Medical Marijuana for Pets: What We Know and What We Don t Know Lee V. Herold DVM, DACVECC DoveLewis Annual Conference Speaker Notes

Medical Marijuana for Pets: What We Know and What We Don t Know Lee V. Herold DVM, DACVECC DoveLewis Annual Conference Speaker Notes This lecture will be a broad exploration of the topic of medical use of cannabinoids in pets including an introduction to the physiology of the endocannabinoid system. The current and changing regulatory climate around medical marijuana use in humans and the implications to veterinary medicine will be discussed. Why Veterinarians Should Care About Cannabis: Numerous client perception surveys in different disease states including dogs with epilepsy, cats with heart disease, and small animal cancer patients support the notion that clients are more interested in improved quality of life rather than longevity with respect to many diseases and their treatments. Most of us would say that this mirrors our personal experience with many of our clients. In some diseases we have limited traditional options for palliation. In addition some of the options we have are ineffective, are associated with significant side effects or drug interactions, or are logistically difficult for clients to continue with the regular and repeated treatment that is needed for highest success. Chronic pain is a good example of this type of condition but certainly is not the only condition in which we struggle to find the best treatment choice. Of course veterinarians have many options for pain control in our patients but as our patients age we are often faced with having to use combination therapies-combining chronic NSAIDs, chronic opioids, gabapentin, amantadine, acupuncture, laser, and physical therapies in order to keep our patients comfortable. Cannabis therapies may provide another tool in our toolbox to meet the needs of some of these patients. Finally we know that clients are already using cannabis with or without veterinary guidance or discussion. In a survey of pet owners who visited a site to purchase pet cannabis products 34% of respondents said they had not told their veterinarians that they were using cannabis products. Although the survey does not pinpoint the reasons why clients are not telling their vets, most veterinarians irrespective of their personal perceptions about cannabis are likely to agree that when veterinarians are shut out of the conversation about care entirely it can only be detrimental to the pet. Introduction to Cannabis and Endocannabinoid Physiology: Definitions: Cannabis refers to all products from the Cannabis genera of plants which include the most common species Cannabis sativa but also two other species. Marijuana and hemp are both C. sativa derived products. Marijuana has a higher THC concentration v. hemp which is used primarily for industrial cultivation of fiber. For therapeutic purposes both marijuana and hemp products can be used. Cannabinoids refer to substances active on the endogenous cannabinoid receptors. Endocannabinoids are naturally occurring within the body and are the natural ligands for the cannabinoid receptors. The endogenous cannabinoids best characterized are N-arachidonoyl ethanolamide also called AEA or 1

anandamide, and 2 arachidonoyl glycerol or 2-AG. Palmitoylethanolamide or PEA is an endogenous substance which has some affinity for the CB2 receptor but rather than acting as a ligand facilitates the action of other endocannabinoids at the receptor. The term phytocannabinoid refers to a multitude of compounds (>80) that occurs in the C. sativa plant that are all structurally similar and may bind with action on cannabinoid receptors. Delta-9- tetrahydrocannabinol or THC, and cannabidiol (CBD) are the best characterized of the phytocannabinoids. Delta 9 tetrahydrocannabinol or THC is thought to be responsible for much of the psychotropic and toxic effects of marijuana with high affinity for cannabinoid 1 receptor. Cannabidiol is a phytocannabinoid that has low affinity for cannabinoid receptors and is thought to be the primary effector for many of the desirable therapeutic potentials of marijuana Synthetic cannabinoids- are made to be cannabinoid receptor agonists or sometimes antagonists. The term synthetic cannabinoid does not distinguish between cannabinoids that are created to be used therapeutically (some commercially marketed for people) and the synthetic cannabinoids that that are illicit street drugs under the street names K2, Spice and others. Physiology of the Endocannabinoid System: The physiology of the endocannabinoid system has only relatively recently been investigated considering cannabis has been used by many cultures for millennia. Previously the observed effects of THC were thought to be related to action on opioid or other known receptors. However discovery of endogenous cannabinoid receptors and agonists at those receptors has improved our understanding of potential therapeutic effects of cannabinoids. Most of the work has been done over the last 4 decades from the 70 s onward. The first endogenous cannabinoid was found in 1992. There remain gaps in our complete knowledge of the endocannabinoid system in physiology and pathology but some gains have been made in this area. CB1 (cannabinoid 1 receptor) is located primarily in the central nervous system in basal ganglia, cerebellum, hippocampus, cerebral cortex, spinal cord and to a lesser extent in some peripheral tissues. CB1 receptors are in locations that modulate patient perception, memory, movement and the CB1 receptor is thought to modulate most of the effects seen with recreational cannabis use as well. CB2 receptors are located in immune cells and organs-bcells, spleen, and to a lesser degree the CNS. After discovery of the cannabinoid receptors, several endogenous ligands were discovered that bind to these receptors. These endocannabinoids have a physiologic function of modulating pain and inflammation. Some of this modulation may be due to action at receptors other than cannabinoid receptors. Additionally there is suggestion that the endocannabinoid system has a basal level of function. For example it is not just turned on/activated and turned off but rather functions normally at the tonic level- which means it may be possible to decrease the tonicity of the system without completely shutting it off- this mechanism is sometimes referred to as inverse agonism. PEA an endocannabinoid that does not have much affinity for cannabinoid receptors is thought to have action by enhancing effect of AEA or having an entourage effect. Based on the broad distribution of the CB receptors the physiologic role of the endocannabinoid system are likely diverse with functions including pain and sensory modulation, cognitive and memory processing, mood and behavior modification, motor control and coordination, endocrine functions, control and regulation of appetite, temp, heart rate, control of nausea and vomiting, regulation of intraocular pressure, modulation of inflammation and regulation of the immune response. Based on the physiology there are many potential therapeutic targets and mechanisms of action of those therapies. Targets can either increase the effect of cannabinoid receptors and the endocannabinoid system or alternatively decrease the endocannabinoid effect. These goals can be achieve by use of CBR agonists, or enhancing endocannabinoid function (inhibiting degradation 2

enzymes, blocking endocannabinoid reuptake). Decreasing basal level of endocannabinoid tone might be achieved by CBR antagonists/inverse agonists. THC was identified as the psychoactive component of cannabis in the 1960 s and is thought to be responsible for most of the recreational effects as well impairment noted with marijuana use- euphoria, impaired motor function, memory and executive function. Not surprisingly THC is thought to act more at CB1 receptors (the receptors located in regions of the brain that control memory, motor function, and modulate pain). Cannabidiol is the second most evaluated phytocannabinoid that has been investigated second only to THC. Cannabidiol does not have psychotropic effects and thus there is speculation that increasing the CBD:THC ratio in therapeutic formulas would mitigate some of the adverse and undesirable effects of cannabis use but still retain the analgesic, anti-inflammatory and anti-cancer effects. Cannabidiol interestingly has low affinity for CB1 and CB2 receptors and its pharmacologist effects may be secondary to inverse agonism of the CB2 receptor as well as interaction with other receptors- vallinoid, and 5HT receptors. There are many more phytocannabinoids than THC and cannabidiol. Advocates of whole plant use or extract point to the large diversity of phytocannabinoids and their interactions with THC and cannabidiol as accounting for the true therapeutic potential of cannabis use. Phytocannabinoids (plant derived molecules that have action at CB receptors or interact with the endocannabinoid system) have been found in other plants species other than the Cannabis genus with unknown but possibly therapeutic potential. Cannabis in Specific Conditions Pain: The work on cannabinols in modulating pain was performed in lab animal species and there is good evidence from these studies that exogenously administered cannabinoids are anti-hyperalgesia, antinociceptive in these animal models. In a metanalysis of randomized controlled trials evaluating cannabinoid use in humans published in the Journal of American Medical Association in 2015 the odds ratio favored a positive effect of the cannabinoid use in the treatment of pain in people. Authors concluded that there is moderate quality evidence to support the use of cannabinoids in chronic pain. The Journal of the American Holistic Veterinary Medical Association published in spring 2016 a survey of clients visiting an online hemp pet product site to survey their use and perceptions about the hemp products. Despite some of the methodologic limitations and bias provided by the fact that the survey respondents were visiting a hemp product site, the results of the survey do give us some useful information about the choices that clients are making and why they are making those choices regarding hemp and cannabis products. In that survey 64.3% of clients felt like the product helped a moderate to a great deal with pain relief when administered to dogs and 66% of clients felt that it provided moderate to great pain relief in cats. Cancer: Cannabidiol has been demonstrated to have anti-proliferative effects on lung, breast, and colon cancer cell lines by multiple different mechanisms. Not only does this have implication for treating primary tumor but possibly reducing metastasis. Cannabidiol has been shown to enhance apoptosis in cancer cell lines and is anti-angiogenic as it reduces the tumors ability to secrete angiogenic factors. These apoptotic, anti-proliferative effects appear in vitro to be selective for cancer cells and spares normal or healthy cells. It is important to note that these observations are in-vitro and more needs to be done 3

before we can lean very heavily on the benefits of cannabis in cancer therapy but again cannabis products show some promise in this. Cannabis for Nausea/Vomiting/Weight Gain: In the previously referenced 2015 JAMA metanalysis of randomized controlled trials of cannabinoids, the effects of the use of cannabinoids in reducing nausea, vomiting, and promoting weight gain were a bit mixed. Whereas there seemed to be an association of cannabinoid use with improved nausea, vomiting, and weight gain- the quality of evidence to support that assertion was low. In some studies they recognized a trend in support of cannabinoids that did not reach statistical significance. Results from the dog and cat owner perception survey of hemp products mirrored the human metanalysis results in that only 18.8% of respondents felt like it reduced vomiting and nausea a moderate or great deal in dogs. Whereas in cats the number was a bit more at 34.5% of respondents reporting the product used resulted in moderate to great deal of help in reducing vomiting and nausea in cats. The anticancer effects of cannabis mentioned previously are quite preliminary but a more promising avenue in the use of cannabinoids in cancer therapy might be the palliative gains that we can get from some of the cannabis effects in the arena of reduction of nausea, vomiting associated with chemo and improvements in weight gain if these gains are real. Recall that client s perception of quality of life in pets with many different diseases was more important than overall longevity. Client perceived quality of life improvements are often linked to appetite, and weight gain, use of cannabis may be helpful in this arena. Epilepsy or Seizures: Studies have shown that dogs with epilepsy died earlier than normal dogs. Median age at death of dogs with epilepsy was 7 years compared to 10years in historical data. Acceptable seizure control in these studies of epilepsy was varied among owners but generally, owners were able to tolerate monthly seizures, and even weekly seizures for a short time. They were less tolerant of status epilepticus, cluster seizures, or anti-convulsant side effects. Clearly controlling cluster seizures and status epilepticus combined with client education and support by veterinary staff can have positive implications in increasing the lifespan of dogs with epilepsy and can cannabis have a role in this? The interest in the use of cannabis in people to control seizures has gained increasing visibility in the media due to some reports of improvement or even elimination of previously refractory seizures in a few children. There is evidence from animal studies that cannabinoids may have anti-seizure effects. Some of those studies have mixed results for example some report reduced seizures, others increased seizures, and others no effects of cannabis. These differences are thought to be differences in the experimental model of how seizures were induced and the component of cannabis studied as well as the dose. For example THC may increase seizure potential, but cannabidiol (CBD) may decrease it. Case surveys of humans on a cannabis medication that is >90% CBD seemed to support improvement in seizure control with a low incidence of severe adverse effects. Randomized controlled trials of that drug are now ongoing to strengthen evidence in humans. We don t have published reports of use of cannabis in dogs with epilepsy but do have research that suggests an alteration in endogenous cannabinoid levels in canines with epilepsy. Gesell, et. al. measured endogenous cannabinoid levels in dogs with epilepsy and saw an increase in AEA levels in dogs with epilepsy compared with controls. AEA levels were also higher in dogs with longer duration and increased severity of seizures. What is unknown is whether the seizures caused AEA levels to be higher or if AEA levels are higher to compensate for the seizures. Even with this gap in knowledge we can at least say that the endocannabinoid system is altered in dogs with seizure activity. Manipulation 4

of the endocannabinoid system may provide therapeutic potential (hopefully with few side effects) in our canine species though more work and clinical trials need to be performed. Regulation of cannabis: State regulations: Medical marijuana was approved by ballot initiatives in CA, WA, and OR from 1996-1998. Recreational marijuana use was approved in WA in 2012. A similar ballot initiative failed in the 2012 voting year but was approved in 2015 in OR. A recreational legalization initiative will be on this November s ballot in CA with predications that it will likely pass. The individual state legalization of medical marijuana has increased the exposure and experience of people including pet owners to the anecdotal efficacies of marijuana. Recreational use will likely continue to decrease the stigma of possession of marijuana. Both of these effects in our region will increase the translational use of marijuana products to pets. Federal scheduling of cannabis: The drug enforcement administration (DEA) classifies cannabis in Schedule I according to the controlled substances act. Schedule I drugs have no current accepted medical use with high abuse potential and no documented safety and includes drugs such as LSD, peyote, ecstasy, and heroine. Most injectable opioids are schedule II drugs. Both schedule I and schedule II drugs acknowledge the potential for abuse. The difference between schedule I and II drugs are the existence of medically accepted uses for S II drugs, and the demonstrated safety when used under medical supervision. Petitions to the DEA to change the scheduling of cannabis have been rejected. Most recently efforts by Washington Governor Jay Inslee and others as recently as July of 2016 were rejected. The Department of Justice (DOJ-the legal enforcement arm of the federal government) in August of 2013 issued a memorandum to US attorney generals providing guidance regarding marijuana enforcement stating that the federal government will focus its enforcement priorities on: Preventing marijuana distribution to minors, preventing marijuana revenue from going to criminal enterprises, preventing diversion from legal states to illegal marijuana states, preventing marijuana to be a cover for trafficking in other illegal drugs, preventing violence in the cultivation and distribution of marijuana, preventing growing on public lands, and preventing possession on federal property. Otherwise the DOJ defers to state and local enforcement to address marijuana activity. Physicians are stuck in the uncertainty between balancing state and federal rules regarding cannabis. Whereas in medical marijuana legal states, the DOJ is not likely to enforce marijuana law outside of their previously stated initiatives, physicians are licensed to prescribe controlled drugs through the DEA not the DOJ. Physicians remain subject to sanctions from DEA for violation of the controlled substances act with regard to ability to prescribe other controlled drugs (opioids). Physicians may risk their accreditation from the DEA to have opioid inventory or dispensing rights if found in violation of the controlled substances act. In medical marijuana legal states- physicians do not dispense or prescribe the marijuana but rather recommend it to avoid these sanctions. The patient with a recommendation is then able to purchase through a dispensary or is authorized to grow/cultivate marijuana based on specific state statutes. Veterinarians remain in a similar regulatory no man s land as physicians. A veterinarian s ability to have controlled substances (opioids, barbiturates) that we use every day in inventory and our ability to dispense those drugs are subject to DEA licensing. If the regulations lag behind in human healthcare, there is very little incentive to provide guidance to veterinarians with respect to cannabis use and dispensing for animals. Veterinary boards have taken a cautious approach to guiding their membership about cannabis use in veterinary species. Oregon Veterinary Medical Examining Board sent the following statement to licensees via the executive director of OVMEB: Veterinarians may discuss veterinary use of cannabis with clients, and are advised to inform clients about published data on toxicity in animals, as well as lack of scientific data on benefits. Please be aware that a client s written consent is needed for any unorthodox treatment. 5

The Washington State Department of Health veterinary license division stated on their website in regard to marijuana use in pets stated: The law doesn't allow veterinarians to authorize medical marijuana for animals or humans, and doesn t authorize the use of medical marijuana for pets. Toxicity: Clinical signs of toxicity associated with acute marijuana ingestions in dogs have been well characterized with onset of signs usually within 1-2hrs of ingestion. Clinical signs are predominantly central nervous system signs including ataxia, incoordination, hypersalivation, depression, disorientation, hypothermia, mydriasis, and tremors. Bradycardia and urinary incontinence have also been observed with high prevalence. Rarely obtundation, coma and death have been reported. Lethal oral dose is high ~ 3g/kg but this dose is much higher than that required to see clinical signs of toxicity. Toxicity may be associated with other toxic exposures (chocolate) based on route of exposure with edibles (brownies, chocolates), marijuana butter, joints, bong water, etc. A diagnosis of THC toxicity is made presumptively based on clinical signs, and history of possible exposure. Urine drug screening tests are inaccurate for evaluation in dogs. Therapy is symptomatic and supportive. GI decontamination (emesis and activated charcoal) is rarely required unless large ingestions are known. Duration of clinical signs can range from 1day to up to 5 days. IV lipid therapy has been reported in the treatment of some severe cases of synthetic cannabinoid exposure in dogs with reported success in improvement in clinical signs. Veterinarians should keep in mind that the wide distribution and therapeutic potential of the cannabinoid receptor physiology also lends itself to having wide and possibly varied toxic effects when attempting to use cannabinoids therapeutically. Challenges or Opportunities: There are many challenges I can see to using cannabis routinely in veterinary species and underlying all of these is a lack of information. Research and good studies even if observational studies need to be done so we can identify which specific diseases and patients this therapy might benefit. We don t know enough about dose effects, routes of administration, and what formulation of cannabis might offer the best treatment outcomes with the least side effects. For example should we be using more purified agonists or is using the whole plant extract better? The best route of delivery might be different for different diseases. Topical routes may be more appropriate for cutaneous allergic disease or in the treatment of glaucoma for example. Obviously we need to know more about side effects and adverse effects. Finally we need some guarantee of active ingredient concentration- For example if we find that a 3% cannabidiol solution is the most therapeutic then products should have some guarantee of concentration of that active ingredient. These regulations of product consistency remain elusive today even in human cannabis products. All of these obstacles and restrictive regulatory scheduling has resulted in a vacuum of clinically useful research on cannabis in veterinary species. This is underscored by the fact that we have much more published literature on the toxicity and toxic presentations with marijuana than we do on the therapeutic indications in companion animals. References/Suggested Readings: 1. Ceitec AS. The use of cannabinoids in animals and therapeutic implications for veterinary medicine : A review The use of cannabinoids in animals and therapeutic implications for veterinary medicine : a review. 2016;2016(August):111 22. 2. Campora L, Miragliotta V, Ricci E, Cristino L, Biol D, Marzo V Di, et al. Cannabinoid receptor Type I and 2 expression in the skin of healthy dogs and dogs with atopic dermatitis. Am J Vet Res. 2012;73(7):988-994. 3. De Petrocellis L, Cascio MG, Di Marzo V. The endocannabinoid system: a general view and latest additions. Br J Pharmacol. 2004;141(5):765 74. 6

4. Fischer KM, Ward DA, Hendrix DVH. Effects of a topically applied 2% delta-9- tetrahydrocannabinol opthalmic solution on intraocular pressure and aqueous humor flow rate in ate in clinically normal dogs. Am J Vet Res 2013;74(2) :275 80. 5. Fitzgerald KT, Bronstein AC, Newquist KL. Marijuana Poisoning. Top Companion Anim Med. Elsevier; 2013;28(1):8 12 6. Friedman E, Gershon S, Hine B, Torrelio M. Cardiovascular effects of delta9- tetrahydrocannabinol in conscious and anaesthetized dogs. Br J Pharmacol 1977;59(4):561 3. 7. Gesell FK, Zoerner AA, Brauer C, Engeli S, Tsikas D, Tipold A. Alterations of endocannabinoids in cerebrospinal fluid of dogs with epileptic seizure disorder. BMC Vet Res. 2013;9:262. 9. Massi P, Solinas M, Cinquina V, Parolaro D. Cannabidiol as potential anticancer drug. Br J Clin Pharmacol. 2013;75(2):303 12. 10. Meola SD, Tearney CC, Haas SA, Hackett TB, Mazzaferro EM. Evaluation of trends in marijuana toxicosis in dogs living in a state with legalized medical marijuana: 125 dogs (2005-2010). J Vet Emerg Crit Care. 2012;22(6):690 6. 11. Nunamaker E, Newhall K, Thompson C, Lucas A, Owens J, Sherman JG. Safety evaluation and treatment affect of LY2190416, a CB-1 antagonist/inverse agonist in growing beagle dogs. J Vet Pharmacol Ther. 2011;34(6):577 82. 13. Richardson JD. Cannabinoids modulate pain by multiple mechanisms of action. J Pain. 2000;1(1):2 14. 14. Ritter JM. Exploiting modern cannabinoid pharmacology for therapeutic gain? Br J Clin Pharmacol. 2012;73(5):671 3. 15. Sachs J, McGlade E, Yurgelun-Todd D. Safety and Toxicology of Cannabinoids. Neurotherapeutics. 2015;12(4):735 46. 16. Svíženská I, Dubový P, Šulcová A. Cannabinoid receptors 1 and 2 (CB1 and CB2), their distribution, ligands and functional involvement in nervous system structures - A short review. Pharmacol Biochem Behav. 2008;90(4):501 11. 18. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez A V, et al. Cannabinoids for Medical Use. Jama. 2015;313(24):2456. 8 19. Williams K, Wells RJ, McLean MK. Suspected synthetic cannabinoid toxicosis in a dog. J Vet Emerg Crit Care. 2015;25(6):739 44. 20. Kogan LR, Hellyer PW, Robinson NG. Consumer Perceptions of Hemp Products For Animals. Journal of AHVMA. 2016;42(3): 40-8. 21. Teitler JB. Evaluation of Human On-site Urine Multi-drug test for Emergency Use with Dogs. J Am Anim Hosp Assoc 2009;45:59-66 22. Filloux FM. Cannabinoids for pediatric epilepsy: Up in smoke or real science. Transl Pediatr 2015:4(4):271-82 23. Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and Epilepsy. Neurotherapeutics 2015;12:747-68. Selected Internet Resources: For a chart documenting legislation in the current 25 Legal Medical Marijuana States and the District of Columbia: http://medicalmarijuana.procon.org/view.resource.php?resourceid=000881 Washington State Department of Health- Veterinary Licensing Division: http://www.doh.wa.gov/licensespermitsandcertificates/professionsnewreneworupdate/veterinarian Drug Enforcement Agency Responses to Petitions for Marijuana Rescheduling: https://www.dea.gov/divisions/hq/2016/hq081116.shtml 7