Translating CBD Treatment for Heroin Addiction

将 CBD 治疗海洛因成瘾

基本信息

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
项目类别：
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

项目摘要

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.

阿片类药物的滥用和误用已导致大规模流行病，影响到所有人美国的社会人口群体，每年导致难以估量的死亡人数。数以百万计的人中当今患有阿片类药物使用障碍的人中，常规治疗方法是阿片类激动剂药物具有明显耻辱性并受到政府法规限制的疗法，不幸的是，可以治疗的人数有限。此外，尽管此类阿片类药物治疗策略已虽然改善了物质使用结果，但它们不能有效地治疗可能导致高比例阿片类药物的渴望复发。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，我们临床前啮齿动物研究此前已证明大麻二酚 (CBD) 是一种无回报成分大麻，特别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在短期 CBD 暴露后，行为在最后一次给药后持续两周或更长时间。有趣的是，这些效应在一项随机双盲人体研究中得到了复制，其中戒断海洛因滥用者报告说，在急性 CBD 施用和即使在上次使用 CBD 一周后，效果仍然持续。事实上，药物渴望普遍存在由暴露于条件暗示而触发表明 CBD 可能是海洛因的有效治疗方法渴望和相关行为维持了这种疾病的慢性复发性质。因此 CBD 代表是开发作为人类阿片类药物渴望的潜在治疗剂的有力候选者预防复发。然而，CBD 的神经生物学作用仍不清楚。这是本次活动的目标转化项目 (1) 表征 CBD 对神经连接和提示诱导神经的影响使用系统级功能分析戒断海洛因受试者中皮质边缘脑回路的活动磁共振成像 (fMRI)，(2) 确定 CBD 对体内谷氨酸能（以及相关使用质子磁共振波谱 (1H MRS) 和 (3) 阐明谷氨酸能以及 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（神经活动）以及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。总而言之，从这项独特的转化研究中获得的知识将促进对导致成瘾的表型背后的神经生物学的基本理解为 CBD 作为一种新的治疗工具的发展提供科学证据，以帮助解决阿片类药物危机。