Cannabidiol and Δ⁹-Tetrahydrocannabinol in Polypharmacy: Mapping the Potential Clinically Significant Interactions

Background: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are main phytocannabinoids in Cannabis sativa L. CBD is non-intoxicating, whereas THC produces psychoactive effects. Both undergo extensive hepatic metabolism, primarily involving CYP3A4, CYP2C9, and CYP2C19, and may also inhibit metabolic enzymes and drug transporters.

Aim: To identify database-classified potential significant interactions of CBD and THC with medicines used in pharmacotherapy and characterize their principal clinical mechanisms.

Methods: Potential drug interactions were identified using the drugs.com Interaction Checker in September, 2026. The database was searched using the terms “cannabidiol” and “cannabis (THC-containing products)” to assess their database-classified potential interactions with other medicinal products. The identified interactions were categorized according to severity as major, moderate, or minor. The analysis focused primarily on interactions classified as major.

Results: Cannabidiol was associated with 26 major, 667 moderate, and 32 minor potential interactions, whereas THC-containing products were associated with 28 major and 379 moderate interactions. Selected major CBD-interacting medicines included buprenorphine, colchicine, citalopram, doxorubicin, edoxaban, ketoconazole, ketamine, lomitapide, methadone, morphine, mipomersen, pexidartinib, teriflunomide, and venetoclax. The underlying risks included altered drug exposure through CYP450 or P-glycoprotein modulation, additive hepatotoxicity, QT prolongation, bleeding, and central nervous system (CNS) depression. Major THC interactions occurred predominantly with opioids and CNS depressants, including alfentanil, brexanolone, codeine, fentanyl, hydromorphone, ketamine, oxycodone, remifentanil, tapentadol, and tramadol, potentially resulting in profound sedation and respiratory depression.

Conclusion: Among the major interactions identified, CBD interactions appear primarily pharmacokinetic or toxicity-related, whereas THC interactions are predominantly pharmacodynamic. Concomitant use warrant avoidance when possible or careful clinical management, or managed through medication review, individualized dose adjustment, and appropriate clinical and laboratory monitoring. Prospective studies are required to distinguish predicted interactions from clinically confirmed risks.