by Chris D. Meletis, ND, and Kimberly Wilkes
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
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.
The 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
The Microbiota and the Endocannabinoid System
Perhaps one of the most interesting aspects of the endocannabinoid system’s role in gut health is its interaction with the gut microbiota. The gut microbiota can modulate intestinal endocannabinoid tone.48 A microbiota profile associated with obesity also correlates with an increased intestinal concentration of anandamide, which leads to increased gut permeability (leaky gut).48 In fact, the link between the gut microbiota and obesity may be mediated by the endocannabinoid system.48 The results of a study where the bacterium, Akkermansia muciniphila, was administered to obese and type 2 diabetic mice daily support this concept.49 In that study, the bacterium reversed diet‐caused obesity. It accomplished this by increasing intestinal levels of endocannabinoids that control inflammation, the gut barrier, and gut peptide secretion.
On the other end of the spectrum, endocannabinoids from adipose tissue can also modulate the composition of the gut microbiota.35 This indicates there is bidirectional communication between the microbiota and the endocannabinoid system.35 Evidence of this cross-talk between the endocannabinoid system and the microbiota is reinforced by studies showing that the beneficial effects of probiotic supplementation on gut health may in part involve this system. The probiotic Lactobacillus given orally to rodents reduced visceral pain while simultaneously upregulating CB2 receptors in the intestinal epithelium.50 Inhibiting CB2 eliminated the beneficial effects of the probiotic. In a model of chronic colonic hypersensitivity, Lactobacillus acidophilus NCFM resulted in analgesia.50 This study also indicated that CB2 receptors may be involved in the association between gut microbiota and visceral hypersensitivity. Furthermore, dysbiosis of the gut microbiota caused by antibiotics correlates with a general inflammatory state and alteration of certain endocannabinoids in the gut of mice as well as accompanying depression.51 However, in a human study of individuals consuming Lactobacillus acidophilus NCFM over a period of 21 days, CB2 receptors were not upregulated in colonic mucosal biopsies.52
An abundance of evidence is pointing to the conclusion that the endocannabinoid system is involved in gut health and that it may even be an important mediator of the actions of the gut-brain axis. The damaging effects of chronic psychological stress on the intestinal tract may also be driven by the endocannabinoid system. Targeting this system by the use of CBD oil or other phytocannabinoids may be one way to reduce colonic inflammation and reduce the effects of stress on the gut. In my clinical practice I also use a specific high potency PEA that has helped many patients.
Download Article: [download id=”13503″]
1. DiPatrizio NV. Endocannabinoids in the Gut. Cannabis Cannabinoid Res. 2016 Feb;1(1):67-77.
2. Sharkey KA, Wiley JW. The Role of the Endocannabinoid System in the Brain-Gut Axis. Gastroenterology. 2016 Aug;151(2):252-66.
3. Hasenoehrl C, Taschler U, Storr M, et al. The gastrointestinal tract – a central organ of cannabinoid signaling in health and disease. Neurogastroenterol Motil. 2016 Dec;28(12):1765-80.
4. Hornby PJ, Prouty SM. Involvement of cannabinoid receptors in gut motility and visceral perception. Br J Pharmacol. 2004 Apr;141(8):1335-45.
5. Furness JB, Kunze WAA, Clerc N. Nutrient tasting and signaling mechanisms in the gut II. The intestine as a sensory organ: Neural, endocrine, and immune responses. Am J Physiol Gastrointest Liver Physiol. 1999 Nov;277(5 Pt 1):G922-8.
6. Trautmann SM, Sharkey KA. The Endocannabinoid System and Its Role in Regulating the Intrinsic Neural Circuitry of the Gastrointestinal Tract. Int Rev Neurobiol. 2015;125:85-126.
7. Wright K, Rooney N, Feeney M, et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology. 2005 Aug;129(2):437-53.
8. Aviello G, Romano B, Borrelli F, et al. Chemopreventive effect of the non-psychotropic phytocannabinoid cannabidiol on experimental colon cancer. J Mol Med (Berl). 2012 Aug;90(8):925-34.
9. Romano B, Borrelli F, Pagano E, et al. Inhibition of colon carcinogenesis by a standardized Cannabis sativa extract with high content of cannabidiol. Phytomedicine. 2014 Apr 15;21(5):631-9.
10. Izzo AA, Piscitelli F, Capasso R, et al. Peripheral endocannabinoid dysregulation in obesity: relation to intestinal motility and energy processing induced by food deprivation and re-feeding. Br J Pharmacol. 2009 Sep;158(2):451-61.
11. Márquez L, Abanades S, Andreu M. [Endocannabinoid system and bowel inflammation]. [Article in Spanish]. Med Clin (Barc). 2008 Oct 18;131(13):513-7.
12. Krowicki ZK, Moerschbaecher JM, Winsauer PJ, et al. Delta9-tetrahydrocannabinol inhibits gastric motility in the rat through cannabinoid CB1receptors. Eur J Pharmacol. 1999 Apr 29;371(2-3):187-96.
13. de Filippis D, Iuvone T, d’amico A, et al. Effect of cannabidiol on sepsis-induced motility disturbances in mice: involvement of CB receptors and fatty acid amide hydrolase. Neurogastroenterol Motil. 2008 Aug;20(8):919-27.
14. Bashashati M, Nasser Y, Keenan CM, et al. Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation. Br J Pharmacol. 2015 Jun;172(12):3099-111.
15. Cluny NL, Reimer RA, Sharkey KA. Cannabinoid signalling regulates inflammation and energy balance: the importance of the brain-gut axis. Brain Behav Immun. 2012 Jul;26(5):691-8.
16. DiPatrizio NV, Piomelli D. The thrifty lipids: endocannabinoids and the neural control of energy conservation. Trends Neurosci. 2012 Jul;35(7):403-11.
17. Berthoud HR. The vagus nerve, food intake and obesity. Regul Pept. 2008 Aug 7;149(1-3):15-25.
18. DiPatrizio NV, Igarashi M, Narayanaswami V, et al. Fasting stimulates 2-AG biosynthesis in the small intestine: role of cholinergic pathways. Am J Physiol Regul Integr Comp Physiol. 2015 Oct 15;309(8):R805-13.
19. Monteleone P, Piscitelli F, Scognamiglio P, et al. Hedonic eating is associated with increased peripheral levels of ghrelin and the endocannabinoid 2-arachidonoyl-glycerol in healthy humans: a pilot study. J Clin Endocrinol Metab. 2012 Jun;97(6):E917-24.
20. Rigamonti AE, Piscitelli F, Aveta T, et al. Anticipatory and consummatory effects of (hedonic) chocolate intake are associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults. Food Nutr Res. 2015 Nov 4;59:29678.
21. Mennella I, Ferracane R, Zucco F, et al. Food Liking Enhances the Plasma Response of 2-Arachidonoylglycerol and of Pancreatic Polypeptide upon Modified Sham Feeding in Humans. J Nutr. 2015 Sep;145(9):2169-75.
22. Alhouayek M, Lambert DM, Delzenne NM, et al. Increasing endogenous 2-arachidonoylglycerol levels counteracts colitis and related systemic inflammation. FASEB J. 2011 Aug;25(8):2711-21.
23. Schicho R, Bashashati M, Bawa M, et al. The atypical cannabinoid O-1602 protects against experimental colitis and inhibits neutrophil recruitment. Inflamm Bowel Dis. 2011 Aug;17(8):1651-64.
24. Borrelli F, Aviello G, Romano B, 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.
25. De Filippis D, Esposito G, Cirillo C, et al. Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PLoS One. 2011;6(12):e28159.
26. Wright K, Rooney N, Feeney M, et al. Differential expression of cannabinoid receptors in the human colon: cannabinoids promote epithelial wound healing. Gastroenterology. 2005 Aug;129(2):437-53.
27. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010 Apr;126(1):21-38.
28. Massa F, Marsicano G, Hermann H, et al. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest. 2004 Apr;113(8):1202-9.
29. Storr MA, Keenan CM, Emmerdinger D, et al. Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J Mol Med (Berl). 2008 Aug;86(8):925-36.
30. Sasso O, Migliore M, Habrant D, et al. Multitarget fatty acid amide hydrolase/cyclooxygenase blockade suppresses intestinal inflammation and protects against nonsteroidal anti-inflammatory drug-dependent gastrointestinal damage. FASEB J. 2015 Jun;29(6):2616-27.
31. Darmani NA, Izzo AA, Degenhardt B, 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.
32. Borrelli F, Romano B, Petrosino S, et al. Palmitoylethanolamide, a naturally occurring lipid, is an orally effective intestinal anti-inflammatory agent. Br J Pharmacol. 2015 Jan;172(1):142-58.
33. Jamontt JM, Molleman A, Pertwee RG, et al. The effects of Delta-tetrahydrocannabinol and cannabidiol alone and in combination on damage, inflammation and in vitro motility disturbances in rat colitis. Br J Pharmacol. 2010 Jun;160(3):712-23.
34. Borrelli F, Fasolino I, Romano B, et al. Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochem Pharmacol. 2013 May 1;85(9):1306-16.
35. Sharkey KA, Wiley JW. The Role of the Endocannabinoid System in the Brain-Gut Axis. Gastroenterology. 2016 Aug;151(2):252-66.
36. Camilleri M, Kolar GJ, Vazquez-Roque MI, et al. Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. Am J Physiol Gastrointest Liver Physiol. 2013 Mar 1;304(5):G553-60.
37. Park JM, Choi MG, Cho YK, et al. Cannabinoid receptor 1 gene polymorphism and irritable bowel syndrome in the Korean population: a hypothesis-generating study. J Clin Gastroenterol. 2011 Jan;45(1):45-9.
38. Fichna J, Wood JT, Papanastasiou M, 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. 2013 Dec 27;8(12):e85073.
39. Camilleri M, Carlson P, McKinzie S, et al. Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation. Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G13-9.
40. Camilleri M, Kolar GJ, Vazquez-Roque MI, et al. Cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. Am J Physiol Gastrointest Liver Physiol. 2013 Mar 1;304(5):G553-60.
41. Jiang Y, Nie Y, Li Y, et al. Association of cannabinoid type 1 receptor and fatty acid amide hydrolase genetic polymorphisms in Chinese patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2014 Jun;29(6):1186-91.
42. Irving PM, Iqbal T, Nwokolo C, et al. A Randomized, Double-blind, Placebo-controlled, Parallel-group, Pilot Study of Cannabidiol-rich Botanical Extract in the Symptomatic Treatment of Ulcerative Colitis. Inflamm Bowel Dis. 2018 Mar 10. [Epub ahead of print.]
43. Storr MA, Sharkey KA. The endocannabinoid system and gut-brain signalling. Curr Opin Pharmacol. 2007 Dec;7(6):575-82.
44. Marco EM, Echeverry-Alzate V, López-Moreno JA, 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.
45. Morena M, Patel S, Bains JS, et al. Neurobiological Interactions Between Stress and the Endocannabinoid System. Neuropsychopharmacology. 2016 Jan;41(1):80-102.
46. Hong S, Zheng G, Wiley JW. Epigenetic regulation of genes that modulate chronic stress-induced visceral pain in the peripheral nervous system. Gastroenterology. 2015 Jan;148(1):148-57.e7.
47. Muccioli GG, Naslain D, Bäckhed F, et al. The endocannabinoid system links gut microbiota to adipogenesis. Mol Syst Biol. 2010 Jul;6:392.
48. Everard A, Belzer C, Geurts L, et al. Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci U S A. 2013 May 28;110(22):9066-71.
49. Rastelli M, Knauf C, Cani PD. Gut Microbes and Health: A Focus on the Mechanisms Linking Microbes, Obesity, and Related Disorders. Obesity (Silver Spring). 2018 May;26(5):792-800.
50. Rousseaux C, Thuru X, Gelot A, et al. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007 Jan;13(1):35-7.
51. Guida F, Turco F, Iannotta M, et al. Antibiotic-induced microbiota perturbation causes gut endocannabinoidome changes, hippocampal neuroglial reorganization and depression in mice. Brain Behav Immun. 2017 Sep 7. [Epub ahead of print.]
52. Ringel-Kulka T, Goldsmith JR, Carroll IM, et al. Lactobacillus acidophilus NCFM affects colonic mucosal opioid receptor expression in patients with functional abdominal pain – a randomised clinical study. Aliment Pharmacol Ther. 2014 Jul;40(2):200-7.