The Impact of Cannabidiol on the Pharmacokinetics and Pharmacodynamics of Oral Delta-9-Tetrahydrocannabinol - PROJECT SUMMARY/ABSTRACT The recent expansion of cannabis legalization has led to the emergence of a thriving retail cannabis marketplace. Among this marketplace, oral cannabis products, or edibles, have gained significant popularity. Like other forms of cannabis consumption, edibles that contain delta-9-tetrahydrocannabinol (THC) as the primary constituent have abuse liability and can produce unwanted adverse acute effects (e.g., impairment of cognitive/psychomotor functioning, dysphoria). Preclinical and clinical research has shown that oral cannabidiol (CBD) can markedly increase the absorption of THC and its metabolites, leading to significantly increased subjective intoxication, impaired cognitive/psychomotor function, and elevated heart rate. Thus, products containing CBD mixed with THC may directly impact the magnitude of THC absorption and THC-related acute effects in humans. However, controlled clinical research on THC/CBD mixtures commonly found in edibles is limited and only a few studies have evaluated if the THC:CBD ratio of these products influences THC pharmacokinetic (PK) or pharmacodynamic (PD) outcomes. This proposal aims to compare the PK and PD effects of varying THC:CBD ratios and THC doses commonly found in cannabis edibles using two double-blind, placebo-controlled human laboratory studies. Aim 1 will examine the effects of various THC:CBD ratios (1:0, 1:1, 1:5, 1:10, 1:30, and 0:1) fixed at 2 standard THC units (STUs; 10mg). Aim 2 will characterize the dose-dependent effects of STUs (0, 1, 2, 4) alone or combined with CBD at an ecologically-valid, fixed THC:CBD ratio of 1:30. We hypothesize that THC absorption and resultant PD effects will be significantly greater for THC:CBD ratios with increasing concentrations of CBD relative to THC alone (Study 1), and significantly greater for THC:CBD ratios relative to its comparator STU (Study 2). In each study, healthy adults will attend 7 outpatient laboratory sessions. For each session, they will consume a brownie containing placebo, THC, CBD, or a THC:CBD mixture. Sessions will be completed in a randomized order and separated by at least 1 week. Blood plasma will be collected to quantify concentrations of THC, CBD, and their primary metabolites. PD assessments will include a subjective drug effect questionnaire, a battery of cognitive/psychomotor performance tasks, and simulated driving performance, which all have shown to be sensitive to THC at the proposed STUs in each study. This project will determine whether mixtures of THC and CBD in cannabis edibles influence the THC PK/PD effects when 1) the ratio of THC:CBD varies at a fixed commonly-represented STU, and 2) STUs vary across an ecologically-relevant ratio (i.e., 1:30), which are both of growing importance given initiatives to utilize STU for research and regulatory purposes. Data derived from these studies can potentially inform educational initiatives aimed at reducing negative outcomes associated with cannabis edibles and offer valuable insight on whether edible THC:CBD ratios should be taken into account alongside STUs when making informed research, regulatory, and clinical choices.
