Respiratory health effects of aerosolized delta-8-THC and its oxidation products

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PROJECT SUMMARY/ABSTRACT Legalization of cannabidiol (CBD) in 2018 opened the door to intentional chemical conversion of CBD to Δ8- tetrahydrocannabinol (Δ8-THC), an unregulated psychoactive cannabinoid. Vaping products containing Δ8-THC have since rapidly gained popularity with consumers; however, little is known about their respiratory health effects. There is an urgent need to evaluate the effects of vaping Δ8-THC as the recent outbreak of e-cigarette and vaping product associated lung injury (EVALI) included Δ8-THC vaping product users. Additionally, vaping- induced thermal oxidation processes can convert Δ8-THC into reactive electrophiles, including Δ8-THC quinone and CBD quinone (Δ8-THCq and CBDq), which may cause lung injury. Our long-term goal is to enhance the health of all individuals by providing the public with accurate safety information about vaping Δ8-THC and guiding regulatory decision making on Δ8-THC and other cannabinoids. The objective of this proposal is to understand how vaping Δ8-THC alters normal lung cell function and the mechanism mediating these effects. The central hypothesis is that aerosolized Δ8-THC vaping liquids containing pro-oxidant impurities generate reactive Δ8- THCq and CBDq, which adduct protein thiol residues and impair normal biological pathways in human airway epithelial cells. Our specific aims will determine (aim 1) how aerosolized Δ8-THC vaping products alter normal airway epithelial cell function, (aim 2.1) how impurities including metals and flavoring chemicals affect the oxidation of Δ8-THC to quinones Δ8-THCq and CBDq, and (aim 2.2) airway epithelial cell protein adducts formed from vaping Δ8-THC. The results of this proposal will be significant as they will identify for the first time the effects of aerosolized Δ8-THC on normal airway function and the vaping-induced Δ8-THC “adductome”. This project is innovative in its use of (1) a novel in vitro Vaping Product Exposure System (VaPES) to assess the effects of Δ8- THC aerosols on primary human bronchial epithelial cells grown at air-liquid interface and (2) alkynyl-tagged cannabinoids and click chemistry methodologies to uncover the “adductome” of proteins covalently modified by Δ8-THC oxidation products. This proposal will provide training opportunities in technical skills including chemical analysis of vaped condensates, click chemistry, and proteomic analysis, which will be critical for my development as an independent scientist. Finally, I will enhance my training in science communication and the impact of this work on the health of our community by translating the findings of this proposal into a lesson plan that I will implement at local middle and high schools.