On The Cover
Loren Bonner
Pharmacists know patients are using cannabis or are taking cannabidiol (CBD) for things like insomnia and pain—use of these products is only growing as is the number of different cannabinoid formulations. But little is known about the unintended interactions between cannabinoids and medications.
Right now, pharmacists and other health care providers don’t have system alerts that can pop up with contraindications about cannabinoids in combination with other medications patients are taking.
“The most important thing pharmacists and health care providers can do is ask patients ‘are you using a cannabinoid product?’ and then do the medication reconciliation to see if that is having an effect on an important drug like warfarin,” said Kent Vrana, PhD, professor and chair of the Department of Pharmacology at Penn State University College of Medicine. Vrana helped develop a free URL through Penn State that assesses cannabinoid products against a database of prescription and OTC medications.
“The perception is that cannabinoids are safe, but we have kind of redirected the conversation to yes maybe they are safe, but how do they affect other medications?” said Paul Kocis, RPh, PharmD, MPH, a clinical pharmacist at Penn State Health Milton S. Hershey Medical Center.
“It’s still an evolving area, which we are hoping to contribute to down the road,” said Kocis, who drove the development of the tool called the CANNabinoid Drug Interaction Review (CANN-DIR). He said the resource is intended for both health care providers and patients or caregivers.
“We want patients going to their doctor and for them to recognize that they should be telling them about using CBD oil,” Kocis said.
What is cannabis?
The cannabis plant contains 554 compounds. These compounds, or active chemicals, include 113 cannabinoids, two of which are tetrahydrocannabinol (THC) and cannabidiol (CBD).
“As we look at pharmacological actions and expected therapeutic responses, a name label is not going to help us, but instead knowing whether it’s a THC type, or CBD type, or hybrid type,” said Kari Franson, PharmD, PhD, BCPP, professor and associate dean at the University of Southern California.
Although it’s still an area of evolving research, cannabinoids such as THC and CBD are known to have different effects on the body. THC binds to cannabinoid receptors in the body, while CBD may interact indirectly with cannabinoid receptors. THC is the chemical responsible for the psychoactive quality of cannabis, but it also has antinausea and analgesic effects. CBD, which has no psychoactive properties, is said to help with inflammation. Other compounds in the plant, such as the terpenes and flavonoids, may play a synergistic role in the therapeutic effects of cannabis—what’s known as the “entourage effect.”
Fiona Oxsher, PhD, cofounder and general manager of LKN Extractions, said that learning about the body’s endocannabinoid system—which was only discovered in 2002—helps us understand how cannabinoids work.
The endocannabinoid system controls a person’s response to stress, as well as one’s mood, appetite, energy balance, and more. Oxsher explained that our bodies have been increasingly void of cannabinoids because of our environment, the food we eat, and other factors. Plants with cannabinoids are a way to saturate this system—the CB1 and CB2 receptors, specifically—she said.
Cannabinoids are also present in rosemary, echinacea, kava, and other plants. “But cannabis has the highest percentage of cannabinoids,” said Oxsher.
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Metabolic drug–drug interactions between cannabidiol and enzyme substrates, inhibitors, or inducers
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Enzyme
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Medication examples
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Effect/Recommendation
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CYP3A4 substrates
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Immunosuppressants, chemotherapeutics, antidepressants, antipsychotics, opioids, benzodiazepines, z-hypnotics, statins, calcium channel blockers, others
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Increased risk of adverse effects related to substrate.
Avoid coadministration, reduce substrate dose, monitor for adverse effects and toxicity.
Avoid prescribing cascade with new treatment for adverse effects.
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CYP3A4 inhibitors
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Strong: Protease inhibitors, ketoconazole, loperamide, nefazodone
Moderate: Amiodarone, verapamil, cimetidine, aprepitant, imatinib
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Increased CBD bioavailability, possible increase in risk of adverse effects. Reduce CBD dose.
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CYP3A4 inducers
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Strong: Enzalutamide, phenytoin
Moderate: Carbamazepine, topiramate, phenobarbital, rifampicin, efavirenz, pioglitazone
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Decreased CBD bioavailability, possible decrease in CBD effectiveness. Increase CBD dose.
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CYP2C19 substrates
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Antidepressants, antiepileptics, proton pump inhibitors, clopidogrel, propranolol, carisoprodol, cyclophosphamide, warfarin
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Increased risk of adverse effects related to substrate.
Avoid coadministration, reduce substrate dose, monitor for adverse effects and toxicity.
Avoid prescribing cascade with new treatment for adverse effects.
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CYP2C19 inhibitors
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Strong: Fluvoxamine, fluoxetine
Other: Proton pump inhibitors, cimetidine, ketoconazole, clopidogrel, fluconazole, efavirenz
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Increased CBD bioavailability, possible increase in risk of adverse effects. Reduce CBD dose.
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CYP2C19 inducers
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Rifampin, carbamazepine, phenobarbital, phenytoin, St. John’s Wort
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Decreased CBD bioavailability, possible decrease in CBD effectiveness. Increase CBD dose.
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CYP2C8/9 substrates
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Rosiglitazone, burprenorphine, montelukast, celecoxib, sulfonylureas, losartan, naproxen, phenobarbital, phenytoin, rosuvastatin, valsartan, warfarin
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Increased risk of adverse effects related to substrate.
Avoid coadministration, reduce substrate dose, monitor for adverse effects and toxicity.
Avoid prescribing cascade with new treatment for adverse effects.
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Reprinted from: Brown and Winterstein. Journal of Clinical Medicine. 2019.
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What to know about ∆-8 THC, a potentially dangerous new synthetic cannabis product
∆-8 tetrahydrocannabinol, also known as ∆-8 THC, is a new synthetic cannabis product—a psychoactive substance found in the cannabis sativa plant—that’s quickly gaining popularity among consumers. But FDA has received hundreds of adverse event reports involving ∆-8 THC and is warning the public about the serious health risks associated with its use.
Saswat Kabisatpathy, PharmD, from Avant Pharmacy and Wellness Center in Charlotte, NC, said he has concerns about what may actually be in a product labeled as ∆-8 because of the chemical process behind making this synthetic product. Additional chemicals are needed to convert other cannabinoids in hemp, like CBD, into ∆-8 THC, and products can be contaminated with other cannabinoids and heavy metals. In addition, there is lack of regulation in many states—although some have banned the sale of ∆-8 THC.
Here are 5 things to know from FDA about ∆-8 THC:
- ∆-8 THC products have not been evaluated or approved by FDA for safe use and may be marketed in ways that put the public health at risk.
- FDA has received adverse event reports involving ∆-8 THC–containing products.
- ∆-8 THC has psychoactive and intoxicating effects.
- ∆-8 THC products often involve use of potentially harmful chemicals to create the concentrations of ∆-8 THC claimed in the marketplace.
- ∆-8 THC products should be kept out of the reach of children and pets.
More information can be found here: www.fda.gov/consumers/consumer-updates/5-things-know-about-delta-8-tetrahydrocannabinol-delta-8-thc
Inhibitors or inducers
CBD is one of over one hundred cannabinoids in the cannabis plant. It is metabolized by the liver with isoenzymes CYP2C19 and CYP3A4, which are major players in drug metabolism.
Concomitant use with moderate or strong inhibitors or strong inducers of these isoenzymes may result in increased risk of potentially serious adverse effects associated with CBD or reduced therapeutic response to CBD, respectively.
For example, if a patient is using a CBD product and is on carbamazepine, which is a CYP2C19 inducer, the CBD dose might not be as effective for them. Maybe the patient is not getting any benefits from CBD after being on it for a while. Maybe their dose is too low because they are on an inducer medication. The opposite can also hold true when a patient is on a CYP2C19 inhibitor, in which CBD might not be metabolized as well and could be causing an adverse effect.
The common drug warfarin, which is used to treat and prevent blood clots, is a well-known example. Cannabinoid products could affect how warfarin is metabolized, either reducing its effectiveness or leading to toxicity, such as bleeding.
The safety profile of CBD comes largely from the clinical data of the FDA-approved, prescription-only cannabidiol, Epidiolex (Greenwich Biosciences), the first-ever product containing CBD. The drug is indicated for two rare and severe forms of epilepsy in patients ages 2 years and older. The clinical trial results showed that use was associated with dose-related increases in liver function tests, specifically, elevations in AST, ALT and total bilirubin, and liver injury.
CBD interacts with several of the other antiepileptic medications used for the treatment of these same disorders, in fact. Pharmacists should know that medication doses for diazepam, clobazam, and stiripentol, for example, will likely need to be reduced to prevent toxicity in patients.
Elevations in liver enzymes seem to occur more readily with coadministration of valproic acids, as well.
Full- versus broad-spectrum cannabis products
Full spectrum has the full complement of major and minor cannabinoids—these products have both CBD and THC as well as terpenes and phytochemicals. On the other hand, broad-spectrum products are a THC alternative to full-spectrum products; they have everything in them but THC.
Hemp and marijuana or cannabis fall under different federal designations. Hemp is a variety of cannabis grown specifically for fiber that is used for industrial purposes. The 2018 Farm Bill legalized the production and sale of hemp and its extracts. Hemp has less than 0.3% of THC. Cannabis has greater than 0.3% of THC. Cannabis is considered a Schedule I drug by DEA and is federally illegal.
Patients need their pharmacist
Given the lack of information on cannabinoids and specific drug interactions, it’s an area where a pharmacist’s expertise is needed.
“We are one of the most accessible health care providers and this is an example of where that’s important,” said Saswat Kabisatpathy, PharmD, from Avant Pharmacy and Wellness Center in Charlotte, NC. “I think we have an obligation to our patients to be educated on this topic.”
For the past few years, Kabisatpathy has hosted a continuing education webinar on cannabis for health care personnel and said he’s always flooded with questions at the end of the presentation. “This goes to show that we still have a lot of pharmacists and health care providers who are not knowledgeable about this but want to be.”
Kabisatpathy encourages patients to talk to their pharmacist about cannabis. “We have our systems to check drug interactions and we have resources at our fingertips,” he said.
Pharmacists have opportunities within a medication reconciliation consultation to ask questions related to a patient’s cannabis and CBD use. For example, in a discussion about smoking, a pharmacist can ask about cannabis use. Another key component of medication reconciliation is a discussion about OTC products. Pharmacists have an opportunity to ask about CBD use during that conversation.
“And if they say ‘yes,’ then as pharmacists, we can educate patients on those products and emphasize the potential for drug interactions and offer resources,” Kabisatpathy said.
He said for those teams doing medication reconciliations, pharmacists need to make sure cannabinoid use is noted in the patient profile. Medication therapy management platforms and dispensing systems have ways to identify those products.
In follow-up conversations with patients, Kabisatpathy said pharmacists can ask patients if they’ve noticed any differences since using cannabinoid products and also let them know it’s important to communicate use of these products with their physician, as well.
Resources
CANN-DIR, the free resource from Penn State University for cannabinoids and drug interactions, can be accessed at www.cann-dir.psu.edu/#/.
“All the drug interactions are based on drug prescribing information and FDA resources,” said Kocis. The link to the prescribing information is also included, which Kocis said was a suggestion to them from one of the Pennsylvania cannabis-dispensing pharmacists they consulted for the project.
Vrana emphasized that the tool is a general reference and educational resource, not a substitute for professional medical advice, diagnosis, or treatment. “This is potential identification of interactions, it is not practicing medicine,” he noted. A disclaimer on the opening page of the site states this clearly.
“We don’t have a business model here, this is an important harm reduction tool that is freely available,” said Vrana.
FDA also has a host of resources on FDA regulation of cannabis and cannabis-derived products, which can be accessed here: www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd#relatedinfo ■
What’s the difference between CBD and cannabis?
Cannabis is the scientific name of the plant, while CBD, or cannabidiol, is one of the most abundant of the hundreds of active chemicals contained in the cannabis plant.