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

项目摘要/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”)是最受欢迎的食物之一。与传统形式的大麻类似，含有Delta-9的可食性食品- 作为主要成分的四氢大麻酚(THC)有滥用的可能性，并会产生不必要的负面影响 影响(例如，认知/精神运动障碍、惊慌性反应)。大麻使用者经常报告说，可食用的 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 负责与大麻过度中毒有关的大部分急诊室就诊。大麻中的不一致 食用效果可能在一定程度上源于这一多样化产品类别中的各种配方。 临床前研究表明，当摄入脂质或其他物质时，THC的吸收显著增加 相对于非脂类或非纳米乳剂的“纳米乳剂”；纳米乳剂是一种过程 用来使大麻素更亲水，据称更具生物利用度。因此，这些提法 特性可能直接影响人类对THC的吸收程度和与THC相关的急性效应。 然而，关于大麻食用的受控临床研究是有限的，而且很少有研究评估 这些产品的配方会影响药代动力学(PK)或药效学(PD)结果。 这项拟议的双盲、安慰剂对照的人体实验室研究将比较PK和PD的效果 3种流行的大麻食品：注入了THC的巧克力、口香糖和饮料。我们假设THC 巧克力的吸收和由此产生的PD效应将显著更大(高脂浓度)和 饮料(纳米乳剂配方)相对于胶水(低脂肪浓度和不含纳米乳剂)。健康 成人将参加9个门诊实验室会议。每一次，他们将消费3种可食用大麻中的1种 配方(巧克力、口香糖或纳米乳饮料)为0毫克THC(安慰剂)、10毫克THC或25毫克THC (即2个和5个标准THC单位，STU)；会议之前将有8个小时的监测通宵禁食。 课程将以随机顺序完成，间隔至少1周。PD评估将包括 一系列认知/精神运动表现任务和主观药物效应问卷，所有这些都显示 在拟建的核电厂对大麻保持敏感。将收集血浆以量化THC的浓度 及其主要代谢物(11-OH-THC、THCCOOH)。这个项目将决定是否制定 当剂量保持不变时，大麻食用会影响PK/PD效应，这一点越来越重要 考虑到将STU用于研究和监管目的的倡议。此项目生成的数据可以 有可能为教育工作提供信息，以减少大麻食品造成的不良事件的发生率 提供关于大麻可食用配方是否应与STU一起考虑的见解，以便 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.