# Drug-drug interactions between cannabis and hydrocodone.

> **NIH NIH F31** · WASHINGTON STATE UNIVERSITY · 2022 · $38,521

## Abstract

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.

## Key facts

- **NIH application ID:** 10536444
- **Project number:** 1F31DA056197-01A1
- **Recipient organization:** WASHINGTON STATE UNIVERSITY
- **Principal Investigator:** Shelby Coates
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $38,521
- **Award type:** 1
- **Project period:** 2022-08-16 → 2025-08-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10536444

## Citation

> US National Institutes of Health, RePORTER application 10536444, Drug-drug interactions between cannabis and hydrocodone. (1F31DA056197-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10536444. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*