CANNABINOID SYSTEM

The 1960s were a time of unparalleled scientific discovery and social experimentation. It seems fitting, then, that in 1964 Δ9-tetrahydrocannabinol (THC) was isolated and defined. Since then, significant progress had been made in the discovery and understanding of the endogenous cannabinoid, or endocannabinoid, system.

Endocannabinoids are incredibly diverse in function. The numerous identified endocannabinoids are known to undergo various methods of metabolism, with many byproducts themselves being active. Receptors are found on many cell types and can vary in effect based on factors as mundane as species, muscle sub-type, and diet. Research has shown both positive and negative effects of endocannabinoids – they both promote and fight heart and liver disease; reduce bone development in fetuses and neonates but reduce osteoporosis in the elderly; and improve female fertility but decrease sperm quality. To complicate matters further, the effects of plant cannabinoids, or phytocannabinoids, appear to overlap only partially with endocannabinoids. Our understanding of the delicate balance in the endocannabinoid system is in its infancy.

It is not difficult to appreciate the therapeutic promise of endocannabinoids and their related phytocannabinoids, most prominent of which is cannabidiol (CBD). There exists a large, complex, untapped pharmacological target with many effects. However, it would be prudent to not outpace our understanding of the endocannabinoid system. Few in vivo studies have been performed in humans and even fewer in our core veterinary species. From what we do know of our veterinary species, cannabidiols may be metabolized differently and into different metabolites and CBD has low bioavailability with oral administration in dogs likely due to poor absorption and a large hepatic first pass effect. The argument should not be if CBD has therapeutic effects but if CBD products can and should be recommended or sold.

FOOD AND DRUG ADMINISTRATION

The only FDA (Food and Drug Administration) approved CBD product is the seizure medication EPIDIOLEX®. Although found to be effective and safe enough for approval, the FDA noted many unknowns in the summary review of the approved new drug application. Animal models used for toxicology studies may have been inappropriate as their metabolism of CBD produces different byproducts than those of humans. Peak drug concentrations could be up to five times higher if the product is taken with a high-fat meal. Product usage increased liver enzymes in a dose-dependent manner. There was limited review of concomitant drug interactions.

The pharmaceutic industry seeks to assure the identity, strength, quality, purity, and potency of drug products. The FDA is tasked with assessing investigational new drug applications (INDs) and new drug applications (NDAs) for safety and efficacy. Pharmaceutical companies submit an IND after completing research, development, and pre-clinical toxicology testing. After approval of an IND, the company can begin testing on humans: Phase 1 clinical testing for safety, Phase 2 for efficacy, and large-scale Phase 3 for population and dosage variation with consultation from FDA. Should the drug continue to appear promising, the company will submit an NDA for FDA review. The FDA will assess the data, labelling, and production facility prior to granting approving for the new drug. The new drug will be approved only at specific dose(s) for specific condition(s) under certain manufacturing conditions.

While the FDA thoroughly reviews drug products, oversight of supplements is more limited. In fact, supplements, in most cases, do not need approval prior to being sold. There is no review process to ensure quality and efficacy, determine appropriate dosages, and ascertain interactions and side effects. FDA resources are not leveraged against supplement manufacturers unless they are investigating adverse effects, reported issues, adulterated products, or false claims. A supplement may not “claim that it will diagnose, cure, mitigate, treat, or prevent a disease” – by making those claims a supplement becomes a drug in the eyes of the FDA. Additionally, the FDA does not recognize animal supplements – only animal drugs and foods.

CBD PRODUCTS

FDA personnel have been closely monitoring the CBD industry. Manufacturers are claiming CBD supplements are entirely legal because the Farm Bill removed hemp, or cannabis with less than 0.3% THC, from the Controlled Substances Act. Manufacturers neglect to realize that the Farm Bill did not change the FDA’s duty to regulate drugs and supplements, nor the definition of a supplement. Adding a substance approved as a drug – in this case, CBD – to a supplement means the supplement has either been adulterated, and should be removed from the market, or it is truly a drug product that must seek FDA approval.

Some manufacturers push the envelope further by making explicit or implicit therapeutic claims of their supplement products. Recall, therapeutic claims can only be made for approved drugs. A quick internet search of animal marketed CBD products yields claims such as “alleviating allergies”, “treating a range of disorders”, “does no harm to the kidney, liver, or GI tract”, “stimulate deep tissue healing”, “reduce itchiness and rashes”, and “reduce the anxiety experienced by many animals.” Some products do not have claims but vaguely suggest a product may be good for an animal with a certain condition. There does not appear to be a well-defined line in the sand of how much you can say, but keep in mind that the FDA defines a drug this way:

  • A substance recognized by an official pharmacopoeia or formulary.
  • A substance intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease.
  • A substance (other than food) intended to affect the structure or any function of the body.
  • A substance intended for use as a component of a medicine but not a device or a component, part or accessory of a device.
  • Biological products are included within this definition and are generally covered by the same laws and regulations, but differences exist regarding their manufacturing processes (chemical process versus biological process.)

The FDA is quick to act, however, when obvious and distinct claims are made of CBD products. Take as an example Curaleaf, who received a warning letter from the FDA in 2019 regarding claims made for both human and animal CBD products. The FDA determined that based upon therapeutic claims made the CBD products were unapproved new animal drugs. These claims included “pain relief”, “relief of muscle spasms”, and treating “diabetes.” Claims were not only made in product descriptions, but also on company blogs and social media accounts. Other warning letters include quotations from consumer testimonials and claims that may appear vague.

The legality of CBD products is further muddled on a state level. In decriminalizing and/or legalizing hemp or marijuana products for people, states have presented a message inconsistent with the FDA’s. Some states believe that regulatory changes will lead to agricultural gains. Manufacturers and suppliers may feel sheltered by state or local laws and look to market products with therapeutic claims. In fact, the FDA itself states that it may consult with state partners prior to pursuing enforcement against offending products and that it “supports researchers who conduct adequate and well-controlled clinical trials which may lead to the development of safe and effective marijuana products to treat medical conditions”.

States that have approved human medical usages of hemp or marijuana products were obligated to ensure human physicians could determine a patient might benefit from the product. Human physicians became sheltered under select state laws and are now able to openly discuss and recommend or prescribe CBD products. In some instances, states may require a human physician provide written documentation for patients.

However, veterinarians and animals were excluded in state medical marijuana laws. California attempted to fill the legislative gap in 2018 by allowing veterinarians to discuss CBD within a valid VCPR (veterinarian-client-patient relationship) but forbids administrating or dispensing any product for an animal patient. The AVMA (American Veterinary Medical Association) notes FDA approved product usage is allowed in an extra-label fashion under AMDUCA (Animal Medicinal Drug Use Clarification Act) in select circumstances. Should the patient be a food producing species, veterinarians must attempt to determine withdrawal times.

Veterinary medical associations are aware that veterinarians have been placed into a difficult spot. Clients can obtain products for themselves – sometimes at their doctor’s suggestion – and know of animal CBD products. Clients want to discuss CBD with their veterinarian and veterinarians want to provide their professional opinions. Medical associations have tried to cautiously weigh in on the topic. The AVMA dodges the discussion, stating that non-FDA products are not known to be safe or effective. The Colorado Veterinary Medical Association notes an increase in toxicities but suggests conversations can occur within a VCPR. Unsurprisingly, the California Veterinary Medical Association allows veterinarians to discuss CBD products, noting that administration is still illegal. The Michigan Veterinary Medical Association vaguely states there may be increased legal risk if things go wrong and that they will not recommend something until the FDA says it is safe. Some states – such as Connecticut, Missouri, and Tennessee – are attempting to prevent medical board disciplinary action if a veterinarian discusses CBD. Ironically, the FDA advises consumers interested in pet CBD products to consult with their veterinarian.

PRUDENT ACTIONS

It is entirely reasonable that a veterinarian seems confused about what prudent actions can or should be taken. It is obvious to the FDA, clients, and veterinarians that there is therapeutic potential in CBD. Veterinarians want to find new ways to care for their patients and assure their position as an authority source. However, they are not legally shielded, and the legality of available products is questionable.

Thankfully, the FDA has committed to clearing the air. The FDA is on the record saying they want to make regulatory approval more efficient for CBD products and are actively considering ways to allow marketing of non-drug CBD supplements and foods. Agency representatives regularly give very transparent speeches which are posted on the FDA webpage. They reaffirm the FDA’s goal of providing a layer of safety and reliability for both the prescriber and the patient in all products and look to obtain the same assurances for CBD products. It would be wise to pay attention to the FDA updates that will surely be coming – the FDA is active on social media.

The FDA is more than willing to partner with research institutions to learn more about the pharmacokinetics and pharmacodynamics of CBD. Veterinary schools are leading the charge to find out how and how well CBD products work for dogs. For example, UPenn’s (University of Pennsylvania) School of Veterinary Medicine is currently performing a double-blinded study on the effects of a CBD product on dog mobility. This study, along with most other similar studies, is sponsored by the product manufacturer. Veterinarians should be skeptical of sponsored studies and thoroughly evaluate study methodology, results, and conclusions, but can look forward to learning more about the efficacy and side effects of specific products.

Despite all the uncertainty, many clinicians are interested in making specific product recommendations or stocking CBD items. Veterinarians need to make themselves aware of the most current information regarding safety of CBD and the efficacy, purity, and stability of the product they promote. It is important the product does no harm to the patient and is not an unwise expense for the client. Consider things such as:

  • How pure is the product?
  • What pesticide residues are present?
  • Are there heavy metals or solvents in the product?
  • What additives are in the product?
  • How does the product need to be stored? Will it go rancid?


The product selected should be reviewed for unapproved claims – on the product, on product packaging and literature, on the webpage, and on social media –to limit risk of product shortage due to FDA enforcement actions or liability.

Many other unknowns plague veterinarians carrying CBD products. State laws and medical boards offer very little protection, but we do not know how this will change in the future. Laws, both local and federal, influence insurance coverage and banking services. It remains unclear if veterinarians assume risks that are not covered under the insurance policies or if other policies, leases, and banking agreements would be violated by carrying and selling CBD products.

Although the prospect of CBD products is great, there remains much that is unknown and unclear. The legal landscape is ever evolving. A prudent veterinarian will watch FDA, legislative, and medical board actions, review current literature, and will consider all risks associated with discussing, recommending, stocking, and/or selling products. They will not be tricked by the smokes and mirrors of opinions but make decisions based upon facts and consideration of risk.

Works Cited

  • Abernethy, A., & Schiller, L. (2019, July 17). FDA is Committed to Sound, Science-based Policy on CBD. Retrieved from FDA: https://www.fda.gov/news-events/fda-voices-perspectives-fda-leadership-and-experts/fda-committed-sound-science-based-policy-cbd
  • Ashley, D. (2019, July 22). Warning Letter Curaleaf, Inc MARCS-CMS 579289 — JULY 22, 2019. Retrieved from FDA: https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/curaleaf-inc-579289-07222019
  • AVMA. (2019, February). State Legislative Update February 2019. Retrieved from https://www.avma.org/Advocacy/StateAndLocal/Documents/SLU-February2019.pdf
  • Boulder Holistic Vet. (n.d.). HempRx SoftChewz for Cats & Small Dogs. Retrieved from https://boulderholisticvet.com/shop/anxiety/hemprx-softchewz-for-cats-small-dogs/
  • CVMA. (2017). CVMA Position Statement on Marijuana and Marijuana-derived Products in Companion Animals. CVMA Voice, p. 9.
  • CVMA. (2019, September 12). Cannabis and Industrial Hemp FAQ 9-13-19. Retrieved from CVMA: https://cvma.net/wp-content/uploads/2019/09/Cannabis-and-Industrial-Hemp-FAQ_9-13-19.pdf
  • Di Marzo, V., & Piscitelli, F. (2015). The Endocannabinoid System and its Modulation. Neurotherapeutics, 12:692–698.
  • Dixie Brands, Inc. (2019, May 28). Clinical Trial at the University of Pennsylvania’s School of Veterinary Medicine to Study Effectiveness of Cannabinoids to Treat Dogs for Joint Immobility Using Dixie Brands’ Therabis Formulation. Retrieved from https://dixie.mediaroom.com/2019-05-28-Clinical-Trial-at-the-University-of-Pennsylvanias-School-of-Veterinary-Medicine-to-Study-Effectiveness-of-Cannabinoids-to-Treat-Dogs-for-Joint-Immobility-Using-Dixie-Brands-Therabis-Formulation
  • FDA. (2015, August 24). FDA’s Drug Review Process: Continued. Retrieved from https://www.fda.gov/drugs/drug-information-consumers/fdas-drug-review-process-continued
  • FDA. (2017, November 1). WARNING LETTER That’s Natural MARCS-CMS 513302 — OCTOBER 31, 2017. Retrieved from https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/thats-natural-513302-10312017
  • FDA. (2018). CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210365Orig1s000 SUMMARY REVIEW. FDA.
  • FDA. (2018, June 19). FDA and Marijuana. Retrieved from https://www.fda.gov/news-events/public-health-focus/fda-and-marijuana
  • FDA. (2018, August 14). WARNING LETTER Signature Formulations, LLC MARCS-CMS 545017 — JULY 31, 2018. Retrieved from https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/signature-formulations-llc-545017-07312018
  • FDA. (2019, October 16). FDA Regulation of Cannabis and Cannabis-Derived Products, Including Cannabidiol (CBD). Retrieved from https://www.fda.gov/news-events/public-health-focus/fda-regulation-cannabis-and-cannabis-derived-products-including-cannabidiol-cbd
  • FDA. (2019, April 2). WARNING LETTER Advanced Spine and Pain, LLC MARCS-CMS 565256 — MARCH 28, 2019. Retrieved from https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/advanced-spine-and-pain-llc-565256-03282019
  • FDA. (n.d.). Drugs@FDA Glossary. Retrieved from https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=glossary.page
  • Leafly. (n.d.). Pet First Aid Spray. Retrieved from https://www.leafly.com/products/details/rxcbd-pet-first-aid-spray
  • Maccarrone, M., Bab, I., Bíró, T., Cabral, G., Dey, S., Di Marzo, V., . . . Zimmer, A. (2015). Endocannabinoid signaling at the periphery: 50 years after THC. Trends in Pharmacologic Science, 36(5): 277–296.
  • MVMA. (2019, March 11). MVMA Statement on Medical Marijuana, Hemp, and CBD. Retrieved from https://michvma.org/news/7217306
  • Neurogan. (n.d.). CBD Horse Massage Oil 1000mg – Topicals for Horses | Neurogan. Retrieved from https://www.neurogan.com/cbd-products/for-pets/horse-massage-oil/
  • ProCon.org. (2019, July 24). Legal Medical Marijuana States and DC: Laws, Fees, and Possession Limits. Retrieved from https://medicalmarijuana.procon.org/view.resource.php?resourceID=000881
  • Pure Hemp. (n.d.). CBD Pet Shampoo – 20mg — Pure Hemp. Retrieved from https://purehempshop.com/products/pet-shampoo
  • Samara, E., Bialer, M., & Mechoulam, R. (1988). Pharmacokinetics of Cannabidiol in Dogs. Drug Metabolism and Disposition, 16(3): 469-472.
  • Schiller, L. (2019, August 13). Remarks at the National Industrial Hemp Council 2019 Hemp. Retrieved from FDA: https://www.fda.gov/news-events/speeches-fda-officials/remarks-national-industrial-hemp-council-2019-hemp-business-summit-08132019