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Introduction

Presently, there exists a lack of reliable treatments for chronic pain, inflammation, stroke, and dementia. Recently, evidence has emerged that supports the use of plant-derived aromatic compounds and cannabinoids for the efficacious treatment of these debilitating disorders.

Current scientific literature suggests there are health benefits associated with phytocannabinoids, endocannabinoids, and various plant-derived aromatic compounds including linalool, alpha-humulene, limonene, and beta-caryophellene 1–6. Significant recognition has been given to the phytocannabinoids delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), phytocannabinoids found at varying amounts within Cannabis S. and are responsible for mediating various effects within the human and mouse Central Nervous System (CNS), peripheral somatic and neural tissue7–10. Perhaps most notably, are their significant roles in neuroimmune function. Both humans and mice harbor microglial (a macrophage-like immune cell of the CNS) expression of the cannabinoid receptors: Cannabinoid Receptor 1 (CB1R) and Cannabinoid Receptor 2 (CB2R) within the CNS1. Both endogenous (2-arachidonoyl glycerol) and exogenous (CBD and THC) cannabinoids bind these microglial receptors to either mitigate or enhance immune responses to pathogens and localized injury1,9,10. Therefore, researchers and pharmaceutical companies have been focusing on these compounds as potential novel therapies for various forms of Epilepsy, Fibromyalgia, Alzheimer’s Disease, Hypoxic and Ischemic stroke, Fragile X Syndrome, Depression, Sleep Disorders, and Allodynia2,3,9,11–14. Interestingly, the effects of linalool and beta-caryophellene, constituents of numerous essential oils, provide similar health benefits, to those of phytocannabinoids4,6,15–17. Here we review current literature on exogenous cannabinoids and essential oils. We propose the parallel use of Cannabis-derived phytocannabinoids and select essential oils, through co-action, enhance the therapeutic potential of these plant-based constituents and presents patients with a safe and efficacious treatment of pain, inflammation, stroke, and dementia.

Cannabinoids and Inflammation:

Several studies have shown that Cannabis has a significant role in mediating inflammation. It has been discovered that cannabinoid receptors are expressed in a range of immune cells. By binding to these receptors, cannabinoids can induce downregulation of cytokine and chemokine production and, in some models, upregulate T-regulatory cells as a mechanism to suppress inflammatory responses10. Some recent studies have demonstrated immunosuppression in mice after the administration of THC via enhanced rates of apoptosis in T-regulatory and dendritic cells10. Therefore, the use of exogenous cannabinoids has been nominated as a potential efficacious therapy for inflammatory disorders.

Cannabinoids and Nociception:

Endocannabinoids have been discovered to mediate nociceptive signaling (pain). Specifically, research in animal models has revealed that pharmacological interference of endocannabinoid metabolism results in anti-nociceptive activity, mediated by the CB1 and CB2 receptors18. More recently, exocannabinoids (phytocannabinoids) have been evaluated as a novel pain treatment. A study done using Fibromyalgia (chronic pain syndrome) patients demonstrated that 10-15mg dose/day THC attenuated electrically induced and daily baseline pain12. Moreover, fMRI evidence implies that THC targets visceral aspects of pain in humans by targeting the amygdala and modulating its functional connectivity19. Therefore phytocannabinoids present in Cannabis variants are promising candidates for treating pain as they have been shown to influence both the pharmacological and neuronal mechanism of nociception.

Implications for Cannabinoids in Neuroprotection: Relevance to Alzheimer’s and Ischemic Stroke

The discovery of CB1 and CB2 Receptor expression on Microglia (macrophage-like cells in the CNS) has prompted further investigation into the neuroprotective properties of Cannabinoids. This quality is particularly relevant in Alzheimer’s Disease research (AD). AD is characterized by reduced hippocampal volume due to neuronal cell death (apoptosis). Apoptosis is triggered by a buildup of beta-amyloid protein at the synapse, rendering neurons dysfunctional and signaling cell death. In turn, a neuronal inflammatory response is activated with increased levels of pro-inflammatory molecules (cytokines and interleukins) and causes an increased rate of cell death. Interestingly, administration of CBD reduces the release of proinflammatory molecules from activated microglia and can therefore inhibit this increased rate of cell death9. These effects induced by cannabinoids are also relevant in patients suffering from ischemic stroke. In studies, the activation of CB1 receptors in cerebral blood vessels can have beneficial anti-ischemic effects18. Further studies into the neuroprotective potential of Cannabinoids may reveal novel therapies for these and other neurodegenerative diseases.

Essential Oils Can Aid Chronic Pain, Inflammation, and Dementia

Recent literature has proposed essential oil constituents as potential therapies for treating pain, inflammation, and dementia4–6,15,20,21. This is of particular interest as cannabinoids share similar effects through the same receptors in some cases. Studies have revealed that the essential oil constituents beta-caryophellene, linalool, and limonene exert analgesic effects4,5,22. Notably, beta-caryophellene ameliorates pain through activation of cannabinoid receptors15. As an effective suppressor of inflammation, alpha-humulene and trans-caryophyllene have been shown to induce anti-inflammatory effects comparable to dexamethasone, a common therapy for inflammatory disease21. Furthermore, some essential oils have been shown to improve some memory and motor functions in patients suffering from Alzheimer’s Disease (AD). Specifically, Lemon/Orange/Rosemary/Lavender oils applied twice daily for 28 days markedly improved AD patients abstract cognitive ability and touch panel-type dementia assessment scale (TDAS) scores16. It has been suggested that the simultaneous use of these constituents may enhance their therapeutic potential. As treatment for pain and inflammation is limited to opioids or steroids with adverse effects and high mortality rates, the use of essential oils for alleviating hyperalgesia and inflammatory disease provides a safe and effective alternative. In addition, essential oils offer a potential alternative therapy for enhancing cognitive ability in patients with dementia.

Discussing the Combined Use of Cannabinoids and Essential Oils

Separate research for exocannabinoids and essential oils has elucidated concurrent results. In one study, the injection of linalool reduced nociceptive-like behavior in mice6 while in another, THC was suggested to be responsible for the dissociation of pain observed in fMRI19. In both cases, the perception of pain was significantly reduced. Furthermore, beta-caryophyllene, a major constituent of black pepper and its essential oil, has been shown to inhibit the inflammatory immune response through cannabinoid receptor-mediated activity6,10. Similarly, CBD and THC have both demonstrated inhibition of the inflammatory response through the activation of cannabinoid receptors on microglia9. Suggesting, co-therapy with b-caryophyllene and Cannabinoids as a possible treatment in inflammatory diseases. In the case of AD, Lemon/Orange/Rosemary/Lavender oil treatments improved cognitive ability of patients. Separately, administration of CBD reduces the release of proinflammatory molecules which in turn decreases the rate of cell death characteristic of AD9,16. Taken together, this research implies that the combined use of essential oils and exogenous cannabinoids may be potential novel therapy for the treatment of neurodegeneration, and associated symptoms. of the broad range of diseases which present inflammation and pain, these compounds present promise in the development of numerous, future novel therapies. Although the underlying mechanisms are not fully understood, their potential as treatments has prompted research into their health benefits.

Works Cited

1. Cabral, G. A., Raborn, E. S., Griffin, L., Dennis, J. & Marciano-Cabral, F. CB2 receptors in the brain: role in central immune function. Br. J. Pharmacol. 153, 240–251 (2008).

2. El-Alfy, A. T. et al. Antidepressant-like effect of Δ9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L. Pharmacol. Biochem. Behav. 95, 434–442 (2010).

3. Fusar-Poli, P. et al. Distinct effects of {delta}9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Arch. Gen. Psychiatry 66, 95–105 (2009).

4. Katsuyama, S. et al. Effect of plantar subcutaneous administration of bergamot essential oil and linalool on formalin-induced nociceptive behavior in mice . Biomed. Res. 36, 47–54 (2015).

5. Katsuyama, S. et al. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception. Eur. J. Pain Lond. Engl. 17, 664–675 (2013).

6. Horváth, B. et al. β-caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radic. Biol. Med. 52, 1325–1333 (2012).

7. Beaumont, H. et al. Effect of Δ9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans. Br. J. Pharmacol. 156, 153–162 (2009).

8. Cota, D. et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J. Clin. Invest. 112, 423–431 (2003).

9. Martín-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).

10. Nagarkatti, P., Pandey, R., Rieder, S. A., Hegde, V. L. & Nagarkatti, M. Cannabinoids as novel anti-inflammatory drugs. Future Med. Chem. 1, 1333–1349 (2009).

11. England, T. J., Hind, W. H., Rasid, N. A. & O’Sullivan, S. E. Cannabinoids in Experimental Stroke: A Systematic Review and Meta-Analysis. J. Cereb. Blood Flow Metab. 35, 348–358 (2015).

12. Schley, M. et al. Delta‐9-THC based monotherapy in fibromyalgia patients on experimentally induced pain, axon reflex flare, and pain relief. Curr. Med. Res. Opin. 22, 1269–1276 (2006).

13. Busquets-Garcia, A. et al. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat. Med. 19, 603–607 (2013).

14. Murillo-Rodriguez, E., Aguilar-Turton, L., Mijangos-Moreno, S., Sarro-Ramirez, A. & Arias-Carrion, O. Phytocannabinoids as NovelTherapeutic Agents for Sleep Disorders. (2014). doi:10.1093/acprof:oso/9780199662685.003.0029

15. Gertsch, J. et al. Beta-caryophyllene is a dietary cannabinoid. Proc. Natl. Acad. Sci. 105, 9099–9104 (2008).

16. Jimbo, D., Kimura, Y., Taniguchi, M., Inoue, M. & Urakami, K. Effect of aromatherapy on patients with Alzheimer’s disease. Psychogeriatrics 9, 173–179 (2009).

17. Rombolà, L. et al. Rational Basis for the Use of Bergamot Essential Oil in Complementary Medicine to Treat Chronic Pain. Mini Rev. Med. Chem. 16, 721–728 (2016).

18. Pini, A. et al. The Role of Cannabinoids in Inflammatory Modulation of Allergic Respiratory Disorders, Inflammatory Pain and Ischemic Stroke. Curr. Drug Targets 13, 984–993 (2012).

19. Lee, M. C. et al. Amygdala activity contributes to the dissociative effect of cannabis on pain perception. PAIN 154, 124 (2013).

20. Mitić-Ćulafić, D. et al. Protective effect of linalool, myrcene and eucalyptol against t-butyl hydroperoxide induced genotoxicity in bacteria and cultured human cells. Food Chem. Toxicol. 47, 260–266 (2009).

21. Fernandes, E. S. et al. Anti-inflammatory effects of compounds alpha-humulene and (-)-trans-caryophyllene isolated from the essential oil of Cordia verbenacea. Eur. J. Pharmacol. 569, 228–236 (2007).

22. Gurgel do Vale, T., Couto Furtado, E., Santos, J. G. & Viana, G. S. B. Central effects of citral, myrcene and limonene, constituents of essential oil chemotypes from Lippia alba (Mill.) N.E. Brown. Phytomedicine 9, 709–714 (2002).