Functional Gastro-Intestinal Disorders

Functional Gastro-Intestinal Disorders form a spectrum of disorders to the gastro-intestinal tract ranging from heartburn to diarrhea. Cannabis has been used for centuries to treat diseases such as diarrhea and research now shows a strong involvement of the endocannabinoid system in the function of the gastro-intestinal tract and the regulation of bowel movement. Therefore the prospects of cannabinoid-based therapy for these diseases are good.

Alternative Names: 
Crohn's disease
Irritable Bowel Syndrome
Irritable Bowel Disease
Diarrhea
Heartburn
Endocannabinoids: 
Phytocannabinoids: 
Literature Discussion: 

In humans, a Single Nucleotide Polymorphism (SNP) in Fatty Acid Amide Hydrolase (FAAH), C385A or rs324420 is associated with increased risk of Functional Gastro-Intestinal Disorders in general (P=0.01) and more specifically with diarrhea-type Irritable Bowel Syndrome (IBS)(P=0.008) and mixed-type IBS (P=0.01). As this mutation reduces functional expression of FAAH and FAAH is the major degrading enzyme for Anandamide this suggests the involvement of the endocannabinoid system in gastro-intestinal function (Camilleri et al., 2008).

DAGLα is expressed in the enteric nervous system including the gastrointestinal tract. Genetically constipated mice and CB1 deficient mice reversed their symptoms of slow gastrointestinal motility, intestinal contractility and constipation after DAGLα inhibition. These effects were mediated by 2-AG and CB1 receptors (Bashashati et al., 2015).

Polymorphisms (small, single nucleotide mutations) in the CB1 gene/receptor are linked to the susceptibility to develop Crohn’s Disease, suggesting the involvement of the endocannabinoid system in Crohn’s Disease (Storr et al., 2010).

Intracerebrovascular application of Anandamide and 2AG appeared gastro-protective in ethanol-induced ulcers suggesting the involvement of endocannabinoids in the central nervous system (Gyires and Zádori, 2016).

In patients with diarrhea-type IBS higher levels of 2AG and lower levels of OEA and PEA were found. In contrast, patients with constipation-type IBS had higher levels of OEA and lower levels of FAAH. Also, PEA levels were inversely correlated with abdominal pain suggesting substantial involvement of the endocannabinoid system in the pathophysiology of IBS (Fichna et al., 2013).

Apart from CB1 and CB2, there is evidence for the involvement of PPARγ and TRPV1 in Crohn’s Disease (de Fontgalland et al., 2014; Schicho and Storr, 2014) Patients with Crohn’s Disease have significantly reduced levels of Anandamide, but not 2AG or PEA, supporting a role for the endocannabinoid system in Crohn’s Disease (Di Sabatino et al., 2011).

cannabinoid-mediated reduction in gastro-intestinal motility appears to be mediated by CB1 but not CB2 (Aviello et al., 2008).

CB1 and TRPV1 signaling are both required for the development of stress-induced visceral hyperalgesia and TRPV4 and TRPA1 may also be involved (Lin et al., 2013).

TRP receptors (TRPV1-4, TRPA1, TRPM8) are classically known for their role in pain sensation but may also be involved in inflammation. TRPs bind to most plant cannabinoids and endocannabinoids with varying affinities (De Petrocellis et al., 2011, 2012), tentatively making TRPs excellent targets and plant cannabinoids excellent substrates for pain and inflammation management.

A study in mice showed that GPR55 is involved in neurogenic gut contractions (Ross et al., 2012).

In mice, selective inhibition of FAAH inhibited colonic motility (Fichna et al., 2014).

Many Crohn’s Disease patients self-administer cannabis suggesting a role for cannabinoids in the treatment of Crohn’s or in the alleviation of its symptoms. Although many patients reported symptomatic improvement of abdominal pain (83.9%), abdominal cramping (76.8%), joint pain (48.2%) and diarrhea (28.6%), cannabis use was also associated with increased hospitalization (Storr et al., 2014). This could be explained as cannabis (or the vehicle it comes in, like tobacco) being harmful in Crohn’s. Alternatively, patients with more severe Crohn’s Disease may be sooner inclined to use cannabis to alleviate the symptoms.

In rats, intra-colonic application of 1 to 10 mg/kg cannabis extract dose-dependently reduced colitis severity but oral application did not (Wallace et al., 2013). This effect was independent of CB1 or CB2 receptors. However, oral extract did prevent NSAID-induced gastric damage at 10 mg/kg in a CB1-dependent way. Cannabis extract also reduced visceral pain at 3 mg/kg in a CB2-dependent way suggesting cannabis extract has distinct beneficial effects in gastro-intestinal disorders via CB1/2-dependent and independent pathways (Wallace et al., 2013).

Interestingly, injection of 100 mg/kg THC produced strong diarrhea in CB1 deficient mice but not in controls suggesting complex involvement of CB1 in the regulation of intestinal transit (Zimmer et al., 1999).

Apart from THC, (relatively) non-psychotropic cannabinoids such as THCV, CBD and CBG were found to have anti-inflammatory effects in experimental intestinal inflammation (Alhouayek and Muccioli, 2012).

In the TNBS mouse model of colitis, 5 mg/kg CBD i.p. twice daily for three days attenuated colitis and promoted endothelial and epithelial wound healing (Krohn et al., 2016). 

In the DNBS mouse model of colitis, both oral and i.p. CBD decreased tissue damage and intestinal hypermotility. CBD in extract was more effective than pure CBD, suggesting a significant entourage effect (Pagano et al., 2016). 

In the LPS mouse model of colitis, 10 mg/kg i.p. CBD decreased reactive gliosis, mast cell and macrophage recruitment, TNFα expression and intestinal apoptosis. In ulcerative colitis patient rectal biopsies also reduced reactive gliosis, at least partially through PPARγ (De Filippis et al., 2011).

In mice, CBD seems to inhibit intestinal motility in both CB1 dependent and independent ways (Fride et al., 2005).

CBG attenuates colitis in animal models, reduces nitric oxide production in macrophages and reduces ROS formation in intestinal epithelial cells, showing therapeutic potential to treat gastrointestinal inflammation (Borrelli et al., 2013).

References:

Alhouayek, M., and Muccioli, G.G. (2012). The endocannabinoid system in inflammatory bowel diseases: from pathophysiology to therapeutic opportunity. Trends Mol. Med. 18, 615–625.

Aviello, G., Romano, B., and Izzo, A.A. (2008). cannabinoids and gastrointestinal motility: animal and human studies. Eur. Rev. Med. Pharmacol. Sci. 12 Suppl 1, 81–93.

Bashashati, M., Nasser, Y., Keenan, C. M., Ho, W., Piscitelli, F., Nalli, M., … Sharkey, K. A. (2015). Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation. British Journal of Pharmacology, 172(12), 3099-3111. https://doi.org/10.1111/bph.13114

Borrelli, F., Fasolino, I., Romano, B., Capasso, R., Maiello, F., Coppola, D., … Izzo, A. A. (2013). Beneficial effect of the non-psychotropic plant cannabinoid cannabigerol on experimental inflammatory bowel disease. Biochemical Pharmacology85(9), 1306-1316. https://doi.org/10.1016/j.bcp.2013.01.017

Camilleri, M., Carlson, P., McKinzie, S., Grudell, A., Busciglio, I., Burton, D., Baxter, K., Ryks, M., and Zinsmeister, A.R. (2008). Genetic variation in endocannabinoid metabolism, gastrointestinal motility, and sensation. Am. J. Physiol. Gastrointest. Liver Physiol. 294, G13-19.

De Filippis, D., Esposito, G., Cirillo, C., Cipriano, M., De Winter, B.Y., Scuderi, C., Sarnelli, G., Cuomo, R., Steardo, L., De Man, J.G., et al. (2011). Cannabidiol reduces intestinal inflammation through the control of neuroimmune axis. PloS One 6, e28159.

De Fontgalland, D., Brookes, S.J., Gibbins, I., Sia, T.C., and Wattchow, D.A. (2014). The neurochemical changes in the innervation of human colonic mesenteric and submucosal blood vessels in ulcerative colitis and Crohn’s disease. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 26, 731–744.

De Petrocellis, L., Ligresti, A., Moriello, A.S., Allarà, M., Bisogno, T., Petrosino, S., Stott, C.G., and Di Marzo, V. (2011). Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br. J. Pharmacol. 163, 1479–1494.

De Petrocellis, L., Orlando, P., Moriello, A.S., Aviello, G., Stott, C., Izzo, A.A., and Di Marzo, V. (2012). cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol. Oxf. Engl. 204, 255–266.

Di Sabatino, A., Battista, N., Biancheri, P., Rapino, C., Rovedatti, L., Astarita, G., Vanoli, A., Dainese, E., Guerci, M., Piomelli, D., et al. (2011). The endogenous cannabinoid system in the gut of patients with inflammatory bowel disease. Mucosal Immunol. 4, 574–583.

Fichna, J., Wood, J.T., Papanastasiou, M., Vadivel, S.K., Oprocha, P., Sałaga, M., Sobczak, M., Mokrowiecka, A., Cygankiewicz, A.I., Zakrzewski, P.K., et al. (2013). 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, e85073.

Fichna, J., Sałaga, M., Stuart, J., Saur, D., Sobczak, M., Zatorski, H., Timmermans, J.-P., Bradshaw, H.B., Ahn, K., and Storr, M.A. (2014). Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 26, 470–481.

Fride, E., Ponde, D., Breuer, A., and Hanus, L. (2005). Peripheral, but not central effects of cannabidiol derivatives: mediation by CB(1) and unidentified receptors. Neuropharmacology 48, 1117–1129.

Gyires, K., and Zádori, Z.S. (2016). Role of cannabinoids in Gastrointestinal Mucosal Defense and Inflammation. Curr. Neuropharmacol. 14, 935–951.

Krohn, R.M., Parsons, S.A., Fichna, J., Patel, K.D., Yates, R.M., Sharkey, K.A., and Storr, M.A. (2016). Abnormal cannabidiol attenuates experimental colitis in mice, promotes wound healing and inhibits neutrophil recruitment. J. Inflamm. Lond. Engl. 13, 21.

Lin, X.-H., Wang, Y.-Q., Wang, H.-C., Ren, X.-Q., and Li, Y.-Y. (2013). Role of endogenous cannabinoid system in the gut. Sheng Li Xue Bao 65, 451–460.

Pagano, E., Capasso, R., Piscitelli, F., Romano, B., Parisi, O.A., Finizio, S., Lauritano, A., Marzo, V.D., Izzo, A.A., and Borrelli, F. (2016). An Orally Active Cannabis Extract with High Content in Cannabidiol attenuates Chemically-induced Intestinal Inflammation and Hypermotility in the Mouse. Front. Pharmacol. 7, 341.

Ross, G.R., Lichtman, A., Dewey, W.L., and Akbarali, H.I. (2012). Evidence for the putative cannabinoid receptor (GPR55)-mediated inhibitory effects on intestinal contractility in mice. Pharmacology 90, 55–65.

Schicho, R., and Storr, M. (2014). Cannabis finds its way into treatment of Crohn’s disease. Pharmacology 93, 1–3

Storr, M., Emmerdinger, D., Diegelmann, J., Pfennig, S., Ochsenkühn, T., Göke, B., Lohse, P., and Brand, S. (2010). The cannabinoid 1 receptor (CNR1) 1359 G/A polymorphism modulates susceptibility to ulcerative colitis and the phenotype in Crohn’s disease. PloS One 5, e9453.

Storr, M., Devlin, S., Kaplan, G.G., Panaccione, R., and Andrews, C.N. (2014). Cannabis use provides symptom relief in patients with inflammatory bowel disease but is associated with worse disease prognosis in patients with Crohn’s disease. Inflamm. Bowel Dis. 20, 472–480.

Wallace, J.L., Flannigan, K.L., McKnight, W., Wang, L., Ferraz, J.G.P., and Tuitt, D. (2013). Pro-resolution, protective and anti-nociceptive effects of a cannabis extract in the rat gastrointestinal tract. J. Physiol. Pharmacol. Off. J. Pol. Physiol. Soc. 64, 167–175.

Zimmer, A., Zimmer, A.M., Hohmann, A.G., Herkenham, M., and Bonner, T.I. (1999). Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. U. S. A. 96, 5780–5785.

Clinical Trials: 

Until the 1920s cannabis was often used to treat gastro-intestinal problems such as diarrhea and abdominal pain (Storr et al., 2006).

Colonic motility is controlled by CB1 receptors on cholinergic colonic motor neurons (Hinds et al., 2006).

In a small-scale trial, 5 mg of oral THC (CB1 agonist) decreased colonic motility and increased colonic compliance in patients with IBS (Wong et al., 2011) and in healthy volunteers (Esfandyari et al., 2007), while antagonizing CB1 with rimonabant increases defecation (Wong et al., 2011).

The effect of THC on colonic motility depended to some extent on a CB1 polymorphism (CNR1 rs806378 with faster colonic motility for the CC phenotype) but not on FAAH or MAGL polymorphisms (Camilleri et al., 2013; Wong et al., 2011, 2012).

In a 13-patient trial, inhaled cannabis increased weight, the perception of general health and the abilities to perform daily tasks (Lahat et al., 2012).

In a survey among patients with inflammatory bowel disease 16.4% found cannabis helpful to treat abdominal pain, lack of appetite and nausea but not to reduce diarrhea (Ravikoff Allegretti et al., 2013).

In a small study with Crohn’s disease patients cannabis use improved symptoms and reduced the use of other medication in 10 out of 11 patients versus 4 out of 10 for placebo treatment. Complete remission was achieved in 5 out of 11 patients versus 1 out of 10 for placebo treatment (Naftali et al., 2014).

References:

Camilleri, M., Kolar, G.J., Vazquez-Roque, M.I., Carlson, P., Burton, D.D., and Zinsmeister, A.R. (2013). cannabinoid receptor 1 gene and irritable bowel syndrome: phenotype and quantitative traits. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G553-560.

Esfandyari, T., Camilleri, M., Busciglio, I., Burton, D., Baxter, K., and Zinsmeister, A.R. (2007). Effects of a cannabinoid receptor agonist on colonic motor and sensory functions in humans: a randomized, placebo-controlled study. Am. J. Physiol. Gastrointest. Liver Physiol. 293, G137-145.

Hinds, N.M., Ullrich, K., and Smid, S.D. (2006). cannabinoid 1 (CB1) receptors coupled to cholinergic motorneurones inhibit neurogenic circular muscle contractility in the human colon. Br. J. Pharmacol. 148, 191–199.

Lahat, A., Lang, A., and Ben-Horin, S. (2012). Impact of cannabis treatment on the quality of life, weight and clinical disease activity in inflammatory bowel disease patients: a pilot prospective study. Digestion 85, 1–8.

Naftali, T., Mechulam, R., Lev, L.B., and Konikoff, F.M. (2014). Cannabis for inflammatory bowel disease. Dig. Dis. Basel Switz. 32, 468–474.

Ravikoff Allegretti, J., Courtwright, A., Lucci, M., Korzenik, J.R., and Levine, J. (2013). Marijuana use patterns among patients with inflammatory bowel disease. Inflamm. Bowel Dis. 19, 2809–2814.

Storr, M., Yüce, B., and Göke, B. (2006). [Perspectives of cannabinoids in gastroenterology]. Z. Gastroenterol. 44, 185–191.

Wong, B.S., Camilleri, M., Busciglio, I., Carlson, P., Szarka, L.A., Burton, D., and Zinsmeister, A.R. (2011). Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology 141, 1638-1647.e1-7.

Wong, B.S., Camilleri, M., Eckert, D., Carlson, P., Ryks, M., Burton, D., and Zinsmeister, A.R. (2012). Randomized pharmacodynamic and pharmacogenetic trial of dronabinol effects on colon transit in irritable bowel syndrome-diarrhea. Neurogastroenterol. Motil. Off. J. Eur. Gastrointest. Motil. Soc. 24, 358-e169.

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