The Current State of Cannabis Research in Veterinary Medicine
https://todaysveterinarypractice.com/table-of-contents-july-august-2020/
Integrative/Alternative Medicine , Today's Veterinary News

The Current State of Cannabis Research in Veterinary Medicine

Gary Richter DVM, MS

Gary Richter, DVM, MS, graduated from the University of Florida with a Bachelors of Science, Masters of Science in Veterinary Medical Science, and Doctorate of Veterinary Medicine. He began his career as a full-time emergency medicine clinician and general practitioner in Berkeley, California. He has been the owner and medical director of Montclair Veterinary Hospital since 2002 and Holistic Veterinary Care since 2009. He is certified in veterinary acupuncture and veterinary chiropractic.

The Current State of Cannabis Research in Veterinary Medicine
CBD-based products have become popular in recent years, but lack of veterinary-specific studies and the legal landscape leave veterinarians at a loss on fielding client questions. HQuality/Shutterstock.com
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In recent years, pet owners and the veterinary profession have been inundated with cannabidiol (CBD) products. Widespread availability and Internet “buzz” have made over-the-counter hemp-based CBD very popular, and cannabis in general has become one of the most impactful natural medicines to be introduced into modern veterinary practice.

With only a handful of veterinary-specific studies currently available, however, many veterinarians are at a loss regarding how to approach client questions. To address the needs of our clients and patients, we must use veterinary and human medical data in order to better understand how CBD and other cannabis products may be of benefit to animals.

Letter of the Law

Discussion of cannabis as medicine starts with an understanding of the legal framework surrounding these products. All medical cannabis is derived from Cannabis sativa L. Legally speaking, cannabis plants that naturally produce greater than 0.3% tetrahydrocannabinol (THC) are considered to be “marijuana” and are federally illegal. Despite this, over 30 states have laws allowing for medical and/or recreational use. Conversely, plants producing less than 0.3% THC are considered “hemp” and, as of 2018, are federally legal.

Medicinal hemp plants contain relatively large amounts of CBD, which, while legal, is regulated by the U.S. Food and Drug Administration (FDA). At present, only one hemp-based drug has FDA approval. All other hemp-based CBD products available are sold as nutritional supplements. These products still generally contain CBD, and in order to remain legal, companies must be very careful in their labeling, advertising, and marketing. As with any other nutritional supplement, the FDA is watchful to ensure products do not make “drug claims” or are otherwise suggesting their product is a pharmaceutical. This landscape is responsible for the unusual terms sometimes seen on products, such as “phytocannabinoid rich (PCR) oil,” “hemp extract,” and “full extract cannabis oil (FECO).” All of these terms reflect the creative ways companies use to promote their products while keeping the FDA at a safe distance.

One constant in botanical medicine is that medicinal plants rarely, if ever, contain only one biologically active compound. Cannabis plants produce a wide range of phytochemicals including phytocannabinoids and terpenes. Phytocannabinoids are plant-based compounds that act on endocannabinoid receptors throughout the body. There have been over 100 phytocannabinoids isolated from cannabis, and many of these compounds, like CBD and THC, have profound physiologic effects and are the subject of intense medical research.1,2 By contrast, terpenes are isoprene-based essential oils produced by cannabis, many of which also have biological/medicinal activity, including some that have direct endocannabinoid activity.3,4 While the current veterinary research is focused on CBD, it is important to realize that cannabis is not a single active compound. Cannabis is a combination of biologically active phytochemicals working synergistically. This is known as the entourage effect and is believed by many researchers and clinicians to be critical to the efficacy of botanical medicines and cannabis in particular.5,6

Publications from Colorado State University (CSU) and Cornell University documented the pharmacokinetics of CBD in dogs. The CSU study showed orally administered CBD was absorbed better than CBD applied transdermally, although transdermal application does show significant absorption. To demonstrate safety, the CSU study administered oral CBD to dogs at 10 mg/kg/day or 20 mg/kg/day for 6 weeks and found it to be well tolerated in the study population. More than one-third (36%) of animals in the study showed elevations of serum ALP (alkaline phosphatase level) while all other blood parameters remained normal. The elevation in ALP could indicate CBD has the potential to interfere with the metabolism of other hepatically metabolized pharmaceuticals. Additionally, dogs displayed mild enteritis (diarrhea), pinnal erythema, and nasal/ocular discharge.7 The half-life of CBD administered orally at both 2 mg/kg and 8 mg/kg (Cornell) was found to be 4.2 hours.8

A 2018 clinical trial evaluating the effect of CBD on osteoarthritis (OA) in dogs showed reduction in pain scores when treated with CBD at 2 mg/kg q12h vs. placebo with no negative side effects.8 CBD’s efficacy in controlling pain is likely due to its anti-inflammatory effects as well as allosteric modulation of opioid receptors.9 While not yet shown in veterinary-specific research, this implies CBD may be useful for control of other types of pain beyond OA. These pain-relieving effects also extend to other cannabinoids including THC, which may have additional analgesic properties via direct central nervous system effects.10 Clinical experience of many veterinarians and reports from pet owners support this hypothesis.

Cannabis has long been used to treat seizures, and the research confirms what many people have stated for a long time about its ability to decrease seizure severity and/or frequency.11,12 A recent retrospective, non–placebo-controlled study of children with intractable breakthrough seizures despite being on multiple anti-epileptic drugs showed over 50% of participants had a 50% to 100% reduction in seizures with the addition of CBD-rich cannabis.13 In 2018, the FDA approved the first federally legal use of a hemp-based CBD medication, Epidiolex (greenwichbiosciences.com), for the treatment of pediatric seizures caused by Lennox-Gastaut and Dravet syndromes.

The first data for veterinary-specific use of CBD for seizures were evaluated and published in 2019. Seizure frequency of dogs was evaluated with and without the use of cannabidiol in conjunction with other drugs. The study showed a statistically significant 89% reduction in seizure frequency in dogs receiving CBD at 2.5 mg/kg q12h compared to a 43% reduction in the control group. Both study groups were concurrently receiving conventional anti-epileptic drug therapy.14 Despite the statistical significance, the authors noted the “portion of responders was similar between groups.” Additional research was suggested to determine if the correlation between plasma CBD concentration and frequency of seizures indicates higher doses of cannabidiol will provide greater evidence of the anti-seizure properties of CBD in dogs. No severe adverse effects were noted in the study, and blood levels of anti-epileptic drugs in participants were not affected by the addition of CBD.

The two veterinary clinical trials described above evaluated CBD for the treatment of OA and seizures, respectively. It should be noted the formulas used in both studies contained entourage compounds (non-CBD cannabinoids, terpenes, etc.). The role these compounds played in the study results was not evaluated, and it is unknown if the same results would have been found if a pure CBD isolate were used.

Looking Ahead

Cannabis research for veterinary patients is in its earliest stages, with more studies planned and currently underway. While we wait for these to materialize, we can look to previously published research regarding how cannabis may help animals with conditions other than OA and seizures. Pre-clinical and human studies have shown cannabis’ potential efficacy for neuroprotection, anxiety, cancer, gastrointestinal support, and other conditions.15-18 Although veterinary clinical trials are the gold standard, the available current data and a wealth of anecdotal evidence show cannabis (and CBD in particular) to be safe when used appropriately. In the absence of established, and proven effective, treatment options for a variety of conditions, veterinarians need to familiarize themselves and keep current with the state of veterinary cannabis research. In addition, veterinary professionals must stay updated as to the current local and federal legal landscape. Progress in veterinary cannabis research and legal considerations must both be considered when veterinarians decide how they are (or aren’t) going to incorporate cannabis into their practices.

References

1. Russo EB, McPartland JM. Cannabis is more than simply delta(9)-tetrahydrocannabinol. Psychopharmacology (Berl) 2002;165(4):431-432.

2. Pertwee RG. The pharmacology of cannabinoid receptors and their ligands: an overview. Int J Obes (Lond) 2006;30(Suppl 1):S13-S18.

3. Andre CM, Hausman JF, Guerriero G. Cannabis sativa: the plant of the thousand and one molecules. Front Plant Sci 2016;19.

4. Gertsch J, Leonti M, Raduner S, et al. Beta-caryophyllene is a dietary cannabinoid. Proc Natl Acad Sci USA 2008;105(26):9099-9104.

5. Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol 2011;163(7):1344-1364.

6. Russo EB. The case for the entourage effect and conventional breeding of clinical cannabis: no “strain,” no gain. Front Plant Sci 2019;9:1969.

7. Bartner LR, McGrath S, Sangeeta R, et al. Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Can J Vet Res 2018;82(3):178-183.

8. Gamble LJ, Boesch JM, Frye CW, et al. Pharmacokinetics, safety, and clinical efficacy of cannabidiol treatment in osteoarthritic dogs. Front Vet Sci 2018;5:165.

9. Kathmann M, Flau K, Redmer A, et al. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol 2006;372(5):354-361.

10. Weizman L, Dayan L, Brill S, et al. Cannabis analgesia in chronic neuropathic pain is associated with altered brain connectivity. Neurology 2018;91(14):e1285-e1294.

11. Zaheer S, Kumar D, Khan MT, et al. Epilepsy and cannabis: a literature review. Cureus 2018;10(9):e3278.

12. Mack A, Joy J. Can marijuana help? In: Mack A, Joy J, eds. Marijuana As Medicine? The Science Beyond the Controversy. Washington (DC): National Academies Press; 2000:13.

13. Tzadok M, Uliel-Siboni S, Linder I, et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: the current Israeli experience. Seizure 2016;35:41-44.

14. McGrath S, Bartner LR, Rao S, et al. Randomized blinded controlled clinical trial to assess the effect of oral cannabidiol administration in addition to conventional antiepileptic treatment on seizure frequency in dogs with intractable idiopathic epilepsy. JAVMA 2019;254(11):1301-1308.

15. Maroon J, Bost J. Review of the neurological benefits of phytocannabinoids. Surg Neurol Int 2018;9:91.

16. Jurkus R, Day HL, Guimarães FS, et al. Cannabidiol regulation of learned fear: implications for treating anxiety-related disorders. Front Pharmacol 2016;7:454.

17. Hinz B, Ramer R. Anti-tumour actions of cannabinoids. Br J Pharmacol 2019;176(10):1384-1394.

18. Ambrose T, Simmons A. Cannabis, cannabinoids, and the endocannabinoid system-is there therapeutic potential for inflammatory bowel disease? J Crohns Colitis 2019;13(4):525-535.

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