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

项目摘要：随着大麻管制的迅速变化（即，合法化）和扩大可用性 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δ-9-四氢大麻酚负面影响的人群中， 大麻的精神活性成分。这些人群包括新兴的成年人（18-25岁）， 成人（≥ 55岁）和女性。大麻使用的流行率在新兴成年人中最高;这是 特别值得关注的是，考虑到在青春期后期接触THC的已知风险， 神经发育和大脑成熟。虽然女性的使用率曾经是男性的一半， 两性之间的差距正在缩小，5.6%的女性新兴成年人报告几乎每天使用。敏感性 THC对女性的影响也被假设会导致负面结果，包括加速 发展到CUD。大麻使用增加最显着的是老年人。过去的流行率 从2013年到2019年，55-64岁的成年人每月使用量增加了一倍多，超过25%的老年人 成人报告每周使用1-4次。由于生理和神经生物学的变化， 在衰老过程中，老年人可能特别容易受到四氢大麻酚的负面影响。尽管越来越 在这些人群中使用大麻，迄今为止还没有研究前瞻性地探讨急性大麻中毒的不良影响。 在成年期接触四氢大麻酚。另一个影响老年人和女性对艾滋病毒/艾滋病脆弱性的趋势是， 大麻的不利影响是这些人群中医用大麻的使用率很高， 使用的主要症状。这一趋势进一步确立了迫切需要评估THC镇痛 以及增加风险的不利影响，包括滥用责任、中毒和损害。 为了了解大麻的急性影响，表明这些脆弱人群的暴露风险增加， 人群中，拟议的研究将比较吸烟和口服THC的剂量依赖性影响， 常用给药途径，与使用不良后果（包括滥用）直接相关的终点 责任、中毒和损伤作为年龄和性别的函数。具体来说，健康的男性和女性 新生儿成人（18-25岁; N=30，15 M，15 F）、中年成人（35-45岁; N=30，15 M，15 F）和晚期 将招募偶尔使用大麻的中年成人（55-65岁; N=30，15 M，15 F） 双盲、双模拟、安慰剂对照研究。使用受试者内设计，所有参与者将 通过给药安慰剂（0 mg THC）、2.5 mg单位剂量的THC（10 mg）和4.5 mg单位剂量的THC（20 mg）， 吸食大麻和口服给药。不良反应、镇痛和THC药代动力学将在 在吸烟和口服THC给药后进行多次评估。这项研究的结果将有助于 在建立年龄和性别作为生物变量的预防，干预和治疗负 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.