In geriatric practice and palliative medicine, we can see a wide range of medical conditions, oftentimes with multiple ailments coexisting in the same patient. Attempting to treat them all can be exhausting for clients, raises the risks associated with polypharmacy, and in some cases, results in patients outright refusing treatment. The focus of palliative and hospice care is to achieve the best quality of life possible for the patient and the family. Sometimes, this can be difficult for doctors who are trained so well in what we “can do,” that it can be hard to let go and focus instead on what we “should do.” Part of that goal should include finding ways to best support our patients in a way that also strengthens the human-animal bond and puts the least stress on both parties. With people spending more time at home due to COVID-19, many pet owners perhaps have more time to provide nursing care for their aging or ill animal companions. As we seek new ways to help support aging and ailing pets and their loving families, medical cannabis holds considerable promise and is a therapy that may be considered. For millennia, people have used the cannabis plant as a source of medicine, not only for themselves, but for their animals.1 In recent years, there has been a resurgence of interest in its medical applications—again, not just for people, but for the animals with whom we share our lives. Although various states have legalized recreational and/or medical marijuana, veterinarians are not yet able to legally prescribe, dispense, or recommend most cannabis-based therapies. That said, change is afoot. In 2019, California became the first state to give veterinarians legal protection to discuss the use of medical cannabis for their animal patients in their licensed practice. If history is any indication, other states will likely follow suit. As such, it is incumbent upon us to have a basic understanding of how cannabis works, and the conditions where it shows the most promise. Cannabis and the ECS The cannabis plant has been found to contain more than 400 chemical compounds, including over 100 cannabinoids, 120 terpenes, as well as phenolic compounds, bioflavonoids, and antioxidants. The composition of each plant’s compounds can vary significantly depending on several factors, including the cultivar strain, growing conditions, harvest time, drying and curing, and the final processing methods. We are only just beginning to understand how these many compounds work within the body, and how they interact with each other to produce a specific effect. The endocannabinoid system (ECS)—which is found in all vertebrates (as well as some invertebrates)—may well be the largest receptor system in the mammalian body. The two primary cannabinoid receptors, CB1 and CB2, along with the many other receptors that work within the ECS, can be found in almost every organ system. CB1 receptors are located primarily in the brain, and when activated by their primary exogenous ligand—tetrahydrocannabinol (THC)—are responsible for the psychoactive effects commonly associated with cannabis use. However, these receptors are also found in muscle, fat, gonad, glandular, gastrointestinal, liver, kidney, and lung tissues. Found primarily within the immune system, CB2 receptors are also expressed in the brain, peripheral nervous system, and the gastrointestinal system, and are also activated by THC, along with β-caryophyllene, a terpene found in cannabis. Others such as serotonin (5-HT) receptors, glycine receptors, vanilloid (TRPV) receptors, peroxisome proliferator-activated receptors (PPARs), and G protein-coupled receptors (e.g. GPR18, GPR55, and GPR118) are also directly involved in the ECS through activation by cannabinoids, including cannabidiol (CBD). While no cannabis-based products have been approved for animal use, we know from experience this has not stopped pet owners from seeking out and administering them to their pets. The focus of palliative and hospice care is to achieve the best quality of life possible for the patient and the family. Considering its wide range of effects on the body, cannabis is a promising treatment for numerous conditions, and as some human patients have reported, can provide relief and sometimes reduce or replace a number of conventional therapies. Extrapolating from these reports, cannabis may hold similar promise for animals. Let’s take a look at three diverse, though common conditions in geriatric and palliative medicine, and explore the science behind the potential effects we could reasonably expect cannabinoid medicine to play. 1) Chronic pain, including pain from osteoarthritis: Chronic pain, and particularly pain from osteoarthritis, is a condition most practitioners deal with on a daily basis among our senior patients. When treatment options are exhausted or become cost- and/or time-prohibitive, unmanageable chronic pain can lead to the humane euthanasia of a beloved pet. Current therapeutic options have typically included the use of nutraceuticals, NSAIDs, gabapentin, tramadol, other opioids, amantadine, acupuncture, massage, photomodulation (i.e. laser therapy), and rehabilitation. Clinical studies have shown cannabis can reduce pain and improve mobility in animal studies of osteoarthritis,2,3,4 including several recent papers assessing the effectiveness of CBD-based products on dogs with this condition.5,6,7 What makes cannabis so unique to many other treatments is its potential to address arthritic pain through multiple mechanisms, including chondroprotection, anti-inflammatory action, and analgesia. Chondroprotection Studies show chondrocytes from osteoarthritic joints were found to express a wide range of cannabinoid receptors even in degenerate tissues, demonstrating these cells could respond to cannabinoids.8 This is an exciting area to watch as further research becomes available. Inflammation Peripherally, modulation of TRPV1 receptors by CBD and activation of CB2 receptors on immune cells by either THC or β-caryophyllene reduce the release of proinflammatory molecules, thereby lessening the inflammatory response, which is a direct cause of pain. Additionally, a number of minor cannabinoids, including cannabidiolic acid (CBDA), tetrahydrocannabinolic (THCA), cannabigerolic acid (CBGA), and cannabigerol (CBG), have all been found to reduce COX-2 activity by at least 30 percent when sufficient tissue levels are achieved.9 Analgesia The following are ways in which cannabis can reduce pain at multiple levels of pain processing, including peripheral, spinal, and supraspinal pathways.10 By reducing inflammation as noted previously, nociceptor signaling decreases, resulting in lower pain levels Activation of CB1 decreases the release of excitatory neurotransmitters (glutamate and glycine) in the dorsal horn of the spinal cord. CB2 receptors are upregulated during chronic neuropathic and inflammatory pain, and are blocked by THC. Activation of CB1 receptors in the brain by exogenous THC modulates the emotional processing of pain signals. In other words, cannabinoid therapy can reduce the inflammation triggering a pain response, diminish the signal getting to the brain, and once in the brain, alter the brain’s perception of that pain. 2) Cognitive dysfunction and anxiety: Anxiety in senior pets can be due to many causes, including pain, a reduction in hearing/vision that can make them feel less secure, and cognitive changes. Pet owners using hemp-derived CBD products for their pets have reported that age-related behavioral changes and general anxiety are some of the most common reasons for using cannabis. They also report a high degree of satisfaction with the results (93 percent and 83 percent, respectively, reported cannabis products helped either “a moderate amount” or “a lot” for the given condition).11 Several of the terpenes in cannabis, including limonene (found in citrus fruits) and linalool (found in lavender), are known to contain anxiolytic properties.10 CBD also has been shown to reduce anxiety through a number of pathways, aside from its role in reducing pain and pain-associated anxiety. CBD acts as a 5-HT1A receptor agonist. Activation of these serotonin receptors leads to a boost in serotonin levels, as well as increased dopamine release. (Our more commonly prescribed selective serotonin reuptake inhibitors [SSRI] work by increasing serotonin levels through inhibition of reuptake.) When treatment options are exhausted or become cost- and/or time-prohibitive, unmanageable chronic pain can lead to humane euthanasia of a beloved pet. CBD also has been shown to promote neurogenesis in the hippocampus. Human patients with depression or anxiety often have a smaller hippocampus, and successful treatment of depression is associated with the birth of new neurons (neurogenesis) within the hippocampus. Similar changes, if they occur in companion animals, could provide a method to measure changes and assess the therapeutic effects of cannabis treatment. However, the anxiolytic properties extend beyond the terpenes and CBD, as THC facilitates fear extinction and has been shown to aid in post-traumatic stress disorder (PTSD) and similar conditions. Although we do not yet have studies looking specifically at canine and feline cognitive dysfunction syndrome (CDS) and cannabis use, CDS in dogs has been found to be a reasonable model for human Alzheimer’s disease (AD). Here, the use of cannabis has been shown beneficial in animal models of Alzheimer’s, as well as clinically in people with dementia. Studies using mice as a model for AD demonstrate the use of THC/CBD in early stages, as well as in advanced stages, can help reduce symptoms and memory impairment. THCA—the naturally occurring acidic form of THC—is shown to have neuroprotective effects in neurodegenerative/neuroinflammatory diseases. In models of AD, cannabinoids were found helpful due to several actions on the associated buildup of beta-amyloid plaques and the aggregation of tau proteins. Cannabinoids were shown to: reduce both beta-amyloid production and aggregation; facilitate the removal of amyloid plaques by macrophages; reduce the hyperphosphorylation of tau proteins, which leads to tau protein aggregation; and reduce neuroinflammation, oxidative stress, and microglial activation.11 Supporting these findings are the human studies that revealed patients with dementia taking cannabis oil were reported to have reduced delusions, agitation/aggression, irritability, apathy, anorexia, sleep disturbances, and caregiver distress. 3) Cancer: Of all conditions discussed, perhaps the one that has attracted the most attention is the use of cannabis in the support and treatment of cancer. Consider this: A PubMed search for “cannabinoid cancer” produces 1,541 results. Yet, despite all this research, we are only beginning to scratch the surface on how we can best use cannabis clinically, and in what conditions. Indeed, the research shows various cannabinoids and terpenes can have a direct effect on tumor growth through a multi-targeted approach, as well as providing palliative support for many of the symptoms accompanying both cancer and cancer therapy. Cannabis extracts, as well as CBD and THC isolates, have been shown through a variety of both in vivo and in vitro studies to have anticancer properties in various neoplastic conditions. They exert their antineoplastic effects by promoting apoptosis, reducing tumor cell proliferation, and improving response to some chemotherapeutics and radiotherapy.13,15,16 The response varies depending on the type of cancer and the composition of the extract used17, but nonetheless cannabis-derived therapies show tremendous promise as part of oncology treatment. Even without targeting a resolution of cancer itself, cannabis also has proven beneficial in reducing some of the symptoms associated with this disease. Through various pathways, compounds found within cannabis can help manage pain, reduce nausea (including chemo-induced nausea), improve appetite, allow improved sleep quality, and reduce anxiety and depression. Final thoughts It is clear there is still much work to be done to further our understanding of ECS, the various compounds found within cannabis, and how they all work together. Given the extensive variation of cannabis product composition and the individual differences in response to cannabinoids, establishing clear dosing guidelines for patients has been difficult. Nonetheless, with the appropriate guidance and dose titration, many human patients have found the use of cannabis to be extremely beneficial for a range of medical conditions. The expectation is that the same will be said of animal patients in the near future. As we move forward, let us strive to understand more about cannabis as a medicine, keeping our minds open to the possible therapeutic roles it may play in improving our patients’ overall quality of life. Every day we have with our pets is a gift. Perhaps cannabis could help us share more of them. Sarah Silcox, DVM, CVA, CVSMT, is a founding director and current president of the Canadian Association of Veterinary Cannabinoid Medicine (CAVCM), a national nonprofit corporation founded by a group of veterinary professionals. Dr. Silcox can be reached via email at sarah.cavcm@gmail.com. References 1 James L. Butrica (2002) The Medical Use of Cannabis Among the Greeks and Romans, Journal of Cannabis Therapeutics, 2:2, 51-70, DOI: 10.1300/J175v02n02_04 2 Hammell DC, Zhang LP, Ma F, et al. Transdermal cannabidiol reduces inflammation and pain-related behaviours in a rat model of arthritis. European Journal of Pain (London, England). 2016;20(6):936-948. doi:10.1002/ejp.818. 3 Burston JJ, Sagar DR, Shao P, et al. Cannabinoid CB2 Receptors Regulate Central Sensitization and Pain Responses Associated with Osteoarthritis of the Knee Joint. Price TJ, ed. PLoS ONE. 2013;8(11):e80440. doi:10.1371/journal.pone.0080440. 4 Philpott HT, O’Brien M, McDougall JJ. Attenuation of Early Phase Inflammation by Cannabidiol Prevents Pain and Nerve Damage in Rat Osteoarthritis. Pain. 2017;158(12):2442-2451. doi:10.1097/j.pain.0000000000001052. 5 Gamble L-J, Boesch JM, Frye CW, et al. Pharmacokinetics, Safety, and Clinical Efficacy of Cannabidiol Treatment in Osteoarthritic Dogs. Frontiers in Veterinary Science. 2018;5:165. doi:10.3389/fvets.2018.00165. 6 Verrico CD, Wesson S, Konduri V, Hofferek CJ, Vazquez-Perez J, Blair E, Dunner K Jr, Salimpour P, Decker WK, Halpert MM. A randomized, double-blind, placebo-controlled study of daily cannabidiol for the treatment of canine osteoarthritis pain. Pain. 2020 Apr 24:10.1097/j.pain.0000000000001896. doi: 10.1097/j.pain.0000000000001896. Epub ahead of print. PMID: 32345916; PMCID: PMC7584779. 7 Kogan, Lori & Hellyer, Peter & Downing, Robin. (2020). The Use of Cannabidiol-Rich Hemp Oil Extract to Treat Canine Osteoarthritis-Related Pain: A Pilot Study. 8 Dunn SL, Wilkinson JM, Crawford A, Bunning RAD, Le Maitre CL. Expression of Cannabinoid Receptors in Human Osteoarthritic Cartilage: Implications for Future Therapies. Cannabis and Cannabinoid Research. 2016;1(1):3-15. doi:10.1089/can.2015.0001. 9 Ruhaak, Lucia & Felth, Jenny & Christina Karlsson, Pernilla & Rafter, Joseph & Verpoorte, Robert & Bohlin, Lars. (2011). Evaluation of the Cyclooxygenase Inhibiting Effects of Six Major Cannabinoids Isolated from Cannabis Sativa. Biological & Pharmaceutical Bulletin. 34. 774-8. 10.1248/bpb.34.774. Volume 157, 2018, Pages 198-228, ISSN 0223-5234, https://doi.org/10.1.16/j.ejmech.2018.07.076. 10 Pál Pacher, Sándor Bátkai and George Kunos, The Endocannabinoid System as an Emerging Target of Pharmacotherapy. Pharmacological Reviews. 2006 Sept; 58 (3) 389-462; DOI: https://doi.org/10.1124/pr.58.3.2 11 Kogan LR, Hellyer PW, Robinson NG. Consumers’ Perceptions of Hemp Products For Animals. J Am Holist Vet Med Assoc. 2016;42:40–48 12 Tarmo Nuutinen. Medicinal Properties of Terpenes Found in Cannabis Sativa and Humulus Lupulus, European Journal of Medicinal Chemistry,Volume 157, 2018, Pages 198-228, ISSN 0223-5234, 13 Watt G, Karl T. In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer’s Disease. Frontiers in Pharmacology. 2017;8:20. doi:10.3389/fphar.2017.00020. 14 Velasco G, Sánchez C, Guzmán M. Anticancer Mechanisms of Cannabinoids. Current Oncology. 2016;23(Suppl 2):S23-S32. doi:10.3747/co.23.3080. 15 R. Ferro et al. GPR55 Signalling Promotes Proliferation of Pancreatic Cancer Cells and Tumor Growth in Mice, and Its Inhibition Increases Effects of Gemcitabine, Oncogene (2018). DOI: 10.1038/s41388-018-0390-1 16 Yasmin-Karim S, Moreau M, Mueller R, et al. Enhancing the Therapeutic Efficacy of Cancer Treatment With Cannabinoids. Frontiers in Oncology. 2018;8:114. doi:10.3389/fonc.2018.00114. 17Baram L, Peled E, Berman P, Yellin B, Besser E, Benami M, Louria-Hayon I, Lewitus GM, Meiri D. The heterogeneity and complexity of Cannabis extracts as antitumor agents. Oncotarget. 2019 Jun 25;10(41):4091-4106. doi: 10.18632/oncotarget.26983. PMID: 31289609; PMCID: PMC6609248. 18 See bit.ly/2P5D0hs 19 Financial Post, “Boomers ‘bringing cannabis use with them’ as StatsCan paints picture of shifting demographics,” Jan. 25, 2018
