Module 3: Cannabinoid Metabolism and Drug:Drug Interactions

Cannabinoid Metabolism and Drug:Drug Interactions

The majority of cannabinoid metabolism occurs in the liver by the cytochrome P450 (CYP450) enzyme complex. Metabolism of THC is particularly well documented and involves allylic oxidation, epoxidation, decarboxylation, and conjugation by the xenobiotic-metabolizing oxidases: CYP2C9 and CYP3A4. It is via this process that THC gets converted to the active metabolite 11-OH-THC and the non-active THCCOOH (1). CBD is also metabolized by CYP2C9 and CYP3A4, in addition to the oxidase; CYP2C19 (2). Therefore, drugs that induce CYP2C9, CYP3A4 or CYP2C19 isoenzymes such as; carbamazepine, rifampicin, phenytoin, phenobarbital, primidone, troglitazone and rifabutin, may act to decrease the bioavailability of cannabinoids THC and CBD, and may ultimately reduce the therapeutic effectiveness of the cannabinoid therapy (3,4). Conversely, substances that inhibit these CYP isoenzymes such as HIV protease inhibitors (e.g. ritonavir), certain anti-depressants (e.g. fluvoxamine, fluoxetine and nefazodone), proton pump inhibitors (e.g. cimetidine and omeprazole), macrolides (e.g. erythromycin, clarithromycin), anti-mycotics (e.g. ketoconazole, itraconazole, fluconazole, miconazole), and calcium antagonists (e.g. verapamil, diltiazem), may result in an increase in the bioavailability of THC and hence increase the chance of a patient experiencing THC-related side effects (3,4).

Cannabis also has the potential to affect the bioavailability of certain drugs when taken concomitantly. THC, CBD, and CBN have been reported to inhibit CYP1A1, CYP1A2, and CYP1B1 (5). Therefore, drugs metabolized by these enzymes such as; phenacetin, amitryptiline, theophylline, granisetron, flutamide and granisetron, may have increased bioavailability when taken with cannabis (5).

Opioids and Anti-Epileptic Drugs

It is therefore important that the clinician is aware, and that patients are encouraged to divulge, all medication that is being taking in order to effectively monitor and assess any potential risks. Currently, cannabinoids are regularly being prescribed for the control of chronic pain and seizures in refractory epilepsy. An opioid-cannabinoid interaction study performed on n = 21 patients (n = 10 taking morphine, n = 11 on oxycodone) who inhaled vaporized cannabis, revealed that there were no statistically significant changes in the AUC for either opiate. Cannabis was reported to have no effect on oxycodone kinetics or metabolite levels, however, it did decrease the Cmax of morphine sulfate. Interestingly this still resulted in an average pain reduction of 27% (6).

CBD has been reported to interact with anti-epileptic drugs (AEDs) through CYP metabolism. Serum AED levels were measured during active titration of CBD in refractive epilepsy patients enrolled in an open label study. Increase in the serum levels of rufinamide (p < 0.01), topiramate (p < 0.01), and desmethyclobazam (p < 0.01, active metabolite of clobazam), and a decrease in the levels of clobazam (p < 0.01) was seen with increasing CBD dose in the combined pediatric and adult arms. Furthermore, a significant increase in serum levels of zonisamide (p=0.02) and eslicarbazepine (p=0.04) with increasing CBD dose was seen in the adult arm only. No significant interactions were observed between CBD and the other AEDs investigated, which included valproate, levetiracetam, lacosamide, and perampanel (7).



  1. Huestis, M. A. (2007). Human cannabinoid pharmacokinetics. Chem.Biodivers. 4: 1770-1804.
  2. Stephen M. Stout & Nina M. Cimino (2014). Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metabolism Reviews Vol. 46 , Iss. 1,
  3. Office of Medicinal Cannabis, The Netherlands Ministry of Health Welfare and Sports. Medicinal Cannabis, Information for Health Care Professionals. 2008.
  4. Spina, E., Santoro, V., and D’Arrigo, C. (2008). Clinically relevant pharmacokinetic drug interactions with second- generation antidepressants: an update. Clin.Ther. 30: 1206-1227.
  5. Yamaori, S., Kushihara, M., Yamamoto, I., and Watanabe, K. (2010). Characterization of major phytocannabinoids, cannabidiol and cannabinol, as isoform-selective and potent inhibitors of human CYP1 enzymes. Biochem.Pharmacol. 79: 1691-1698.
  6. Abrams, Couey, Shade, Kelly and Benowitz. (2011). Cannabinoid–Opioid Interaction in chronic Pain. Nature. Vol. 90 N0. 6
  7. Gaston, T, Liu, Y, Cutter, G, Bebin, E, & Szaflarski, J. (2016). Drug interactions between pharmaceutical grade cannabidiol (CBD) oil and commonly used anti-epileptic drugs (AEDs). Presented at the 2016 American Epilepsy Society Annual Meeting, Abstract 2.208.