EUFORIS SCIENTIFIC SUBSTANTIATION

Hemp extract

There are many clinical studies underway regarding the use of cannabis or CBD to treat different disorders: cancer, anxiety, epilepsy, etc. that can be checked at the U.S. National Library of Medicine1.

At a veterinary level, three professionals in the USA that have been working with cannabis extracts for treating cats and dogs stand out: Gary Richter, Robert Silver and Caroline Coile. We can read about their clinical experiences and recommendations on the therapeutic use of cannabis on different publications2-4. Although in the USA the legal situation of cannabis is complex, the therapeutic efficacy of this plant has allowed to find a way to enable its safe administration to pets.

It is therefore undeniable that cannabinoids have fully entered the research field because of their novel and safe mechanism of action. They are also providing an answer to disorders that can currently only be tackled partially or symptomatically, and that is why the clinical expectations and interest are even greater.

Delta (9)-tetrahydrocannabinol binds cannabinoid (CB (1) and CB (2)) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of Delta (9)-tetrahydrocannabinol, which are mediated by activation of brain CB (1) receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than Delta (9)-tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to Delta (9)-tetrahydrocannabivarin, a novel CB (1) antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity5. Cannabidiol has extended proof on its powerful anti-

inflammatory, analgesic, anxiolytic, antioxidant and neuroprotective properties6-8.

The ECS has been shown to be involved in the development of canine OA in a very recent study in which endogenous molecules that regulate the ECS activity were measured9. Surprisingly, it was seen that the levels of two of them (2-AG and oleoylethanolamide) where higher in the patients with OA in comparison with healthy dogs, this suggesting, for the first time, a direct involvement of the ECS in the development of this joint disease in dogs. The authors of the article point out that the CBR agonists, such as phytocannabioids from Cannabis sativa, can become an innovative treatment for canine OA9. In fact, therapies with different (synthetic or plant) cannabinoids have been already developed for human patients with OA or rheumatoid arthritis (RA)10. Moreover, in year 2000, researchers from the Kennedy Institute of Rheumatology in London showed that CBD has an anti-arthritic ability in mice11.

Cannabinoids have proved their analgesic effects through different mechanisms12. One of them is related to the neurotransmission of glutamate. The activation of the glutamate receptor in the postsynaptic neuron induces the synthesis of 2-AG, that releases and activates CBR1 in the presynaptic neurons. This blocks the calcium inflow and stops the release of neurotransmitters. Cannabinoids exert a negative feedback mechanism (retrograde signaling), that can act directly, by activating the CBR1, or indirectly, by modifying the activity of the enzymes that synthesize or break down cannabinoids (FAAH or MGL, for example). Probably, the antinociceptive effect may be mediated by the inhibition of the release of glutamate in the areas related to pain.

A report drafted by the National Academies of Sciences Engineering Medicine affirms that there are substantial or conclusive evidences that show the efficacy of cannabis in the treatment of chronic pain in adults13, highlighting, once more, the great potential of cannabis for treating pain. Likewise, there are a pair of examples that serve, once more, as a great indication of this analgesic effect:

  • The improvement of pain was the most noted effect in the pets that were administered a cannabis-containing product14.
  • In those countries where medicinal cannabis has been legalized, the use of opioids has dropped dramatically15.

A reason that causes frequent visits to the veterinarian is itching, because it bothers both the pet and the owner. In these disorders there is a clear immune, nervous and inflammatory problem for which cannabis extract offers a therapeutic window. Along these lines, a study discovered an overexpression of CBR1 and CBR2 in epithelia of dogs with atopic dermatitis16. In addition, the immunomodulating ability of phytocannabinoids17 can also help to control the skin disorders not only for reducing the annoying symptoms, but also to regulate the hyperactivity of the immune cells implied in their physiopathology.

Epilepsy is one of the most common chronic neurologic disorders in dogs, and it is characterized by an imbalance in the neuronal excitability that causes recurrent convulsions18. It is deemed that this disease cannot be controlled in 25% of the dogs that suffer it19, showing the urgent need for finding alternative treatments with less side effects. There is a great deal of research with regard to the use of cannabinoids against epilepsy in humans20, including five Chinese studies1. Although the use of phytocannabinoids for canine and feline epilepsy has not been thoroughly studied, the great number of veterinary clinical experiences, coupled with the good results as anticonvulsants in human patients, suggest that phytocannabinoids can be an excellent therapeutic support tool for these disorders.

Cannabinoids have proven their ability in modulating the activity of microglia in several in vitro and in vivo models21. In an Alzheimer’s disease model in mice, the administration CBD reduced the expression of several proinflammatory cytokines released from microglia (such as iNOS and IL-1β)22, that caused an improvement in cognitive function23. Likewise, in animals with memory loss, CBD helps to improve it24.

Last but not least, it is not surprising that phytocannabinoids, particularly cannabidiol, have an anxiolytic effect, because they can regulate the activity of the ECS at the central nervous system level and thus modulate the processes related to anxiety25. In pets, a report revealed that almost 50% of the owners noticed an obvious improvement of anxiety in their dogs when they administered them a product containing cannabis26.

Fish oil and omega-3 fatty acids

Omega-3 fatty acids have an antioxidant and anti-inflammatory ability, and therefore they are very useful in cases of joint problems in dogs. A study conducted in 2010 showed that the supplementation with omega-3 fatty acids improved the walking ability in dogs with osteoarthritis (OA) in one or more joints27. Along the same lines, dogs with OA showed a decrease in lameness and an increase in the weight bearing ability when they were provided an omega-3 rich diet28. Bearing these results in mind, it is not a surprise that the supplementation with omega-3 fatty acids allows to reduce the amount of anti-inflammatory medications (carprofen) needed by dogs with OA29.

Bearing in mind the key role of omega-3 fatty acids on brain performance, it is not surprising that the supplementation with omega-3 fatty acids has shown important benefits in the improvement of cognitive dysfunction. For instance, the supplementation with docosahexaenoic acid (DHA) from seaweed improved the cognitive performance parameters in an in vivo study of canine ageing in Beagles30. Likewise, omega-3 fatty acids also have a positive impact in the neuronal development of puppies. By fortifying the diet of pregnant bitches, the DHA levels are increased in the pups, and this turns into an improvement in the electroretinogram responses31.

  1. S. National Library of Medicine. Clinical Trials. Available at: https://clinicaltrials.gov/ct2/home
  2. Coile, D. C. Cannabis and CBD science for dogs: natural supplements to support healthy living and graceful aging. (Assisi Bio Press, 2016).
  3. Richter, G. The ultimate pet health guide: breakthrough nutrition and integrative care for dogs and cats. (Hay House, Inc., 2017)
  4. Silver, R. J. Medical marijuana and your pet: the definitive guide. (Lulu Publishing Service, 2015)
  5. Izzo, A. A., Borrelli, F., Capasso, R., Di Marzo, V. & Mechoulam, R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 30, 515–527 (2009)
  6. Pisanti, S. et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Ther. 175, 133–150 (2017)
  7. Booz, G. W. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Biol. Med. 51,1054–61 (2011).
  8. Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome. N Engl J Med. 2017 May 25;376(21):2011-2020.
  9. Valastro, C. et al. Characterization of endocannabinoids and related acylethanolamides in the synovial fluid of dogs with osteoarthritis: a pilot study. BMC Vet. Res. 13, 309 (2017)
  10. Barrie, N. et al. Endocannabinoids in arthritis: current views and perspective. Int. J. Rheum. Dis. 20, 789–797 (2017)
  11. Malfait, A. M. et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc. Natl. Acad. Sci. 97, 9561–9566 (2000)
  12. Woodhams, S. G., Chapman, V., Finn, D. P., Hohmann, A. G. & Neugebauer, V. The cannabinoid system and pain. Neuropharmacology 124, 105–120 (2017)
  13. National Academies of Sciences, E. and M. The Health Effects of Cannabis and Cannabinoids. (National Academies Press, 2017).
  14. MacFarlane, P. D., Tute, A. S. & Alderson, B. Therapeutic options for the treatment of chronic pain in dogs. Small Anim. Pract. 55, 127–134 (2014).
  15. Boehnke KF, Litinas E, Clauw DJ. Medical Cannabis Use Is Associated With Decreased Opiate Medication Use in a Retrospective Cross-Sectional Survey of Patients With Chronic Pain. J Pain. 2016 Jun;17(6):739-44
  16. Campora, L. et al. Cannabinoid receptor type 1 and 2 expression in the skin of healthy dogs and dogs with atopic dermatitis. Am. J. Vet. Res. 73, 988–995 (2012).
  17. Booz, G. W. Cannabidiol as an emergent therapeutic strategy for lessening the impact of inflammation on oxidative stress. Free Radic. Biol. Med. 51,1054–61 (2011)
  18. Gesell, F. K. et al. Alterations of endocannabinoids in cerebrospinal fluid of dogs with epileptic seizure disorder. BMC Vet. Res. 9, 262 (2013).
  19. Thomas, W. B. Idiopathic Epilepsy in Dogs and Cats. Vet. Clin. North Am. Small Anim. Pract. 40, 161–179 (2010)
  20. Capasso, A. Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview. Open Neurol. J. 11, 61–73 (2017)
  21. Martin-Moreno, A. M. et al. Cannabidiol and Other Cannabinoids Reduce Microglial Activation In Vitro and In Vivo: Relevance to Alzheimer’s Disease. Mol. Pharmacol. 79, 964–973 (2011)
  22. Esposito, G. et al. Cannabidiol in vivo blunts β-amyloid induced neuroinflammation by suppressing IL-1β and iNOS expression. Br. J. Pharmacol. 151,1272–1279 (2009)
  23. Ramirez, B. G., Blázquez, C., Gómez del Pulgar, T., Guzmán, M. & de Ceballos, M. L. Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation. J. Neurosci. 25,1904–1913 (2005)
  24. Lee, J. L. C., Bertoglio, L. J., Guimarães, F. S. & Stevenson, C. W. Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. J. Pharmacol. 174, 3242–3256 (2017).
  25. Blessing, E. M., Steenkamp, M. M., Manzanares, J. & Marmar, C. R. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics 12, 825–836 (2015)
  26. Kogan, L. R., Hellyer, P. W. & Robinson, N. G. CONSUMERS’ PERCEPTIONS OF HEMP PRODUCTS FOR ANIMALS Scientific Report. AHVMA J. @BULLET 42, (2016)
  27. Roush, J. K. et al. Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs. J. Am. Vet. Med. Assoc. 236, 59–66 (2010).
  28. Roush, J. K. et al. Evaluation of the effects of dietary supplementation with fish oil omega-3 fatty acids on weight bearing in dogs with osteoarthritis. J. Am. Vet. Med. Assoc. 236, 67–73 (2010).
  29. Fritsch, D. A. et al. A multicenter study of the effect of dietary supplementation with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis. J. Am. Vet. Med. Assoc. 236, 535–539 (2010).
  30. Hadley, K. B., Bauer, J. & Milgram, N. W. The oil-rich alga Schizochytrium sp . as a dietary source of docosahexaenoic acid improves shape discrimination learning associated with visual processing in a canine model of senescence. Prostaglandins, Leukot. Essent. Fat. Acids 118, 10–18 (2017).
  31. Heinemann, K. M. & Bauer, J. E. Docosahexaenoic acid and neurologic development in animals. J. Am. Vet. Med. Assoc. 228, 700–705 (2006).