Sex-dependent effects of cannabis: Assessing abuse-related and pharmacokinetic differences between men and women

大麻的性别依赖性影响：评估男性和女性之间滥用相关和药代动力学的差异

• 批准号: 9816973
• 负责人: ZIVA D COOPER
• 金额: $ 74.14万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9816973
• 关键词: Absence of pain sensation; Acute; Address; Agonist; Analgesics; Behavioral; Biological; CNR1 gene; Cannabinoids; Cannabis; Cannabis Abuse; Chronic; Clinical Research; Development; Dose; Double-Blind Method; Drug Kinetics; Epidemiology; Estradiol; Exhibits; Female; Frequencies; Gender; Human; Investigation; Knowledge; Laboratories; Laboratory Animals; Laboratory Study; Light; Marijuana Smoking; Medical; Medical Marijuana; Menstrual cycle; Pain; Participant; Pharmaceutical Preparations; Placebos; Plasma; Preventive Intervention; Progesterone; Prospective Studies; Public Health; Rattus; Report (document); Reporting; Risk; Self Administration; Sex Differences; Sex Functioning; Smoke; Smoker; Smoking; THC exposure; Testing; Tetrahydrocannabinol; Time; Treatment Efficacy; Woman; design; epidemiology study; male; marijuana use; marijuana use disorder; marijuana user; men; pre-clinical; preclinical study; prevent; proliferative phase Menstrual cycle; prospective; recruit; response; sex; trend; volunteer

Project Summary: Rates of Cannabis Use Disorder (CUD) have doubled over the last ten years in the US. Although increasing, overall rates of cannabis use and CUD are still lower among women relative to men. However, epidemiological reports document a telescoping effect; women transition from first use to CUD at a faster rate than men. Preclinical studies with laboratory animals demonstrate that relative to males, females are more sensitive to the reinforcing effects of cannabinoids, perhaps explaining the accelerated progression to CUD observed in the epidemiological reports. To date, no studies have prospectively probed cannabis’s sex- dependent differences in abuse-liability in humans. To understand cannabis’s acute effects that underlie the accelerated trajectory to CUD observed in women, the proposed study will compare the dose-dependent effects of smoked cannabis on endpoints directly associated with abuse-liability between light- and heavy- cannabis using men and women, including positive subjective effects and cannabis self-administration. In addition to abuse-related endpoints, understanding sex differences in the analgesic responses to smoked cannabis have significant public health implications. Nearly 50% of medical cannabis users are women, with pain cited as the primary indication for which treatment is sought. Thus, assessing both the abuse liability and analgesic efficacy of cannabis as a function of sex is of critical importance. Preclinical studies point to three factors that contribute to sex-dependent responses to Δ-9- tetrahydrocannabinol (THC) and other cannabinoid 1 receptor (CBR1) agonists; 1) estradiol increases the sensitivity to CBR1 agonist abuse-related effects, 2) pharmacokinetics (pK) of THC differ, with females exhibiting faster conversion from THC to its primary psychoactive metabolite than males and 3) enhanced development of tolerance to the antinociceptive effects (but not other endpoints) in females after chronic administration. The proposed prospective clinical study will directly address sex-dependent differences in cannabis’s effects as a function of these factors. We will 1) compare the abuse-related and analgesic effects of smoked cannabis between men to women while controlling for menstrual cycle effects, 2) evaluate differences in the pK of THC and respective metabolites between men and women, and 3) investigate cannabis’s sex-dependent effects as a function of frequency of cannabis use (light versus heavy cannabis users). Specifically, healthy light (N=60, 30M, 30F) and heavy (N=60, 30M, 30F) cannabis users will be recruited for this 3-session, double-blind, placebo-controlled, laboratory study. All participants will be administered placebo (0% THC), lower (3% THC), and higher (10% THC) strengths of cannabis in counter- balanced order. Cannabis’s abuse-related effects, analgesia, and pharmacokinetics will be assessed as a function of sex and frequency of cannabis use. Findings from this study will fill a critical gap in our knowledge and be integral in understanding sex as a biological variable in predicting, preventing, and treating CUD.

项目摘要：在美国过去十年中，大麻使用障碍（CUD）的率翻了一番。 尽管增加了大麻使用和CUD的总体率相对于男性而言仍然较低。 但是，流行病学报告记录了电信效果。妇女从初次使用到cud 比男性快的速度。实验动物的临床前研究表明，相对于男性，女性 对大麻素的增强作用更敏感，也许可以解释加速的进展 在流行病学报告中观察到的CUD。迄今为止，尚无前瞻性证明大麻的性别的研究 - 人类虐待责任的依赖差异。了解大麻的急性影响是 加速轨迹与女性观察到的CUD，拟议的研究将比较剂量依赖性 烟熏大麻对与光线和重型之间的滥用责任直接相关的终点的影响 大麻使用男性和女人，包括积极的主观效果和大麻自我管理。在 除了与滥用相关的终点外，了解对烟熏的镇痛反应中的性别差异 大麻具有重大的公共卫生影响。近50％的医用大麻使用者是女性， 疼痛被认为是治疗是SCART的主要迹象。这是评估虐待责任和 大麻随性的函数的镇痛效率至关重要。 临床前研究指出了三个因素依赖性反应的因素 四氢大麻酚（THC）和其他大麻素1受体（CBR1）激动剂； 1）雌二醇增加 对CBR1激动剂滥用相关效果的敏感性，2）THC的药代动力学（PK）与女性不同 从THC到其主要的精神活性代谢物的转化速度比男性更快，3）增强 慢性后女性中对抗伤害感受效应的耐受性（但没有其他终点） 行政。拟议的前瞻性临床研究将直接解决性别依赖性的差异 大麻的影响是这些因素的函数。我们将1）比较与滥用相关的镇痛作用 在控制月经周期效果的同时，男性与女性之间的烟熏大麻的烟熏大麻，2）评估 男性和女性之间THC的PK和相对代谢物的差异，以及3）调查 大麻的性别依赖性效果是大麻使用频率的函数（光与重大麻 用户）。特别是健康的光（n = 60，30m，30f）和重量（n = 60，30m，30f）大麻用户将是 为这项三阶段，双盲，安慰剂对照，实验室研究招募。所有参与者都会 在反 - 平衡订单。大麻与滥用相关的效果，镇痛和药代动力学将被评估为一种 性别和大麻使用频率的功能。这项研究的发现将填补我们所知的关键空白 并在理解性作为预测，预防和治疗CUD的生物变量方面是不可或缺的。