Age-and sex-dependent pharmacodynamics and pharmacokinetics of oral and smoked delta-9-THC

项目摘要：随着大麻法规的迅速变化(即合法化)和扩大供应 在整个美国，大麻使用率和大麻使用障碍(CUD)都有所增加 在易受三角洲-9-四氢大麻酚(THC)负面影响的人群中，主要的 大麻的精神活性成分。这些人群包括新兴成年人(18-25岁)、老年人 成年人(≥55岁)和女性。大麻使用率在新兴成年人中最高；这是 特别令人担忧的是，在青春期后期，暴露于THC的风险已知 神经发育和大脑成熟。虽然女性的使用率过去是男性的一半，但 性别之间的差距正在缩小，5.6%的女性新兴成年人报告说几乎每天都在使用。对以下内容敏感 THC对女性的影响也被认为会导致负面结果，包括加速 进展到CUD。大麻使用量最显著的增长是在老年人中。过去的流行率 在55岁的成年人中，月使用量在2013年至2019年间翻了一番以上，其中超过25%的人是55岁以上的人 据报告，成年人每周使用1-4次。因为发生的生理和神经生物学变化 在老龄化过程中，老年人可能特别容易受到THC的负面影响。尽管增加了 在这些人群中使用大麻，到目前为止还没有研究前瞻性地探讨急性 整个成年期的暴露。另一个影响老年人和女性易患艾滋病的趋势 大麻的不良影响是医用大麻在这些人群中的高使用率，疼痛被认为是 使用时的主要症状。这一趋势进一步确立了评估THC止痛的迫切需要 此外还有增加风险的不良反应，包括滥用责任、醉酒和损害。 了解大麻的急性影响，表明这些易受伤害的人接触大麻的风险增加 这项拟议的研究将比较吸烟和口服THC的剂量依赖效应，两种 在与使用包括滥用在内的不良后果直接相关的终端上的常用给药途径 作为年龄和性别的函数的责任、醉酒和损害。具体来说，健康的男性和女性 新兴成人(18-25岁；N=30，15M，15F)、中年成人(35-45岁；N=30，15M，15F)和晚年 偶尔吸食大麻的中年成年人(55-65岁；N=30，15M，15F)将为此招募 双盲、双模拟、安慰剂对照研究。使用受试者内部设计，所有参与者都将 给予安慰剂(0毫克THC)、2.5毫克单位剂量的THC(10毫克)和4.5毫克单位剂量的THC(20毫克) 吸食大麻和口服给药。不良反应、止痛和药代动力学 在吸烟和口服THC后进行多次评估。这项研究的发现将是有益的 将年龄和性别确定为预防、干预和治疗阴性疾病的生物变量 与大麻使用有关的后遗症。

Project Summary: With rapid changes in cannabis regulation (i.e., legalization) and expanded availability across the United States (US), rates of cannabis use and Cannabis Use Disorder (CUD) have increased among populations vulnerable to the negative effects of delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent of cannabis. These populations include emerging adults (18-25 years of age), older adults (≥ 55 years of age), and females. Prevalence of cannabis use is highest among emerging adults; this is of particular concern given the known risks of THC exposure during this period of late-adolescent neurodevelopment and brain maturation. While rates of use among females used to be half that of males, the gap between sexes is closing with 5.6% of female emerging adults reporting near daily use. Sensitivity to THC’s effects in females is also hypothesized to lead to negative outcomes including the accelerated progression to CUD. The most remarkable increase in cannabis use is among older adults. Prevalence of past month use among adults ages 55-64 years more than doubled between 2013 to 2019, with over 25% of older adults reporting use 1-4 times per week. Because of physiological and neurobiological changes that occur during aging, older adults may be particularly vulnerable to the negative effects of THC. Despite the increase in cannabis use among these groups, no studies to date have prospectively probed the adverse effects of acute THC exposure across adulthood. Another trend impacting the vulnerability of older adults and females to adverse effects of cannabis is the high rate of medical cannabis use in these populations with pain cited as the predominant symptom for use. This trend further establishes the urgent need to assess THC analgesia alongside adverse effects that increase risk including abuse liability, intoxication, and impairment. To understand cannabis’s acute effects that indicate increased risk of exposure among these vulnerable populations, the proposed study will compare the dose-dependent effects of smoked and oral THC, two popular routes of administration, on endpoints directly related to adverse consequences of use including abuse liability, intoxication, and impairment as a function of age and sex. Specifically, healthy male and female emerging adults (18-25 years; N=30, 15M, 15F), middle-aged adults (35-45 years; N=30, 15M, 15F) and late middle-aged adults (55-65 years; N=30, 15M, 15F) who occasionally use cannabis will be recruited for this double-blind, double-dummy, placebo-controlled study. Using a within-subjects design, all participants will be administered placebo (0mg THC), 2, 5mg unit-doses of THC (10mg), and 4, 5mg unit-doses of THC (20mg) via smoked cannabis and by oral administration. Adverse effects, analgesia, and THC pharmacokinetics will be assessed several times after smoked and oral THC administration. Findings from this study will be instrumental in establishing age and sex as biological variables in the prevention, intervention, and treatment of negative sequelae associated with cannabis use.