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

项目概要（家长奖）过去十年来，美国大麻使用障碍 (CUD) 的发生率翻了一番。与男性相比，女性大麻使用率和 CUD 总体比例仍然较低。流行病学报告记录了伸缩效应；女性从首次使用过渡到 CUD 的速度更快实验动物的临床前研究表明，相对于雄性，雌性的发病率高于男性。对大麻素的增强作用更加敏感，这也许可以解释加速进展的原因 CUD 在流行病学报告中观察到，迄今为止，还没有研究前瞻性地探讨过大麻的性别。了解大麻对人类滥用的严重影响。在女性中观察到 CUD 的加速轨迹，拟议的研究将比较剂量依赖性吸食大麻对与轻度和重度滥用倾向直接相关的终点的影响男性和女性使用大麻，包括积极的主观影响和大麻自我管理。除了与滥用相关的终点外，了解吸烟镇痛反应的性别差异大麻对公共卫生有重大影响，近 50% 的医用大麻使用者是女性。疼痛被视为寻求治疗的主要适应症，因此，评估这两种滥用情况。大麻的责任和镇痛功效作为性别的函数至关重要。临床前研究指出了导致 Δ-9- 性别依赖性反应的三个因素四氢大麻酚 (THC) 和其他大麻素 1 受体 (CBR1) 激动剂 1) 雌二醇增加对 CBR1 激动剂滥用相关效应的敏感性，2) THC 的药代动力学 (pK) 因女性而异与男性相比，THC 转化为其主要精神活性代谢物的速度更快，并且 3) 增强女性在慢性治疗后对抗菌作用（但不是其他终点）产生耐受性拟议的前瞻性临床研究将直接解决给药方面的性别依赖性差异。我们将 1) 比较大麻的滥用相关作用和镇痛作用。男性和女性之间吸食大麻，同时控制月经周期影响，2）评估差异男性和女性之间 THC 及其各自代谢物的 pK，以及 3）调查大麻的性别 - 依赖效应是大麻使用频率的函数（轻度大麻使用者与重度大麻使用者）。这 3 次会议将招募健康轻度（N=60、30M、30F）和重度（N=60、30M、30F）大麻使用者，双盲、安慰剂对照的实验室研究。所有参与者都将服用安慰剂（0% THC），大麻的滥用程度较低（3% THC）和较高（10% THC）。相关效应、镇痛和药代动力学将根据性别和频率进行评估这项研究的结果将填补我们知识中的一个关键空白，并且是不可或缺的。

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.