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

This is the third and final installment of a series of articles discussing cannabinoid-rich hemp oil and a new certification program for dietary supplement manufacturers and healthcare practitioners offered by the International Center for Cannabis Therapy (ICCT). As Chief Medical Officer–USA of the ICCT, a Czech Republic-based partnership of qualified doctors and scientists who specialize in the medical application of cannabis, Dr. Meletis is an expert on the clinical applications and research supporting the use of cannabinoid-rich hemp oil and its effects on the endocannabinoid system. Last month, we discussed the endocannabinoid system, its role in health, and how the endocannabinoid system interacts with the adrenals, sex hormones, and gut. We also shared pre-clinical and clinical research and Dr. Meletis’ observations about the use of cannabinoid-rich hemp oil in clinical practice, with an emphasis on the management of pain and inflammation and how to balance the endocannabinoid system without overwhelming its receptors. In this article, we’ll address the use of cannabinoid-rich hemp oil in applications such as Alzheimer’s disease, depression, anxiety, irritable bowel syndrome, stroke, schizophrenia, autoimmunity, and epilepsy, among other uses. We’ll also discuss the role of cannabinoids in the gut-brain axis.

Healthcare practitioners who want to delve deeper into the benefits of cannabinoid-rich hemp oil, understand the legal ramifications of prescribing it, and become certified as a respected hemp oil expert who understands proper dosing and other nuances of hemp oil use, can sign up for the ICCT online medical certification program at www.icctcertification.com.

A Brief Review of the Endocannabinoid System

Endogenous endocannabinoids that are produced within the body including anandamide (arachi-donylethanolamide) and 2-arachidonylglycerol (2-AG) are able to activate receptors in the endocannabinoid system. Phytocannabinoids such as Δ9-tetrahydrocannabinol (THC), the psychoactive component of Cannabis sativa, and cannabidiol (CBD), a non-psychoactive component, are also able to activate endocannabinoid receptors. Two of the main receptors in the endocannabinoid system are CB1 and CB2. CB1 is the primary receptor in the nervous system. It is also found in the adrenal gland, adipose tissue, heart, liver, lungs, prostate, uterus, ovary, testis, bone marrow, thymus, and tonsils. CB2 is primarily expressed in the immune system. Endocannabinoids and phytocannabinoids also act upon other receptors to achieve some of their beneficial effects. When the endocannabinoid system is stressed, there is a loss of homeostasis; and a number of diseases can result. For more detail about endocannabinoids and their receptors as well as supporting references, we recommend you read part two of this article.

The Endocannabinoid System and Neurological Diseases

An impaired endocannabinoid system may play a role in neurodegenera­tive disorders including Alzheimer’s, Parkinson’s, and Huntington’s disease. Endogenous cannabinoid signaling performs many functions in the central nervous system (CNS), such as modulating neuroinflammation and neurogenesis, as well as regulating synaptic plasticity, and the response to stress.1,2 Furthermore, upregulation of type-2 cannabinoid (CB2) receptors is associated with many neurodegenerative disorders. Consequently, influencing CB2 receptor signaling may be neuroprotective.2

Endocannabinoids possess a broad-spectrum of activity, which is advantageous in neurodegenerative diseases where neural dysfunction is caused by a combination of different factors including protein misfolding, neuroinflammation, excitotoxicity, oxidative stress, and mitochondrial dysfunction.2 The endocannabinoid signaling system is thought to regulate each of these factors.2 The endocannabinoid system also modulates brain tissue homeostasis during aging and/or neuroinflammation.2

CB2 receptors exert neuroprotective properties through their ability to suppress inflammation.3 Activation of CB2 receptors regulates the production of cytokines, proteins that play a significant role in immune function and inflammatory responses.4 Conversely, rather than inhibiting neurodegenerative diseases via an immunological pathway, the CB1 receptor suppresses cell death through protecting against excitotoxicity, overstimulation of excitatory receptors and simultaneous calcium release.2

In the neurons of healthy brains, there is a lower expression of CB2 receptors. However, a significant increase in expression of these receptors is noted in reactive microglia and activated astrocytes during neuroinflammation.5,6 Microglia are cells in the brain and spinal cord. When they become reactive, it is associated with neurodegenerative diseases. Activated microglia modulate inflammatory responses to pathogens and injury by signaling the synthesis of pro-inflammatory cytokines. Similarly, diseases that impact the central nervous system activate astrocytes. The fact that CB2 receptors are highly expressed when both these types of cells are activated may indicate they are needed to combat inflammation. This led researchers to conclude, “Therefore, the CB2 receptors have the potential to restrain the inflammatory processes that contribute to the declines in neural function occurring in a number of neurodegenerative disorders.”2

The involvement of CB2 receptors in Alzheimer’s disease was demonstrated in a number of human studies. Inspections of postmortem brains from individuals with Alzheimer’s disease showed that CB2 receptors are upregulated in cells that are linked to amyloid beta (Aβ)-enriched neuritic plaques.7-10 The deposition of amyloid beta plaques in the brain are involved in Alzheimer’s disease pathology. Other researchers found markedly higher CB2 receptor levels in individuals with severe Alzheimer’s disease compared with age-matched controls or people with moderate Alzheimer’s.11 Activation of the CB2 receptor has resulted in beneficial effects in Alzheimer’s disease, including the inhibition of microglial activation in mice.12

Further support for the role of the endocannabinoid system in Alzheimer’s is provided by preclinical studies showing that cannabidiol, the non-psychoactive component of Cannabis sativa, may be beneficial in Alzheimer’s. In one of these studies, mice inoculated with Aβ then injected with CBD (2.5 or 10 mg/kg) for seven days had anti-inflammatory and neuroprotective effects as evidenced by its ability to suppress a marker of activated astrocytes.13 A rat model of Alzheimer’s-related neuroinflammation further elucidated the role CBD may play in Alzheimer’s. In this study, adult male rats were inoculated with human Aβ42 in the hippocampus.14 Then, for 15 days, they were given 10 mg/kg CBD either with or without a PPAR-γ or PPAR-α receptor antagonist. CBD counteracted many of the pathogenic mechanisms of Aβ, and its effects involved the regulation of PPAR-γ. This makes sense since PPAR-γ receptors are increased in people with Alzheimer’s disease.

Parkinson’s Disease

The progressive loss of dopaminergic neurons primarily in the substantia nigra (SN) is the distinguishing characteristic of Parkinson’s disease. This dopaminergic neuron loss impairs the basal ganglia leading to bradykinesia (slowness of movement), rigidity, and tremors. Inflammation is a prominent player in Parkinson’s disease pathogenesis. Post-mortem evaluations of Parkinson’s disease patients observed microglia activation in the SN.15  Structural brain imaging studies have also shown that activated microglia and an increase of proinflammatory cytokines occur in the nigrostriatal system of Parkinson’s disease patients.16,17 A post-mortem study indicated that individuals with Parkinson’s disease have increased expression of CB2 receptors in microglial cells of the SN.18 This and other evidence suggests that targeting the CB2 receptor may serve as an anti-inflammatory approach in Parkinson’s.2

In support of the idea that modulating the endocannabinoid system is beneficial in Parkinson’s disease are a number of small studies investigating the use of cannabidiol in this group of patients. In a double-blind, placebo-controlled study of 21 Parkinson’s patients without dementia or comorbid psychiatric conditions, 300 mg/day cannabidiol enhanced well-being and quality of life.19 In an open-label pilot study, six Parkinson’s disease outpatients (four men and two women) who suffered from psychosis for at least three months received CBD starting with an oral dose of 150 mg/day for four weeks combined with their usual therapy.20 CBD intervention resulted in a marked decline in psychotic symptoms as measured by the Brief Psychiatric Rating Scale and the Parkinson Psychosis Questionnaire. CBD also lowered the total scores of the Unified Parkinson’s Disease Rating Scale. Furthermore, cannabidiol significantly reduced the frequency of sleep behavior disorder (RBD) in four patients with Parkinson’s disease.21

Anxiety and Post-Traumatic Stress Disorder

The endocannabinoid system regulates stress and anxiety, and modulation of the endocannabinoid system has been found to reduce anxiety. Repeated injections of cannabidiol to mice exposed to chronic unpredictable stress reduced anxiety in the animals.22 This effect was mediated by CB1, CB2, and serotonin (5HT1A) receptors. In a double-blind randomized trial investigating subjects with generalized social anxiety disorder not receiving medication, 600 mg of cannabidiol reduced anxiety and cognitive impairment caused by simulated public speaking and improved the participants’ comfort level in their speech performance.23 Another study of 10 individuals with generalized social anxiety disorder observed that 400 mg of cannabidiol was associated with markedly reduced subjective anxiety.24 Furthermore, advanced imaging studies indicate that the endocannabinoid system is underactive in post-traumatic stress disorder.25 Preliminary studies in humans have observed that cannabinoids may improve PTSD symptoms such as sleep quality and hyperarousal.26 Nabilone, a synthetic cannabinoid, reduced PTSD-related nightmares in a small group of Canadian military personnel.27 In an animal model, cannabinoids given shortly after experiencing a traumatic event blocked the development of a PTSD-like phenotype.26

For more information about the interaction between the endocannabinoid system and anxiety, we recommend you enroll in the ICCT medical certification program at www.icctcertification.com. This is a vast topic that cannot be addressed in one article alone.

Depression

Dysregulation of the endocannabinoid system may be involved in the development of depression. Suppressing the CB1 receptor results in a phenotypic state that is comparable to melancholic depression, with identical symptoms such as decreased appetite, increased anxiety, arousal, and wakefulness, an inability to release aversive memories, and increased sensitivity to stress.28 Furthermore, some antidepressant medications enhance endocannabinoid activity.28

One mechanism by which CBD reduces depression may be via its ability to protect against the effects of stress. Stress can lead to anxiety and depression. In animal models, CBD lowers autonomic indices of stress and behavioral effects of depression and anxiety and improves the delayed emotional consequences of stress via mechanisms that involve serotonin receptors.29,30 CBD is also thought to reduce depressive symptoms by enhancing hippocampal neurogenesis. Ongoing administration of CBD in mice undergoing chronic unpredictable stress improved depressive- and anxiety-like behaviors and triggered hippocampal progenitor proliferation and neurogenesis.31

CBD is thought to stimulate neurogenesis by elevating hippocampal levels of the endocannabinoid anandamide (AEA). A clinical study found that higher serum concentrations of AEA were associated with reduced anxiety in patients with major depression, although in this group of patients AEA levels were not associated with major depressive symptoms.32 Conversely, in people with minor depression, AEA concentrations were elevated compared to controls, suggesting that these levels might be raised as the body’s way to compensate for the depression and that they may have a neuroprotective role in patients with less severe depressive symptoms.

The role of cannabinoids in depression is a vast topic, and we recommend that you enroll in the ICCT medical certification program to understand how phytocannabinoids can be safely used in depression.

Gut-Brain Axis and Endocannabinoids

The gut-brain axis refers to the bidirectional interplay between the gut microbiota and the nervous system whereby the gut microbiota can impact behavior and cognition and the central nervous system can influence enteric microbiota composition. The gut-brain axis is thought to explain the association between chronic inflammatory bowel disease and depression.33

Accumulating evidence points to the endocannabinoid system’s important role in both normal gastrointestinal function and gastrointestinal pathology.34 The endocannabinoid system is involved in the regulation of motility, gut-brain-mediated fat intake and hunger signaling, and inflammation and gut permeability.34 The endocannabinoid system also works together with the gut microbiota to maintain gut health.34 Additionally, cannabinoids help recruit immune cells to the site of intestinal inflammation.35 In models of colitis, cannabidiol also has been shown to suppress the synthesis of pro-inflammatory cytokines, such as TNF-α and IFN-γ.35-38 This anti-inflammatory role in gut health was also reflected in a study where intestinal tissues of individuals with ulcerative colitis had concentrations of the endocannabinoid PEA that were 1.8 fold higher compared with healthy patients, likely in an attempt to help heal the inflammation.39 The anti-inflammatory effect of cannabinoids in the gastrointestinal system may be mediated by the gut microbiota. In mice, dysbiosis of the microbiota caused by antibiotics resulted in a general inflammatory state and altered endocannabinoids in the gut.33 (The concept of an endocannabinoidome will be addressed in much further detail in the ICCT certification program). Mitochondrial transport in enteric nerves may also be controlled by CB1 receptors, further lending support to the role of cannabinoids in gut health.40

The interplay between the gut, the brain, and the endocannabinoid system is involved in the development and progression of inflammatory bowel disease and irritable bowel syndrome. CB1 receptors in sensory ganglia modulate visceral sensation. During ongoing psychological stress, epigenetic pathways change the transcription of CB1 receptors, a mechanism which may explain the link between stress and abdominal pain.41 Furthermore, in rodent models, the endocannabinoid system is altered by early-life stress, leading to the development of irritable bowel syndrome (IBS).42,43

In tissue from humans with inflammatory bowel disease, there is elevated epithelial CB2-receptor expression.44 This indicates that CB2 receptors modulate immunity in this disorder.45 The CB2 receptors impact mucosal immunity and act together with CB1 receptors in the colonic epithelium to encourage epithelial wound healing.44

Research suggests that type 1 vanilloid receptors (TRPV1) may regulate some cannabinoid effects. One study observed a 3.5-fold increase in TRPV1-immunoreactive nerve fibers in biopsies from IBS sufferers compared with controls.45 This elevation may promote visceral hypersensitivity and pain in IBS.45 One scientist concluded, “Thus, a rationale exists for therapeutic interventions that would boost AEA levels or desensitize TRPV1, such as cannabidiol (CBD), to treat the condition [IBS].”25

Cannabinoids, Autoimmunity, Strokes, Epilepsy, and Other Disorders

Cannabidiol may have a role to play in autoimmune health. Animal models indicate it exerts beneficial actions in a number of autoimmune disorders including multiple sclerosis (MS), type 1 diabetes, and autoimmune myocarditis.46,47 Autoimmune disease develops due to transformed subsets of T cells into autoreactive memory T cells. These cells are falsely directed to target the body’s own cells resulting in tissue degeneration and autoimmune disease development such as type 1 diabetes, rheumatoid arthritis, and MS.46 CBD is able to modulate autoreactive T cell function.46 In one study it weakened the function of encephalitogenic Th17 cells.46 CBD also increased anti-inflammatory actions in activated memory T cells including enhanced synthesis of the anti-inflammatory IL-10 cytokine.48 Furthermore, CBD produced anti-inflammatory effects in animal models of T cell-mediated collagen-induced arthritis,49 autoimmune diabetes,50 and autoimmune hepatitis.51 It also has reversed the development of type 1 diabetes mellitus in mice.52 Most of the human studies showing cannabinoids are beneficial in multiple sclerosis have used a pharmaceutical combination of THC and CBD.53,54

Cannabinoids are important to other aspects of immunity. Specifically, they possess strong antibacterial activity. All five major cannabinoids (cannabidiol, cannabichromene, cannabigerol, Delta (9)-tetrahydrocannabinol, and cannabinol) significantly inhibited a number of methicillin-resistant Staphylococcus aureus (MRSA) strains.55 THC use by itself, however, was associated with increased susceptibility of mice to infection with the pathogen Legionella pneumophila.56

Another application of CBD may include protection against stroke.57 In vivo and in vitro stroke models indicate cannabidiol reduces infarct size.57 A study of human brain microvascular endothelial cells and human astrocyte co-cultures suggests that CBD can prevent permeability changes in the blood brain barrier.57

Another promising role for cannabidiol is in the improvement of schizophrenia. Modulating the endocannabinoid system using THC, the main psychoactive component in cannabis, can cause acute psychotic effects and cognitive impairment in schizophrenia patients.58 Conversely, CBD may possess antipsychotic actions and may have a role to play in supporting schizophrenia patients. Evidence to this effect is emerging thanks to small-scale clinical studies with CBD for the treatment of patients with psychotic symptoms.59 The results demonstrated that CBD is effective, safe, and well-tolerated in patients with schizophrenia, although large randomized clinical trials are needed.59

Cannabidiol has also been used successfully in clinical practice and in human studies in patients with epilepsy. It has been found to improve brain tumor-related seizures.60 Additionally, patients with Sturge-Weber syndrome, a disorder characterized by medically refractory epilepsy, stroke, and cognitive impairments, experienced up to a 50% reduction in seizures after supplementation with cannabidiol.61 It’s important to note that CBD supplementation can alter the serum levels of certain anti-epilepsy medications. This is not always a bad thing as CBD may reduce the side effects of some epilepsy medications by lowering their dosage.62 However, the blood levels of these pharmaceuticals should be monitored when taking CBD.

Dr. Meletis will discuss these and other clinical applications of CBD in the ICCT medical certification course and will also talk about the proper dosing to ensure that doctors who suggest CBD aren’t doing more harm than good. This is especially important in regard to seizures as too much CBD may actually cause seizures.

Dosing, Side Effects, and Drug Interactions

Cannabidiol is a safe substance, with a half-life of 18-32 hours,63 but it can have minor adverse effects in some people. Potential side effects are dry mouth, low blood pressure, light-headedness, drowsiness, tiredness, diarrhea, and changes of appetite or weight.62,64 There is also cross-reactivity between medical marijuana and certain foods as well as molds, dust mites, plants, and cat dander.65 It’s unclear whether these same reactions occur with cannabidiol. In fact, one mouse study indicated CBD in a dose-dependent manner markedly reduced inflammatory reactions associated with delayed-type hypersensitivity reactions.66 These are allergic reactions that develop days after exposure to the offending substance.

It is also important to keep in mind that cannabidiol can affect levels of medications. This is indicated by the fact it is an inhibitor of multiple cytochrome P450 enzymes, which are involved in the metabolism of drugs.67

The issues of potential side effects, proper dosing, and how to balance the endocannabinoid system without overwhelming its receptors are complex topics that Dr. Meletis and other scientists and doctors at the ICCT discuss in the certification program.

Conclusion

This three-part series began with an article discussing the ICCT’s certification for cannabinoid-rich hemp oil manufacturing facilities and products and how American Nutritional Products was the first company in the US to become ICCT-certified. It also discussed a new medical certification program for healthcare practitioners. This certification program is essential for any doctor recommending cannabinoid-rich hemp oil who wants to be aware of the legal ramifications and develop a greater level of trust among patients. The second part of the series discussed the endocannabinoid system’s interaction with the adrenals, sex hormones, and gut with an emphasis on the management of pain and inflammation. Finally, we wrapped up our discussion in this article with many of the clinical applications for cannabidiol.

Cannabinoid-rich hemp oil is being used successfully for a number of conditions. But we want to leave you with the caution that, as noted in the first part of this series, many manufacturers are producing inferior-quality products contaminated with pesticides. Healthcare practitioners who enroll in the certification program at https://www.icctcertification.com/international-cannabinoid-therapy-clinical-mastery/ will know how to differentiate between these poor quality products and ones that are more likely to benefit patients in a safe and effective manner.

References

  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. https://www.webmd.com/vitamins-supplements/ingredientmono-1439-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.