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 … Many people turn to marijuana or cannabidiol to ease their achy joints and help them, but a new study suggests that could wreak havoc with any other medications they’re taking. Effect of combining CBD with standard breast cancer therapeutics Breast cancer is the most common malignancy in women worldwide. Sixty-five percent of breast cancers are estrogen and/or
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.
Marijuana could mess with medicines, risking harm, doctors say
Many people turn to marijuana or cannabidiol to ease their achy joints and help them, but a new study suggests that could wreak havoc with any other medications they’re taking.
Why? Because the body uses the same set of enzymes to process them all, scientists report.
The chemicals in marijuana — THC, cannabidiol, or CBD, and cannabinol, or CBN — are metabolized in the body by at least two families of enzymes that also help process and eliminate more than 70% of the most commonly used prescription drugs from the body, the researchers said.
That means there’s a risk that pot might dangerously amp up the effects of some prescription drugs, or cause other medications to flush through your system so quickly that they do you no good, said lead researcher Philip Lazarus.
He’s a professor of pharmaceutical sciences at Washington State University, in Spokane.
“We saw some significant inhibitions,” Lazarus said. “The concentrations we see in the lab are probably an indicator there is at least some inhibition of these enzymes in real-time.”
Some drugs that could be affected by pot use include the blood thinner warfarin, the breast cancer drug tamoxifen, and painkillers like acetaminophen, such as Tylenol, or ibuprofen, such as Motrin, said Lazarus and Ed Bednarczyk, a clinical associate professor of pharmacy practice at the University at Buffalo, in New York.
In two lab reports published in the December issue of the journal Drug Metabolism and Disposition, Lazarus served as senior author. One study looked at a family of enzymes known as cytochrome P450s (CYPs), and the other analyzed the enzyme group UDP-glucuronosyltransferases (UGTs).
The CYPs are involved in the early stages of metabolizing THC and CBD, while the UGTs are involved in the later stages.
THC and CBD stay in your body for only about 30 minutes before the enzymes break them down, but the chemicals that result from the process can linger in your body for up to two weeks, the study authors said in background notes.
In the lab, the researchers tested how the pot chemicals might interfere with these enzymes’ ability to break down other drugs, using cultured human kidney cells to test a single enzyme at a time.
The investigators found that the major THC metabolites inhibited key CYP enzymes, including several that serve key roles in the liver.
And all three cannabis chemicals, but especially CBD, inhibited two of the primary UGT enzymes in the liver.
CBD was also found to block three enzymes that account for about 95% of UGT metabolism in the kidney, which helps clear toxins and some drugs from the body.
CBD, THC block enzymes
“It’s a very, very good reminder that these interactions are real,” Bednarczyk said. “It’s important for physicians and pharmacists who are working with patients to explore this.”
This is the first research effort to demonstrate the potential effects of pot on UGT enzymes, the researchers said. The study also sheds more light on marijuana’s effect on CYP enzymes.
It’s been known for some time that pot could interact with other drugs, said Paul Armentano, deputy director of NORML, a group that advocates for the reform of marijuana laws.
The U.S. Food and Drug Administration’s labeling of a form of synthetic THC called dronabinol, which has been available as a prescription drug for more than 30 years, indicates that it might influence CYP levels, Armentano noted.
And the agency’s warning for Epidiolex, a plant-based prescription CBD drug, also addresses how the substance could affect the liver, he added.
But Armentano questioned how powerful these interactions could be, given how long marijuana has been used both recreationally and medicinally.
“Adults — and patients in particular — have been consuming cannabinoids medicinally for centuries, and this practice has become quite commonplace over the past few decades,” Armentano said.
“Many of these patients are older and many of them may also be prescribed other medications. Were cannabinoids to be significantly contraindicated among this population, one would presume that there would be ample empirical evidence already available substantiating this concern,” Armentano said.
Pot’s effect on metabolism wouldn’t likely affect someone who takes a recreational toke or three on the weekend, Lazarus said.
“Even though it probably inhibits these enzymes, it doesn’t inhibit them enough to interfere with your everyday metabolism,” Lazarus acknowledged.
The problem comes when you mix regular pot use with other drugs, or if you’re taking a marijuana-derived product alongside your prescription.
“Generally,” Bednarczyk said, “CBD is thought to inhibit metabolic pathways, and THC is thought to induce metabolic pathways. THC can make your blood levels of other drugs fall, and CBD can make your blood levels rise.”
A dangerous combo
One well-known example is warfarin, “a very, very potent blood thinner,” Bednarczyk said.
A case study published a couple of years ago noted one warfarin patient who “had the effects of this drug go way up into the danger zone shortly after starting CBD,” Bednarczyk said.
“That one, you don’t mess with. The effects of having too high a level even transiently for a few days can be lethal,” he warned.
“That’s the king of the hill for risk, because it’s all over the map in terms of patient-to-patient variability,” Bednarczyk said of warfarin and pot. “One patient can need a bucket of this stuff to have the same effect as another patient who’s on the lowest dose manufactured.”
The opposite occurs when you mix pot with tamoxifen, a hormone therapy drug used to treat breast cancer by blocking the effects of estrogen, Lazarus said.
For tamoxifen to work, he noted, it must be broken down by the body into another chemical called endoxifen, which is 100 times more active than tamoxifen.
If pot interferes with the processing of tamoxifen, it could cause the breast cancer patient to receive little to no benefit from the drug, Lazarus explained.
Lazarus said he’s also concerned about the interaction pot might have with over-the-counter pain medications.
Ibuprofen “is toxic to your liver and your kidney anyway, but you start taking marijuana on top of that, then you’re going to see some significant effects,” Lazarus said.
“It would probably cause toxicity because you’re slowing down its metabolism, so that means you’re not excreting the stuff and you have more of it sitting in your body,” Lazarus said.
However, all these concerns are based on lab studies. What’s needed now are clinical trials to establish the true effects of pot on other drugs, Lazarus noted.
“We have to do some clinical studies to show in people that if you’re taking a specific drug and then you also smoke a marijuana cigarette that morning, you see higher or lower levels of that drug in your body,” Lazarus said.
In the meantime, people should discuss their use of pot products with their doctor and their pharmacist to make sure they aren’t putting their health at risk, Lazarus and Bednarczyk said.
Effect of combining CBD with standard breast cancer therapeutics
Breast cancer is the most common malignancy in women worldwide. Sixty-five percent of breast cancers are estrogen and/or progesterone receptor positive. Estrogen receptor expression is a prognostic and predictive biomarker of response to endocrine therapy, which consists of the selective estrogen receptor modulator tamoxifen, aromatase inhibitors, and the selective estrogen receptor degrader fulvestrant. Cannabidiol is a phytocannabinoid that is emerging as a potential therapeutic agent. The aim of this study was to investigate the effect of cannabidiol on estrogen receptor-positive and estrogen receptor-negative representative breast cancer cell lines in combination with standard therapeutic agents used in clinical practice. To compare the effects of cannabidiol on breast cancer cell viability, cancer cell lines were exposed to increasing concentrations of cannabidiol. The effects of cannabidiol in combination with the endocrine therapeutics tamoxifen, fulvestrant, and the cyclin-dependent kinase inhibitor palbociclib on breast cancer cell viability were examined. We demonstrated that cannabidiol dose-dependently decreased the viability of all breast cancer cell lines independent of estrogen receptor expression. The addition of cannabidiol to tamoxifen had an additive negative effect on cell viability in ER+ in estrogen receptor positive T-47D line. Cannabidiol did not attenuate the effect of standard treatment of hormone receptor-positive breast cancer with fulvestrant and palbociclib. In addition, cannabidiol did not attenuate the effect of standard treatment of triple-negative breast cancer and human epidermal growth factor receptor 2 positive breast cancer cell lines with trastuzumab and cisplatin.
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