Can CBD change drug levels in your patients?

By Narda G. Robinson, DO, DVM, MS, FAAMA

Up to a third of dogs and cats receive dietary supplements,¹ many of which contain derivatives of plants. Despite this widespread use, veterinary schools teach nearly nothing about botanical medicine. Consequently, most students graduate with limited ability to critique, consult, or cautiously consider the rational implementation of plant-based medicines.

From cannabidiol (CBD) to Chinese formulations, "natural" remedies vary widely in both the quality and transparency of their ingredients. Most veterinary supplements lack research-backed, species-specific information about mechanisms of action, risks, benefits, and contraindications for each ingredient in a particular mixture. Unofficial "seals of approval" for animal supplements, whether by a manufacturer-based organization, veterinarian-salesperson, or self-proclaimed master herbalist, may increase consumer confidence but lack factual substantiation.

Perhaps the most baffling example of unwarranted complacency involves the uncritical acceptance of Chinese herbs. Typically untested, unmonitored, and under-regulated, Chinese proprietary products usually combine 10 or more extracts of plants, minerals, insects, and/or animals into a pill, powder, or capsule. Ingredients may not list the species name, English translation, or amount, thereby keeping the contents, strength, quality, and toxicity secret. Worse still, the lack of pharmacokinetic (PK) information about practically every component, hidden or disclosed, puts veterinarians at a deep disadvantage as they try to predict clinical outcomes.²

In contrast to the glaring uncertainties noted above, CBD products bring a welcome change. Most notably, the cannabis industry has developed standards, such as certificates of analysis (COA), which, when performed by a reliable third-party laboratory, help to build confidence about quality and purity. Some CBD suppliers have also subjected their supplements to rigorous, independent research in academic institutions.

The clinical benefits attributed to CBD include anxiolytic, anti-inflammatory, immunomodulatory, anticonvulsant, and analgesic activities.³ The mechanisms by which CBD exerts its effects involve more than 50 molecular targets, including enzymes, ion channels, and metabotropic receptors.⁴ Yet, even after decades of investigations into cannabis, we still have relatively little solid evidence about how and when they alter serum levels of co-administered medications.

Here's what we know: Orally administered substances, also known as "xenobiotics," become absorbed by the small intestine and then enter the systemic circulation following processing in the liver. Both enterocytes (cells in the intestine) and hepatocytes (cells in the liver) contain proteins classified as cytochrome P450 enzymes (CYPs) that convert xenobiotics from active to inactive forms (except in the case of pro-drugs). The body is then more able to excrete the end product through urine or feces.

Scientists have categorized CYPs into families and subfamilies according to their amino acid sequences. These membrane-bound hemoproteins account for most of the oxidative (phase I) type of drug metabolism. CYP enzyme levels within an organ may be elevated (induced) or reduced (inhibited) based on the chemicals they encounter. Except for prodrugs, higher levels of CYPs lead to more inactive forms of the drugs, whereas lower CYP levels allow more of the active, unmetabolized drug to stay in the system.

Mixing two xenobiotics (e.g. drugs, herbs, or food) that rely on the same CYP family can create unexpected results. What was previously a safe and sufficient dose of an herb or drug may become ineffective or toxic depending on how the more powerful inducer or inhibitor (i.e. the "perpetrator") changes the processing of its counterpart (i.e. the "victim").

For now, most of what we know about CBD is that the CYP families, known as CYP2C19 and CYP3A4, are responsible for much of its hepatic metabolism.⁵

CYP2C19 detoxifies about 10 percent of medications. These include antiplatelet agents, proton pump inhibitors, and antidepressants.⁶

CYP3A4 serves as the primary enzyme responsible for metabolizing most other drugs, heightening the likelihood of interactions.⁷ Well-characterized inducers of CYP3A4 include phenobarbital, phenytoin, rifampin, glucocorticoids, and St. John's wort. Potent inhibitors include erythromycin, diltiazem, ketoconazole, goldenseal, and grapefruit.

Given the widespread overlap between CYP enzymes that process both CBD and medications, a strong likelihood exists for herb-drug interactions. If CBD inhibits drug detoxification pathways in the liver, kidney, or elsewhere, this could raise the risk of the pharmaceutical side effects. That said, it might be difficult to determine whether an animal is doing poorly because of the CBD itself or the ways in which CBD has affected the pharmacokinetics of co-administered medications. Furthermore, CBD's effects on CYP enzymes may change over time. That is, at first, it may inactivate CYP enzymes and, later, induce them with ongoing administration.⁸

What should we look for, specifically, in our patients? Let's see what the research says for three of the most popular conditions for which dogs receive CBD: seizure disorders, mobility disorders, and cancer.

Seizure disorders

According to a 2021 paper by Balachandran et al., CBD interacts with at least six anti-epileptic drugs (AEDs).⁹ They determined that sometimes the AED reduces circulating levels of CBD; other times, CBD changes the effectiveness of the AED. The authors made clinical suggestions about increasing or decreasing the dosage of CBD, the seizure medication, or both, depending on the putative mechanisms of interactions.

A veterinary study on dogs assessed the PK interactions between CBD and phenobarbital. Researchers reported no significant interactions, but the study tested only nine healthy, "purpose-bred," intact female beagles.¹⁰ Five out of the nine dogs showed mild gastrointestinal disturbances and hyporexia.

According to the authors, "All dogs in our study had significant increase in ALP activity from baseline (day 0) at day 14 in all dosing groups." Too, "The increase in ALP activity is likely due to the induction and inhibition of various CYP450 isoenzymes in the liver because of metabolism of CBD as is seen in humans."

Later, they noted, "In human studies, CBD has significantly affected serum concentration of several antiepileptics (AEDs) including clobazam, topiramate, zonisamide (in adults), eslicarbazepine, and rufinamide because of CBD's inhibition of CYP450 enzymes."

While the authors did not recommend changing dosages of CBD or phenobarbital based on their findings, questions remain.

What would have happened to ALP levels over a longer test period than two weeks? At what point are negative side effects considered unacceptable? How do genetics, age, and various health conditions influence drug metabolism and the likelihood of CBD-phenobarbital interactions? Moreover, how does CBD change serum levels of drugs when dogs require multiple medications to adequately control their seizures?

Musculoskeletal pain

A prospective, double-blind, crossover, placebo-controlled study of 42 client-owned dogs with mobility impairments showed improved client-assessment outcomes in subjects that received CBD, compared to placebo.¹¹ ALP increased when CBD was co-administered with non-steroidal anti-inflammatory medications, as did alanine aminotransferase (ALT).

Notably, per the authors, "Of the patients with any elevation in liver enzymes, six owners consented to focused hepatic ultrasound and five to fine needle aspirates of the liver. Changes to the liver included glycogen accumulation (n=2), vacuolar hepatopathy (n=5), and mild lymphocytic inflammation (n=2). One dog additionally had multifocal necrosis on cytology. This patient had a mildly elevated ALP at the time of enrollment with moderate elevation following CBD administration, and fasted bile acids at the time of that elevation were within normal limits." They continued, "Side effects were uncommon but included gastrointestinal signs such as vomiting and diarrhea."

Based on this clinical trial, we might be asking whether it is worth adding CBD to nonsteroidal anti-inflammatory drugs (NSAIDs), given changes in liver values. Further, is it worth the quality-of-life impairment when so many animals experience inappetence, vomiting, and diarrhea from the product?

Cancer

CBD demonstrates many positive effects for cancer patients on chemotherapy, including antinausea, analgesic, and anti-anxiety effects. However, if CBD inhibits the CYP enzymes that metabolize chemotherapeutics, it could increase their toxicity.

A human study investigating CBD-drug interactions in cancer patients receiving chemotherapy found potential interactions occurring in those who were also taking CBD.¹² Researchers identified the main risks as central nervous system depression and hepatotoxicity.

On the other hand, CBD has demonstrated the ability to enhance the sensitivity of some types of cancer cells (breast and glioblastoma) to chemotherapy and radiation. In these instances, CBD administration might be able to improve outcomes overall, whether herb-drug interactions may be occurring.

Conclusion

Real-world implications of herb-drug interactions can affect us personally as well as professionally. Perhaps the most notable example pertains to the antidepressant herb, St. John's wort. This popular plant product reduces circulating levels of oral contraceptives and can, under certain circumstances, lead to an unplanned pregnancy. Is that not something veterinary students should know?

Narda G. Robinson, DO, DVM, MS, FAAMA, practices osteopathic medicine and veterinary medicine. Dr. Robinson taught science-based integrative medicine at the Colorado State University College of Veterinary Medicine and Biomedical Sciences for 20 years. In 2016, Robinson established her own academy in Fort Collins, Colo., where she teaches medical acupuncture, integrative rehabilitation, medical massage, and other integrative medical approaches. Columnists' opinions do not necessarily reflect those of Veterinary Practice News.

References

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