CBD at a low dose of 40 mg/day resulted in the potential inhibition of CYP3A4 and/or CYP2D6. Patients receiving CBD and interacting chemotherapeutic drugs, such as tamoxifen, require monitoring to identify possible subtherapeutic response to treatment. Further pharmacokinetic studies are required to … Despite medical cannabis’s legalization for medical use throughout 31 different jurisdictions in the United States, practicing providers have little research and few guidelines for patient care. To ad…
Reduction in Tamoxifen Metabolites Endoxifen and N-desmethyltamoxifen With Chronic Administration of Low Dose Cannabidiol: A CYP3A4 and CYP2D6 Drug Interaction
Background: Cannabidiol (CBD) serves as a promising medicine, with few known adverse effects apart from the potential of drug interactions with the cytochrome P450 system. It has been hypothesized drug interactions may occur with chemotherapeutic agents, but no supporting evidence has been published to date.
Case: A 58-year-old female with a history of bilateral breast carcinoma in remission, was treated with tamoxifen for breast cancer prevention for over 6 years. CBD was instituted to treat persistent postsurgical pain, inadequately managed by alternate analgesics. It was postulated that CBD may diminish tamoxifen metabolism by CYP3A4 and 2D6 to form active metabolite endoxifen, which exerts the anticancer benefits. Endoxifen, tamoxifen, N-desmetyltamoxifen and 4-hydroxytamoxifen levels were collected while the patient chronically received CBD 40 mg/day, and after a 60-day washout. Upon discontinuation of CBD 40 mg/day, it was observed that endoxifen levels increased by 18.75% and N-desmethyltamoxifen by 9.24%, while 4-hydroxytamoxifen remained unchanged.
Conclusion: CBD at a low dose of 40 mg/day resulted in the potential inhibition of CYP3A4 and/or CYP2D6. Patients receiving CBD and interacting chemotherapeutic drugs, such as tamoxifen, require monitoring to identify possible subtherapeutic response to treatment. Further pharmacokinetic studies are required to ascertain the dynamics of this drug interaction.
Keywords: CYP2D6; CYP3A4; cannabidiol; drug interaction; tamoxifen.
Ximenez JPB, de Andrade JM, Marques MP, Coelho EB, Suarez-Kurtz G, Lanchote VL. Ximenez JPB, et al. BMC Pharmacol Toxicol. 2019 Dec 19;20(Suppl 1):81. doi: 10.1186/s40360-019-0358-y. BMC Pharmacol Toxicol. 2019. PMID: 31852530 Free PMC article.
Maximov PY, McDaniel RE, Fernandes DJ, Korostyshevskiy VR, Bhatta P, Mürdter TE, Flockhart DA, Jordan VC. Maximov PY, et al. Br J Pharmacol. 2014 Dec;171(24):5624-35. doi: 10.1111/bph.12864. Br J Pharmacol. 2014. PMID: 25073551 Free PMC article.
Antunes MV, Timm TA, de Oliveira V, Staudt DE, Raymundo S, Gössling G, Biazús JV, Cavalheiro JA, Rosa DD, Wallemacq P, Haufroid V, Linden R, Schwartsmann G. Antunes MV, et al. Ther Drug Monit. 2015 Dec;37(6):733-44. doi: 10.1097/FTD.0000000000000212. Ther Drug Monit. 2015. PMID: 25853922
Fleeman N, Martin Saborido C, Payne K, Boland A, Dickson R, Dundar Y, Fernández Santander A, Howell S, Newman W, Oyee J, Walley T. Fleeman N, et al. Health Technol Assess. 2011 Sep;15(33):1-102. doi: 10.3310/hta15330. Health Technol Assess. 2011. PMID: 21906462 Free PMC article. Review.
Xiong W, Zhao JJ, Wang L, Jiang XH, Tao XQ. Xiong W, et al. Yao Xue Xue Bao. 2016 Sep;51(9):1356-67. Yao Xue Xue Bao. 2016. PMID: 29924509 Review. Chinese.
Park YJ, Na HH, Kwon IS, Hwang YN, Park HJ, Kwon TH, Park JS, Kim KC. Park YJ, et al. Pharmaceuticals (Basel). 2022 Jul 6;15(7):836. doi: 10.3390/ph15070836. Pharmaceuticals (Basel). 2022. PMID: 35890134 Free PMC article.
Hatziagapiou K, Bethanis K, Koniari E, Christoforides E, Nikola O, Andreou A, Mantzou A, Chrousos GP, Kanaka-Gantenbein C, Lambrou GI. Hatziagapiou K, et al. Pharmaceutics. 2022 Mar 26;14(4):706. doi: 10.3390/pharmaceutics14040706. Pharmaceutics. 2022. PMID: 35456540 Free PMC article.
Olivas-Aguirre M, Torres-López L, Villatoro-Gómez K, Perez-Tapia SM, Pottosin I, Dobrovinskaya O. Olivas-Aguirre M, et al. Pharmaceuticals (Basel). 2022 Mar 17;15(3):366. doi: 10.3390/ph15030366. Pharmaceuticals (Basel). 2022. PMID: 35337163 Free PMC article. Review.
What the Research Says About Drug Interactions and Medical Cannabis
Despite medical cannabis’s legalization for medical use throughout 31 different jurisdictions in the United States, practicing providers have little research and few guidelines for patient care.
To address the gap, in 2018 the National Council of State Boards of Nursing published Nursing Guidelines for Medical Marijuana, which provides general nursing education and guidance—yet doesn’t discuss drug interactions, specifically. To understand how medical cannabis affects concomitant pharmaceuticals, nurses must have a basic knowledge of the endocannabinoid system (ECS).
Cannabis can interact with drugs in three main ways:
- Metabolic interactions that inhibit or activate the metabolism
- How the drugs are absorbed and distributed throughout the body
- Convergent pathways (i.e., similar biologic pathways that either work synergistically [making it work better] or antagonistically [producing an opposite effect]).
How Cannabis Affects Body Systems
The enzymes in the body that synthesize ingested drugs are in the CYP450 family. Cannabidiol (CBD) inhibits or slows the metabolism of the CYP1 family when given 20 minutes before the pharmaceutical. The timing of applying Delta-9-tetrahydrocannabinol (THC) and cannabinol does not slow its metabolism. High concentrations of CBD or THC can boost the production of those enzymes a day later.
In the liver, CYP1 enzymes metabolize caffeine, melatonin, smoke, and several pharmaceuticals. Whether CBD is inhaled or ingested, drug interactions with CYP1 are less likely if it is administered after the other drug. A cannabis-infused edible may also slow drug metabolism, which in the case of THC could intensify and prolong the effect of melatonin.
The CYP2C enzymes metabolize many antiepileptic drugs, phytocannabinoids (including THC and CBD), and some endocannabinoids, as well as nonsteroidal anti-inflammatory drugs, warfarin, diazepam, and other pharmaceuticals. THC has a more varied effect on drugs metabolized by CYP2. People with certain genetic differences in CYP2C enzymes are likely to experience more significant cannabinoid-drug interactions and at lower doses. CBD isolates, like Epidiolex ® cannabidiol, have caused significant interactions with antiepileptic drugs, whereas whole-plant extracts generally have not.
The CYP2B family metabolizes chemicals, pesticides, valproate, methadone, ketamine, and anesthetics. CBD changes the 2B enzymes, inhibiting the body’s ability to metabolize the drug. The CYP3A family is perhaps the most significant group of CYP enzymes. They metabolize 30% of all pharmaceuticals and are distributed in the intestines and liver.
CYP2D6 metabolizes many opiates, antipsychotics, and antidepressants (both tricyclic antidepressants and selective serotonin reuptake inhibitors). CYP2D6 activates the prodrug tamoxifen, a pharmaceutical treatment for breast cancer. Because CBD inhibits the ID-1 gene, which can reduce breast cancer metastasis, it’s worth studying potential interactions.
The mode of administration affects the amount of cannabinoids in the liver and how quickly they get there. Ingested cannabinoids are primarily absorbed through the intestines and processed by the liver before being distributed through the body. Cannabinoids are absorbed more if ingested on a full stomach, but the absorption is slower ranging from two to four hours. Ingested cannabinoids will also have higher peak liver concentrations than inhaled cannabinoids and thus more potent drug interactions.
When administered sublingually, cannabinoids aren’t immediately processed but neither do they go directly to the brain and heart—like inhaled drugs. Topical administration does not enter the blood stream therefore has no potential for drug interactions.
Are cannabinoid-drug interactions dangerous? High doses of CBD isolates are the main culprit in issues with adverse drug interactions. Moreover, CBD isolates, unlike whole-plant extracts, generally require higher doses to be effective. A safe rule of thumb is to take cannabis 20 minutes after pharmaceuticals and alert physicians to monitor changes in drug clearance of antiglycemic, antiepileptic, and anticoagulation pharmaceuticals to adjust a patient’s dose accordingly. Further advice can be obtained from a cannabis provider.
To discuss the information in this article with other oncology nurses, visit the ONS Communities.
To report a content error, inaccuracy, or typo, email [email protected]