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A Closer Look At The Podiatric Implications Of Cannabidiol And Drug Interactions

Given that a percentage of podiatric patients may be using cannabidiol (CBD) on a regular basis, this author looks at how CBD may interact with prescription drugs.

Cannabidiol (CBD) is the most prominent naturally-occurring cannabinoid component found in cannabis, constituting up to 40 percent of the plant.1 Hemp CBD use ranges from dietary aids to pet health, and comes in a variety of forms. Retail sales of hemp-derived CBD products reportedly reached $170 million in the United States in 2016 and CBD product sales are projected to have a compound annual growth rate of 55 percent over the next five years.2 Additionally, 64.5 percent of the CBD product sales come through online channels followed by 17.8 percent at smoke shops.2 CVS, the nation’s largest pharmacy, recently announced it will begin to sell topical CBD products from Axcentria Pharmaceutical’s Elevate brand at stores in Alabama, Califormia, Illinois, Indiana, Kentucky, Maryland and Tennessee.3

Reporting findings from a self-selected convenience sample survey involving over 2,400 people, Corroon and Phillips reported that CBD users are balanced across gender (52 percent female and 48 percent males), tend to be older (43.4 percent being older than 55 years of age) and college-educated (71 percent earned a college degree or higher), and sixty-two percent use CBD to treat a specific medical condition.4

Given the emerging, exploding CBD product marketing and resulting consumer CBD consumption, a significant percentage of podiatric patients may be using the dietary botanical supplement on a regular basis. Many people may be reluctant to reveal their CBD use to their health care providers for fear of being judged. Cannabis is increasingly present in society both recreationally, as either natural cannabis or as synthetic cannabinoids, as well as for medical use.

Over the last few years, the medical literature has shown CBD levels may have an important impact on chronic illnesses. Podiatric physicians should become familiar with the pharmacologic profile of cannabidiol to avoid potential adverse effects from this herbal product that may result in harmful drug-drug interactions.5 Accordingly, let us take a closer look at the medicinal chemistry of cannabis and cannbinoids so the podiatric physician has a strong understanding of the mechanisms of the drug and an awareness of potential cannabidoid interactions.

Understanding The Medicinal Chemistry of Cannabidoid

Grotenhermen investigated and reported the pharmacokinetics and pharmacodynamics of cannabinoids.6 Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues.6 The non-psychotropic CBD, some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses.7

Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including the spleen, leukocytes, reproductive, urinary and gastrointestinal tracts, endocrine glands, arteries and the heart.7 Cannabis and its component cannabinoids exert their effects primarily via the endogenous cannabinoid system. The primary receptors of endogenous cannabinoid system are cannabinoid 1 receptors (CB1Rs) and cannabinoid 2 receptors (CB2Rs).8 Both these receptors are G-protein coupled receptors with CB1Rs predominantly located on neurons in the central and peripheral nervous systems and CB2Rs primarily located in immune cells with a minority located in some neurons.8 The activity of cannabinoids at the mu and delta opioid receptors and transient receptor potential vanilloid type-1 cation channels has no psychotomimetic effects but may have antipsychotic effects.8 CBD has no psychotomimetic effects but may have antipsychotic effects. CBD may have potential clinical effects on anxiety disorders, movement disorders, neuropathic pain, epilepsy, cancers and anti-inflammatory effects.8  

In their review examining human metabolites of cannabidol, Ujváy and Hanuš summarized the current knowledge on the pharmacokinetics and metabolic fate of CBD in humans.9 This review validated other published studies centered on the biological activity of CBD metabolites, either in vitro or in vivo, and presented validation on relevant drug-drug interactions.9

The clinical significance of CBD abundant metabolites is not fully appreciated at this time because of the lack of further human studies. It is believed that CBD has a strong affinity to fatty acid binding proteins that are responsible for accompanying lipids to the cell interior. Hence, CBD’s anti-inflammatory effect may be related in that CBD delays adenosine uptake in the cell which is responsible for inflammation. CBD’s anti-angiogenic effect is related in that CBD activates PPAR receptors. Therefore, it prevents vessel migration and inhibits endothelial morphogenesis. CBD modulates reactive oxygen species pathways to inhibit autophagy and apoptosis. CBD’s analgesic effect is related to interacting with vanilloid receptor agonists by unclogging the blood vessels and causing desensitization. Finally, it is believed that CBD inhibits serotonin action, reducing pain, insomnia and anxiety by binding with G-coupled protein serotonin receptors.

What You Should Know About CBD Drug Interactions

As a class, cannabis and synthetic cannabinoids are associated with a variable therapeutic index with a wide variability between individuals in response and may have potentially life-threatening toxicity without monitoring. The podiatric physician cannot be expected to memorize the staggering number of pharmaceuticals available and the equally daunting potential for drug interactions. However, prescribers should recognize that patients often come to them medicated with scores of multiple drugs and chemicals acquired from different sources.

A meticulous drug history should include an examination of the patient’s prescribed medications as well as over-the-counter drugs, illicit drugs, tobacco use, alcohol consumption and herbal supplementation, which is greatly being utilized by patients. Clinicians should understand the general principles of how cannabinoids are metabolized and how they may cause potential drug interactions with principal drug classes prescribed to their patients.

The podiatric physician should realize any drug metabolized by cytochrome P450 enzymes could potentially interact with cannabidiol. There are three main ways by which two drug products may interact: metabolic interactions, drug distribution and convergent pathways. There are a number of mechanisms by which drugs interact with each other and we can divide most of them into two general categories: pharmacokinetic and pharmacodynamic interactions. With pharmacokinetic drug interactions, one drug affects the absorption, distribution, metabolism or excretion of another. When pharmacodynamic drug interactions occur, two drugs have additive or antagonistic pharmacologic effects. Either type of drug interaction can result in adverse effects in some individuals.10

The primary mechanisms of drug interactions include: the effects of drugs on the hepatic metabolism of pharmaceuticals; effects on cytochrome (CYP) P450 enzymes or effects on glucuronidation; medication effects on the function of the drug transporter P-glycoprotein; and effects on absorption of drugs.11 Cytochrome P450 enzymes are most heavily expressed in the liver but are also present in the lungs and intestinal tract. The P450 type cytochromes are responsible for the metabolism of a wide variety of xenobiotics and endogenous compounds.

Although P450-catalyzed reactions are generally thought to lead to detoxication of xenobiotics, the reactions can also produce reactive intermediates that can react with cellular macromolecules leading to toxicity or react with the enzymes that form them, leading to irreversible inactivation. Most cannabinoids are metabolized by one or more of the cytochrome P450 isoenzymes, and this process typically results in the generation of multiple metabolites.

In addition, other prescription medications, over-the-counter (OTC) medications, “herbals,” dietary supplements and smoking can inhibit or induce the activity of CYP450 enzymes involved in the metabolic pathways of opioid medications.

Cannabinoids modulate several cytochrome (CYP) 450 enzymes that are of potential interest in investigating interactions with other medications. Biotransformation via a hydrolytic pathway is the major route of endocannabinoid metabolism and the deactivation of substrates is characteristic in contrast to the minor oxidative pathway via CYP involved in the bioactivation reactions. Phytocannabinoids are extensively metabolized by CYPs. The enzymes CYP2C9, CYP2C19 and CYP3A4 catalyze most of their hydroxylations.12 Cannabidiol, which forms as tetrahydrocannabinol ages, is a very potent inhibitor of CYPs 1A1, 1A2, and 1B1. Individuals with less functional CYP2C2 enzymes are likely to experience more significant cannabinoid-drug interactions.

The number of drugs processed by Cytochrome P450 is considerably great. Therefore, podiatric physicians should consider a potential drug interaction with CBD when reviewing and reconciling a patient’s medication regimen. As I previously stated, cannabidiol can inhibit the cytochrome P450 system’s ability to metabolize certain drugs, leading to an overall increase in processing times. When the CYP450 system is impacted in this way, it leads to higher levels of certain drugs in a patient’s system at one time. This can cause unwanted side effects and sometimes an overdose.

Any drug metabolized by CYP450 enzymes could potentially interact with CBD. To summarize cannabinoid actions on the cytochrome system, when CBD inhibits a CYP enzyme, it affects the metabolism of the other drugs. The effect will be a delay or increase in the given drug’s pharmacokinetics (i.e. metabolism and elimination), thus increasing or decreasing the drug blood levels in the body. On the other hand, when CBD induces a CYP enzyme, causing more enzymes to be made, this will lead to a shorter life span of another drug, which is a substrate for the same CYP.

Respecting the principles of how drugs are metabolized by the CYP450 enzymes, coadministration with a moderate or strong inhibitor of CYP3A4 can potentially increase CBD plasma concentrations, which may result in a greater risk of side effects of cannabidiol. On the other hand, coadministration with a moderate or strong inducer of CYP3A4 can potentially decrease CBD plasma concentrations, which may result in a lowered therapeutic effect of CBD. In the same respect as CYP3A4, co-administration with a moderate or strong inhibitor of CYP2C19 could increase CBD plasma concentration. Coadministration with a strong inducer of CYP2C19 could decrease CBD concentrations.

In addition, to the potential interactions I mentioned above, CBD may also interact with CYP1A2 substrates like both theophylline and caffeine. CBD compounds interact with both CYP2B6 substrates like bupropion and efavirenz, and uridine 5' diphospho-glucuronosyltransferase 1A9 (UGT1A9) substrates like diflunisal, propofol and fenofibrate. Lastly, CBD drug interactions have occurred with UGT2B7 substrates like gemfibrozil, lamotrigine, morphine, and lorazepam.

For a list of potential interactions with CBD and frequently prescribed medications, please download a PDF of the table “Potential Drug Interactions With CBD Products” here.13

Key Steps To Educating Patients On How To Avoid Drug-Drug Interactions With CBD

Despite many complex details involved, the concept of drug-drug interactions can be relatively simple to manage. It is important to consider the dosage of cannabinoids a patient is using when discussing the potency of CYP inhibition drug interactions. Clinicians may advise patients to be consistent in purchasing the same potency CBD product.

The first step to avoid CBD drug interactions is to remind the patient to look for quality CBD products, not the lowest price. With so many products only one click away on the Internet, patients may be more than tempted to grab the most affordable CBD oil they can find online but the cheaper product is not necessarily the better CBD product. The quality of CBD oil is defined by concentration. The higher the concentration of cannabidiol in a product, the more powerful its effects and thus the wiser the investment.

Secondly, patients have heard and read a lot about CBD products and claims that they can cure different forms of cancer, and how hemp oil has miraculously healed patients from anxiety, tumors, diabetes and whatnot. The prudent podiatric clinician should advise his or her patients to be aware of products with claims that sound too good to be true.

CBD oil is a powerful antioxidant with strength greater than that of vitamin C and E.14 However, the reported health effects of CBD oil have not been fully explored or investigated.

Some of the hemp and marijuana products available on the market contain psychoactive compounds. However, cannabidiol is scientifically proven to be anti-psychoactive so it is important to have the patient check the label before buying a CBD oil and choose only products that have no psychoactive effects. As long as the patient sticks with non-psychoactive products, there is no risk of getting high from them. But again, patients should beware of cheap products. Making a good CBD oil that retains only the beneficial compounds from hemp requires a certain technology and that technology is costly.

Lastly, the podiatric physician can advise their patients to perform the “grapefruit test” evaluation with their current medication regimen.15 The “grapefruit test” is a method to assess if any of the patient’s medications may be affected by the coadministration of CBD products. CBD reacts similarly to grapefruit’s metabolism and pharmacokinetic profile on how it impacts many drugs that are widely used by our patients.16 CBD acts in precisely the exact same manner chemically as a grapefruit but it is more powerful in its effect and drug interactions.

In Conclusion

There are several potential drug interactions with CBD but many of them are not well studied. There have not been studies evaluating potential CBD interactions with all drugs. They are more theoretical based on what is known about how they are metabolized and how they affect drug metabolism. The administration of CBD with a drug identified as a moderate or strong inhibitor of CYP3A4 can potentially increase CBD (cannabidiol) plasma concentrations, which may result in a greater risk of side effects. Moreover, the co-administration with a moderate or strong inducer of CYP3A4 can potentially decrease cannabidiol plasma concentrations, which may result in a lowered therapeutic effect.  

It is important for podiatric clinicians to check for potential drug interactions when their patients are considering using CBD products. Podiatric physicians should become familiar with the pharmacologic profile of cannabidiol to avoid potential adverse effects from this herbal product that may result in harmful drug-drug interactions.5

Dr. Smith is in private practice at Shoe String Podiatry in Ormond Beach, Fla.

References
1. Zachar L. Everything you ever need to know about CBD and hemp. CBD Testers. https://www.cbdtesters.co/2018/03/29/everything-you-ever-need-to . Published March 28, 2018. Accessed April 30, 2019.

2. Borchardt D. Hemp cannabis product sales projected to hit $1 billion in 3 years. Forbes. https://www.forbes.com/sites/debraborchardt/2017/08/23/hemp-cannabis-product-sales-projected-to-hit-a-billion-dollars-in-3-years/#5baca389474c . Published August 23, 2017. Accessed April 29, 2019.
3. Charles S. CVS to sell CBD products in 800 stores in 8 states. NBC News. https://www.nbcnews.com/health/health-news/cvs-sell-cbd-products-800-stores-8-states-n986016 . Published March 21, 2019. Accessed April 29, 2019.
4. Corroon J, Phillips JA. A cross-sectional study of cannabidiol users. Cannabis Cannabinoid Res. 2018;3(1):1-10.
5. Smith RG. An appraisal of herbal and drug interactions: podiatric implications. Podiatry Management. 2014;33(4):173-181.
6. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327-60.
7. Grotenhermen F. Pharmacology of cannabinoids. Neuro Endocrinol Lett. 2004;25(1-2):14-23.
8. Boggs DL, Nguyen JD, Morgenson D et al. Clinical and preclinical evidence for functional interactions of cannabidiol and ∆9-Tetrahydrocannabinol. Neuropyschopharmacology. 2018;43(1):142-154.
9. Ujváry I, Hanuš L. Human metabolites of cannabidiol: a review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res. 2016;1(1):90-101.
10. Hansten P Horn J. The Top 100 Drug Interactions, 2017. H&H Publications, Freeland, WA.
11. Karan L, McCance-Katz EF. Pharmacokinetics. In: Kosten TR, Gorelick D, Fiellin D (eds.). Principles of Addiction Medicine, Fourth Edition, 2009. American Society of Addiction Medicine Publishers.
12. Zendulka O, Dovrtělová G, Nosková K, et al. Cannabinoids and cytochrome P450 interactions. Curr Drug Metab. 2016;17(3):206-26.
13. Staiger B. CBD oil drug interactions. PharmacistAnswers.com . https://www.pharmacistanswers.com/questions/cbd-oil-drug-interactions . Published November 9, 2018. Accessed April 29, 2019.
14. Schettino R. CBD is a more powerful antioxidant than vitamins C and E. Ask CBD. https://www.askcbd.org/cbd-more-powerful-antioxidant-vitamins-c-and-e . Published September 5, 2017. Accessed April 30, 2019.
15. Drugs that interact with cannabidiol. CBD Dosage Calculator.com. https://cbddosagecalculator.com/CBD-Drug-Interactions/ . Updated January 27, 2019. Accessed April 30, 2019.
16. Food and Drug Administration. Grapefruit juice and some drugs don’t mix. https://www.fda.gov/downloads/ForConsumers/ConsumerUpdates/UCM567226.pdf . Published July 18, 2017. Accessed April 29, 2019.
Additional References
17. Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch Arztebl Int. 2012;109(29-30):495-501.
18. Smith RG. An appraisal of potential drug interactions in cigarette smokers and alcohol drinkers. J Am Podiatr Med Assoc. 2009;99(1):81-88.

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By Robert G. Smith, DPM, MSc, RPh, CPed, CPRS
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