Translating CBD Treatment for Heroin Addiction

滥用和误用阿片类药物导致了一种大规模的流行病，影响了所有人 在美国的社会人口学群体中，并导致每年难以估量的死亡人数。数百万人中的一员 在当今患有阿片类药物使用障碍的人中，通常的治疗方法是阿片类激动剂药物。 带有明显污名的治疗方法，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已经 改善物质使用结果，但它们不能有效治疗阿片类药物渴望，这种渴望可能导致高比率 旧病复发。使用一种间接调节神经系统的策略来调节阿片类药物相关行为，我们的 临床前啮齿动物研究先前证明，大麻二酚(CBD)，一种非奖励性成分 大麻，特别是抑制线索诱导的海洛因寻找行为。CBD在药物寻觅中的选择作用 在短期接触CBD后的最后一次给药后，行为持续了两周或更长时间。 有趣的是，这些效应在一项随机、双盲的人体研究中得到了复制，在该研究中，戒除海洛因 滥用者报告说，在急性服用CBD和 即使在CBD最后一次服药一周后，这种影响仍然存在。事实上，对毒品的渴求通常是 由条件线索引发的提示CBD可能是治疗海洛因的有效方法 渴求和相关行为，维持这种疾病的慢性复发性质。CBD因此代表着 作为人类阿片类药物渴求和治疗的潜在治疗剂，该药物的开发潜力很大 预防复发。然而，CBD的神经生物学效应仍不清楚。这就是我们的目标 翻译计划：(1)描述CBD对神经连接和线索诱导神经的影响 应用系统水平功能研究海洛因戒除者中脑皮质边缘环路的活动 磁共振成像(FMRI)，(2)测定CBD对体内谷氨酸能(及相关 神经代谢物)和(3)阐明谷氨酸能 CBD对大鼠海洛因寻找行为影响的突触可塑性机制 利用MRS、体内测光(神经活性)、分子和表观遗传学建立转基因啮齿动物模型 对离散的大脑区域进行排序。总之，从这项独特的翻译研究中获得的知识将 促进对驱动成瘾和成瘾的表型潜在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 阿片类药物危机。

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.