Effects of Pregnancy-associated Hormones on THC Metabolism in Women

Overview

Cannabis use is prevalent among pregnant women, but the effects of use on both the developing fetus and pregnant woman are unknown. Importantly, drug exposure could be influenced by the impact of pregnancy-associated hormones on the metabolism of tetrahydrocannabinol (THC), the main psychoactive component of cannabis. The goal of this study is to determine whether cortisol and estradiol - hormones that rise dramatically during pregnancy - increase the clearance of dronabinol (THC) in reproductive age women to simulate the pregnant state. The collected data will then be used to predict the time course and magnitude of changes in THC metabolism in pregnant women, particularly with gradually increasing estradiol and cortisol concentrations that evolve over the course of pregnancy. The overall objective of this study is to better understand the effects of THC use during pregnancy on the health of the pregnant woman and developing fetus.

Tetrahydrocannabinol (THC) is approved as a medicinal treatment under the trade name dronabinol but is also a drug of abuse when consumed as part of cannabis products. With the legalization of recreational cannabis use and increased use among pregnant women, there is new urgency to understand the dose-exposure relationship for THC, the mechanisms by which THC is eliminated from the body, and the impact of the hormonal milieu of pregnancy on these mechanisms. As approximately 4% of all pregnant women in the United States use cannabis, there is a critical need for studies evaluating how cannabis metabolism may change during pregnancy leading to altered exposures, pharmacology, and toxicology. Recent studies suggest that cannabis exposure during pregnancy may adversely affect the developing fetus, and administration of cannabis \[or dronabinol (THC)\] to pregnant women is therefore not ethical. Analysis of THC exposures and effects during pregnancy is significantly hindered by the lack of accurate, quantitative biomarkers of THC exposure and the unreliable self-report of cannabis use. To address these gaps, the current study is designed to 1) characterize the dose-exposure relationship of THC and its major metabolites 11-OH-THC and 11-nor-carboxy-THC in reproductive age women following consumption of dronabinol orally and 2) to determine how THC metabolism is altered by the pregnancy-associated hormones estradiol and cortisol. Existing data show that THC and its major metabolites are cleared by metabolizing enzymes whose activity increases during pregnancy and further has been shown to be induced specifically by estradiol and cortisol, hormones that are markedly increased during pregnancy. Based on these data, we hypothesize that increasing estradiol and cortisol concentrations during pregnancy will increase the clearance of THC and its metabolites, leading to an altered metabolism in pregnant women when compared to non-pregnant individuals. Our clinical study seeks to determine the magnitude of changes in THC pharmacokinetics in healthy female volunteers following exposures to increased estradiol and cortisol. We predict that increased estradiol and cortisol concentrations will result in induction of THC-metabolizing enzymes in the liver and intestine, resulting in increased clearance of THC and its metabolites. The clinical study will provide the foundation for modeling and simulation of THC disposition during human pregnancy. These studies will also provide seminal data to allow modeling of the THC metabolome in human plasma and urine as a function of THC dose and time after consumption, making a significant impact on development of reliable biomarkers of THC exposures in humans.