Systematic Assessment of Cannabinoid Interactions: Impairment, Abuse Potential and Pharmacokinetic Effects - Abstract Global cannabis use is at record high levels, with 4% of the world’s population reporting past-year cannabis use and 18 million individuals in the U.S. reporting daily/near-daily use. Access to cannabis is also increasing, with nearly 80% of Americans living in a county with a cannabis dispensary. Despite high rates of use and widespread availability of products, there are relatively few controlled studies examining cannabinoid interactions. Specifically, the two major cannabinoids, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are nearly omnipresent in a wide variety of products, including plant cannabis, vape pens, gummies/edibles, drinks, and transdermal patches. Despite their popularity, there are no well controlled data to determine their interaction effects. There have been no controlled studies to date that have systematically assessed this interaction (e.g., testing multiple active THC/CBD dose combinations; including a wide dose range of both cannabinoids, testing doses relevant to dispensary products; including a comprehensive array of outcome measures). Thus, the current project aims to determine the effects of an expansive dose range of THC and CBD, administered alone and in combination, to determine the interaction effects on: 1) abuse potential, 2) simulated driving performance and the impairing effects of cannabis, 3) the pharmacokinetic outcomes, and 4) safety and physiological effects. An exploratory aim will determine if a unique signature for cannabinoid impairment can be detected in plasma (>120 endocannabinoid/lipid analytes assessed). Two independent inpatient studies will be conducted during this 5-year project, each utilizing a randomized, within- subject, double-blind, placebo-controlled design and enrolling current heavy cannabis users (n=15 per study). Study 1 will examine inhaled plant cannabis containing a 6-fold dose range of THC (0, 10, 30, 60 mg) and a 6- fold dose range of CBD (0, 5, 10, 30 mg), administered alone and in combination. Study 2 will examine the effects of inhaled concentrates, including high doses of both THC (0, 45, 60, 75 mg) and CBD (0, 200, 400, 800 mg), administered alone and in combination. Importantly, these studies model ecologically relevant products that are currently marketed in dispensaries, including high potency cannabis (Study 1) and inhaled concentrates (Study 2). Together, these studies include a 7.5-fold range of THC and a 160-fold dose range of CBD doses. Overall, this project will provide controlled, Together, these studies will provide controlled, comprehensive, empirical data on the interaction effects of the two most commonly used cannabinoids – a public health necessity in the current landscape of widespread cannabis use.
