Cannabis in Veterinary Medicine

Cannabis in the veterinary industry is a hot topic these days. It’s important to recognize that owners are considering these products for their pets whether recommended by a veterinarian or not. Learn from Jordan McKinney, DVM about the basic information of cannabis for effect conversations with owners.

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As a small animal veterinary professional, particularly one practicing in Portland, OR, it seems highly likely that you have been or will be asked about cannabis as a treatment option for a pet’s condition. It is tempting to just say no, explain we do not have any veterinary studies evaluating therapeutic effects of cannabis and have ample evidence of the toxic effects. However, while true, this answer may not be the most beneficial t­­­o your patient, your client or your practice. A paper published in 2016 in the Journal of the American Holistic Veterinary Medical Association (AHVMA) illustrates that owners are experimenting with medical cannabis for their pets with or without the guidance of a veterinarian. For that reason alone, it behooves us as practitioners to become knowledgeable about the subject. Furthermore, cannabis, and the multitude of biochemical components that that term encompasses, may be a new frontier of therapy for humans and animals alike.

Cannabis

Marijuana historically referred to strains or parts of the Cannabis sativa L plant used for illicit activity. The modifier “medical” was added to distinguish the goal of therapeutics from that of recreation. Given the ambiguity of term “marijuana”, the term cannabis is preferable. Cannabis refers to all aspects of the plant Cannabis sativa L. and products originating from the whole plant.

THC and CBD

To date, 400-500 different chemical constituents originating from the Cannabis sativa L plant have been identified.  ∆-9-tetrahydrocannabinol (THC) is by far the best known of these and is the compound responsible for the “high” associated with cannabis. For nearly all veterinary patients and owners, as well as many people using cannabis for medical purposes, the psychotropic effects are considered adverse. But THC has many potential therapeutic benefits unrelated to the psychotropic effects. Cannabidiol (CBD) is the other compound with which the layperson and scientific community are most familiar. The medicinal potential of CBD is of particular interest, especially in veterinary patients, as it is not associated with the same psychotropic effects as THC. While there is overlap, CBD’s potential benefits are different than THC’s.

Hemp

Both hemp and what has been traditionally referred to as marijuana are cultivars of Cannabis sativa L however they have different biochemical profiles that have afforded them different fates. Hemp is high in fiber, low in THC and high in CBD. For the veterinary patient (and owner), hemp is appealing given its content as well as differing legal status.

Cannabinoids

TCH and CBD are examples of cannabinoids. Approximately 90 cannabinoids, also called phytocannabinoids to designate production in the plant, have been identified in Cannabis sativa L and many have therapeutic potential in addition to THC and CBD. These include, but are not limited to, cannabinol (CBN), cannabichromene (CBC) and cannabigerol (CBG). When discussing therapeutic potential, the term cannabinoid can be used to refer to both phytocannabinoids and synthetic analogs.

In the plant, cannabinoids exist in the carboxylated form. For example, THC is ∆-9-tetrahydrocannabinolic acid, or THCA. THCA is not psychotropic and therefore its medicinal potential has been of interest separate from THC. While it does have therapeutic potential, its effects are not the same as THC. THCA starts to convert to THC at temperatures of 220˚F.  CBDA converts to CBD at around 248 ˚F. This difference is just one illustration of the potential and challenge in creating reliable medicine from cannabis and performing controlled studies on its effects.

The Entourage Effect

In addition to cannabinoids, terpenes, flavonoids and lignans are found in Cannabis sativa L. These are not unique to cannabis but contribute to its biochemical effects both through individual properties and synergistic interactions with cannabinoids. This synergy is sometimes called the entourage effect. THC and CBD also work in consort. For that reason, many proponents of medicinal cannabis feel that using the whole plant provides the greatest benefits and a great deal of energy is put into cultivating plants that have differing and reliable ratios of the many constituents of Cannabis sativa L.

 

The Endocannabinoid System

The endocannabinoid system is responsible for the effects of cannabis and its constituents in the mammalian body. Our understanding of this system is nascent. The THC molecule was discovered in 1964; the first cannabinoid receptor was discovered in 1988. We now know there are at least two major receptors in the endocannabinoid system, CB1 and CB2. These receptors have endogenous ligands, called endocannabinoids.

The major endocannabinoids are N-arachidonoylethanolamine (AEA), which is also called anandamide after the sanskrit word for bliss, and 2-arachidonoylglycerol (2-AG). Anandamide has high affinity for the CB1 receptor and low affinity for CB2 receptors. THC mimics this behavior and is considered anandamide’s phytocannabinoid analog. 2-AG is active at both the CB1 and CB2 receptors, as is CBD, which is considered its phytocannabinoid analog. Several other endocannabinoids have also been identified, including N-palmitoyl-ethanolamine (PEA).

The exact distribution of cannabinoid receptors has not yet been determined for our canine or feline species. In general, CB1 receptors are most densely located in the brain (basal ganglia, hippocampus, cerebral cortex, cerebellum, and amygdala) and spinal cord but are also found in the cardiovascular system, gastrointestinal tract, reproductive tract, liver, muscles, and epidermis. In the nervous system, CB1 receptors are primarily located on pre-synaptic neurons that release glutamate and GABA, inhibiting the release of these neurotransmitters. Endocannabinoids are released from the post-synaptic neuron and undergo a unique process of retrograde signaling called depolarization induced suppression of inhibition (DSI).

CB2 receptors are located in the immune system including spleen, tonsils, thymus, monocytes, macrophages, B-cells and T-cells. They are also found in the gastrointestinal system, brain, though much less densely than CB1 receptors, the peripheral nervous system, cardiovascular system, skin, muscles, and bones. Not as much is known about the CB2 receptor. The two receptors have similar amino acid sequences but while the CB1 receptor is conserved across species, the CB2 receptor structure is more divergent.

Receptor

CB1

CB2

Endocannabinoid

 

Anandamide, (2-AG)

2-AG

Phytocannabinoid

 

THC (CBD)

CBD

Distribution

Brain

Cardiovascular system, gastrointestinal tract, reproductive tract, liver, muscles, and epidermis

Immune system

Gastrointestinal tract, brain, peripheral nervous system, cardiovascular system, skin, muscles, bones

 

Therapeutic Potential

Given the many locations where cannabinoid receptors are found, it is not surprising that the list of potential therapeutic uses of cannabis and cannabinoids is long and growing. No veterinary studies on medicinal uses of cannabinoids have been performed, although one study investigated endocannabinoids in canine atopic dermatitis and another looked at them in canine epilepsy. In the absence of this information, human medical studies and clients who are already using cannabinoids for their pets can help us understand the therapeutic potential for our patients.

In human medicine, cannabinoids are relatively well accepted as treatment for chronic pain, particularly that associated with cancer or neuropathy, muscle spasticity associated with multiple sclerosis, and vomiting/nausea induced by chemotherapy. They are being investigated for use in seizure disorders, cancer, IBD, anorexia, glucose regulation, sleep disorders, depression, anxiety disorders, psychosis, glaucoma, Tourette syndrome, anti-microbiosis and more. The Journal of the American Medical Association published a meta-analysis in 2015 evaluating some of the therapeutic uses of cannabinoids and providing a good overview of the current evidence for those conditions. For other uses, in vitro, laboratory or individual studies are all that is available.

The American Holistic Veterinary Medical Association (AHVMA) surveyed 632 pet owners visiting an online hemp company over the course of a month in 2015 asking what conditions owners were seeking cannabis to treat, the perceived benefit and side effects. The most common conditions for which treatment was sought in dogs were seizures, cancer, anxiety and arthritis; in cats they were cancer, anxiety and arthritis. Other reasons people report administering cannabinoids to their pets include intestinal disorders, nausea/vomiting, appetite stimulation, bacterial or fungal infections, muscle spasms, skin conditions, and glucose regulation. Information about common uses is discussed in more detail below along with the available evidence, if any.

Pain

In the 2015 JAMA meta-analysis, 28 studies evaluating the use of cannabinoids for chronic neuropathic or cancer pain were reviewed and moderate-quality evidence was found supporting it. Thirteen studies evaluated a cannabis extract mouth spray (~ 1:1 THC:CBD ratio), 8 evaluated THC, 1 cannabis (vaporized) and the remainder synthetic cannabinoids. In the AHVMA survey, 64.3% of dog owners and 66% of cat owners felt the cannabis product helped with pain. Analgesic effects are a function of cannabinoid receptors (mainly CB1) in the brain, spinal cord, and peripheral nerves. CBD is thought to have anti-inflammatory properties that also contribute to its analgesic effects.

Cancer

The role of cannabinoids in management of cancer-related pain and nausea/vomiting associated with chemotherapy is relatively well accepted.  However, in vitro and pre-clinical studies have suggested anti-tumor effects as well. The mechanism of action through which this occurs may include induction of apoptosis, inhibition of growth and inhibition of angiogenesis. Interestingly, cannabinoids appear to have these effects on neoplastic cells while protecting non-neoplastic cells. Both TCH and CBD have reported anti-tumor effects. CBD may also increase efficacy of traditional chemotherapy by increasing the uptake of cytotoxic agents into malignant cells and potentiating certain drugs. The feedback from owners in the AHVMA survey regarding tumor growth was equivocal.

Anxiety

In the AHVMA survey, the perceived efficacy of cannabis as an anti-anxiety agent was high for dogs with about 50% of owners reporting beneficial effects. Nearly 40% of cat owners felt the product helped anxiety. The JAMA meta-analysis reviewed one small but limited study that reflected favorably on anti-anxiety potential, however this was considered very low-quality evidence.

Sleep

In the AHVMA survey, both dog and cat owners felt the cannabis product helped with sleep (50.5% and 44%, respectively). Two studies on sleep disorders, both of which used a synthetic cannabinoid, were looked at in the JAMA meta-analysis. Low-quality evidence was found for efficacy.

Seizures

In many ways, the “Charlotte’s Web” story brought medical marijuana into mainstream consciousness. This was the story of a young girl with a refractory seizure disorder whose family turned to a low THC, high CBD strain of cannabis in desperation and found it to be lifesaving. For that reason, seizures are one of the conditions most likely to invoke the cannabis question. However, the evidence supporting efficacy of cannabis in epilepsy is inconsistent.

CBD is reported to have anti-epileptic effects but the mechanism of action is not fully understood. In 2013, a study was published showing that dogs with idiopathic epilepsy had statistically significant increase in concentration of anandamide in their CSF and that this increase was correlated with the severity and duration of their seizure condition. 2-AG was also measured and found to be unaffected. Seizures were perceived to be reduced in 29% of dogs in the AVMHA survey.

Nausea/Vomiting

The JAMA meta-analysis reviewed 28 studies on nausea and vomiting secondary to chemotherapy; the majority of these looked at synthetic cannabinoids. In this analysis only low-quality evidence was found for the anti-emetic effects of cannabinoids however other reviews have shown cannabinoids to be more effective than conventional medications. In the AHVMA survey, few dog or cat owners responded regarding benefit for vomiting/nausea, of those who did the majority felt it was moderately or very helpful. THC is generally considered to be more effective than CBD in reducing nausea/vomiting.

Appetite stimulation

Four studies on appetite stimulation and weight gain from a synthetic THC were assessed by the 2015 JAMA meta-analysis. They were considered low-quality evidence for efficacy of cannabinoids in the application. Appetite stimulation was not assessed as positive outcome in the AHVMA survey but was reported as the second most common side effect for both dogs and cats (after sedation), reported in about 16% of both species.

 

Barriers to Treatment

Despite the promise shown by cannabinoids, there remain significant challenges in using them therapeutically. For veterinary patients, these include legal ramifications, risks of toxicity and dosing dilemmas.

Legal Status

“Marijuana” was criminalized in 1937.  In 1996 California was the first state to legalize cannabis for medical use; since then 27 more states and Washington DC have followed suit. Recreational cannabis was legalized in Colorado and Washington State in 2012; in Alaska, Oregon and Washington DC in 2014; and in California, Maine, Massachusetts, and Nevada in 2016. In 1970, hemp cultivation was outlawed. Since 2014, hemp cultivation has again been legal in the US on a state-by-state basis. “Legal states” are mostly aligned in hemp and medical marijuana laws but not completely.

Regardless of state law, cannabis continues to be a DEA Schedule I substance. Substances in this category have no accepted medical use and a high potential for abuse and include heroin, ecstasy and peyote. The Department of Justice guidelines and subsequent appeals court rulings indicate that legal action will not be taken against medical cannabis in states where it is legal. But even in states where medical and recreational cannabis are legal, veterinarians have no legal right to dispense or prescribe cannabis and doing so could result in loss of license or even criminal charges. According to the OVMEB, “veterinarians may discuss veterinary use of cannabis…. [however] a client’s written consent is needed for any unorthodox treatment.”

Toxicity

No conversation about cannabis in veterinary medicine is complete without discussion of toxicity, a topic with which we are far more familiar than any other.

In 2012, a study evaluating trends in marijuana toxicity in dogs in Colorado was published in JVECCS. The study, conducted from 2005-2010, showed a 4-fold increase over that time period which was correlated with the increase in people registered as medical marijuana users. Only medical cannabis was legal during the study. The most common clinical signs were ataxia, dull mentation, mydriasis, urinary incontinence, hyperesthesia, tremors and vomiting.  In the AHVMA survey, the most common adverse effects reported were sedation and over-active appetite.

Toxicity was more severe with baked goods and two dogs died secondary to ingestion of these products despite the high margin of safety with cannabis: the reported LD50 for THC in dogs is 3000mg/kg. Clinical signs may be seen at doses as low as 0.5mg/kg, although that dose was based on IV administration of THC. Onset of clinical signs is generally within 1-2 hours, however it may be longer, particularly before an owner notices signs. Unfortunately, urine drug tests are not reliable in diagnosing THC toxicity in dogs. A study performed in 1989 reporting cannabinoid receptor localization across multiple species showed dogs have the highest concentration of CB1 receptors in the cerebellum and hindbrain of any species tested. This is likely one reason for the relative sensitivity to cannabis seen in dogs.

Dosing

Intertwined with legal and toxicity issues is an absence of products with reliable cannabinoid concentration or dose delivery. There are a number of synthetic THC pharmaceuticals in the US but few to no options for products with reliable CBD or CBD: THC ratios. Cannabis’ federal legal status means the market remains unregulated. Options are greater elsewhere where products like nabiximols (Sativex) are legal providing a 1:1 THC: CBD ratio in oromucosal spray form. Even with a reliable product, dosing is a challenge; in both humans and veterinary patients, oral bioavailability is inconsistent, particularly of CBD. These variables, along with the rapid development of tolerance in certain individuals, may be why the anecdotal dosing range is so broad: anywhere from 0.1mg/kg/day to 10mg/kg/day has been reported.

 

Conclusion

Cannabis holds many promises for therapeutic use in veterinary medicine however, currently, there is little evidence available and more questions than answers. Clients have shown that they will not wait for the data before using therapeutic cannabis for their pets, though. And so veterinary practitioners are being involved in the conversation and the more studies and research available, the more we will be able to benefit our patients, either in guiding use of cannabis or in educating about its lack of efficacy. To that end, perhaps it is time that the veterinary community join the AMA and other human health care organizations in urging the DEA reschedule cannabis so that further research can be done on cannabinoids’ medical potential.

 

Reference/Further reading:

  1. Abramo F, et al. “Inreased levels of palmitoylethanolamide and other bioactive lipid mediators and enhanced local mast cell proliferation in canine atopic dermatitis.” BMC Veterinary Research. 2014; 10:21.
  2. Andre CM, Hausman JF, Guerriero G. “Cannabis sativa: the plans of the thousand and one molecules.” Frontiers in Plant Science. 2016; 7: 19.
  3. Boothe DM. The high points of medical marijuana. In: Proceedings from the Western States Veterinary Conference; February 2015.
  4. Gesell, FK, et al. “Alterations of endocannabinoids in cerebrospinal fluid of dogs with epileptic seizure disorder.” BMC Veterinary Research. 2013; 9:262.
  5. Herkenham, M, et al. “Cannabinoid receptor localization in brain”. Procedings of the National Academy of Sciences 1990; 87: 1932-1936.
  6. Herold LV. Medical marijuana for pets: what we know and what we don’t know. Proceedings from DovewLewis Annual Conference, 2016.
  7. Krogen, LR , Hellyer PW, Robinson NG. “Consumers’ perceptions of hemp products for animals. JAHVMA. 2016; Volume 42.
  8. Maccorrone M, et al. “Encocannabinoid signaling at the periphery: 50 years after THC.” Trends in Pharmacological Sciences. 2015; 36(5): 277-296.
  9. Meola SD, et al. “Evaluation of trends in marijuana toxicosis in dogs living in a state with legalized medical marijuana: 125 dogs (2005-2010). JVECCS. 2012; 22(6): 690-696
  10. Nolen SR. “Veterinary marijuana?” JAVMA. 2013; 242 (12): 1604-1609.
  11. Nolen SR. “Bad medicine or natural remedy?” JAVMA. 2014; 245 (7): 726-729.
  12. PDQ Cancer Information Summaries: Cannabis and Cannabionoids. 2016. [Internet] https://www.ncbi.nlm.nih.gov/books/NBK65755/
  13. Podell M. Highs and lows of medical marijuana in the treatment of epilepsy. Proceedings from ACVIM, June 2015.
  14. Silver RJ. Medical Marijuana – What every veterinarian needs to know. Proceedings from Wild West Veterinary Converence 2014.
  15. Whiting PF, et al. “Cannabinoids for medical use: a systematic review and meta-analysis.” JAMA. 2015; 313(24): 2456-2473.

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