Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial.
Assessment of Orally Administered Δ9-Tetrahydrocannabinol When Coadministered With Cannabidiol on Δ9-Tetrahydrocannabinol Pharmacokinetics and Pharmacodynamics in Healthy Adults: A Randomized Clinical Trial.
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DOI：
10.1001/jamanetworkopen.2022.54752
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发表时间：
2023-02-01
影响因子：
13.8
通讯作者：
Vandrey, Ryan
中科院分区：
文献类型：
--
作者：
Zamarripa, C. Austin;Spindle, Tory R.;Surujunarain, Renuka;Weerts, Elise M.;Bansal, Sumit;Unadkat, Jashvant D.;Paine, Mary F.;Vandrey, Ryan
这项随机临床试验比较了在美国健康成年人中含有相同Δ9-THC剂量的口服Δ9-tetrahydrocannabinol （THC）为主和大麻二酚为主的大麻提取物的药代动力学和药效学。在不经常使用大麻的健康成年人中，口服Δ9-tetrahydrocannabinol （Δ9-THC）优势大麻提取物与相同Δ9-THC剂量（20mg）的大麻二酚（CBD）优势提取物之间是否存在急性药代动力学或药效学差异？在这项包括18名成年参与者的随机临床试验中，摄入20mg Δ9-THC + 640 mg CBD导致更强的主观药物效应，认知和精神运动能力的更大损害，以及心率的更大增加，相对于单独20mg Δ9-THC和安慰剂。这些作用似乎是由CBD抑制Δ9-THC和11-OH-Δ9-THC代谢介导的。这些结果表明，在不含CBD的情况下，高剂量（> 600mg）口服CBD可以抑制口服Δ9-THC的代谢，产生比Δ9-THC更强的药物作用。对照临床实验室研究表明，大麻二酚（CBD）有时可以减轻或加剧Δ9-tetrahydrocannabinol （Δ9-THC）的影响。没有研究评估过口服大麻提取物在Δ9-THC和CBD浓度不同的情况下Δ9-THC的药代动力学（PK）和药效学（PD）的差异。比较含有相同Δ9-THC剂量（20mg）的口服Δ9-THC-dominant和cbd优势大麻提取物的PK和PD。该随机临床试验是一项参与者内、双盲、交叉研究，于2021年1月至2022年3月在马里兰州巴尔的摩市约翰霍普金斯大学行为药理学研究中心进行。18名健康成年人完成了3次随机门诊实验测试，每次测试间隔至少1周。布朗尼不含(1)大麻提取物（即安慰剂）；(2) Δ9-THC-dominant提取物（20 mg Δ9-THC，不含CBD）；(3)在给予细胞色素P450 （CYP）探针药物鸡尾酒前30分钟给予参与者CBD优势提取物（20 mg Δ9-THC + 640 mg CBD），该药物鸡尾酒由100 mg咖啡因，20 mg奥美拉唑，25 mg氯沙坦，30 mg右美沙芬和2 mg咪达唑仑组成。Δ9-THC或Δ9-THC代谢物与基线血浆浓度的变化以及主观药物效应、认知和精神运动表现以及生命体征的评分。测定血浆-浓度-时间曲线下面积（AUC）和最大血浆浓度（Cmax）。18名成年人的参与者队列包括11名男性（61.1%）和7名女性（38.9%），平均（SD）年龄为30(7)岁，在研究开始前至少30天未使用大麻（自上次使用大麻以来的平均[SD]天，86[66]天）。CYP鸡尾酒+安慰剂布朗尼和CYP鸡尾酒不影响任何PD评估。相对于CYP cocktail + Δ9-THC， CYP cocktail + Δ9-THC + CBD对Δ9-THC、11-OH-Δ9-THC和Δ9-THC-COOH产生更高的Cmax和血药浓度-时间曲线下面积。与CYP鸡尾酒+ Δ9-THC和CYP鸡尾酒+安慰剂相比，CYP鸡尾酒+ Δ9-THC + CBD增加了自我报告的焦虑、镇静和记忆困难，增加了心率，并产生了更明显的认知和精神运动表现障碍。在这项口服Δ9-THC和CBD的随机临床试验中，与相同Δ9-THC剂量的Δ9-THC-dominant大麻提取物相比，以CBD为主的大麻提取物引发了更强的不良反应，这与CBD减轻Δ9-THC不良反应的常见说法相矛盾。CBD抑制Δ9-THC和11-OH-Δ9-THC代谢可能是观察到的差异的机制。需要更好地了解大麻素-大麻素和大麻素-药物相互作用，以便为有关大麻产品的治疗和非治疗使用的临床和监管决策提供信息。clinicaltrials.gov标识号：NCT04201197
This randomized clinical trial compares the pharmacokinetics and pharmacodynamics of orally administered Δ9-tetrahydrocannabinol (THC)-dominant and cannabidiol-dominant cannabis extracts that contained the same Δ9-THC dose in a healthy adult population of US adults. Are there acute pharmacokinetic or pharmacodynamic differences between oral ingestion of a Δ9-tetrahydrocannabinol (Δ9-THC)-dominant cannabis extract compared with a cannabidiol (CBD)-dominant extract at the same Δ9-THC dose (20 mg) in healthy adults who use cannabis infrequently? In this randomized clinical trial including 18 adult participants, ingestion of 20 mg Δ9-THC + 640 mg CBD resulted in stronger subjective drug effects, greater impairment of cognitive and psychomotor ability, and greater increase in heart rate relative to 20 mg Δ9-THC alone and placebo. These effects appear to be mediated by CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism. These findings suggest that high doses (>600 mg) of oral CBD can inhibit the metabolism of oral Δ9-THC, resulting in stronger drug effects compared with Δ9-THC in the absence of CBD. Controlled clinical laboratory studies have shown that cannabidiol (CBD) can sometimes attenuate or exacerbate the effects of Δ9-tetrahydrocannabinol (Δ9-THC). No studies have evaluated differences in pharmacokinetics (PK) of Δ9-THC and pharmacodynamics (PD) between orally administered cannabis extracts that vary with respect to Δ9-THC and CBD concentrations. To compare the PK and PD of orally administered Δ9-THC-dominant and CBD-dominant cannabis extracts that contained the same Δ9-THC dose (20 mg). This randomized clinical trial was a within-participant, double-blind, crossover study conducted from January 2021 to March 2022 at the Johns Hopkins University Behavioral Pharmacology Research Unit, Baltimore, MD. Eighteen healthy adults completed 3 randomized outpatient experimental test sessions that were each separated by at least 1 week. Brownies containing (1) no cannabis extract (ie, placebo); (2) Δ9-THC-dominant extract (20 mg Δ9-THC with no CBD); and (3) CBD-dominant extract (20 mg Δ9-THC + 640 mg CBD) were administered to participants 30 minutes prior to administering a cytochrome P450 (CYP) probe drug cocktail, which consisted of 100 mg caffeine, 20 mg omeprazole, 25 mg losartan, 30 mg dextromethorphan, and 2 mg midazolam. Change-from-baseline plasma concentrations for Δ9-THC or Δ9-THC metabolites and scores for subjective drug effects, cognitive and psychomotor performance, and vital signs. The area under the plasma vs concentration vs time curve (AUC) and maximum plasma concentration (Cmax) were determined. The participant cohort of 18 adults included 11 males (61.1%) and 7 females (38.9%) with a mean (SD) age of 30 (7) years who had not used cannabis for at least 30 days prior to initiation of the study (mean [SD] day since last cannabis use, 86 [66] days). The CYP cocktail + placebo brownie and the CYP cocktail did not affect any PD assessments. Relative to CYP cocktail + Δ9-THC, CYP cocktail + Δ9-THC + CBD produced a higher Cmax and area under the plasma concentration vs time curve for Δ9-THC, 11-OH-Δ9-THC, and Δ9-THC-COOH. The CYP cocktail + Δ9-THC + CBD increased self-reported anxiety, sedation, and memory difficulty, increased heart rate, and produced a more pronounced impairment of cognitive and psychomotor performance compared with both CYP cocktail + Δ9-THC and CYP cocktail + placebo. In this randomized clinical trial of oral Δ9-THC and CBD, stronger adverse effects were elicited from a CBD-dominant cannabis extract compared with a Δ9-THC-dominant cannabis extract at the same Δ9-THC dose, which contradicts common claims that CBD attenuates the adverse effects of Δ9-THC. CBD inhibition of Δ9-THC and 11-OH-Δ9-THC metabolism is the likely mechanism for the differences observed. An improved understanding of cannabinoid-cannabinoid and cannabinoid-drug interactions are needed to inform clinical and regulatory decision-making regarding the therapeutic and nontherapeutic use of cannabis products. clinicaltrials.gov Identifier: NCT04201197
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影响因子：
15.9
作者：
LEMBERGER, L;MARTZ, R;ROWE, H
通讯作者：
ROWE, H
影响因子：
3.4
作者：
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影响因子：
4.2
作者：
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影响因子：
4.1
作者：
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通讯作者：
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影响因子：
3.7
作者：
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通讯作者：
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