Learn more about the dangers of drug-drug interactions with United Patients Group. 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. 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 …
Breast Cancer, Cannabis, and Tamoxifen: Understanding the Dangers of Drug-Drug Interactions
For many people living with life-limiting and life-threatening diseases like cancer, medical cannabis has long been hailed as a gift, both for symptom control and for its potential to limit the disease process itself.
But especially in the case of breast cancer—or, more accurately, breast cancers—the therapeutic potential of cannabis also comes laden with the potential for harm, and, like all medications, patients need to understand that powerful drugs can create unanticipated interactions with other powerful drugs.
This may be the case with cannabis and tamoxifen.
Kristin Wohlschlagel, R.N., a Hospice and Oncology Nurse who is a fierce patient advocate with a passion for investigating and educating about the evidence surrounding cannabis and cancer, recently broke down some of the most recent evidence and issues in a recent interview.
“New and emerging research from the past several years reveals that tamoxifen, and other Selective Estrogen Receptor Modulators, or SERMS, bind not only to estrogen receptors. They also bind with high affinity to one or both cannabinoid receptors, for CB1 and CB2,” said Wohlschlagel. “Tamoxifen apparently binds to both receptors, as what is called an ‘inverse agonist.’ The possible effects caused by that binding are just beginning to be explored.’”
Breast Cancer: Not Just One Disease
Unlike most forms of cancer, “breast cancer” is actually a blanket term rather than a single diagnosis. It covers several distinct types of cancer that are further distinguished by diagnostic laboratory tests. The specific diagnosis drives individual considerations among patients and their medical teams regarding which treatments are most likely to produce the optimal outcomes for each patient.
- Estrogen-receptor positive or negative (ER+ or PR-): Roughly 80% of breast cancer cells tested in labs are positive for estrogen receptors, which means estrogen may support and fuel the cancer’s growth. The remainder are estrogen-receptor negative.
- Progesterone-receptor positive or negative (PR+ or PR-): In addition to receptors for estrogen, tumors may also have receptors for progesterone. About 65% of breast cancers are both ER+/PR+, while 13% are ER+/PR-, 2% are ER-/PR+, and a final 25% are ER-/PR- (receptors for neither estrogen nor progesterone).
- HER2 status: Human epidermal growth factor receptor 2, or HER2, is a gene that plays a role in about 25% of breast cancers. The gene malfunctions, creating too many copies of itself, which ultimately makes HER2-positive breast cancers grow and spread more rapidly than other types of breast cancer.
- Triple-positive: With receptors for both estrogen and progesterone as well as overexpression of the HER2 gene, triple-positive breast cancer has more conventional treatment options than others.
- Triple-negative: These breast cancers do not show receptors for estrogen, progesterone, or HER2 gene overexpression. Because of this lack of receptors, this type of breast cancer is difficult to target with hormones or drugs that target HER2.
Tamoxifen, Hormones, Receptors, and the Immune Response
Tamoxifen is the oldest and most widely used of a class of drugs called Selective Estrogen Receptor Modulators (SERMS). Tamoxifen and other SERMS are commonly prescribed for women with hormone-sensitive breast cancers as one option to attempt to control the growth and spread of the cancer. The intended benefit is to block the estrogen receptors and to interfere with circulating estrogen’s ability to bind and stimulate the tumor cells.
Tamoxifen is a “pro-drug,” which means it is not fully effective until it is metabolized by the liver into its more potent anticancer form through a specific enzyme and metabolic pathway. This metabolic process can be interrupted, inhibited, or even entirely blocked by other substances, both common and uncommon–including large doses of cannabis.
Perhaps the most common food-drug interaction that many people are already familiar with from warning labels and their own physicians is the grapefruit interaction; many pharmaceuticals come with specific warnings not to take them with grapefruit, because grapefruit contains enzymes that inhibit CYP450 metabolism. Tamoxifen is one of these drugs. And cannabinoids, like grapefruit, are known to inhibit CYP450 metabolism.
To date, it appears that THC is mostly metabolized and inhibits the metabolism pathways CYP2C9 and CYP3A4. CBD is reported to be mostly metabolized via and inhibits the pathways CYP2C19 and CYP3A4. CBD appears to inhibit at least CYP3A4 more significantly than THC. But more research is needed to begin to clarify what constitutes a small or large dose. Individuals will also learn that they may metabolize certain medicines and foods differently due to genetic variations affecting metabolism.
“Because grapefruit is a commonly-encountered food that is famous as a CYP450 inhibitor, which should not be used with some medications, I often use it as a surrogate for CBD and THC to check for potential drug interactions,” says Wohlschlagel. ”Due to the historic lack of research on cannabis, we do not have a wealth of research on its potential drug-drug interactions. But when I educate patients, I tell them to check for grapefruit interactions on trustworthy pharmaceutical websites like WebMD. There, they will see that using tamoxifen with grapefruit—and, we must conclude, large doses of cannabinoids as well—could risk reducing the hormone-blocking effects of tamoxifen for breast cancer patients. This could be critical for their outcomes.”
Other drugs metabolized through the same pathways, including popular antidepressants like Paxil, are also on the list of drugs to avoid while taking tamoxifen.
It’s well-known that many forms of cancer respond positively to the anti-proliferative (anti-growth) properties of THC, which binds to cannabinoid receptors in tumors and causes them to stop growing or even to shrink. But a 2015 European study found at least 20% of breast cancer biopsies samples examined did not over-express any CB2 cannabinoid receptors, even in low numbers. There will also likely be various individual tumor mutations that can potentially cause resistance to the effects of THC, as can happen with any therapy. That means the potential benefits of cannabis for treating breast cancer are not as cut-and-dry as oversimplified “natural healing” blogs and headlines sometimes imply. Most patients are using cannabis medicines integrated with conventional therapies.
In fact, in addition to possibly interfering with hormone-suppressing activity of tamoxifen, larger doses of THC can also suppress the body’s T-cell proliferation, which is a part of the immune system that is critical for tumor cell growth suppression. In these cases, the use of high-THC forms of cannabis could theoretically not only not help, but could also make matters worse, allowing the tumor cells to grow more rapidly.
Medical Guidance is Critical
Only a patient’s physician and medical team can offer individual medical advice. If a breast cancer patient feels strongly that cannabis is important to use, those who have been prescribed tamoxifen should be forthright, up-front, and completely honest with her (or his) physicians about using cannabis – especially because the most beneficial amounts of THC and CBD could be quite different depending on the diagnosis.
Small doses of cannabis medicines used are much less likely to cause any significant drug interactions, but some patients are using doses much higher than historically common. Because CBD-rich medicines will not cause as much psychoactivity, people can easily use large doses (75 mg CBD per day or more) without feeling any significant side effects. While large doses may be considered generally safe, the potential for side effects and potential interactions with other therapies is increased at these levels.
Tamoxifen and SERMS
Someone taking tamoxifen or one of the other SERMS needs to understand that there may be some risk of drug-drug interaction, including a possible competition for cannabinoid receptors by the SERMS. This could potentially reduce the effectiveness of the cannabis medicines.
Because large doses of cannabinoids like CBD and THC can inhibit metabolism or processing of substances by the liver, reviewing this potential with your healthcare team is important.
There are alternatives to Tamoxifen which are effective and considered “standard of care” by oncologists. One of the main alternatives is to suppress the ovarian function, including estrogen production, using injectible medications such as Lupron or Zoladex. Again, this is a matter to review and discuss with a comprehensive health care team. Managing the hormonal aspect of most breast cancers can be crucial to treatment.
The Importance of Informed Medical Guidance
Above all, Wohlschlagel is a fierce and outspoken advocate for women and men who are living with and through the constellation of diseases we call “breast cancer.” And while she recognizes that there is a place in the treatment regime for cannabis for many of them, she also wants to emphasize that it is not a panacea, and it is not a cure-all.
“There is not enough evidence-based, scientifically sound information available for patients to do this on their own,” she says. “It’s impossible to fully address the pros, the cons, the potential for benefits and the potential for harm in a blog post or on a Facebook page. There are multiple potential drug interactions that could leave any single patient better or worse off. It is critically important to get a medical team who understands the implications of cannabis and breast cancer on board. I’ve interviewed young women with hormone-positive breast cancer who have reported doing poorly when they tried to use high doses of THC—their disease advanced rapidly, sometimes in a matter of weeks. Some reported that they were also using tamoxifen during that time. Did the tamoxifen interfere with cannabinoid actions? Or did the tamoxifen metabolism get reduced by the large doses of THC they were taking? Since they reported they had been using 100 or more milligrams of THC each day, it is impossible to know for certain. But it certainly raised my awareness of the potential issues that patients may experience.”
“How this is all interacting is a question that will take time to clarify,” she says, “and more research is urgently needed. Then there’s another factor: All tumors can mutate or change when it is treated or spreads, which can change the efficacy of all medications, even when they have been previously helpful. Close monitoring with scans or tumor markers of cancer status is very important, possibly including genomic reassessment of the tumors over time. We are thankfully getting much closer to precision or personalized therapies for many forms of cancer. Unfortunately not all patients and doctors realize how rapidly genomic testing is changing cancer therapy choices, potentially opening up treatment options customized to their unique needs.”
Beyond Tamoxifen: Cannabis and Aromatase Inhibitors
For women (and men) with breast cancer who are not taking tamoxifen—those who are post-menopausal, are using ovarian suppression medications, or who have no ovaries—a physician may prescribe an aromatase inhibitor (Arimidex, Aromasin, or Femara) to help reduce estrogen produced in body tissues other than ovaries. Wohlschlagel says some of these appear to be significantly safer to use with cannabis extracts because they are not metabolized in the same way as tamoxifen, and they do not appear to bind with CB1 and CB2 receptors, leaving those potential targets open for THC to bind to. However several of those (one example is Arimidex) also may be impacted if taken along with strong inhibitors of the CYP3A4 enzyme pathway, such as large doses of CBD and THC. Please speak to your doctor or pharmacist about this.
If there are no medical experts in your area with knowledge of medical marijuana, or if you do not live in a state where cannabis is legal, you can schedule a phone or video consultation with a medical professional at United Patients Group.
Since 2011, John Malanca has been the “go to”, expert and trusted professional in education and information in medical cannabis and the health/wellness sectors. His extensive knowledge of cannabis, the endocannabinoid system, patient needs, and disease care, combined with his upbeat and genuine concern for his audience makes him a favorite among industry hosts.
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.
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.
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