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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要甲基苯丙胺 (MA) 对个人造成毁灭性伤害，但尚无批准的治疗方法 MA使用障碍。女性 MA 用户抑郁症发病率增加，且抑郁程度更严重症状多于男性。抑郁症可能会增加复发的风险，因为负面情绪与此相关马渴望。我们之前的神经影像学研究发现，女性 MA 使用者的额叶有所减少与男性 MA 使用者和女性健康对照者相比，磷酸肌酸 (PCr) 水平。跟进关于这一关键的转化发现，我们网站收集的初步数据表明，当管理女性 MA 使用者，补充一水肌酸与增加脑部 PCR、N-乙酰基有关天冬氨酸（NAA，神经元健康的标志物）和 γ-氨基丁酸（GABA，主要抑制物质）大脑的神经递质）。 PCr 是肌酸激酶反应的底物库，该反应可逆地进行将 PCr 转化为三磷酸腺苷 (ATP)（大脑的主要能量供应）和肌酸。临床上，肌酸给药与抑郁和焦虑症状的减轻有关。也可能会减少 MA 使用情况，通过尿液药物筛查测量。该提案遵循了针对认知目标的专家建议增强和神经元修复，开发兴奋剂成瘾的药物疗法。长期来看该研究项目的目标是确定 MA 使用障碍背后的大脑化学变化，以及利用平移 MRS 神经影像来确定合理的基于大脑的治疗目标。一旦有一个假设—— 确定了驱动干预后，MRS 就可以进一步用于治疗研究，以验证“目标参与”得以实现。对于患有 MA 使用障碍的女性，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，并改善认知功能。 5年多来在此期间，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，并随机分组他们接受肌酸或安慰剂治疗 8 周。 MA 用户的神经影像和认知测试将在基线时进行，并在治疗 8 周后重复。作为成果衡量标准，多层次将对大脑化学、认知功能和临床症状进行评估。这将是在女性 MA 使用者中确定肌酸补充剂与安慰剂相比是否会 1) 修复 MA- 在额叶区域诱导神经化学毒性，将使用磷 31 和 proton-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，将使用威斯康星卡片分类任务进行评估，斯特鲁普颜色词测试和韦克斯勒记忆量表。此外，尿液药物检测结果将旨在确定补充肌酸后减少 MA 使用的可能性。