What we know about cannabinoid therapy is “tip of the iceberg”

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Cannabis therapy has received increasing attention from human and veterinary medical professionals in the last several years. Hemp products, which became more widely available after the passage of the 2018 Farm Bill, are the subject of ongoing research and have been hailed as a therapy for many conditions that ail both humans and animals. But cannabis is not a panacea, according to Tim Shu, DVM, founder and CEO of VETCBD. “There are very specific things for which cannabis can be effective,” he said during a recent Fetch dvm360® virtual conference session.

Cannabis basics

Cannabis is classified into hemp and nonhemp products. Hemp, which is legally defined in the United States as cannabis with 0.3% tetrahydrocannabinol (THC) or less by dry weight, is the product that has become widely studied and commercially available, although it is still not legal in all states. Nonhemp products, colloquially referred to as marijuana, are still considered Schedule 1 drugs by the US Drug Enforcement Administration, although in some states marijuana is allowed for certain medical conditions.

The cannabis plant contains more than 500 active compounds. Phytocannabinoids are the molecules that interact with the body and may have anxiolytic, anticonvulsant, neuroprotective, analgesic, antiemetic, antineoplastic, and anti-inflammatory effects. Although some cannabinoids cause intoxication, most do not.

THC and cannabidiol (CBD) are the major phytocannabinoids. THC is the molecule known for causing dose-dependent intoxication when used recreationally. CBD is the nonintoxicating substance that has been proposed to have numerous therapeutic properties, many of which are supported by preclinical studies and clinical trials.

The endocannabinoid system: what you didn’t learn in vet school

The therapeutic effects of cannabinoids are produced through the interaction of these molecules with the endocannabinoid system (ECS), which is present in all vertebrates and plays a role in homeostasis of bodily functions. Our understanding of this system and its role in both health and disease processes is still developing.

The endocannabinoid system was discovered in the late 1980s and has yet to be widely taught in nursing, medical, or veterinary schools. To highlight the large amount of education about this system that is currently lacking, Shu challenged the audience to “imagine if the endocrine system wasn’t taught in vet school.”

This body system works through lipid signaling and contains 3 major components:

• Receptors, most notably CB1 in the central nervous system and CB2, which plays a role in immunomodulation
• Endogenous cannabinoids, which are synthesized in the body and known as endocannabinoids
• Enzymes that produce, transport, and degrade the endocannabinoid molecules

As with many other body systems, the ECS does not operate in a vacuum. Endocannabinoids have been found to interact with many receptors in the body, and the term endocannabinoidome has been used to refer to this interaction of the ECS with other body systems.

Evidence for efficacy

One of the major critiques of cannabinoid therapy has been a lack of clinical evidence. Shu explained that research historically has been limited due to the classification of cannabis as a Schedule 1 substance. Although the classification of THC is unchanged, the 2018 Farm Bill legalized hemp and hemp derivatives, leading to a growing body of clinical research on CBD.

“We want people to understand that in terms of scientific evidence, there are specific uses for which [cannabinoids] have a lot of established benefits,” Shu said. He uses the acronym PAINS for the uses that are currently supported by the literature in human and veterinary medicine: pain, anxiety, inflammation, nausea, and seizures.

Since 2018, several clinical studies of cannabinoid therapy in dogs have been released. Osteoarthritis pain has been the focus of many studies, which have shown increased mobility and decreased pain in dogs with this condition.^1-3 This research includes 2 randomized, placebo-controlled studies.^1,2

An additional double-blind, placebo-controlled study from 2019 showed a significant reduction in seizure frequency in dogs with epilepsy when cannabinoid therapy was added to their existing treatment protocol.⁴ However, the placebo group showed a similar proportion of dogs with a reduction in seizure frequency.

Although many have suggested that cannabinoids are useful in cancer treatment, clinical evidence is lacking. Several preclinical studies using in vitro testing and animal models have demonstrated antitumor effects through various mechanisms, but until true clinical studies are published, the efficacy of cannabinoids as therapy for neoplasia remains debatable.

Keys to effective use of cannabinoid therapy

The optimal dosing for cannabinoids varies by the condition being treated and the individual patient. This variability is due to individual differences in the ECS, likely due to genetics, and variances in individual bioavailability. “The best way to dose is to start low and gradually titrate upward until you see optimal effects,” Shu said. It is known that the peak plasma concentration after oral administration in dogs occurs within 1 to 2 hours.¹

Even though CBD has a wide safety margin, some situations bring potential for increased adverse effects. Because cannabinoids interact with multiple body systems, they should be used with caution in patients with cardiovascular disease. Additionally, there is potential for drug interactions because CBD is a competitive inhibitor of cytochrome P450, which could result in higher blood plasma levels of drugs that are metabolized in this pathway. Finally, ataxia or other movement-related adverse effects may be seen more often in dogs when utilizing cannabinoids that are CB1 agonists, such as THC.

Shu also encouraged practitioners to look at the cannabinoid profile of different products when choosing a product to prescribe. Some products are a single isolate, whereas others are full-spectrum products containing multiple cannabinoids. The “entourage effect” theory suggests that the effect of multiple cannabinoids used together is greater than the effect of any 1 cannabinoid used in isolation, which means full-spectrum products may be more efficacious. This is currently being studied.

What comes next?

Shu likened the current knowledge of the ECS and cannabinoid therapy to being “at the tip of a very, very large iceberg. One that, quite frankly, we don’t know [the size of].” As more is learned about the function of the ECS in both health and disease, practitioners will gain a better understanding of potential uses for cannabinoids. This knowledge, combined with existing data, will help to guide future clinical research to maximize the use of cannabinoid therapy for veterinary patients.

Kate Boatright, VMD, a 2013 University of Pennsylvania graduate, is a practicing veterinarian, freelance speaker, and author who lives in western Pennsylvania. She is passionate about mentorship, education, and addressing common sources of stress for veterinary teams and recent graduates. Outside of clinical practice, Boatright is actively involved in organized veterinary medicine at the local, state, and national levels.

References

1. 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. doi:10.3389/fvets.2018.00165
2. Verrico CD, Wesson S, Konduri V, et al. A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. Pain. 2020;161(9):2191-2202. doi:10.1097/j.pain.0000000000001896
3. Kogan L, Hellyer P, Downing R. The use of cannabidiol-rich hemp oil extract to treat canine osteoarthritis-related pain: a pilot study. J Am Holistic Vet Med Assoc. 2020;58:35-43.
4. McGrath S, Bartner LR, Rao S, Packer RA, Gustafson DL. 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. J Am Vet Med Assoc. 2019;254(11):1301-1308. doi:10.2460/javma.254.11.1301