According to the World Health Organization, 2.5% of the world’s population consumes cannabis. While the recreational use of cannabis is still a controversial topic, the wide variety of therapeutic applications has now, uniquevically, convinced the scientific world of its medical importance. Despite that, only 6% of existing studies on cannabis analyze its medicinal properties. Meanwhile, an increasing number of stories depicting how this amazing plant has helped people and their medical conditions are appearing on web platforms, contributing to a deeper social awareness about the multiple benefits of this incredible plant.

Healthcare practitioners have found staying ahead of public awareness difficult. To close the wide gaps between what research, clinicians and the lay public are learning from the internet on their own, this report will aim to equip the healthcare practitioner with the fundamentals and important clinical applications of cannabis medicine that are based in validated scientific research. In particular, the roles of the endocannabinoid system and phytocannabinoids will be discussed in detail, with an emphasis on the medical use of CBD.

Since the Food and Drug Administration (FDA) has not yet taken a clean stance on the health benefits of cannabinoid-based products, patients are looking to their healthcare providers for information and validation. It is time that clinicians are supported in helping patients to find answers and comprehensive solutions to their medical cannabis questions and medical concerns.

Read: CBD Oil Statistics 2021 - The Who, How, and Why of Using CBD Oil for Health

The Endocannabinoid System (ECS) and Cannabidoil (CBD)

“Relax, eat, sleep, forget and protect” - Di Marzo

The major components of the ECS:

- Receptors: CB1 and CB2
- Endocannabinoids: Anandamide (N-arachidonoylethanolamine or AEA) and 2-arachidonoylglycerol (2-AG )
- Synthesizing enzymes: Diacylglycerol lipase (DGL)
- Degrading enzymes: Fatty acid amide hydrolase (FAAH), Monoacylglycerol lipase (MGL)

The ECS was discovered in 1989 as a lipid-based signaling system now known to be common to all mammals - all vertebrate organisms have one. The ECS is comprised of cannabinoid (CB) receptors, endogenous ligands, and the synthesizing and degrading enzymes that build and break down the endogenous ligands on demand. The primary CB receptors are named CB1 (c. 1988) and CB2 (c. 1990).

CB1 receptors are neuromodulating, G-protein-coupled receptors located throughout the central and peripheral nervous systems, while sparing the brain stem. They can also be found on end organs, such as the lungs, liver and kidneys, as well as on endocrine and reproductive organs. CB2 receptors are immunomodulating and are found in immune tissues, hematopoietic cells, the digestive tract, and throughout the circulatory system. CB receptors are also found in adipocytes and in musculoskeletal tissues.(1, 4–7, 9, 10, 14–17, 19–34)

The brain not only contains the densest concentration of CB receptors in the body, but therein exists more CB receptors than any other receptor type. The ECS manages excitatory and inhibitory processes in the brain, modulating the neurogenesis of hippocampal granule cells, which regulate the timing of endocannabinoid release in accordance with the brain’s needs, management of memory, pain perception, mood, synaptic plasticity, motor learning, appetite and taste regulation, and metabolic function (which regulates the storage of energy and transport of cellular nutrition). CB receptor binding sites located in the brain are associated with higher cognitive function, movement control and sensory functions attributed to the autonomic nervous system, and more. (1, 4, 20, 21)

Cannabinoids (whether endogenous or plant-derived) bind to the receptors in the brain and elsewhere they exist. The endogenous cannabinoids, anandamide and 2-AG are physiological ligands for the CB receptors and are produced locally on demand, acting as retrograde transmitters that modulate and balance cellular neurotransmission and signaling. Remember that the ECS modulates homeostasis and therefore chiefly operates in response to over- or under-stimulation at synapse or cell surfaces.

Amongst many mechanisms of action, known and suspected, are the modulation of neurotransmitter release from central and peripheral neurons, and cytokine secretion from macrophages in the marginal zone of the spleen. Phytocannabinoids, in their ability to bind to CB receptors, mimic homeostatic mechanisms. Phytocannabinoids confer unique physiological effects on the human body as well, but yet and still are considered to all have a generally positive effect on modulating homeostasis. (4, 5)

CBD, a non-intoxicating cannabinoid, can be extracted from agricultural hemp. CBD does not bind directly to CB receptors (binding allosterically), but does interact with various other receptors in the body. For example, CBD affects stress genes, such as Soat2 and Cyp27a1, which control sterol (i.e., cholesterol) metabolism. CBD is also an agonist at 5-HT1A (serotonin) receptors and TRPV1 receptors, affecting mood and pain perception respectively.

CBD has also been shown to increase and sustain the concentration of anandamide and other vital lipids by blocking degrading enzyme production. This increases the availability of circulating serum endocannabinoids that might otherwise be subject to premature degradation, and increases the binding rates of endocannabinoids at CB receptors. (6)

CBD can also reduce the ‘high’ that might be experienced with THC intake. THC, upon binding to a cannabinoid receptor can cause a ‘high,’ while CBD, working allosterically to the THC-CB binding site, reduces that ‘high.’

Clinical Endocannabinoid Dysfunction: Deficiency and Excess

A 2004 study proposed that ‘clinical endocannabinoid deficiency’ (CECD) is causative in pathological conditions like migraine, fibromyalgia and IBS. The hypothesis was that all humans have an underlying endocannabinoid tone that is a reflection of levels of the endocannabinoids, their production, metabolism, and the relative abundance and state of cannabinoid receptors. In certain conditions, whether congenital or acquired, this overall endocannabinoid tone becomes deficient and productive of pathophysiological syndromes.

Continued review of studies over the decade that followed this initial hypothesis has more firmly established the case. Given CBD’s effectiveness in raising serum concentrations of endocannabinoids, the research study suggests that the use of CBD could have therapeutic benefits in the treatment of the conditions of endocannabinoid deficiency. (7)

Research reviews have further illustrated that ECS dysfunction goes beyond CECD and can also be characterized by overactivity. Whether overactive or underactive, as in CECD, ECS dysfunction has three primary categories: genetic, acquired and idiopathic autoimmune.

Genetic dysfunction relates to a hereditary acquisition of the disorder; acquired refers to an infectious or traumatic origination, and idiopathic autoimmune refers to etiologies for endocannabinoid deficiencies which do not have apparent genetic or infectious causations, but confer dysfunctional immunomodulatory effects.

Diseases and disorders can be assigned to one or more of these categories, as secondary disorders often arise with the physiological changes associated with primary diagnoses. For example, IBS is considered an acquired CECD condition, as it commonly originates from dietary source or prescription drug exposure. The development thereafter of multiple sclerosis, which affects the neurological system, would be considered an idiopathic autoimmune manifestation of CECD. Because the ECS facilitates communication and coordination between various cell types, deficiencies in any area directly and indirectly affect physiological homeostasis locally and remotely. The direct effect of both CECD and ECS hyperactivity correlates much more broadly to multisystemic clinical outcomes, contributing to conditions such as dementia, cardiovascular disease, multiple sclerosis, hyperinsulinemia, diabetes, and obesity to name a few. (7, 35)

In fact, one of the most common metabolic diseases affecting an upwards of 1.9 billion people worldwide is obesity. According to the World Health Organization, 39% of adults are considered overweight and more than 650 million are obese, and these numbers are increasing. It has reached global epidemic levels, leading to the escalating prevalence of many common medical conditions such as diabetes, cardiovascular disease, cancer, and an increased risk of death. Visceral fat, which is an indicator of GI inflammation, accumulates in the human gastrointestinal system as a consequence of a diet with a high content of fat and refined sugar (i.e. the ‘Western Diet’). Moreover the increased amount of visceral fat can lead to a chronic inflammatory and immunologic response, which is often the cause of many common diseases.

The immune system, which is activated by the inflammation process, is modulated to a considerable degree by the endocannabinoid system. 70-80% of the body’s immune tissue is in the digestive or GI tract and is lined with CB receptors. As such, the inflammatory properties of the Western Diet directly interfere with endocannabinoid production and the system’s overall tone (i.e. health), causing either an acquired CECD or hypertonicity.

When the immune system activates excessive metabolic cascades in response to digestive inflammation and injury, it results in more inflammation, microvascular deterioration and endocannabinoid dysfunction. In the wake of ECS dysregulation, the resultant chronic inflammation and destruction in the GI tract can be a challenge to restore to balance whilst exposed to the Western Diet. This phenomenon, repeated on a daily basis, leads to metabolic syndromes and obesity, which are directly associated with insulin resistance, diabetes mellitus and the consequences thereof. (6, 7, 12-14, 22, 23, 32)

The acquired ECS dysfunctions of metabolic syndrome, obesity, insulin resistance and diabetes are further associated with disorders affecting neurological function. Inflammatory processes in the brain associated with this aspect of endocannabinoid dysfunction include Alzheimer’s and vascular dementia. The decline in vascular system flexibility and increased inflammation prevents synaptic communication and neurological decline. Restoration of proper endocannabinoid function and adequate intake of phytocannabinoids, like CBD, is associated with neurological health and improvement in function. And, indeed, research (and US patent number 6-630-507) supports that plant-derived CBD has neuroprotective benefits.

cellular neurotransmission and signaling in the brain

Read: How is CBD metabolized?

CBD in Lifestyle Medicine

In light of the above-mentioned considerations that classify the ECS as one of the mainstays of human and mammalian homeostasis, preventative education becomes imperative. Metabolic dysfunction is a root cause of morbidity and mortality worldwide, and a healthy ECS is critical in its prevention.

Exercise, sleep and nutrition have always been and will continue to be key lifestyle factors to consider in maintaining good health and balancing physiologic functioning in the human body, and this is especially true in the context of metabolic syndrome and its associated diseases. But they do not tell the whole story. For example, even in the presence of reduced caloric intake, exercise does not always correlate with weight loss or, more importantly, the loss of the visceral fat implicated in metabolic derangement as a consequence of ECS dysfunction, as ECS dysfunction can and does lead to dysregulation in other pertinent physiological processes.

For example, recent studies have shown that the ECS plays a significant role in the modulation of the production and release of nitric oxide (NO), a principal molecule involved in the control and pathogenesis of inflammation. NO gives an anti-inflammatory effect under normal physiological conditions, but is considered a pro-inflammatory mediator that induces inflammation from overproduction in abnormal situations, and is implicated in the development of metabolic syndrome. This makes sense when considering that cardiovascular, immunological and neurological functions are associated with finely tuned NO body levels. Given the ECS’ primary role in maintaining NO metabolism, it might come as no surprise that studies have established the positive correlation between body levels of NO and the consumption of cannabinoids. (15-17, 167)

Lifestyle Medicine involves a non-drug, evidence-based approach to treating, reversing and preventing symptoms and disease through natural diets, exercise, sleep, stress management, and the avoidance of risky substance use. To this list can be added dietary phytocannabinoids to enhance the restoration of healthy ECS tone, thereby correcting downstream metabolic pathways, as well as promoting symptom and disease reversal naturally.

CBD Recapped

To recap, CBD is a psychoactive/psychotropic (denoting any chemical known to change mental states or mood) but non-intoxicating and non-euphoric phytocannabinoid, which has been demonstrated to positively affect the human endocannabinoid system. CBD, derived from C. sativa, demonstrates anti-inflammatory and immune-modulating properties. CBD has a low affinity for CB1 and CB2 receptors in the human body, but acts as 1) an indirect antagonist of their agonists by modulating cytokines and neurotransmitter release and 2) an agonist at other receptor types.

In addition to metabolic disorders, CBD has further shown to be a valuable phytocannabinoid with promising results in preliminary tests conducted in vivo for the treatment of epilepsy, heart failure, emesis, inflammation, cancer, and many other conditions. (8–11)

CBD has been demonstrated to cross the blood-brain barrier and exert antioxidant, antimicrobial and neuroprotective properties, rendering it valuable in the prevention andtreatment of oxidative neurological disorders and diseases, as well as infectious diseases. (4, 6–11, 20, 22–34, 36–97)

CBD is of significant therapeutic relevance. CBD oil from legal agricultural hemp contains less than 0.3% THC, rendering it non-inebriating, and as such, the potential breadth of impact without the unwanted side effects of THC (nor the toxic side effects like those of prescription drugs) cannot be ignored.

Summary

Modulating endocannabinoid activity has therapeutic potential. The ECS is the principal regulator of homeostasis, and when a body is in homeostasis, it can heal itself. A number of molecules, beyond both endocannabinoids and phytocannabinoids, interact with the ECS and can be used in a variety of therapeutic ways, but CBD remains of significant therapeutic relevance.

A number of physiological systems and related conditions can be affected by phyto- cannabinoids: the immune system and immunomodulation; inflammation, pain, stress, and anxiety; appetite and feeding; sleep cycles, mood, memory and the extinction of traumatic memory; blood pressure and blood sugar control; digestion, emesis and nausea; neuroprotection, reproduction and cancer immunosurveillance. The following chapters detail the systems and related conditions, and the ways in which CBD shows major promise.

REFERENCES

1. M.D. Randall, D. A. K. Endocannabinoids: a new class of vasoactive substances. Trends Pharmacol. Sci. 19, 55–58 (1998).

2. Lisa A., M., Lolait, S. J., Brownstein, M. J., Young, A. C. & Bonner, T. I. © 19 90 Nature Publishing Group. Nature 346, 561–564 (1990).

3. Munro S., Thomas K. L., A.-S. M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 365, 61–65 (1993).

4. Pertwee, R. G. & Ross, R. A. Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fat. Acids 66, 101–121 (2002).

5. Di Marzo, V. ‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: Biochemistry and possible physiopathological relevance. Biochim. Biophys. Acta - Lipids Lipid Metab. 1392, 153–175 (1998).

6. Franjo Grotenhermen. Pharmacokinetics and Pharmacodynamics of Cannabinoids. Clin Pharmacokinet 42, 327–360 (2003).

7. Russo, E. B. Clinical endocannabinoid deficiency revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol. Lett. 25, 31–39 (2004).

8. Shannon, S. & Opila-Lehman, J. Cannabidiol Oil for Decreasing Addictive Use of Marijuana: A Case Report. Integr. Med. (Encinitas). 14, 31–35 (2015).

9. Tzadok, M. et al. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience. Seizure 35, 41–44 (2016).

10. Behera, A. K., Shah, S. & Barik, B. B. Development and enhancement of entrapment efficiency of isoniazid loaded poly-ε-caprolactone nanoparticle. Der Pharm. Lett. 5, 43–50 (2013).

11. Pisantia, S. et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol. Ther. in press, (2017).

12. O’Neill, S. & O’Driscoll, L. Metabolic syndrome: A closer look at the growing epidemic and its associated pathologies. Obes. Rev. 16, 1–12 (2015).

13. Haslam, D. & James, W. P. Obesity. Lancet 366, 1197–1209 (2005).

14. Argueta, D. A. & DiPatrizio, N. V. Peripheral endocannabinoid signaling controls hyperphagia in western diet-induced obesity. Physiol. Behav. 171, 32–39 (2017).

15. Gertsch, J. Cannabimimetic phytochemicals in the diet – an evolutionary link to food selection and metabolic stress adaptation? Br. J. Pharmacol. DOI: 10.1111/bph.13676 (2016).

16. Gruden, G., Barutta, F., Kunos, G. & Pacher, P. Role of the endocannabinoid system in diabetes and diabetic complications. Br. J. Pharmacol. 173, 1116–1127 (2015).

17. Lipina, C. & Hundal, H. S. The endocannabinoid system: no longer anonymous in the control of nitrergic signalling? J. Mol. Cell Biol. 1–13 (2017). doi:10.1093/jmcb/mjx008

18. Scarabino, T., Salvolini, U., Salle, F. Di, Duvernoy, H. & Rabishong, P. ATLAS OF MORPHOLOGY AND FUNCTIONAL ANATOMY. (2006).

19. Iversen, L. Cannabis and the brain. Brain 126, 1252–1270 (2003).

20. Pertwee, R. G. Targeting the endocannabinoid system with cannabinoid receptor agonists : pharmacological strategies and therapeutic possibilities. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 367, 3353–3363 (2012).

21. Elphick, M. R. & Egertová, M. The neurobiology and evolution of cannabinoid signalling. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 356, 381–408 (2001).

22. Croxford, J. L. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 17, 179–202 (2003).

23. Booz, G. W. Cannabidiol as Emergent Therapeutic Strategy for Lessening the impact of Inflammation on Oxidative Stress. Radic. Biol. Med 51, 1054–1061 (2011).

24. Espejo-Porras, F., Fernández-Ruiz, J., Pertwee, R. G., Mechoulam, R. & García, C. Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors. Neuropharmacology 75, 155–163 (2013).

25. Mbvundula, E. C., Rainsford, K. D. & Bunning, R. A. Cannabinoids in pain and inflammation. Inflammopharmacology 12, 99–114 (2004).

26. Crandall, J. et al. Neuroprotective and intraocular pressure-lowering effects of (–)Δ9-tetrahydrocannabinol in a rat model of glaucoma. Ophthalmic Res. 39, 69–75 (2007).

27. Costa, B., Trovato, A. E., Comelli, F., Giagnoni, G. & Colleoni, M. The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain. Eur. J. Pharmacol. 556, 75–83 (2007).

28. Elsohly, M. A., Radwan, M. M., Gul, W., Chandra, S. & Galal, A. Phytocannabinoids. 103, (2017).

29. Deiana, S. Medical use of cannabis. Cannabidiol: A new light for schizophrenia? Drug Test. Anal. 5, 46–51 (2013).

30. Cilio, M. R., Thiele, E. A. & Devinsky, O. The case for assessing cannabidiol in epilepsy. Epilepsia 55, 787–790 (2014).

31. Novack, G. D. Cannabinoids for treatment of glaucoma. Curr. Opin. Ophthalmol. 27, 146–50 (2016).

32. Levite, M. Nerve-driven immunity: Neurotransmitters and neuropeptides in the immune system. Nerve-Driven Immunity: Neurotransmitters and Neuropeptides in the Immune System (2012). doi:10.1007/978-3-7091-0888-8

33. El-Remessy, A. B. et al. Neuroprotective Effect of(−)Δ9-Tetrahydrocannabinol and Cannabidiol in N-Methyl-d-Aspartate-Induced Retinal Neurotoxicity. Am. J. Pathol. 163, 1997–2008 (2003).

34. Wei, Y., Wang, X., Zhao, F., Zhao, P. & Kang, X. Cannabinoid receptor 1 blockade protects human retinal pigment epithelial cells from oxidative injury. Mol. Vis. 357, 357–366 (2013).

35. SC, S. & MS, W. Clinical endocannabinoid deficiency revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuroendocrinol. Lett. 35, 198–201 (2014).

36. Esposito, G., De Filippis, D., Carnuccio, R., Izzo, A. A. & Iuvone, T. The marijuana compo- nent cannabidiol inhibits beta-amyloid-induced tau protein hyperphosphorylation through Wnt-catenin pathway rescue in PC12 cells. J. Mol. Med. 84, 253–25 (2006).

37. Liou, G. et al. Cannabidiol As a Putative Novel Therapy for Diabetic Retinopathy: A Postulated Mechanism of Action as an Entry Point for Biomarker-Guided Clinical Development. Curr Pharmacogenomics Pers. Med. 7, 215–222 (2009).

38. Dirikoc, S., Priola, S. A., Marella, M., Zsurger, N. & Chabry, J. Nonpsychoactive Cannabidiol Prevents Prion Accumulation and Protects Neurons against Prion Toxicity. J. Neurosci. 27, 9537–9544 (2007).

39. Barichello, T. et al. Cannabidiol reduces host immune response and prevents cognitive impairments in Wistar rats submitted to pneumococcal meningitis. Eur. J. Pharmacol. 697, 158–164 (2012).

40. Hayakawa, K. et al. Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism. Neuroreport 15, 2381–2385 (2004).

41. Hayakawa, K. et al. Delayed treatment with cannabidiol has a cerebroprotective action via a cannabinoid receptor-independent myeloperoxidase-inhibiting mechanism. J. Neurochem. 102, 1488–1496 (2007).

42. Aparecida, N. et al. Toxicology in Vitro The neuroprotection of cannabidiol against MPP + -induced toxicity in PC12 cells involves trkA receptors , upregulation of axonal and synaptic proteins , neuritogenesis , and might be relevant to Parkinson's disease. TIV 30, 231–240 (2015).

43. Hind, W. H., England, T. J. & O’Sullivan, S. E. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARγ and 5-HT1A receptors. Br. J. Pharmacol. 173, 815–825 (2016).

44. Mishima, K. et al. Cannabidiol prevents cerebral infarction via a serotonergic 5-hydroxytryptamine1A receptor-dependent mechanism. Stroke 36, 1071–1076 (2005).

45. Chen, J., Simon, P. & Fliri, H. Abnormal Cannabidiols as Agents for Lowering Intraocular Pressure. 2, 1–13 (2013).

46. Parray, H. A. & Yun, J. W. Cannabidiol promotes browning in 3T3-L1 adipocytes. Mol. Cell. Biochem. 416, 131–139 (2016).

47. MH, C. et al. Effects of cannabidiol in the treatment of patients with Parkinson’s disease: an exploratory double-blind trial. J Psychopharmacol. 11, 1088–1098 (2014).

48. Liou, G. I. et al. Mediation of Cannabidiol anti-inflammation in the Retina by Equilib ative Nucleoside Transporter and A2A Adenosine Receptor. Invest Ophthamol Vis Sci. 49, 5526–5531 (2009).

49. Hayakawa, K. et al. Repeated treatment with cannabidiol but not Delta9-tetrahydrocannabinol has a neuroprotective effect without the development of tolerance. Neuropharmacology 52, 1079–87 (2007).

50. El-Remessy, A. B. et al. Neuroprotective and blood-retinal barrier-preserving effects of cannabidiol in experimental diabetes. Am. J. Pathol. 168, 235–44 (2006).

51. Do Monte, F. H., Souza, R. R., Bitencourt, R. M., Kroon, J. A. & Takahashi, R. N. Infusion of cannabidiol into infralimbic cortex facilitates fear extinction via CB1 receptors. Behav. Brain Res. 250, 23–27 (2013).

52. Zuardi, A. W. Cannabidiol : from an inactive cannabinoid to a drug with wide spectrum of action Canabidiol : de um canabinóide inativo a uma droga com amplo espectro de ação. 30, 271–280 (2008).

53. Consroe, P. et al. Controlled clinical trial of cannabidiol in Huntington’s disease. Pharmacol. Biochem. Behav. 40, 701–708 (1991).

54. Fernández-ruiz, J. et al. Cannabidiol for neurodegenerative disorders : important new clinical applications for this phytocannabinoid ? Br. J. Clin. Pharmacol. Cannabis 72, 323–333 (2012).

55. Braida, D. et al. Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci. Lett. 346, 61–64 (2003).

56. Sye , Y. Y., McKeage, K. & Scott, L. J. Delta-9-Tetrahydrocannabinol/cannabidiol (Sativex??): A review of its Use in patients with moderate to severe spasticity due to multiple sclerosis. Drugs 74, 563–578 (2014).

57. Iseger, T. A. & Bossong, M. G. A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr. Res. 162, 153–161 (2015).

58. Osborne, A. L., Solowij, N. & Weston-Green, K. A systematic review of the effect of cannabidiol on cognitive function: Relevance to schizophrenia. Neurosci. Biobehav. Rev. doi: 10.1016/j.neu- biorev.2016.11.012 (2016). doi:10.1016/j.neubiorev.2016.11.012

59. Devinsky, O. et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia 55, 791–802 (2014).

60. Schubart, C. D. et al. Cannabidiol as a potential treatment for psychosis. Eur. Neuropsycho- pharmacol. 24, 51–64 (2014).

61. Gururajan, A. & Malone, D. T. Does cannabidiol have a role in the treatment of schizophrenia? Schizophr. Res. 176, 281–290 (2016).

62. Oliveira, L. G. De, Yonamine, M., Andreuccetti, G., Ponce, J. D. C. & Leyton, V. Cannabidiol, a cannabis sativa constituent, as anxiolytic drug. Rev. Bras. Psiquiatr. 34, 116–117 (2012).

63. Waldo Zuardi, A. et al. A Critical Review of the Antipsychotic Effects of Cannabidiol: 30 Years of a Translational Investigation. Curr. Pharm. Des. 18, 5131–5140 (2012).

64. Roser, P., S. Haussleiter, I. & Haussleiter, I. S. Antipsychotic-like effects of cannabidiol and rimonabant: systematic review of animal and human studies. Curr. Pharm. Des. 18, 5141–5155 (2012).

65. Renard, J., Norris, C., Rushlow, W. & Laviolette, S. R. Neuronal and molecular effects of cannabidiol on the mesolimbic dopamine system: Implications for novel schizophrenia treatments. Neurosci. Biobehav. Rev. 75, 157–165 (2017).

66. Szaflarski, J. P. & Martina Bebin, E. Cannabis, cannabidiol, and epilepsy - From receptors to clinical response. Epilepsy Behav. 41, 277–282 (2014).

67. Leo, A., Russo, E. & Elia, M. Cannabidiol and epilepsy: Rationale and therapeutic potential. Pharmacol. Res. 107, 85–92 (2016).

68. Campos, A. C., Moreira, F. A., Gomes, F. V., Del Bel, E. A. & Guimarães, F. S. Multiple

mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos. Trans. R. Soc. Lond. B. Biol. Sci. 367, 3364–78 (2012).

69. Sagredo, O., Pazos, M., Valdeolivas, S. & Fernandez-Ruiz, J. Cannabinoids: novel medicines for the treatment of Huntington’s disease. Recent Pat CNS Drug Discov. 7, 41–48 (2012).

70. Tomida, I. et al. Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study. J. Glaucoma 15, 349–353 (2006).

71. Valdeolivas, S., Satta, V., Pertwee, R. G. & Sagredo, O. Sativex-like Combination of Phyto- cannabinoids is Neuroprotective in Malonate-Lesioned Rats, an Inflammatory Model of Huntington's Disease: Role of CB 1 and CB 2 Receptors. ACS Chem. Neurosci. 3, 400–406 (2012).

72. 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).

73. Laprairie, R. B., Bagher, A. M., Kelly, M. E. M. & Denovan-wright, E. M. Biased Type 1 Cannabinoid Receptor Signaling Influences Neuronal Viability in a Cell Culture Model of Huntington Disease s. Mol. Pharmacol. 89, 364–375 (2016).

74. Hampson, A. J. et al. Neuroprotective Antioxidants. Sci. York 95, 8268–8273 (1998).

75. Di Marzo, V. & Centonze, D. Placebo Effects in a Multiple Sclerosis Spasticity Enriched Clinical Trial with the Oromucosal Cannabinoid Spray (THC/CBD): Dimension and Possible Causes. CNS Neurosci. Ther. 21, 215–221 (2015).

76. Podda, G. & Constantinescu, C. S. Nabiximols in the treatment of spasticity, pain and urinary symptoms due to multiple sclerosis. Expert Opin. Biol. Ther. 12, 1517–1531 (2012).

77. Moreno Torres, I., Sanchez, A. J. & Garcia-Merino, A. Evaluation of the tolerability and efficacy of Sativex in multiple sclerosis. Expert Rev. Neurother. 14, 1243–50 (2014).

78. Koehler, J., Amato, M. P., Oreja-Guevara, C. & Lycke, J. Clinical case reviews in multiple sclerosis spasticity: experiences from around Europe. Expert Rev. Neurother. 13, 61–66 (2013).

79. Di Marzo, V. Endocannabinoid pathways and their role in multiple sclerosis-related muscular dysfunction. Expert Rev. Neurother. 11, 9–14 (2011).

80. Lakhan, S. E. & Rowland, M. Whole plant cannabis extracts in the treatment of spasticity in multiple sclerosis: a systematic review. BMC Neurol. 9, 59 (2009).

81. Zettl, U. K., Rommer, P., Hipp, P. & Patejdl, R. Evidence for the efficacy and effectiveness of THC-CBD oromucosal spray in symptom management of patients with spasticity due to multiple sclerosis. Ther. Adv. Neurol. Disord. 9, 9–30 (2016).

82. Pryce, G., Riddall, D. R., Selwood, D. L., Giovannoni, G. & Baker, D. Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids. J. Neuroimmune Pharmacol. 10, 281–292 (2015).

83. Leussink, V. I. et al. Symptomatic therapy in multiple sclerosis: the role of cannabinnoids in treating spasticity. Ther. Adv. Neurol. Disord. 5, 255–266 (2012).

84. Teare, L. & Zajicek, J. The use of cannabinoids in multiple sclerosis. Expert Opin Investig Drugs 14, 859–869 (2005).

85. Bumb, J. M., Enning, F. & Leweke, F. M. Drug repurposing and emerging adjunctive treatments for schizophrenia. Expert Opin. Pharmacother. 16, 1049–67 (2015).

86. Baron, E. P. Comprehensive Review of Medicinal Marijuana, Cannabinoids, and Therapeutic Implications in Medicine and Headache: What a Long Strange Trip It’s Been. 885–916 (2000). 87. Benbadis, S. R. et al. Medical marijuana in neurology. Expert Rev. Neurother. 14, 1453–65 (2014).

88. Ashton, C. H. & Moore, P. B. Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr. Scand. 124, 250–261 (2011).

89. Ashton, C. H., Moore, P. B., Gallagher, P. & Young, A. H. Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential. J Psychopharmacol 19, 293–300 (2005).

90. Parolaro, D., Realini, N., Vigano, D., Guidali, C. & Rubino, T. The endocannabinoid system and psychiatric disorders. Exp. Neurol. 224, 3–14 (2010).

91. Hill, C., Katz, R., Marzo, V. Di & Jutras-aswad, D. Epilepsy and Other Neuropsychiatric Disorders. 55, 791–802 (2016).

92. Zuardi, A. et al. psychosis in Parkinson's disease. J. Psychopharmacology 979–983 (2009). doi:10.1177/0269881108096519

93. Yu, Y., Chen, H. & Su, S. B. Neuroinflammatory responses in diabetic retinopathy. J. Neuroinflammation 141, 1–15 (2015).

94. Whiting, P. F. et al. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. Jama 313, 2456–2473 (2015).

95. García, C. & Ramos, J. A. Symptom-relieving and neuroprotective effects of the phytocannabinoid D 9 -THCV in animal models of Parkinson's disease. 163, 1495–1506 (2011).

96. Belgrave, B. E. et al. The effect of (-) trans-delta9-tetrahydrocannabinol, alone and in combination with ethanol, on human performance. Psychopharmacology (Berl). 62, 53–60 (1979).

97. Haas, J. The pathophysiology, assessment and management of multiple sclerosis spasticity: An update. Expert Rev. Neurother. 11, 3–8 (2011).

98. Zarei, S. et al. A comprehensive review of amyotrophic lateral sclerosis. Surg. Neurol. Int. 171, (2015).

99. Velayudhan, L. et al. Therapeutic Potential of Cannabinoids in Neurodegenerative Disorders: A Selective Review. Curr. Pharm. Des. 20, 2218–2230 (2014).

100. Giacoppo, S. & Mazzon, E. Can cannabinoids be a potential therapeutic tool in amyotrophic lateral sclerosis? Neural Degener. Res. 11, 1896–1899 (2006).

101. Tezel, G. et al. Mechanisms of Immune System Activation in Glaucoma: Oxidative Stress-Stimulated Antigen Presentation by the Retina and Optic Nerve Head Glia. Invest Ophthamol Vis Sci. 48, 705–714 (2007).

102. Kuo, P. & Holloway, R. H. Beyond acid suppression: New pharmacologic approaches for treatment of gerd. Curr. Gastroenterol. Rep. 12, 175–180 (2010).

103. Cui, Y. Y. et al. Cannabinoid CB2 receptor activation prevents bronchoconstriction and airway oedema in a model of gastro-oesophageal reflux. Eur. J. Pharmacol. 573, 206–213 (2007).

104. Di Carlo, G. & Izzo A, A. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin. Investig. Drugs 12, 39–49 (2003).

105. Beaumont, H. et al. Effect of Δ 9-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).

106. Abalo, R., Vera, G., López-Pérez, A. E., Martínez-Villaluenga, M. & Martín-Fontelles, M. I. The gastrointestinal pharmacology of cannabinoids: Focus on motility. Pharmacology 90, 1–10 (2012).

107. Klooker, T. K., Leliefeld, K. E. M., Van Den Wijngaard, R. M. & Boeckxstaens, G. E. E. The cannabinoid receptor agonist delta- 9- tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients. Neurogastroenterol. Motil. 23, 30 (2011).

108. Fichna, J. et al. Endocannabinoid and cannabinoid-like fatty acid amide levels correlate with pain-related symptoms in patients with IBS-D and IBS-C: A pilot study. PLoS One 8, 6–13 (2013).

109. Wong, B. S. et al. Pharmacogenetic Trial of a Cannabinoid Agonist Shows Reduced Fasting Colonic Motility in Patients with Non- Constipated Irritable Bowel Syndrome. Gastroenterology 141, 1638–1647 (29011).

110. Aviello, G. et al. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J. Mol. Med. 90, 925–934 (2012).

111. Kargl, J. et al. GPR55 promotes migration and adhesion of colon cancer cells indicating a role in metastasis. Br. J. Pharmacol. 173, 142–154 (2016).

112. Romano, B. et al. Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Phytomedicine 21, 631–639 (2014).

113. Sreevalsan, S., Joseph, S., Jutooru, I., Chadalapaka, G. & Safe, S. H. Induction of Anticancer Res. 31, 3799–3807 (2011).

114. Macpherson, T., Armstrong, J. A., Criddle, D. N. & Wright, K. L. Physiological intestinal oxygen modulates the Caco-2 cell model and increases sensitivity to the phytocannabinoid cannabidiol. Vitr. Cell. Dev. Biol. - Anim. 50, 417–426 (2014).

115. Kogan, N. M. et al. A cannabinoid anticancer quinone, HU-331, is more potent and less cardiotoxic than doxorubicin: a comparative in vivo study. J. Pharmacol. Exp. Ther. 322, 646–653 (2007).

116. McAllister, S. D., Soroceanu, L. & Desprez, P.-Y. The antitumor activity of plant-derived non-psychoactive cannabinoids. J Neuroimmune Pharmacol. 10, 255–267 (2015).

117. Ruhaak, L. R. et al. Evaluation of the cyclooxygenase inhibiting effects of six major cannabinoids isolated from Cannabis sativa. Biol. Pharm. Bull. 34, 774–8 (2011).

118. Coutts, A. A. & Izzo, A. A. The gastrointestinal pharmacology of cannabinoids: An update. Curr. Opin. Pharmacol. 4, 572–579 (2004).

119. Joseph Tam et al. Endocannabinoids in Liver Disease. Hepatology 53, 346–355 (2011). 120. Silveira, J. W. et al. Protective effects of cannabidiol on lesion-induced intervertebral disc degeneration. PLoS One 9, 1–13 (2014).

121. Napimoga, M. H. et al. Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. Int. Immunopharmacol. 9, 216–222 (2009).

122. Fitzcharles, M.-A., Baerwald, C., Ablin, J. & Hauser, W. Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials. Schmerz 30, 47–61 (2016).

123. Zurier, R. B. & Burstein, S. H. Cannabinoids, inflammation, and fibrosis. FASEB J. 30, 3682–3689 (2016).

124. Chiurchiù, V., Lanuti, M., De Bardi, M., Battistini, L. & Maccarrone, M. The differential characterization of GPR55 receptor in human peripheral blood reveals a distinctive expression in monocytes and NK cells and a proinflammatory role in these innate cells. Int. Immunol. 27, 153–160 (2015).

125. Robson, P. J. Therapeutic potential of cannabinoid medicines. Drug Test Anal 6, 24–30 (2014).

126. Whyte, L. S. et al. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc. Natl. Acad. Sci. U. S. A. 106, 16511–16516 (2009).

127. Galve-Roperh, I. et al. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog. Lipid Res. 52, 633–650 (2013).

128. Stanley, C. P., Hind, W. H. & O’Sullivan, S. E. Is the cardiovascular system a therapeutic target for cannabidiol? Br. J. Clin. Pharmacol. 75, 313–322 (2013).

129. Rajesh, M. et al. Cannabidiol attenuates cardiac dysfunction, oxidative stress, fibrosis, inflammatory and cell death signaling pathways in diabetic cardiomyopathy. J Am Coll Cardiol. 56, 2115–2125 (2010).

130. Gonca, E. & Darıcı, F. The Effect of Cannabidiol on Ischemia/Reperfusion-Induced Ventricular Arrhythmias: The Role of Adenosine A1 Receptors. (2015). doi:10.1177/1074248414532013

131. Durst, R. et al. Cannabidiol, a nonpsychoactive Cannabis constituent, protects against myocardial ischemic reperfusion injury. Am. J. Physiol. Heart Circ. Physiol. 293, H3602-7 (2007).

132. Walsh, S. K., Hepburn, C. Y., Kane, K. A. & Wainwright, C. L. Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. Br. J. Pharmacol. 160, 1234–1242 (2010).

133. Ribeiro, A. et al. Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: Role for the adenosine A2A receptor. Eur. J. Pharmacol. 678, 78–85 (2012).

134. Ribeiro, A. et al. Cannabidiol improves lung function and inflammation in mice submitted to LPS-induced acute lung injury. Immunopharmacol. Immunotoxicol. 3973, 1–7 (2014).

135. Vuolo, F. et al. Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma. Mediators Inflamm. 2015, 1–5 (2015).

136. Ramer, R., Merkord, J., Rohde, H. & Hinz, B. Cannabidiol inhibits cancer cell invasion via upregulation of tissue inhibitor of matrix metalloproteinases-1. Biochem. Pharmacol. 79, 955–966 (2010).

137. Ramer, R., Rohde, A., Merkord, J., Rohde, H. & Hinz, B. Decrease of plasminogen activator inhibitor-1 may contribute to the anti-invasive action of cannabidiol on human lung cancer cells. Pharm. Res. 27, 2162–2174 (2010).

138. Ramer, R. et al. Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. FASEB J. 26, 1535–48 (2012).

139. Ramer, R. et al. COX-2 and PPAR- Confer Cannabidiol-Induced Apoptosis of Human Lung Cancer Cells. Mol. Cancer Ther. 12, 69–82 (2013).

140. Karmaus, W. F., Wagne, J. G., Harkema, J. R., Kaminski, N. E. & Kaplan, B. L. F. CBD Enhances Lipopolysaccharide (LPS)-Induced Pulmonary Inflammation in C57BL/6 Mice. J Immunotoxicol. 10, 321–328 (2013).

141. Kozlowska, H. et al. Identification of the vasodilatory endothelial cannabinoid receptor in the human pulmonary artery. J. Hypertens. 25, 2240–2248 (2007).

142. Wilkinson, J. D. & Williamson, E. M. Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. J. Dermatol. Sci. 45, 87–92 (2007).

143. Rajesh, M. et al. Cannabidiol attenuates high glucose-induced endothelial cell inflammatory response and barrier disruption. Am J Physiol Hear. Circ Physiol. 293, H610–H619. (2007).

144. Armstrong, J. L. et al. Exploiting Cannabinoid-Induced Cytotoxic Autophagy to Drive Melanoma Cell Death. J. Invest. Dermatol. 135, 1629–1637 (2015).

145. Johnstone, C., Hendry, C., Farley, A. & Mclafferty, E. Endocrine system : part 1. Nurs.Stand. 28, 42–49 (2014).

146. Pagotto, U., Marsicano, G., Cota, D., Lutz, B. & Pasquali, R. The emerging role of the endocannabinoid system in endocrine regulation and energy balance. Endocr. Rev. 27, 73–100 (2006).

147. Battista, N. et al. Regulation of female fertility by the endocannabinoid system. Mol. Cell. Endocrinol. 286, 207–216 (2007).

148. Karasu, T., Marczylo, T. H., Maccarrone, M. & Konje, J. C. The role of sex steroid hormones, cytokines and the endocannabinoid system in female fertility. Hum. Reprod. Update 17, 347–361 (2011).

149. Gruden, G., Barutta, F., Kunos, G. & Pacher, P. Role of the endocannabinoid system in diabetes and diabetic complications. Br. J. Pharmacol. 173, 1116–1127 (2016).

150. Antebi, A. Regulation of longevity by the reproductive system. Exp. Gerontol. 48, 596–602 (2013).

151. Pask, A. in Adv Exp Med Biol. 866:1-12 (2016). doi:DOI: 10.1007/978-94-017-7417-8_1

152. Burnstock, G. Purinergic signalling in the urinary tract in health and disease. Purinergic Signalling 10, (2014).

153. Battista, N. et al. Regulation of male fertility by the endocannabinoid system. Mol. Cell. Endocrinol. 286, (2008).

154. Maccarrone, M. CB2 receptors in reproduction. Br. J. Pharmacol. 153, 189–98 (2008). 155. Vercellini, P., Vigano, P., Somigliana, E. & Fedele, L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 10, 261–275 (2014).

156. Sanchez, A. M., Vigano, P., Mugione, A., Panina-bordignon, P. & Candiani, M. The molecular connections between the cannabinoid system and endometriosis. Mol. Hum. Reprod. 18, 563–571 (2012).

157. Ayakannu, T. et al. Validation of endogenous control reference genes for normalizing gene expression studies in endometrial carcinoma. Mol. Hum. Reprod. 21, 723–735 (2015).

158. Guida, M. et al. The levels of the endocannabinoid receptor CB2 and its ligand 2-arachido- noylglycerol are elevated in endometrial carcinoma. Endocrinology 151, 921–928 (2010).

159. Taylor, A. H., Abbas, M. S., Habiba, M. A. & Konje, J. C. Histomorphometric evaluation of cannabinoid receptor and anandamide modulating enzyme expression in the human endometrium through the menstrual cycle. Histochem. Cell Biol. 133, 557–565 (2010).

160. Pacher, P. Commentary on: Towards the use of non-psychoactive cannabinoids for prostate cancer. Br. J. Pharmacol. 168, 76–78 (2013).

161. De Petrocellis, L. et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: Pro-apoptotic effects and underlying mechanisms. Br. J. Pharmacol. 168, 79–102 (2013).

162. Fraguas-Sánchez, A. I., Fernández-Carballido, A. & Torres-Suárez, A. I. Phyto-, endo- and synthetic cannabinoids: promising chemotherapeutic agents in the treatment of breast and prostate carcinomas. Expert Opin. Investig. Drugs 25, 1311–1323 (2016).

163. Ozdemir, B. et al. Endocannabinoids and inflammatory response in periodontal ligament cells. PLoS One 9, (2014).

164. McDonough, P., McKenna, J. P., McCreary, C. & Downer, E. J. Neuropathic orofacial pain: Cannabinoids as a therapeutic avenue. Int. J. Biochem. Cell Biol. 55, 72–78 (2014).

165. Rawal, S. Y., Dabbous, M. K. & Tipton, D. A. Effect of cannabidiol on human gingival fibroblast extracellular matrix metabolism: MMP production and activity, and production of fibronectin and transforming growth factor β. J. Periodontal Res. 47, 320–329 (2012).

166. McGinnis, Jon (2010). Avicenna. Oxford: Oxford University Press. p. 227. ISBN 978-0-19-533147-9.

167. Role of nitric oxide in inflammatory diseases. Sharma JN, Al-Omran A, Parvathy SS. Inflammopharmacology. 2007 Dec;15(6):252-9. doi: 10.1007/s10787-007-0013-x. Review.

168. Pazos MR, Tolón RM, Benito C, et al. Cannabinoid CB1 Receptors Are Expressed by Parietal Cells of the Human Gastric Mucosa. Journal of Histochemistry and Cytochemistry. 2008;56(5):511-516. doi:10.1369/jhc.2008.950741.

169. Walsh SK, Hepburn CY, Kane KA, Wainwright CL. Acute administration of cannabidiol in vivo suppresses ischaemia-induced cardiac arrhythmias and reduces infarct size when given at reperfusion. British Journal of Pharmacology. 2010;160(5):1234-1242. doi:10.1111/j.1476-5381.2010.00755.x.

170.Weiss, L, M Zeira, S Reich, et al. “Cannabidiol Arrests Onset of Autoimmune Diabetes in NOD Mice.” Neuropharmacology 54.1 (2008): 244-249. Print.