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… 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 …
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.
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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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