Translating CBD Treatment for Heroin Addiction

将 CBD 治疗海洛因成瘾

• 批准号: 10205013
• 负责人: YASMIN L. HURD
• 金额: $ 77.81万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10205013
• 关键词: Acute; Address; Amygdaloid structure; Animal Model; Animals; Anxiety; Autopsy; Behavior; Brain; Brain region; Calcium Signaling; Cannabidiol; Cannabinoids; Cannabis; Caring; Cells; Cessation of life; Chronic; Clinical; Corpus striatum structure; Cues; Development; Disease; Dorsal; Dose; Double-Blind Method; Double-blind trial; Effectiveness; Epidemic; Epigenetic Process; Exposure to; Female; Fiber; Foundations; Functional Magnetic Resonance Imaging; Genes; Glutamate Receptor; Glutamates; Goals; Government regulations; Heroin; Heroin Dependence; Human; Impairment; Individual; Investigation; Knowledge; Magnetic Resonance; Magnetic Resonance Spectroscopy; Measures; Mediating; Medical; Midbrain structure; Modeling; Molecular; Monitor; N-acetylaspartate; Nature; Neurobiology; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Opioid agonist; Oral; Outcome; Patients; Pharmaceutical Preparations; Phase; Phenotype; Photometry; Pilot Projects; Placebos; Population; Prefrontal Cortex; Protons; Randomized; Rattus; Recording of previous events; Relapse; Reporting; Reproducibility of Results; Research Project Grants; Rest; Rodent; Rodent Model; Scanning; Science; Self Administration; Series; Services; Signal Transduction; Study models; Substance of Abuse; Synaptic plasticity; System; Techniques; Therapeutic; Therapeutic Agents; Time; Translating; Translational Research; Treatment Failure; Ursidae Family; Ventral Striatum; addiction; base; craving; disorder later incidence prevention; drug abstinence; drug craving; drug seeking behavior; effective therapy; epigenome; evidence base; follow-up; heroin abuser; heroin use; human model; human study; human subject; improved; in vivo; insight; male; neural circuit; neuroimaging; novel; novel therapeutics; opioid agonist therapy; opioid epidemic; opioid misuse; opioid therapy; opioid use; opioid use disorder; overdose death; phase 1 study; pre-clinical; preclinical study; relating to nervous system; response; social stigma; sociodemographic group; substance use; tool; transcriptome; translational study; treatment strategy

The abuse and misuse of opioids has led to an epidemic of major proportions that has impacted all sociodemographic groups in the USA and led to an unfathomable number of deaths each year. Of the millions of people suffering today from an opioid use disorder, the normal treatments are opioid agonist medication therapies that have marked stigma and are subject to restrict governmental regulations that unfortunately have limited the number of people possible to treat. Moreover, although such opioid treatment strategies have improved substance use outcomes, they do not effectively treat opioid craving that might result in high rates of relapse. Using a strategy of indirectly regulating neural systems to modulate opioid-related behavior, our preclinical rodent studies had previously demonstrated that cannabidiol (CBD), a non-rewarding component of cannabis, specifically inhibited cue-induced heroin-seeking behavior. CBD's selective effect on drug-seeking behavior endured two or more weeks after the last drug administration following short-term CBD exposure. Intriguingly, these effects were replicated in a randomized double-blinded human study where abstinent heroin abusers reported reduced cue-induced drug craving (and anxiety) following acute CBD administration and the effects persisted even a week after the last administration of the CBD. The fact that drug craving is generally triggered by exposure to conditioned cues suggests that CBD might be an effective treatment for heroin craving and related behaviors that maintain the chronic relapsing nature of this disorder. CBD thus represents a strong candidate for the development as a potential therapeutic agent in humans for opioid craving and relapse prevention. However, the neurobiological effects of CBD are still unknown. It is the goal of this translational project to (1) Characterize the effects of CBD on neural connectivity and cue-induced neural activity within mesocorticolimbic brain circuits in abstinent heroin subjects using systems-level functional magnetic resonance imaging (fMRI), (2) Determine CBD effects on in vivo glutamatergic (and related neurometabolites) using Proton-Magnetic resonance spectroscopy (1H MRS) and (3) Elucidate glutamatergic and related synaptic plasticity mechanisms underlying the effects of CBD on heroin seeking behavior in translational rodent models using MRS, in vivo photometry (neural activity) and molecular and epigenetic sequencing of discrete brain regions. Altogether, knowledge obtained from this unique translational study will advance fundamental understanding of the neurobiology underlying phenotypes that drive addiction and provide science-based evidence towards the development of CBD as a new therapeutic tool to help address the opioid crisis.

滥用和误用类阿片导致了一种影响到所有人的大规模流行病， 美国的社会人口群体，并导致每年死亡人数深不可测。数百万 对于今天患有阿片类药物使用障碍的人，正常的治疗方法是阿片类药物激动剂药物， 这些疗法具有明显的耻辱感，并受到政府法规的限制，不幸的是， 限制了可能治疗的人数。此外，尽管这种阿片类药物治疗策略 改善物质使用的结果，他们不能有效地治疗阿片类药物的渴望，可能会导致高利率的 复发使用间接调节神经系统的策略来调节阿片类药物相关行为， 临床前啮齿动物研究先前已经证明，大麻二酚（CBD），一种非奖励成分， 大麻，特别是抑制线索诱导的海洛因寻求行为。CBD对药物寻求的选择性作用 行为持续两个或两个以上星期后，最后一次给药后，短期CBD暴露。 有趣的是，这些效果在一项随机双盲人体研究中得到了复制， 滥用者报告说，在急性CBD给药后，线索诱导的药物渴望（和焦虑）减少， 即使在最后一次施用CBD后一周，效果也持续存在。事实上，对毒品的渴望通常是 由暴露于条件性线索引发的研究表明，CBD可能是海洛因的有效治疗方法。 渴望和相关的行为，保持这种疾病的慢性复发性质。CBD代表 作为人类阿片类药物渴求的潜在治疗剂的强有力的候选者， 预防复发然而，CBD的神经生物学效应仍然未知。这是我们的目标 翻译项目（1）表征CBD对神经连接和线索诱导的神经元的影响。 海洛因戒断者中脑皮质边缘脑回路活动的系统水平功能研究 磁共振成像（fMRI），（2）确定CBD对体内多巴胺能（和相关）的影响 （3）阐明神经代谢物），使用质子磁共振波谱（1H MRS）和（4）阐明神经代谢物 以及CBD对海洛因寻求行为影响的相关突触可塑性机制， 使用MRS、体内光度测定法（神经活性）和分子和表观遗传学的转化啮齿动物模型 对离散的大脑区域进行排序。总之，从这种独特的翻译研究中获得的知识将 推进对驱动成瘾的神经生物学基础表型的基本理解， 为CBD作为一种新的治疗工具的发展提供科学依据， 鸦片危机