Abstract Opioids are commonly utilized in pain management therapies. Opioids are mu-opioid receptor (MOR) agonists that suppress excitatory neurotransmitter release, decrease overall excitability, and hyperpolarize neuronal cells, resulting in the desired analgesic effect. One of the most common opioids used is hydrocodone. Hydrocodone is primarily metabolized by cytochrome P450 (CYP) 3A4 and CYP2D6 through N-demethylation and O- demethylation to form its primary inactive metabolite, norhydrocodone, and an active metabolite, hydromorphone. Hydromorphone is further metabolized by UDP-glucuronosyltransferase (UGT) 2B7 through O- glucuronidation to its inactive metabolite hydromorphone-3-glucuronide. A growing concern over the past decade has been the opioid epidemic, where individuals are misusing prescription opioids including hydrocodone that are often used in combination with other illicit drugs, including cannabis. Our lab and previous studies have shown that major cannabinoids including Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), and cannabinol (CBN), and the THC metabolites 11-hydroxy-Δ9-tetrahydrocannabinol (11-OH-THC), and 11-nor-Δ9- tetrahydrocannabinol-carboxylic acid glucuronide (THC-COO-Gluc) inhibit several major drug metabolizing enzymes. Specifically, THC, 11-OH-THC, THC-COO-Gluc, and CBD inhibit CYP2D6, while THC, 11-OH-THC, and CBD inhibits CYP3A4. Our lab has also shown that THC, 11-OH-THC, THC-COO-Gluc, and CBD inhibit UGT2B7. We hypothesize that major cannabinoids and their metabolites will inhibit hydrocodone metabolism potentially leading to clinically relevant adverse drug-drug interactions (DDI) in individuals who use them concomitantly. The proposed study will examine the inhibitory effect of THC, CBD, CBN, 11-OH-THC, 11-COOH- THC, and THC-COO-Gluc against both wildtype (wt) and prevalent polymorphic variants involved in hydrocodone metabolism in vitro and examine the potential for DDI in vivo. The proposed research will identify the cannabinoids/cannabinoid metabolites that inhibit wt drug metabolizing enzymes (Aim 1) and their major polymorphic variants (Aim 2) that are involved in hydrocodone metabolism. The proposed research will also include a clinical trial investigating the potential DDI between cannabis and hydrocodone, with the pharmacokinetic data used to develop DDI models between hydrocodone and cannabis utilizing physiologically based pharmacokinetic (PBPK) modeling (Aim 3). These in vitro and in vivo studies will aid in evaluating the clinical relevance of the potential DDI between cannabis and hydrocodone in humans.

Project Narrative Hydrocodone is one of the most prescribed and abused opioids in the USA. With the legalization of cannabis across the USA, the use of cannabis for medicinal purposes is also increasing, resulting in increases in the concomitant use of both drugs in the population. As the effect cannabis may have on an individual who is taking hydrocodone is unknown and may cause adverse drug events, the goal of the proposed studies will be to identify potential drug-drug interaction between major cannabinoids and their metabolites and hydrocodone and determine whether these interactions may result in adverse drug events and allow for new medical guidance.