The Impact of Product Formulation on the Pharmacokinetics and Pharmacodynamics of Delta-9THC-Infused Cannabis Edibles

项目总结/摘要 随着大麻合法化的扩大，出现了许多新产品。口服大麻产品（或 “可食用”）是最受欢迎的。与传统形式的大麻类似，含有δ-9- 四氢大麻酚（THC）作为主要成分具有滥用倾向，并可产生不必要的负面影响 效果（例如，认知/心理障碍，恐慌反应）。大麻使用者经常报告说， 产生高度不可预测的影响，使这些产品容易引发不良事件。可食用的是 负责大多数与大麻过度中毒有关的急诊室就诊。大麻中的不一致性 可食用效果可能部分源于该不同产品类别中的多种配方。 临床前研究表明，THC吸收显着增加时，摄入的脂质或 相对于非脂质或非纳米乳液制剂，“纳米乳液”制剂是一种过程， 用于使大麻素更具亲水性，据称，更具生物利用度。因此，这些制剂 这些特征可能直接影响人类THC吸收的程度和THC相关的急性效应。 然而，对大麻食品的对照临床研究是有限的，很少有研究评估，如果 这些产品的制剂影响药代动力学（PK）或药效学（PD）结果。 拟定的双盲、安慰剂对照人体实验室研究将比较以下药物的PK和PD效应： 3种流行的大麻食品：THC注入巧克力，软糖和饮料。我们假设四氢大麻酚 对于巧克力（高脂质浓度），吸收和产生的PD效应将显著更大， 相对于橡皮糖（低脂质浓度且无纳米乳液），纳米乳液制剂是饮料（纳米乳液制剂）的脂质浓度。健康 成人将参加9次门诊实验室会议。每一次，他们将消耗三分之一的大麻 0 mg THC（安慰剂）、10 mg THC或25 mg THC的制剂（巧克力、橡皮糖或纳米乳液饮料） (i.e., 2和5个标准THC单位，STU）;会议之前将进行8小时的监测过夜禁食。 课程将以随机顺序完成，间隔至少1周。PD评估将包括 一组认知/心理表现任务和主观药物效果问卷，所有这些都显示出 在拟议的STU对大麻敏感。将收集血浆以定量THC浓度 及其主要代谢产物（11-OH-THC，THCCOOH）。该项目将确定是否制定 当THC剂量保持恒定时，大麻食品会影响PK/PD效应，这一点越来越重要 * 采取主动行动，将STU用于研究和管理目的。从该项目生成的数据可以 可能为教育工作提供信息，以减少大麻食品引起的不良事件的发生率， 深入了解大麻可食用制剂是否应与STU一起考虑， 研究、监管和临床决策。

PROJECT SUMMARY/ABSTRACT As cannabis legalization has expanded, many novel products have emerged. Oral cannabis products (or “edibles”) are among the most popular. Similar to traditional forms of cannabis, edibles that contain delta-9- tentrahydrocannabinol (THC) as the primary constituent have abuse liability and can produce unwanted negative effects (e.g., cognitive/psychomotor impairment, panicked reactions). Cannabis users often report that edibles produce highly unpredictable effects, making these products prone to eliciting adverse events. Edibles are responsible for most emergency room visits related to cannabis over-intoxication. Inconsistency in cannabis edible effects likely stems, in part, from the large variety of formulations within this diverse product category. Preclinical research has shown that THC absorption is markedly increased when ingested in lipid or “nanoemulsion” formulations relative to non-lipid or non-nanoemulsion formulations; nanoemulsion is a process used to make cannabinoids more hydrophilic and purportedly, more bioavailable. Thus, these formulation characteristics may directly impact the magnitude of THC absorption and THC-related acute effects in humans. However, controlled clinical research on cannabis edibles is limited and few studies have evaluated if the formulation of these products influences pharmacokinetic (PK) or pharmacodynamic (PD) outcomes. The proposed, double-blind, placebo-controlled human laboratory study will compare the PK and PD effects of 3 popular types of cannabis edibles: THC-infused chocolates, gummies, and drinks. We hypothesize that THC absorption and resultant PD effects will be significantly greater for the chocolate (high lipid concentration) and drink (nanoemulsion formulation) relative to the gummy (low lipid concentration and no nanoemulsion). Healthy adults will attend 9 outpatient laboratory sessions. For each session, they will consume 1 of 3 cannabis edible formulations (chocolate, gummy, or nanoemulsion drink) at either 0mg THC (placebo), 10mg THC, or 25mg THC (i.e., 2 and 5 Standard THC Units, STUs); sessions will be preceded by 8 hrs of monitored overnight fasting. Sessions will be completed in a randomized order and separated by at least 1 week. PD assessments will include a battery of cognitive/psychomotor performance tasks and a subjective drug effect questionnaire, all shown to be sensitive to cannabis at the proposed STUs. Blood plasma will be collected to quantify concentrations of THC and its primary metabolites (11-OH-THC, THCCOOH). This project will determine whether the formulation of cannabis edibles influences PK/PD effects when THC doses are held constant, which is of growing importance given initiatives to utilize STUs for research and regulatory purposes. Data generated from this project can potentially inform educational efforts to reduce the incidence of adverse events caused by cannabis edibles and provide insight into whether cannabis edible formulation should be a consideration, in conjunction with STUs, for research, regulatory, and clinical decisions.