CBD: Forget the legal issues—does it work in veterinary patients?

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Veterinarians are being bombarded these days by questions, requests, lofty claims, unrealistic expectations and patchy scientific information about cannabidiol (CBD) products for pets. Public demand is outpacing the research as clients increasingly gain access to these products and, on the advice of a neighbor or internet article, begin using them on Max and Maizy. It's a bit of a free-for-all.

Scientific input from reliable sources is simultaneously vague and overwhelming, largely because this is uncharted territory. Researchers are still investigating the endocannabinoid and phytocannabinoid systems in people and animals, along with the phytopharmacology of the cannabinoids themselves. All of this needs to be unraveled before the veterinary profession has clarity, and while the unraveling is happening, demand is growing faster. Existing research gets a spotty summarization in most veterinary lectures on CBD-for one, there's never enough time to explain it all, and two, the story is not complete.

Even so, research data is not what most veterinarians want to hear. They want to know about clinical usage. Unfortunately, the data is not yet translatable into reliable clinical information for all the claims made. While over 23,000 scientific papers on cannabinoids in humans, lab animals and companion animals in 24 different species have been published, the jury is still out on exactly what CBD products are effective for and what they are not.

Plus, despite a relatively good therapeutic safety index, they can cause harm, so caution is necessary. If they do cause problems, and veterinarians have been involved in recommending them, they can be held legally responsible for the outcome, and this includes both civil and criminal liability.

Legal and regulatory issues aside (because those change almost daily-and you should definitely stay in touch with veterinary legal experts in your state for specifics), what exactly do we know about the science and clinical value of CBD so far?

Several experts spoke at a recent 2019 Fetch dvm360 conference about their experience and knowledge of CBD, including some case-based information on its use in veterinary medicine. Robert Silver, DVM, MS, CVA, chief medical officer for Rx Vitamins and a practicing small animal veterinarian in Colorado, is seeing some trends and passed along what he recommends so far. Stephen Cital, RVT, RLAT, SRA, VCCS, CVPP, VTS-LAM, co-founder of the Veterinary Cannabis Academy and director of education and development for ElleVet Sciences, added his expertise as well.

Dosage

Prior to recent studies, the generally accepted therapeutic dose range for CBD in animals has been 0.1 to 0.5 mg/kg twice daily, but you can go as high as 5 mg/kg twice daily, according to Dr. Silver and Cital. A Cornell study shows that dosing as high as 8 mg/kg is safe,1 but this is not very cost-effective or practical, says Cital, who notes that dosing has been updated to 0.1 to 2 mg/kg twice daily based on now-available canine and feline data.

Also, these experts say, not all patients will respond the same to standardized dosing. It is speculated that animals may need to have an endogenous “deficiency” in the endocannabinoid system to respond to these products.

As far as we know at this time, Dr. Silver says, cats and dogs should be treated the same way.

Route

The most commonly accepted route of administration at this time is oral, these experts say. Although there are many forms of CBD and routes to choose from (concentrates, topicals, transdermals, vaporizers, nebulizers, suppositories, capsules or tablets, soft chews, powders, biscuits and so on), these are all still being studied in animals. Since bioavailability will be different for different routes, the recommendations for each will be different, and there are no guidelines yet.

Cital also warns that any transdermal or inhalation route will bypass first-pass metabolism through the liver. So “inhalers or vaporizers may be the new wave, but be very careful using this route,” he says, noting the lack of evidence in companion animals as well.

Pain management

Lower doses of CBD are generally adequate for neuropathic pain, but higher dosages are often necessary for conditions causing chronic pain and inflammation such as osteoarthritis (OA), says Dr. Silver. Cital suggests starting with 1 to 2 mg/kg twice daily as support for either form of discomfort and titrating to effect. NSAIDs and cannabinoids can act synergistically, so dual use may lower the necessary dose of either.

Dr. Silver has been finding 0.5 mg/kg twice daily to be effective, and he reports that other veterinarians also find lower doses to work well for painful patients. “It's worthwhile to start at this lower dose, which may provide a successful outcome, in order to reduce the cost and amount of hemp extract to be administered,” he says. The use of CBD together with opioids may allow a reduction in opioid doses, as CBD indirectly stimulates opioid receptors, producing an opioid-sparing effect, he says.

Cancer

Cannabinoids appear to be able to fight cancer, possibly through the induction of cancer cell death, anti-angiogenesis and some anti-metastatic properties, these experts say. Cital reports that an in vitro study looking at three different canine cancer cell lines was just completed by Joseph J. Wakshlag, DVM, PhD, at Cornell University, with results expected out by 2020. Dr. Wakshlag is also working on a quality of life in vivo study.

While Dr. Silver cautions that many claims surrounding CBD and cancer are, so far, not based in evidence, he also says researchers have discovered the presence of receptors on tumor cells for cannabinoids. He knows of a veterinary oncologist who was treating a lingual mass using non- tetrahydrocannabinol (THC) CBD as a sole treatment (0.5 mg/kg twice daily). Six weeks later the mass was reduced to nearly nothing.

Another anecdote involved a dog named Olive with an appendicular fibrosarcoma whose owners did not want to amputate. Non-CBD-containing nutraceuticals were used first, with success, for one year, and then the tumor started to grow again. The patient was started on a 1:1 CBD:THC product, and within 90 days the tumor had shrunk dramatically. In another account, a dog with an undifferentiated nasal carcinoma with bone lysis was treated with a non-THC CBD product (0.4 mg/kg twice daily), and the tumor shrunk significantly over six weeks of treatment. The dog was still in remission 14 months later.   

Tolerance

All humans and animals have been shown to develop tolerance to certain cannabinoids, such as THC, with chronic use, these experts say. This means if you're using them successfully for cancer treatment and then stop, the cancer may recur. If it does, as is the case with some other chemotherapeutic drugs, it has usually developed tolerance to CBD products, according to pet owners and oncologists who've observed this phenomenon anecdotally. It's important to warn clients about this. “If you get a tumor response and stop, it will come back, and it will come back resistant,” Dr. Silver warns.

It's also speculated that secondhand smoke may create THC tolerance in animals, Dr. Silver said, but further studies are needed.

Seizures

THC itself is psychotropic, so it is not considered an anti-seizure drug-it has been reported to actually cause seizures. Therefore, any THC in a CBD product could theoretically make a seizure patient worse, but studies are incomplete. Cital notes that the manufacturer of the FDA-approved CBD medication Epidiolex conducted a 56-week-long study of rats and dogs at high doses of both THC and CBD (roughly 25 mg/kg twice daily) and were unable to induce any seizures in dogs.

However, Dr. Silver warns, “we are in the infancy of use [of CBD products] adjunctively with epileptic medications.” He describes a Colorado State University study of CBD for refractory epilepsy (2.5 mg/kg twice daily) in which some dogs experienced a 40% reduction in seizures-not a very impressive result, Dr. Silver says.2 A new study at a higher dose (4.5 mg/kg twice daily) is taking place now, but it's too early to draw valuable conclusions. Still, he says, for uncomplicated seizures that aren't frequent or are well-controlled with anti-convulsant drugs, veterinarians and pet owners are finding that 0.5 to 1.0 mg/kg of CBD twice daily can control seizures and, in some cases, allow for reduced doses of anti-epileptic drugs.

Michelle Carnes, MS, DVM, DACVIM, a veterinary neurologist who gave an update on seizure management at Fetch dvm360 in 2019, does not recommend using CBD products in seizure patients at this time. She says the oral bioavailability of many CBD products is too poor, and CBD is a potent inhibitor of cytochrome P450 with a long half-life in dogs, which could potentially interfere with other medications.

“There are still no extensive studies in dogs,” she says, describing the same CSU study that found little improvement in canine epilepsy when CBD was used as an adjunctive drug.2 She reports that popular thinking surrounding use of CBD in animals with epilepsy originates from the treatment of seizures with Epidiolex in children with severe, difficult-to-treat forms of epilepsy.

“This drug is extremely expensive and has now been reclassified as a schedule 5 drug,” Dr. Carnes says. It would not be affordable, or easily available, for veterinary patients at this time, even if it was found to be effective. “That aside, if we take the average human CBD product, using the current recommended dose in humans (5 to 10 mg/kg), and extrapolate this to dogs, the cost would be $444 per month for a 20-kg dog.”

Dr. Carnes is not opposed to CBD, but at this time her conclusion is that it is “expensive, unregulated, and the purity is not [adequate]” for use in dogs with epilepsy, adding that it may be a long time before it's found useful.

Metabolism

CBD is metabolized by the cytochrome P450 system in the liver, which means drug competition problems are possible. According to Dr. Silver, this process has not been studied well, but rising alkaline phosphatase (ALP) levels with CBD use have been consistently noted in studies.1,2 He says the CSU study found that concurrent use of CBD appeared not to change phenobarbital or potassium bromide blood levels, but this was only a pilot study.2 Larger studies are taking place now.

Dr. Carnes delivered an anecdotal “metabolic” warning in her lecture, describing a case study-her own case-in which (unbeknownst to her) the owner gave CBD to his difficult-to-control epileptic dog for eight months. The dog was already on a moderate dose of phenobarbital. He had no seizures for those eight months, but his phenobarbital levels went from 30 to 50 µg/ml in that time. The dog became ataxic and weak, his liver values went “through the roof,” and the dog died of liver failure shortly thereafter. Dr. Carnes warns veterinarians to “remind clients that CBD is still a drug!”

Cital reports that, despite these concerns, veterinary pharmacologist Dawn Boothe, DVM, MS, PhD, DACVIM, DACVCP, has personally reported no drug interactions or adverse effects associated with CBD and seizure medication combination therapies in her work at Auburn University. He also notes that “not all CBD products are alike.” They may contain varying levels of cannabinoids, terpenes and contaminants that may either help or endanger a patient. When clients are using CBD products on pets without guidance, anything can happen. It's truly “buyer beware,” Cital says.

Adverse effects and toxicity

Diarrhea seems to be a common adverse effect for CBD, but so far studies don't seem to be showing any long-term adverse effects associated with bloodwork or urine testing.3 However, these experts say, the study lengths might be too short and the parameters too narrow at this time, with researchers needing more time for analysis. More recently a 12-week-long study in dogs and cats was published noting no statistical changes or concerns on physical examination, complete blood count or serum chemistry profiles.4

THC toxicoses, on the other hand, are a major problem, and veterinarians need to at least advise clients to avoid harming their pets. “Too often in Colorado people are getting adult medical marijuana and giving it to pets,” says Dr. Silver. “Human dosages of these drugs will send pets to the ER. Hemp products do contain THC and can cause typical signs of THC toxicity, but they are more mild effects.”

Here's one important message that's consistent from all specialists: No human edibles! “There is a huge risk of xylitol toxicity,” Dr. Silver says. Cital reports that products may also include grape and raisin extracts without careful labeling. Cital also notes again that toxic contaminants in poorly produced products could also be dangerous to pets.

Future hopefuls

There's lots of enthusiasm for the therapeutic use of hemp products, even those with THC, for medicinal human and animal use. Cital notes a long list of potential future usages, including eye drops for glaucoma, tumor injections, stimulation of bone growth, safe sedation for puppies and young animals, anesthesia induction, inhalers for lung cancer (CBD may have pulmonary cytoprotective properties), pain relievers from certain parts of the plant, antifungal and antimicrobial bedding for animals, treatment for chronic cystitis in cats, use for chronic dermatitis in dogs and cats, and treatment of inflammatory bowel disease, among others. Another use for hemp products is biowaste cleanup-they're able to absorb pollutants from the environment and can be used to reduce the effects of greenhouse gases.

How to choose a CBD product

In the absence of clear guidelines, what should veterinarians look for in a CBD product? A National Animal Supplement Counsel (NASC) Seal of Quality Assurance is a good start. The NASC is a trade group for nutraceuticals that is taking the lead on trying to regulate the safety of commercial cannabis and hemp products, Dr. Silver says. Both Dr. Silver and Cital recommend that a certificate of analysis indicating potency, per-dosing unit, all ingredients, and the presence of mycotoxins, metals or pesticides can help you determine if a product is reasonably safe. Sadly, many manufacturers do not provide this information or offer only a limited version. Hopefully this will improve over time, these experts say.

Science

Why does this herb have such biomedical value? At least part of it, Dr. Silver reports, is that the body makes its own (endo)cannabinoids as part of the nervous system, or at least as a partner to it. There are cannabinoid receptors in the brain, heart, lungs, liver, spleen, intestinal tract, muscles, bone, reproductive system and circulatory system, among others. There is some evidence to suggest that the endocannabinoid system is responsible for the “runner's high” in people. “It's really the largest system in the body, but we didn't even know about it until recently,” Dr. Silver says.

Conclusion

Many veterinarians have adopted a “Well, it can't hurt” attitude when it comes to CBD. Some of us have been reluctant to discuss these products at all. Neither approach appears to be the correct one. We as veterinarians should be careful recommending these products and urge our clients to be cautious, taking a position of “harm reduction.”

“If we cannot answer client questions at this time, we can at least become more knowledgeable until we can,” Dr. Silver says. Remember, anything that sounds too good to be true usually is, but CBD products may just turn out to have some astonishing medicinal values. We just can't tell you what they are yet.

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.

2. 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. J Am Vet Med Assoc 2019;254(11):1301-1308.

3. 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.

4. Deabold KA, Schwark WS, Wolf L, et al. Single-dose pharmacokinetics and preliminary safety assessment with use of CBD-rich hemp nutraceutical in healthy dogs and cats. Animals 2019;9(10):832.

Dr. Carla Johnson practices emergency medicine at Berkeley Dog and Cat Hospital in Berkeley, California, and general practice at Cameron Veterinary Hospital in Sunnyvale, California. Her nonveterinary loves are writing, dressage with her Iberian warmblood mare, watercolor painting, yoga and running with her dog Tyson. Try as she might, her curly-coated Scottish fold Hootie refuses to go jogging with her.