Insights from the International Center for Cannabis Therapy Part 3: Reviewing the Many Applications of Cannabinoid-Rich Hemp Oil and the Role of the Gut-Brain Axis

by Chris D. Meletis, ND, and Kimberly Wilkes


1. Lu HC, Mackie K. An Introduction to the Endogenous Cannabinoid System. Biol Psychiatry. 2016 Apr 1;79(7):516- 25.

2. Cassano T, et al. Cannabinoid Receptor 2 Signaling in Neurodegenerative Disorders: From Pathogenesis to a Promising Therapeutic Target. Front Neurosci. 2017 Feb 2;11:30.

3. Benito C, et al. Cannabinoid CB2 receptors in human brain inflammation. Br J Pharmacol. 2008 Jan;153(2):277-85.

4. Turcotte C, et al. The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci. 2016 Dec;73(23):4449-70.

5. Stella N. Cannabinoid and cannabinoid-like receptors in microglia, astrocytes, and astrocytomas. Glia. 2010 Jul;58(9):1017-30.

6. Onaivi ES, et al. CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity. J Psychopharmacol. 2012 Jan;26(1):92-103.

7. Benito C, et al. Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains. J Neurosci. 2003 Dec 3;23(35):11136-41.

8. Ramírez BG, et al. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005 Feb 23;25(8):1904-13.

9. Grünblatt E, et al. Gene expression as peripheral biomarkers for sporadic Alzheimer’s disease. J Alzheimers Dis. 2009;16(3):627-34.

10. Solas M, et al. CB2 receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients. Neurobiol Aging. 2013 Mar;34(3):805-8.

11. Halleskog C, et al. WNT signaling in activated microglia is proinflammatory. Glia. 2011 Jan;59(1):119-31.

12. Ehrhart J, et al. Stimulation of cannabinoid receptor 2 (CB2) suppresses microglial activation. Neuroinflammation. 2005 Dec 12;2:29.

13. Esposito G, et al. Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression. Br J Pharmacol. 2007 Aug;151(8):1272-9.

14. Esposito G, et al. Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One. 2011;6(12):e28668.

15. McGeer PL, et al. Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology.1988 Aug;38(8):1285-91.

16. Ouchi Y, et al. Microglial activation and dopamine terminal loss in early Parkinson’s disease. Ann Neurol. 2005 Feb;57(2):168-75.

17. Gerhard A, et al. In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson’s disease. Neurobiol Dis. 2006 Feb;21(2):404-12.

18. Gómez-Gálvez Y, et al. Potential of the cannabinoid CB(2) receptor as a pharmacological target against inflammation in Parkinson’s disease. Prog Neuropsychopharmacol Biol Psychiatry. 2016 Jan 4;64:200-8.

19. Chagas MH, et al. Effects of cannabidiol in the treatment of patients with Parkinson’sdisease: an exploratory double-blind trial. J Psychopharmacol. 2014 Nov;28(11):1088-98.

20. Zuardi AW, et al. Cannabidiol for the treatment of psychosis in Parkinson’s disease. J Psychopharmacol. 2009 Nov;23(8):979-83.

21. Chagas MH, et al. Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson’sdisease patients: a case series. J Clin Pharm Ther. 2014 Oct;39(5):564-6.

22. Fogaça MV, et al. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: Role of neurogenesis and dendritic remodeling. Neuropharmacology. 2018 Mar 3;135:22-33.

23. Bergamaschi MM, Queiroz RH, Chagas MH. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology. 2011 May;36(6):1219-26.

24. Crippa JA, et al. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. J Psychopharmacol. 2011 Jan;25(1):121-30.

25. Russo EB. Clinical Endocannabinoid Deficiency Reconsidered: Current Research Supports the Theory in Migraine, Fibromyalgia, Irritable Bowel, and Other Treatment-Resistant Syndromes. Cannabis Cannabinoid Res. 2016 Jul 1;1(1):154-65.

26. Mizrachi Zer-Aviv T, Segev A, Akirav I. Cannabinoids and post-traumatic stress disorder: clinical and preclinical evidence for treatment and prevention. Behav Pharmacol. 2016 Oct;27(7):561-9.

27. Jetly R, et al. The efficacy of nabilone, a synthetic cannabinoid, in the treatment of PTSD-associated nightmares: A preliminary randomized, double-blind, placebo-controlled cross-over design study. Psychoneuroendocrinology. 2015 Jan;51:585-8.

28. Hill MN, Gorzalka BB. Is there a role for the endocannabinoid system in the etiology and treatment of melancholicdepression? Behav Pharmacol. 2005 Sep;16(5-6):333-52.

29. Resstel LB, et al. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. Br J Pharmacol. 2009 Jan;156(1):181-8.

30. Granjeiro EM, et al. Effects of intracisternal administration of cannabidiol on the cardiovascular and behavioral responses to acute restraint stress. Pharmacol Biochem Behav. 2011 Oct;99(4):743-8.

31. Campos AC, et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol. 2013 Jul;16(6):1407-19.

32. Hill MN, et al. Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry. 2008 Mar;41(2):48-53.

33. Guida F, et al. Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. Brain Behav Immun. 2017 Sep 7. pii: S0889- 1591(17)30417-8. [Epub ahead of print.]

34. DiPatrizio NV. Endocannabinoids in the Gut. Cannabis Cannabinoid Res. 2016 Feb;1(1):67-77.

35. Alhouayek M, et al. Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. FASEB J. 2011 Aug;25(8):2711-21.

36. Schicho R, et al. The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment. Inflamm Bowel Dis. 2011 Aug;17(8):1651-64.

37. Borrelli F, et al. Cannabidiol, a safe and non-psychotropic ingredient of the marijuana plant Cannabis sativa, is protective in a murine model of colitis. J Mol Med (Berl). 2009 Nov;87(11):1111-21.

38. De Filippis D, et al. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS One. 2011;6(12):e28159.

39. Darmani NA, et al. Involvement of the cannabimimetic compound, N-palmitoyl-ethanolamine, in inflammatory and neuropathic conditions: review of the available pre-clinical data, and first human studies. Neuropharmacology. 2005 Jun;48(8):1154-63.

40. Boesmans W, et al. Cannabinoid receptor 1 signalling dampens activity and mitochondrial transport in networks of enteric neurones. Neurogastroenterol Motil. 2009 Sep;21(9):958-e77.

41. Sharkey KA, Wiley JW. The Role of the Endocannabinoid System in the Brain-Gut Axis. Gastroenterology. 2016 Aug;151(2):252-66.

42. Marco EM, et al. Consequences of early life stress on the expression of endocannabinoid-related genes in the rat brain. Behav Pharmacol. 2014 Sep;25(5-6):547-56.

43. Moloney RD, et al. Early-life stress-induced visceral hypersensitivity and anxiety behavior is reversed by histone deacetylase inhibition. Neurogastroenterol Motil. 2015 Dec;27(12):1831-6.

44. Wright K, et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology. 2005 Aug;129(2):437-53.

45. Akbar A, et al. Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut. 2008 Jul;57(7):923-9.

46. Kozela E, et al. Pathways and gene networks mediating the regulatory effects of cannabidiol, a nonpsychoactive cannabinoid, in autoimmune T cells. J Neuroinflammation. 2016 Jun 3;13(1):136.

47. Lee WS, et al. Cannabidiol limits Tcell-mediated chronic autoimmune myocarditis: implications to autoimmunedisorders and organ transplantation. Mol Med. 2016 Jan 8. [Epub ahead of print.]

48. Kozela E, et al. Cannabidiol, a non-psychoactive cannabinoid, leads to EGR2-dependent anergy in activated encephalitogenic T cells. J Neuroinflammation. 2015 Mar 15;12:52.

49. Malfait AM, et al. The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis. Proc Natl Acad Sci U S A. 2000 Aug 15;97(17):9561-6.

50. Weiss L, et al. Cannabidiol lowers incidence of diabetes in non-obese diabetic mice. Autoimmunity. 2006 Mar;39(2):143-51.

51. Hegde VL, Nagarkatti PS, Nagarkatti M. Role of myeloid-derived suppressor cells in amelioration of experimental autoimmune hepatitis following activation of TRPV1 receptors by cannabidiol. PLoS One. 2011 Apr 1;6(4):e18281.

52. Weiss L, et al. Cannabidiol arrests onset of autoimmune diabetes in NOD mice. Neuropharmacology. 2008 Jan;54(1):244-9.

53. Vaney C, et al. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult Scler. 2004 Aug;10(4):417-24.

54. Leocani L, et al. Sativex( )®and clinical-neurophysiological measures of spasticity in progressive multiple sclerosis. J Neurol. 2015 Nov;262(11):2520-7.

55. Appendino G, et al. Antibacterial cannabinoids from Cannabis sativa: a structure-activity study. J Nat Prod. 2008 Aug;71(8):1427-30.

56. Smith MS, et al. Psychoactive cannabinoids increase mortality and alter acute phase cytokine responses in mice sublethally infected with Legionella pneumophila. Proc Soc Exp Biol Med. 1997 Jan;214(1):69-75.

57. Hind WH, England TJ, O’Sullivan SE. Cannabidiol protects an in vitro model of the blood-brain barrier from oxygen-glucose deprivation via PPARγ and 5-HT1A receptors. Br J Pharmacol. 2016 Mar;173(5):815-25.

58. Ceskova E, Silhan P. Novel treatment options in depression and psychosis. Neuropsychiatr Dis Treat. 2018;14:741-7.

59. Leweke FM, Mueller JK, Lange B. Therapeutic Potential of Cannabinoids in Psychosis. Biol Psychiatry. 2016 Apr 1;79(7):604-12.

60. Warren PP, et al. The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy. Neurocase. 2017 Oct - Dec;23(5-6):287-91.

61. Kaplan EH, et al. Cannabidiol Treatment for Refractory Seizures in Sturge-Weber Syndrome. Pediatr Neurol. 2017 Jun;71:18-23.e2.

62. Iffland K, Grotenhermen F. An Update on Safety and Side Effects of Cannabidiol: A Review of Clinical Data and Relevant Animal Studies. Cannabis Cannabinoid Res. 2017;2(1):139-54.

63. Devinsky O, Cilio MR, Cross H, et al. Cannabidiol: Pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders. Epilepsia. 2014 Jun;55(6):791-802.

64. WebMD. cannabidiol.aspx?activeingredientid=1439&activeingredientname=cannabidiol Accessed April 3, 2018.

65. Min JY, Min KB. Marijuana use is associated with hypersensitivity to multiple allergens in US adults. Drug Alcohol Depend. 2018 Jan 1;182:74-7.

66. Liu DZ, et al. Cannabidiol attenuates delayed-type hypersensitivity reactions via suppressing T-cell and macrophage reactivity. Acta Pharmacol Sin. 2010 Dec;31(12):1611-7.

67. Zhornitsky S, Potvin S. Cannabidiol in Humans—The Quest for Therapeutic Targets. Pharmaceuticals (Basel). 2012 May; 5(5): 529-52.