; Bioenergetics; Biological Markers; Brain; Brain Chemistry; Brain region; Categories; Chemicals; Clinical; Clinical Trials; Clinical assessments; Cognitive; Cognitive Therapy; Cognitive deficits; Color; Creatine; Creatine Kinase; Data; Diet; Disease; Double-Blind Method; Drug Screening; Economic Burden; Energy Metabolism; Energy Supply; Enrollment; Equipment and supply inventories; FDA approved; Female; Fishes; GABA Receptor; Gender; Genes; Glutamates; Glutamine; Goals; Hamilton Rating Scale for Depression; Health; Impaired cognition; Individual; Intake; Intervention; Literature; Magnetic Resonance Spectroscopy; Maintenance; Malnutrition; Measures; Meat; Memory; Mental Depression; Methamphetamine; Methamphetamine dependence; Mitochondria; Moods; N-acetylaspartate; Neurobehavioral Manifestations; Neurons; Neuropsychological Tests; Neurotransmitters; Nutritional; Outcome Measure; Pharmaceutical Preparations; Pharmacotherapy; Phosphocreatine; Phosphorus; Placebos; Prevention; Protons; Psychomotor Performance; Psychostimulant dependence; Randomized; Rattus; Reaction; Recommendation; Relapse; Reporting; Research; Rodent; Role; Secondary to; Selective Serotonin Reuptake Inhibitor; Self Administration; Site; Sorting - Cell Movement; Supplementation; Symptoms; System; Test Result; Testing; Time; Toxic effect; Urine; Wisconsin; Withdrawal; Woman; addiction; anxiety symptoms; base; child depression; cognitive enhancement; cognitive function; cognitive performance; cognitive testing; comorbid depression; conditioned place preference; craving; depressive symptoms; drug testing; early onset; executive function; frontal lobe; gamma-Aminobutyric Acid; improved; insight; interest; male; men; methamphetamine abuse; methamphetamine use; methamphetamine user; mitochondrial dysfunction; negative emotional state; negative mood; neurochemistry; neuroimaging; neurotoxicity; novel; novel therapeutic intervention; open label; programs; randomized placebo controlled trial; relapse risk; repaired; restoration; sex; sustained attention; therapeutically effective; volunteer

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.

项目总结 甲基苯丙胺(MA)对个人造成毁灭性的伤害，但目前还没有批准的治疗方法 麻省理工学院使用障碍。使用MA的女性患抑郁症的几率更高，抑郁程度更严重 症状比男性更多。抑郁可能会增加复发的风险，因为负面情绪与 妈妈渴望。我们之前的神经成像研究发现，使用MA的女性额叶减少 与男性MA使用者和女性健康对照组的磷酸肌酸(PCr)水平进行比较。跟进 关于这一关键的翻译发现，我们网站收集的初步数据表明，当管理到 女性MA使用者，补充一水肌酸与脑PCRN-乙酰增加相关 天冬氨酸(NAA，神经元健康的标志)和伽马氨基丁酸(GABA，主要抑制物 大脑的神经递质)。聚合酶链式反应是肌酸激酶反应的底物储存库，它可逆地 将聚合酶链式反应转化为三磷酸腺苷(ATP)，这是大脑的主要能量供应，以及肌酸。在临床上， 肌酸治疗与抑郁和焦虑症状的减少有关。它还可能会减少 马的使用，通过尿液药物筛查来衡量。这项建议遵循专家的建议，以认知为目标 在开发兴奋剂成瘾药物疗法方面的增强和神经元修复。长期的 这项研究计划的目标是确定导致MA使用障碍的大脑化学变化，以及 利用翻译MRS神经成像来确定合理的基于大脑的治疗靶点。曾经有一种假设- 确定驱动干预后，MRS可进一步用于治疗研究，以验证 实现了“参与度”。 在患有MA使用障碍的女性中，肌酸是一种假说产生的干预措施，旨在恢复 神经化学，减轻抑郁和焦虑症状，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岁之间的患有MA使用障碍的女性并随机进行 他们接受8周的肌酸或安慰剂治疗。MA使用者的神经影像和认知测试 将在基线上进行，并在治疗8周后重复。作为结果衡量标准，多层次 将对大脑化学成分、认知功能和临床症状进行评估。会是 在女性MA使用者中确定补充肌酸与安慰剂相比是否会1)修复MA- 额叶脑区诱导的神经化学毒性，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 使用汉密尔顿抑郁量表和贝克焦虑问卷测试进行评估，以及3)恢复 与MA毒性相关的认知缺陷，将使用威斯康星卡片分类任务进行评估， Stroop颜色词测验和韦氏记忆量表。此外，尿液药物检测结果将 探讨了在补充肌酸后减少MA使用的可能性。