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From the Townsend Letter
October 2018

The Endocannabinoid System's Intriguing Role in Gut Health
by Chris D. Meletis, ND, and Kimberly Wilkes
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Cannabis has been used medicinally for centuries in people suffering from disorders associated with the gastrointestinal tract (GI), including abdominal pain, cramps, diarrhea, nausea, and vomiting.1,2 An extensive amount of recent research offers justification for the traditional use of not only cannabis but also other phytocannabinoids such as cannabidiol (CBD) for GI health. This research points to a strong connection between the endocannabinoid system and various aspects of gut health. The gut-brain axis, which refers to the ability of intestinal function to alter various aspects of mental and cognitive health, has drawn considerable attention in the medical literature. New research indicates that actions of the gut-brain axis may be in part mediated by the endocannabinoid system.3

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The endocannabinoid system refers to cannabinoids produced within the body (endocannabinoids), neurotransmitters that bind to cannabinoid receptors 1 and 2 (CB1 and CB2), thus regulating many aspects of health. Enzymes that play an important role in the synthesis and breakdown of endocannabinoids and molecules required for endocannabinoid uptake and transport are also involved in the endocannabinoid system. Phytocannabinoids like CBD may exert their health benefits in part through their actions on this system. It has long been known that the endocannabinoid system regulates many functions in the body including mental health and pain control. Its role in other areas of health has only recently begun to be appreciated. One of those areas is the role it plays in the intestines.

BioDisruptThe Endocannabinoid System's Role in Gut Health
An extensive amount of evidence indicates the endocannabinoid system plays a significant role in intestinal health. High concentrations of the endocannabinoids 2-arachidonoyl-glycerol (2-AG) and anandamide are observed in the colon along with significant fatty acid amide hydrolase (FAAH) activity,4 which is involved in the breakdown of anandamide.
The enteric nervous system (ENS) of the GI tract contains approximately 500 million nerve endings.5 The highest levels of immune cells in the body are also found in the gastrointestinal tract.5 Roughly 20% of the nerves in the GI tract are intrinsic primary afferent neurons, which alert the brain when subtle changes within the GI tract occur.5 This communication occurs through the vagus nerve. Endocannabinoids may regulate neurotransmission in the gut, as indicated by the presence of the CB2 receptor on enteric neurons and its expression by immune and epithelial cells in the GI tract.6,7 Furthermore, altering the activity of CB1 receptors can regulate sensory processing from the gut, brain integration of the brain-gut axis, extrinsic control of the gut, and intrinsic control by the enteric nervous system.4
The effect of both endocannabinoids and phytocannabinoids on colon carcinogenesis in rodents further supports the role of the endocannabinoid system in gut health. Studies using CBD or a Cannabis sativa extract with high cannabidiol content inhibited the initiation of aberrant crypt foci, polyps, and tumors in the colon of mice.8,9 Cannabidiol also suppressed cell proliferation in colorectal carcinoma cell lines.8

The Endocannabinoid System and Gut Motility
Endocannabinoids are known to regulate gut motility, the time it takes for food to move through the intestines. Slow gut motility is more commonly called constipation and fast gut motility is known as diarrhea. Evidence indicates that the endocannabinoid system plays an important role in gut motility. In obese mice fed high-fat diets, the endocannabinoid system in the gut underwent alterations, leading to an increase in gut motility.10 Many studies also indicate that CB1 receptor activation suppresses peristalsis and gastrointestinal contraction.
The CB1 receptor is activated by THC, the psychoactive component in marijuana.11,12 Because CBD does not directly affect the CB1 receptor it may be less likely to produce constipation. This was indicated in a mouse model of sepsis, which demonstrated that CBD slowed gastrointestinal motility in the animals with sepsis but did not affect motility in normal mice.13 Furthermore, CBD regulates the activity of FAAH, an enzyme involved in gastrointestinal motility through its actions on anandamide.13 Additional evidence that the endocannabinoid system is involved in gut motility was provided by a mouse model of constipation in which inhibiting diacylglycerol lipase (DGL), the enzyme responsible for the synthesis of the endocannabinoid 2-AG, improves gut motility.14

Endocannabinoids, the Gut, and Obesity
Through pathways associated with the gut-brain axis, alterations in the endocannabinoid system can result in obesity and accompanying inflammation.15 Endocannabinoid signaling in the gut may modulate food intake and energy balance by indirectly interacting with the vagus nerve,16 which permits neurotransmission between the gut and brain.17
A rodent model found fasting leads to the synthesis of 2-AG and activates the CB1 receptor through efferent vagal activation of receptors in the small intestine, which may signal hunger.18
The endocannabinoid system's role in food intake was shown in a study demonstrating increased endocannabinoid signaling occurs after hedonic eating (consuming food for pleasure).18 In both normal-weight and obese humans, thinking about eating or eating a highly palatable food such as chocolate or pudding, leads to circulating levels of endocannabinoids that are higher compared with a nonpalatable control diet.19-21

The Endocannabinoid System and Inflammatory Bowel Disease
Endocannabinoids and phyto-cannabinoids are involved in inflammatory regulation in the gut. Endocannabinoids help signal immune cell movement to intestinal inflammation sites.22,23 Cannabidiol has been shown to suppress the synthesis of proinflammatory cytokines, such as TNF-α and IFN-γ, and reduce intestinal inflammation.24,25 Due to its role in regulating gut inflammation, it's not surprising that the endocannabinoid system has also been shown to modulate inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS). Tissue from humans with IBD is characterized by increased epithelial CB2-receptor expression, suggesting CB2 receptors act in an immunomodulatory capacity in this disorder.26 This in turn affects mucosal immunity in the inflamed colon and interacts with the actions of CB1 receptors in the colonic lining to promote wound healing.26 In fact, CB1 receptors play an important role in gut health as evidenced by the increased incidence of diarrhea in people administered CB1 receptor antagonists.27
Other evidence supporting the endocannabinoid system's role in modulating colonic inflammation was provided by rodent models showing that suppressing FAAH, leading to a rise in anandamide levels, stops the development of colitis.28,29 Likewise, inhibiting FAAH and the inflammatory enzyme cyclooxygenase (COX) in mice with colitis reduces the severity of the disease by elevating anandamide levels and acting on the CB1 receptor.30 Blocking FAAH and COX correlated with higher concentrations of the endocannabinoids palmitoylethanolamide (PEA) and oleoylethanolamide. In intestinal tissue from ulcerative colitis patients, PEA levels are 1.8-fold higher compared with healthy patients, likely a result of the PEA attempting to help heal the inflammation.31 PEA has pronounced anti-inflammatory properties that inhibit features of colitis in mice as well as the synthesis of inflammatory cytokines.32
The phytocannabinoids CBD, THC, and cannabigerol have significantly reduced intestinal inflammation in animal models. In one of those models, both CBD and THC proved beneficial.33 However, THC was the most effective in rats with experimental colitis, although CBD enhanced the effects of an ineffective THC dose to the point where the combination of CBD and lower-dose THC was the equivalent of a higher THC-only dose.33 The phytocannabinoid cannabigerol (CBG) has also proved beneficial in rodent models of colitis. In one study, CBG inhibited colitis in mice and lowered the synthesis of reactive oxygen species in intestinal epithelial cells.34
Polymorphisms in the gene encoding CB1 receptors are associated with irritable bowel syndrome, further establishing the link between the endocannabinoid system and this disease.35  Variants of the CB1 receptor gene (CNR1) and FAAH genes have been noted in individuals with diarrhea-predominant and alternating forms of IBS.36,37 In intestinal tissues of patients with constipation-predominant IBS, lower levels of FAAH mRNA were observed.38 In a study of patients with constipation predominant IBS (C-IBS), diarrhea-predominant IBS (D-IBS), and mixed IBS (M-IBS) who suffered from chronic abdominal pain and functional dyspepsia, there was a relationship between the non-wild type FAAH genotype and functional bowel disease phenotypes and with increased colonic transit in IBS-D patients.39 Likewise, in another study, there was a pronounced association between a polymorphism in the cannabinoid receptor 1 (CNR1) gene and IBS symptoms, colonic transit in IBS-D, and intestinal gas.40 However, pain was not associated with this polymorphism. Furthermore, researchers found that the CNR1 mutations correlated with the emergence of IBS symptoms, as observed in two studies of a Korean and Chinese population with IBS.41,37
Human research using a CBD supplement further corroborates the potential benefits of modulating the endocannabinoid system in IBD/IBS. In a 10-week study of patients with ulcerative colitis given a CBD-rich botanical extract, the primary endpoint of percentage of patients in remission after treatment was similar between the placebo and CBD group.42 However, subjective physician's global assessment of illness severity, subject global impression of change, and patient-reported quality-of-life outcomes were improved in the CBD group. Additionally, the placebo group experienced more gastrointestinal-associated adverse effects. Furthermore, in human colonic cultures derived from ulcerative colitis patients, CBD suppressed enteric reactive gliosis and reduced inflammation, thus inhibiting intestinal damage.25 The researchers concluded, "Our results therefore indicate that CBD indeed unravels a new therapeutic strategy to treat inflammatory bowel diseases." Clearly, as another group of researchers stated, the endocannabinoid system "in the gut is a potential therapeutic target for IBS and other functional bowel disorders."

Psychological Stress and the Endocannabinoid System
The endocannabinoid system regulates abdominal pain (visceral hyperalgesia) caused by chronic stress and may explain, at least in part, the relationship between chronic stress and IBD/IBS.27,43 Rodent models indicate that early-life stress alters the endocannabinoid system, which increases the susceptibility to IBS.44 The endocannabinoid system is a key player in the regulation of visceral pain and the means by which psychological stress impairs GI function may involve this system.44 Chronic stress reduces levels of the endocannabinoid anandamide while elevating 2-AG in the brain and downregulating CB1 receptors in sensory ganglia, which regulate visceral pain.45 During chronic psychological stress, CB1 receptor activity is altered through epigenetic pathways, which may explain the association between stress and abdominal pain.46 Epigenetics refers to the alteration of gene expression through pathways other than the genetic code. It refers to the changes that occur in our genes due to lifestyle or environmental factors. Through these epigenetic actions, chronic stress affects the CB1 gene promoter, leading to lower levels of CB1 in sensory neurons that innervate the colon and other pelvic organs.47

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