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

基本信息

批准号：
10810597
负责人：
ZIVA D COOPER
金额：
$ 7.04万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-15 至 2025-06-30
项目状态：
未结题

项目摘要

Project Summary (Parent Award) 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

项目摘要（父母奖）在过去的十年中，大麻使用障碍（CUD）的率翻了一番。虽然相对于男性，女性的大麻使用和CUD的总体使用率越来越低。然而，流行病学报告记录了电信效应；妇女从初次使用到cud的速度更快比男人的比率。使用实验动物的临床前研究表明，相对于男性，女性是对大麻素的增强作用更敏感，也许可以解释加速发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感测治疗的主要指示。那两个滥用大麻作为性别的责任和镇痛效率至关重要。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，男性与男性之间的熏制大麻，2）评估差异在男性和女性之间的THC和相对代谢物的PK中，以及3）研究大麻的性别 - 依赖性效果是大麻使用频率的函数（轻度大麻使用者）。具体来说，健康的光（n = 60，30m，30f）和重量（n = 60，30m，30f）大麻使用者将被招募为这三局，双盲，安慰剂对照，实验室研究。所有参与者将被授予安慰剂（0％THC），较低（3％THC）和以平衡顺序的大麻的较高（10％THC）强度。大麻的滥用 - 相关效果，镇痛和药代动力学将作为性别和频率的函数进行评估大麻使用。这项研究的发现将填补我们知识的关键空白，并成为不可或缺的一部分

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Patterns of Use and Self-reported Effectiveness of Cannabis for Hyperemesis Gravidarum.

DOI：
10.1055/a-1749-5391
发表时间：
2022-05
期刊：
Geburtshilfe und Frauenheilkunde
影响因子：
2.7
作者：
通讯作者：

Considering abuse liability and neurocognitive effects of cannabis and cannabis-derived products when assessing analgesic efficacy: a comprehensive review of randomized-controlled studies.

在评估镇痛功效时考虑大麻和大麻衍生产品的滥用倾向和神经认知影响：随机对照研究的全面回顾。

DOI：
10.1080/00952990.2019.1669628
发表时间：
2019
期刊：
The American journal of drug and alcohol abuse
影响因子：
0
作者：
Cooper,ZivaD;Abrams,DonaldI
通讯作者：
Abrams,DonaldI

Understanding Cannabis Use Disorder Diagnoses in the U.S. Veterans Health Administration in the Era of Legalization.

了解合法化时代美国退伍军人健康管理局的大麻使用障碍诊断。

DOI：
10.1176/appi.ajp.20220675
发表时间：
2022
期刊：
The American journal of psychiatry
影响因子：
0
作者：
Lake,Stephanie;Cooper,ZivaD
通讯作者：
Cooper,ZivaD

A systematic review and meta-analysis of sex differences in cannabis use disorder amongst people with comorbid mental illness.

DOI：
10.1080/00952990.2021.1946071
发表时间：
2021-09-03
期刊：
AMERICAN JOURNAL OF DRUG AND ALCOHOL ABUSE
影响因子：
2.7
作者：
Kozak, Karolina;Smith, Philip H.;Lowe, Darby J. E.;Weinberger, Andrea H.;Cooper, Ziva D.;Rabin, Rachel A.;George, Tony P.
通讯作者：
George, Tony P.

Drugs of Misuse: Focus on Vascular Dysfunction.