Skip to main content

Advertisement

Log in

Cannabinoids and GI Disorders: Endogenous and Exogenous

  • Motility (H Parkman and R Schey, Section Editors)
  • Published:
Current Treatment Options in Gastroenterology Aims and scope Submit manuscript

Opinion Statement

Despite the political and social controversy affiliated with it, the medical community must come to the realization that cannabinoids exist as a ubiquitous signaling system in many organ systems. Our understanding of cannabinoids and how they relate not only to homeostasis but also in disease states must be furthered through research, both clinically and in the laboratory. The identification of the cannabinoid receptors in the early 1990s have provided us with the perfect target of translational research. Already, much has been done with cannabinoids and the nervous system. Here, we explore the implications it has for the gastrointestinal tract. Most therapeutics currently on the market presently target only one aspect of the cannabinoid system. Our main purpose here is to highlight areas of research and potential avenues of discovery that the cannabinoid system has yet to reveal.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References and Recommended Reading

Papers of Particular Interest, Published recently, Have Been Highlighted as: • Of importance; •• Of major importance

  1. Mechoulam R. Cannabinoids as therapeutic agents. Boca Raton, Fla.: CRC Press; 1986.

    Google Scholar 

  2. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lutz B. Molecular biology of cannabinoid receptors. Prostaglandins Leukot Essent Fatty Acids. 2002;66:123–42.

    Article  CAS  PubMed  Google Scholar 

  4. 25 Legal Medical Marijuana States and DC: Laws, Fees, and Possession Limits, ProCon.org, 2016.

  5. Abood ME. Molecular biology of cannabinoid receptors. Handb Exp Pharmacol. 2005:81–115.

  6. Howlett AC. Cannabinoid receptor signaling. Handb Exp Pharmacol. 2005:53–79.

  7. Tuma RF, Steffens S. Targeting the endocannabinod system to limit myocardial and cerebral ischemic and reperfusion injury. Curr Pharm Biotechnol. 2012;13:46–58.

    Article  CAS  PubMed  Google Scholar 

  8. Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. Prostaglandins Leukot Essent Fatty Acids. 2002;66:101–21.

    Article  CAS  PubMed  Google Scholar 

  9. Sánchez AJ, García-Merino A. Neuroprotective agents: cannabinoids. Clin Immunol. 2012;142:57–67.

    Article  PubMed  CAS  Google Scholar 

  10. Herkenham M, Lynn AB, de Costa BR, Richfield EK. Neuronal localization of cannabinoid receptors in the basal ganglia of the rat. Brain Res. 1991;547:267–74.

    Article  CAS  PubMed  Google Scholar 

  11. Katona I, Sperlágh B, Sík A, Käfalvi A, Vizi ES, Mackie K, Freund TF. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci. 1999;19:4544–58.

    CAS  PubMed  Google Scholar 

  12. Hájos N, Katona I, Naiem SS, MacKie K, Ledent C, Mody I, Freund TF. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci. 2000;12:3239–49.

    Article  PubMed  Google Scholar 

  13. Di Marzo V. Targeting the endocannabinoid system: to enhance or reduce? Nat Rev Drug Discov. 2008;7:438–55.

    Article  CAS  PubMed  Google Scholar 

  14. Katona I, Sperlágh B, Maglóczky Z, Sántha E, Köfalvi A, Czirják S, Mackie K, Vizi ES, Freund TF. GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus. Neuroscience. 2000;100:797–804.

    Article  CAS  PubMed  Google Scholar 

  15. Elphick MR, Egertová M. The neurobiology and evolution of cannabinoid signalling. Philos Trans R Soc Lond Ser B Biol Sci. 2001;356:381–408.

    Article  CAS  Google Scholar 

  16. Golech SA, McCarron RM, Chen Y, Bembry J, Lenz F, Mechoulam R, Shohami E, Spatz M. Human brain endothelium: coexpression and function of vanilloid and endocannabinoid receptors. Brain Res Mol Brain Res. 2004;132:87–92.

    Article  CAS  PubMed  Google Scholar 

  17. Mestre L, Iñigo PM, Mecha M, Correa FG, Hernangómez-Herrero M, Loría F, Docagne F, Borrell J, Guaza C. Anandamide inhibits Theiler’s virus induced VCAM-1 in brain endothelial cells and reduces leukocyte transmigration in a model of blood brain barrier by activation of CB(1) receptors. J Neuroinflammation. 2011;8:102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu J, Gao B, Mirshahi F, Sanyal AJ, Khanolkar AD, Makriyannis A, Kunos G. Functional CB1 cannabinoid receptors in human vascular endothelial cells. Biochem J. 2000;346(Pt 3):835–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Storr MA, Yüce B, Andrews CN, Sharkey KA. The role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome. Neurogastroenterol Motil. 2008;20:857–68.

    Article  CAS  PubMed  Google Scholar 

  20. Coutts AA, Irving AJ, Mackie K, Pertwee RG, Anavi-Goffer S. Localisation of cannabinoid CB(1) receptor immunoreactivity in the Guinea pig and rat myenteric plexus. J Comp Neurol. 2002;448:410–22.

    Article  CAS  PubMed  Google Scholar 

  21. Kulkarni-Narla A, Brown DR. Localization of CB1-cannabinoid receptor immunoreactivity in the porcine enteric nervous system. Cell Tissue Res. 2000;302:73–80.

    Article  CAS  PubMed  Google Scholar 

  22. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126:21–38.

    Article  CAS  PubMed  Google Scholar 

  23. Nasser Y, Bashashati M, Andrews CN. Toward modulation of the endocannabinoid system for treatment of gastrointestinal disease: FAAHster but not "higher. Neurogastroenterol Motil. 2014;26:447–54.

    Article  CAS  PubMed  Google Scholar 

  24. Bouaboula M, Rinaldi M, Carayon P, Carillon C, Delpech B, Shire D, Le Fur G, Casellas P. Cannabinoid-receptor expression in human leukocytes. Eur J Biochem. 1993;214:173–80.

    Article  CAS  PubMed  Google Scholar 

  25. Van Sickle MD, Duncan M, Kingsley PJ, Mouihate A, Urbani P, Mackie K, Stella N, Makriyannis A, Piomelli D, Davison JS, Marnett LJ, Di Marzo V, Pittman QJ, Patel KD, Sharkey KA. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310:329–32.

    Article  CAS  PubMed  Google Scholar 

  26. Färber K, Kettenmann H. Physiology of microglial cells. Brain Res Brain Res Rev. 2005;48:133–43.

    Article  PubMed  CAS  Google Scholar 

  27. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006;1071:10–23.

    Article  CAS  PubMed  Google Scholar 

  28. Duncan M, Mouihate A, Mackie K, Keenan CM, Buckley NE, Davison JS, Patel KD, Pittman QJ, Sharkey KA. Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats. Am J Physiol Gastrointest Liver Physiol. 2008;295:G78–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Storr M, Gaffal E, Saur D, Schusdziarra V, Allescher HD. Effect of cannabinoids on neural transmission in rat gastric fundus. Can J Physiol Pharmacol. 2002;80:67–76.

    Article  CAS  PubMed  Google Scholar 

  30. Yang H, Zhou J, Lehmann C. GPR55 - a putative "type 3" cannabinoid receptor in inflammation. J Basic Clin Physiol Pharmacol. 2016;27:297–302.

    Article  CAS  PubMed  Google Scholar 

  31. Schicho R, Storr M. A potential role for GPR55 in gastrointestinal functions. Curr Opin Pharmacol. 2012;12:653–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Shore DM, Reggio PH. The therapeutic potential of orphan GPCRs, GPR35 and GPR55. Front Pharmacol. 2015;6:69.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152:1092–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li K, Fichna J, Schicho R, Saur D, Bashashati M, Mackie K, Li Y, Zimmer A, Göke B, Sharkey KA, Storr M. A role for O-1602 and G protein-coupled receptor GPR55 in the control of colonic motility in mice. Neuropharmacology. 2013;71:255–63 Novel research exploring the role of GPR55 in affecting colonic motility. It showed that O-1602, a GPR55 agonist, was able to slow colonic motility. This is important because ligands for GPR55 may lack the central side effects of other cannabinoid agents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Begg M, Pacher P, Bátkai S, Osei-Hyiaman D, Offertáler L, Mo FM, Liu J, Kunos G. Evidence for novel cannabinoid receptors. Pharmacol Ther. 2005;106:133–45.

    Article  CAS  PubMed  Google Scholar 

  36. Cluny NL, Keenan CM, Lutz B, Piomelli D, Sharkey KA. The identification of peroxisome proliferator-activated receptor alpha-independent effects of oleoylethanolamide on intestinal transit in mice. Neurogastroenterol Motil. 2009;21:420–9.

    Article  CAS  PubMed  Google Scholar 

  37. Berdyshev EV. Cannabinoid receptors and the regulation of immune response. Chem Phys Lipids. 2000;108:169–90.

    Article  CAS  PubMed  Google Scholar 

  38. Rhee MH, Bayewitch M, Avidor-Reiss T, Levy R, Vogel Z. Cannabinoid receptor activation differentially regulates the various adenylyl cyclase isozymes. J Neurochem. 1998;71:1525–34.

    Article  CAS  PubMed  Google Scholar 

  39. Rhee MH, Nevo I, Avidor-Reiss T, Levy R, Vogel Z. Differential superactivation of adenylyl cyclase isozymes after chronic activation of the CB(1) cannabinoid receptor. Mol Pharmacol. 2000;57:746–52.

    CAS  PubMed  Google Scholar 

  40. Eljaschewitsch E, Witting A, Mawrin C, Lee T, Schmidt PM, Wolf S, Hoertnagl H, Raine CS, Schneider-Stock R, Nitsch R, Ullrich O. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron. 2006;49:67–79.

    Article  CAS  PubMed  Google Scholar 

  41. Rivest S. Cannabinoids in microglia: a new trick for immune surveillance and neuroprotection. Neuron. 2006;49:4–8.

    Article  CAS  PubMed  Google Scholar 

  42. Mukhopadhyay S, Shim JY, Assi AA, Norford D, Howlett AC. CB(1) cannabinoid receptor-G protein association: a possible mechanism for differential signaling. Chem Phys Lipids. 2002;121:91–109.

    Article  CAS  PubMed  Google Scholar 

  43. Mackie K, Hille B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci U S A. 1992;89:3825–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gebremedhin D, Lange AR, Campbell WB, Hillard CJ, Harder DR. Cannabinoid CB1 receptor of cat cerebral arterial muscle functions to inhibit L-type Ca2+ channel current. Am J Phys. 1999;276:H2085–93.

    CAS  Google Scholar 

  45. Mackie K, Lai Y, Westenbroek R, Mitchell R. Cannabinoids activate an inwardly rectifying potassium conductance and inhibit Q-type calcium currents in AtT20 cells transfected with rat brain cannabinoid receptor. J Neurosci. 1995;15:6552–61.

    CAS  PubMed  Google Scholar 

  46. Gómez Del Pulgar T, De Ceballos ML, Guzmán M, Velasco G. Cannabinoids protect astrocytes from ceramide-induced apoptosis through the phosphatidylinositol 3-kinase/protein kinase B pathway. J Biol Chem. 2002;277:36527–33.

    Article  PubMed  CAS  Google Scholar 

  47. Gómez del Pulgar T, Velasco G, Guzmán M. The CB1 cannabinoid receptor is coupled to the activation of protein kinase B/Akt. Biochem J. 2000;347:369–73.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Cannich A, Wotjak CT, Kamprath K, Hermann H, Lutz B, Marsicano G. CB1 cannabinoid receptors modulate kinase and phosphatase activity during extinction of conditioned fear in mice. Learn Mem. 2004;11:625–32.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Merighi S, Gessi S, Varani K, Simioni C, Fazzi D, Mirandola P, Borea PA, Cannabinoid CB. (2) receptors modulate ERK-1/2 kinase signalling and NO release in microglial cells stimulated with bacterial lipopolysaccharide. Br J Pharmacol. 2012;165:1773–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Bouaboula M, Dussossoy D, Casellas P. Regulation of peripheral cannabinoid receptor CB2 phosphorylation by the inverse agonist SR 144528. Implications for receptor biological responses. J Biol Chem. 1999;274:20397–405.

    Article  CAS  PubMed  Google Scholar 

  51. Bouaboula M, Poinot-Chazel C, Bourrié B, Canat X, Calandra B, Rinaldi-Carmona M, Le Fur G, Casellas P. Activation of mitogen-activated protein kinases by stimulation of the central cannabinoid receptor CB1. Biochem J. 1995;312(Pt 2):637–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Di Marzo V, Petrosino S. Endocannabinoids and the regulation of their levels in health and disease. Curr Opin Lipidol. 2007;18:129–40.

    Article  CAS  PubMed  Google Scholar 

  53. Bifulco M, Laezza C, Valenti M, Ligresti A, Portella G, Marzo VDI. A new strategy to block tumor growth by inhibiting endocannabinoid inactivation. FASEB J. 2004;18:1606–8.

    CAS  PubMed  Google Scholar 

  54. Vandevoorde S, Fowler CJ. Inhibition of fatty acid amide hydrolase and monoacylglycerol lipase by the anandamide uptake inhibitor VDM11: evidence that VDM11 acts as an FAAH substrate. Br J Pharmacol. 2005;145:885–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Nicolussi S, Gertsch J. Endocannabinoid transport revisited. Vitam Horm. 2015;98:441–85 This chapter explores the function of the EMT which is emerging as a target of pharmacological research.

    Article  CAS  PubMed  Google Scholar 

  56. D.A. Drossman, Functional Gastrointestinal Disorders: History, Pathophysiology, Clinical Features and Rome IV, Gastroenterology, (2016).

  57. Saito YA, Schoenfeld P, Locke GR. The epidemiology of irritable bowel syndrome in North America: a systematic review. Am J Gastroenterol. 2002;97:1910–5.

    PubMed  Google Scholar 

  58. Pertwee RG. Cannabinoids and the gastrointestinal tract. Gut. 2001;48:859–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Hornby PJ, Prouty SM. Involvement of cannabinoid receptors in gut motility and visceral perception. Br J Pharmacol. 2004;141:1335–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pinto L, Capasso R, Di Carlo G, Izzo AA. Endocannabinoids and the gut. Prostaglandins Leukot Essent Fatty Acids. 2002;66:333–41.

    Article  CAS  PubMed  Google Scholar 

  61. Pinto L, Izzo AA, Cascio MG, Bisogno T, Hospodar-Scott K, Brown DR, Mascolo N, Di Marzo V, Capasso F. Endocannabinoids as physiological regulators of colonic propulsion in mice. Gastroenterology. 2002;123:227–34.

    Article  CAS  PubMed  Google Scholar 

  62. Abalo R, Chen C, Vera G, Fichna J, Thakur GA, López-Pérez AE, Makriyannis A, Martín-Fontelles MI, Storr M. In vitro and non-invasive in vivo effects of the cannabinoid-1 receptor agonist AM841 on gastrointestinal motor function in the rat. Neurogastroenterol Motil. 2015;27:1721–35 The article explores the use of a new mega-agonist, AM841 which was able to inhibit GI transit in a CB 1 R dependent manner at doses that did not elicit central CB 1 R side effects.

    Article  CAS  PubMed  Google Scholar 

  63. Keenan CM, Storr MA, Thakur GA, Wood JT, Wager-Miller J, Straiker A, Eno MR, Nikas SP, Bashashati M, Hu H, Mackie K, Makriyannis A, Sharkey KA. AM841, a covalent cannabinoid ligand, powerfully slows gastrointestinal motility in normal and stressed mice in a peripherally restricted manner. Br J Pharmacol. 2015;172:2406–18 Also explores the use of AM841 in slowing GI motility without central side effects. This could potentially allow for less restricted use of cannabinoid agents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Li XH, Lin ML, Wang ZL, Wang P, Tang HH, Lin YY, Li N, Fang Q, Wang R. Central administrations of hemopressin and related peptides inhibit gastrointestinal motility in mice. Neurogastroenterol Motil. 2016;28:891–9 Explores the use of a novel group of CB 1 R agonists, hemopressin, and their ability to slow GI motility through a CB 1 R dependent manner.

    Article  CAS  PubMed  Google Scholar 

  65. Wong BS, Camilleri M, Busciglio I, Carlson P, Szarka LA, Burton D, Zinsmeister AR. Pharmacogenetic trial of a cannabinoid agonist shows reduced fasting colonic motility in patients with nonconstipated irritable bowel syndrome. Gastroenterology. 2011;141:1638–47 e1631-1637.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Grider JR, Mahavadi S, Li Y, Qiao LY, Kuemmerle JF, Murthy KS, Martin BR. Modulation of motor and sensory pathways of the peristaltic reflex by cannabinoids. Am J Physiol Gastrointest Liver Physiol. 2009;297:G539–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Abalo R, Vera G, López-Pérez AE, Martínez-Villaluenga M, Martín-Fontelles MI. The gastrointestinal pharmacology of cannabinoids: focus on motility. Pharmacology. 2012;90:1–10.

    Article  CAS  PubMed  Google Scholar 

  68. Sibaev A, Yüce B, Kemmer M, Van Nassauw L, Broedl U, Allescher HD, Göke B, Timmermans JP, Storr M. Cannabinoid-1 (CB1) receptors regulate colonic propulsion by acting at motor neurons within the ascending motor pathways in mouse colon. Am J Physiol Gastrointest Liver Physiol. 2009;296:G119–28.

    Article  CAS  PubMed  Google Scholar 

  69. Izzo AA, Fezza F, Capasso R, Bisogno T, Pinto L, Iuvone T, Esposito G, Mascolo N, Di Marzo V, Capasso F. Cannabinoid CB1-receptor mediated regulation of gastrointestinal motility in mice in a model of intestinal inflammation. Br J Pharmacol. 2001;134:563–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Izzo AA, Mascolo N, Pinto L, Capasso R, Capasso F. The role of cannabinoid receptors in intestinal motility, defaecation and diarrhoea in rats. Eur J Pharmacol. 1999;384:37–42.

    Article  CAS  PubMed  Google Scholar 

  71. Mathison R, Ho W, Pittman QJ, Davison JS, Sharkey KA. Effects of cannabinoid receptor-2 activation on accelerated gastrointestinal transit in lipopolysaccharide-treated rats. Br J Pharmacol. 2004;142:1247–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Capasso R, Matias I, Lutz B, Borrelli F, Capasso F, Marsicano G, Mascolo N, Petrosino S, Monory K, Valenti M, Di Marzo V, Izzo AA. Fatty acid amide hydrolase controls mouse intestinal motility in vivo. Gastroenterology. 2005;129:941–51.

    Article  CAS  PubMed  Google Scholar 

  73. Fichna J, Sałaga M, Stuart J, Saur D, Sobczak M, Zatorski H, Timmermans JP, Bradshaw HB, Ahn K, Storr MA. Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides. Neurogastroenterol Motil. 2014;26:470–81.

    Article  CAS  PubMed  Google Scholar 

  74. Zhang SC, Wang WL, Su PJ, Jiang KL, Yuan ZW. Decreased enteric fatty acid amide hydrolase activity is associated with colonic inertia in slow transit constipation. J Gastroenterol Hepatol. 2014;29:276–83.

    Article  PubMed  CAS  Google Scholar 

  75. Bashashati M, Nasser Y, Keenan CM, Ho W, Piscitelli F, Nalli M, Mackie K, Storr MA, Di Marzo V, Sharkey KA. Inhibiting endocannabinoid biosynthesis: a novel approach to the treatment of constipation. Br J Pharmacol. 2015;172:3099–111 In this report, the authors inhibited DAGL and found a resolution of constipation and increased motility. This occurred in a 2-AG and CB 1 R dependent fashion. DAGL remains a very novel area of drug development for the treatment of constipation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. T.R. Harrison, A.S. Fauci, Harrison’s principles of internal medicine, 14th ed., McGraw-Hill, Health Professions Division, New York, 1998.

  77. Kimball ES, Schneider CR, Wallace NH, Hornby PJ. Agonists of cannabinoid receptor 1 and 2 inhibit experimental colitis induced by oil of mustard and by dextran sulfate sodium. Am J Physiol Gastrointest Liver Physiol. 2006;291:G364–71.

    Article  CAS  PubMed  Google Scholar 

  78. Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF, Ferri GL, Sibaev A, Storr M, Lutz B. The endogenous cannabinoid system protects against colonic inflammation. J Clin Invest. 2004;113:1202–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol. 2008;153:263–70.

    Article  CAS  PubMed  Google Scholar 

  80. Izzo AA, Pinto L, Borrelli F, Capasso R, Mascolo N, Capasso F. Central and peripheral cannabinoid modulation of gastrointestinal transit in physiological states or during the diarrhoea induced by croton oil. Br J Pharmacol. 2000;129:1627–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Storr MA, Keenan CM, Emmerdinger D, Zhang H, Yüce B, Sibaev A, Massa F, Buckley NE, Lutz B, Göke B, Brand S, Patel KD, Sharkey KA. Targeting endocannabinoid degradation protects against experimental colitis in mice: involvement of CB1 and CB2 receptors. J Mol Med (Berl). 2008;86:925–36.

    Article  CAS  Google Scholar 

  82. Sałaga M, Mokrowiecka A, Zakrzewski PK, Cygankiewicz A, Leishman E, Sobczak M, Zatorski H, Małecka-Panas E, Kordek R, Storr M, Krajewska WM, Bradshaw HB, Fichna J. Experimental colitis in mice is attenuated by changes in the levels of endocannabinoid metabolites induced by selective inhibition of fatty acid amide hydrolase (FAAH. J Crohns Colitis. 2014;8:998–1009 In this study, the authors employed PF-3845, a FAAH inhibitor, and found that it diminished colitis. Modulating cannabinoid production and degradation exist as promising avenues to capitalize on the ECS without directly utilizing a CB 1 R agonist.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Stančić A, Jandl K, Hasenöhrl C, Reichmann F, Marsche G, Schuligoi R, Heinemann A, Storr M, Schicho R. The GPR55 antagonist CID16020046 protects against intestinal inflammation. Neurogastroenterol Motil. 2015;27:1432–45 The exploration of GPR55 in GI disorders has only started. The authors here utilized a blockage of GPR55 and found that it reduced intestinal inflammation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Naftali T, Mechulam R, Lev LB, Konikoff FM. Cannabis for inflammatory bowel disease. Dig Dis. 2014;32:468–74.

    Article  PubMed  Google Scholar 

  85. Naftali T, Bar-Lev Schleider L, Dotan I, Lansky EP, Sklerovsky Benjaminov F, Konikoff FM. Cannabis induces a clinical response in patients with Crohn’s disease: a prospective placebo-controlled study. Clin Gastroenterol Hepatol. 2013;11:1276–80 e1271.

    Article  CAS  PubMed  Google Scholar 

  86. Storr M, Devlin S, Kaplan GG, Panaccione R, Andrews CN. 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. 2014;20:472–80.

    Article  PubMed  Google Scholar 

  87. D’Argenio G, Petrosino S, Gianfrani C, Valenti M, Scaglione G, Grandone I, Nigam S, Sorrentini I, Mazzarella G, Di Marzo V. Overactivity of the intestinal endocannabinoid system in celiac disease and in methotrexate-treated rats. J Mol Med (Berl). 2007;85:523–30.

    Article  CAS  Google Scholar 

  88. Battista N, Di Sabatino A, Di Tommaso M, Biancheri P, Rapino C, Vidali F, Papadia C, Montana C, Pasini A, Lanzini A, Villanacci V, Corazza GR, Maccarrone M. Abnormal anandamide metabolism in celiac disease. J Nutr Biochem. 2012;23:1245–8.

    Article  CAS  PubMed  Google Scholar 

  89. Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol. 2014;722:134–46.

    Article  CAS  PubMed  Google Scholar 

  90. Schicho R, Storr M. Targeting the endocannabinoid system for gastrointestinal diseases: future therapeutic strategies. Expert Rev Clin Pharmacol. 2010;3:193–207.

    Article  CAS  PubMed  Google Scholar 

  91. Darmani NA, McClanahan BA, Trinh C, Petrosino S, Valenti M, Di Marzo V. Cisplatin increases brain 2-arachidonoylglycerol (2-AG) and concomitantly reduces intestinal 2-AG and anandamide levels in the least shrew. Neuropharmacology. 2005;49:502–13.

    Article  CAS  PubMed  Google Scholar 

  92. Darmani NA. The potent emetogenic effects of the endocannabinoid, 2-AG (2-arachidonoylglycerol) are blocked by delta(9)-tetrahydrocannabinol and other cannnabinoids. J Pharmacol Exp Ther. 2002;300:34–42.

    Article  CAS  PubMed  Google Scholar 

  93. Van Sickle MD, Oland LD, Ho W, Hillard CJ, Mackie K, Davison JS, Sharkey KA. Cannabinoids inhibit emesis through CB1 receptors in the brainstem of the ferret. Gastroenterology. 2001;121:767–74.

    Article  CAS  PubMed  Google Scholar 

  94. Sharkey KA, Cristino L, Oland LD, Van Sickle MD, Starowicz K, Pittman QJ, Guglielmotti V, Davison JS, Di Marzo V. Arvanil, anandamide and N-arachidonoyl-dopamine (NADA) inhibit emesis through cannabinoid CB1 and vanilloid TRPV1 receptors in the ferret. Eur J Neurosci. 2007;25:2773–82.

    Article  CAS  PubMed  Google Scholar 

  95. Cross-Mellor SK, Ossenkopp KP, Piomelli D, Parker LA. Effects of the FAAH inhibitor, URB597, and anandamide on lithium-induced taste reactivity responses: a measure of nausea in the rat. Psychopharmacology. 2007;190:135–43.

    Article  CAS  PubMed  Google Scholar 

  96. Meiri E, Jhangiani H, Vredenburgh JJ, Barbato LM, Carter FJ, Yang HM, Baranowski V. Efficacy of dronabinol alone and in combination with ondansetron versus ondansetron alone for delayed chemotherapy-induced nausea and vomiting. Curr Med Res Opin. 2007;23:533–43.

    Article  CAS  PubMed  Google Scholar 

  97. Machado Rocha FC, Stéfano SC, De Cássia Haiek R, Rosa Oliveira LM, Da Silveira DX. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care (Engl). 2008;17:431–43.

    Article  CAS  Google Scholar 

  98. Duran M, Pérez E, Abanades S, Vidal X, Saura C, Majem M, Arriola E, Rabanal M, Pastor A, Farré M, Rams N, Laporte JR, Capellà D. Preliminary efficacy and safety of an oromucosal standardized cannabis extract in chemotherapy-induced nausea and vomiting. Br J Clin Pharmacol. 2010;70:656–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Galli JA, Sawaya RA, Friedenberg FK. Cannabinoid hyperemesis syndrome. Curr Drug Abuse Rev. 2011;4:241–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ishaq S, Ismail S, Ghaus S. Roop-E-Zahra, K. Rostami, cannabinoid hyperemesis should be recognised as an effect of chronic cannabis abuse. Gastroenterol Hepatol Bed Bench. 2014;7:173–6.

    PubMed  PubMed Central  Google Scholar 

  101. Callén L, Moreno E, Barroso-Chinea P, Moreno-Delgado D, Cortés A, Mallol J, Casadó V, Lanciego JL, Franco R, Lluis C, Canela EI, McCormick PJ. Cannabinoid receptors CB1 and CB2 form functional heteromers in brain. J Biol Chem. 2012;287:20851–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Malik Z, Baik D, Schey R. The role of cannabinoids in regulation of nausea and vomiting, and visceral pain. Curr Gastroenterol Rep. 2015;17:429.

    Article  PubMed  Google Scholar 

  103. Ravnefjord A, Brusberg M, Kang D, Bauer U, Larsson H, Lindström E, Martinez V. Involvement of the transient receptor potential vanilloid 1 (TRPV1) in the development of acute visceral hyperalgesia during colorectal distension in rats. Eur J Pharmacol. 2009;611:85–91.

    Article  CAS  PubMed  Google Scholar 

  104. Booker L, Naidu PS, Razdan RK, Mahadevan A, Lichtman AH. Evaluation of prevalent phytocannabinoids in the acetic acid model of visceral nociception. Drug Alcohol Depend. 2009;105:42–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Sanson M, Bueno L, Fioramonti J. Involvement of cannabinoid receptors in inflammatory hypersensitivity to colonic distension in rats. Neurogastroenterol Motil. 2006;18:949–56.

    Article  CAS  PubMed  Google Scholar 

  106. Brusberg M, Arvidsson S, Kang D, Larsson H, Lindström E, Martinez V. CB1 receptors mediate the analgesic effects of cannabinoids on colorectal distension-induced visceral pain in rodents. J Neurosci. 2009;29:1554–64.

    Article  CAS  PubMed  Google Scholar 

  107. Naidu PS, Booker L, Cravatt BF, Lichtman AH. Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception. J Pharmacol Exp Ther. 2009;329:48–56.

    Article  CAS  PubMed  Google Scholar 

  108. Neelakantan H, Tallarida RJ, Reichenbach ZW, Tuma RF, Ward SJ, Walker EA. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. Behav Pharmacol. 2015;26:304–14.

    Article  CAS  PubMed  Google Scholar 

  109. Esfandyari T, Camilleri M, Busciglio I, Burton D, Baxter K, Zinsmeister AR. 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. 2007;293:G137–45.

    Article  CAS  PubMed  Google Scholar 

  110. Esfandyari T, Camilleri M, Ferber I, Burton D, Baxter K, Zinsmeister AR. Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study. Neurogastroenterol Motil. 2006;18:831–8.

    Article  CAS  PubMed  Google Scholar 

  111. Klooker TK, Leliefeld KE, Van Den Wijngaard RM, Boeckxstaens GE. The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients. Neurogastroenterol Motil. 2011;23:30–5 e32.

    Article  CAS  PubMed  Google Scholar 

  112. Park JM, Choi MG, Cho YK, Lee IS, Kim SW, Choi KY, Chung IS. Cannabinoid receptor 1 gene polymorphism and irritable bowel syndrome in the Korean population: a hypothesis-generating study. J Clin Gastroenterol. 2011;45:45–9.

    Article  CAS  PubMed  Google Scholar 

  113. Z. Malik, L. Bayman, J. Valestin, A. Rizvi-Toner, S. Hashmi, R. Schey, Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial, Dis Esophagus, (2016).

  114. Reichenbach ZW, Sloan J, Rizvi-Toner A, Bayman L, Valestin J, Schey R. A 4-week pilot study with the cannabinoid receptor agonist dronabinol and its effect on metabolic parameters in a randomized trial. Clin Ther. 2015;37:2267–74.

    Article  PubMed  CAS  Google Scholar 

  115. Kikuchi A, Ohashi K, Sugie Y, Sugimoto H, Omura H. Pharmacological evaluation of a novel cannabinoid 2 (CB2) ligand, PF-03550096, in vitro and in vivo by using a rat model of visceral hypersensitivity. J Pharmacol Sci. 2008;106:219–24.

    Article  CAS  PubMed  Google Scholar 

  116. Rousseaux C, Thuru X, Gelot A, Barnich N, Neut C, Dubuquoy L, Dubuquoy C, Merour E, Geboes K, Chamaillard M, Ouwehand A, Leyer G, Carcano D, Colombel JF, Ardid D, Desreumaux P. Lactobacillus acidophilus modulates intestinal pain and induces opioid and cannabinoid receptors. Nat Med. 2007;13:35–7.

    Article  CAS  PubMed  Google Scholar 

  117. Feng CC, Yan XJ, Chen X, Wang EM, Liu Q, Zhang LY, Chen J, Fang JY, Chen SL. Vagal anandamide signaling via cannabinoid receptor 1 contributes to luminal 5-HT modulation of visceral nociception in rats. Pain. 2014;155:1591–604.

    Article  CAS  PubMed  Google Scholar 

  118. M. Bashashati, I. Sarosiek, R.W. McCallum, Epidemiology and mechanisms of gastroesophageal reflux disease in the elderly: a perspective, Ann N Y Acad Sci, (2016).

  119. Di Carlo G, Izzo AA. Cannabinoids for gastrointestinal diseases: potential therapeutic applications. Expert Opin Investig Drugs. 2003;12:39–49.

    Article  CAS  PubMed  Google Scholar 

  120. Beaumont H, Jensen J, Carlsson A, Ruth M, Lehmann A, Boeckxstaens G. Effect of delta9-tetrahydrocannabinol, a cannabinoid receptor agonist, on the triggering of transient lower oesophageal sphincter relaxations in dogs and humans. Br J Pharmacol. 2009;156:153–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Partosoedarso ER, Abrahams TP, Scullion RT, Moerschbaecher JM, Hornby PJ. Cannabinoid1 receptor in the dorsal vagal complex modulates lower oesophageal sphincter relaxation in ferrets. J Physiol. 2003;550:149–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Lehmann A, Blackshaw LA, Brändén L, Carlsson A, Jensen J, Nygren E, Smid SD. Cannabinoid receptor agonism inhibits transient lower esophageal sphincter relaxations and reflux in dogs. Gastroenterology. 2002;123:1129–34.

    Article  CAS  PubMed  Google Scholar 

  123. Norrod AG, Puffenbarger RA. Genetic polymorphisms of the endocannabinoid system. Chem Biodivers. 2007;4:1926–32.

    Article  CAS  PubMed  Google Scholar 

  124. Camilleri M, Carlson P, McKinzie S, Zucchelli M, D’Amato M, Busciglio I, Burton D, Zinsmeister AR. Genetic susceptibility to inflammation and colonic transit in lower functional gastrointestinal disorders: preliminary analysis. Neurogastroenterol Motil. 2011;23:935–e398.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Jiang Y, Nie Y, Li Y, Zhang L. Association of cannabinoid type 1 receptor and fatty acid amide hydrolase genetic polymorphisms in Chinese patients with irritable bowel syndrome. J Gastroenterol Hepatol. 2014;29:1186–91 Studies genetic variance of the ECS in expression of IBS phenotypes. Underscores the role of the ECS in IBS manifestations.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank Catherine Gibbs for her help in researching several aspects of this review.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ron Schey M.D., FACG.

Ethics declarations

Conflict of Interest

Zachary Wilmer Reichenbach and Ron Schey declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Motility

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reichenbach, Z.W., Schey, R. Cannabinoids and GI Disorders: Endogenous and Exogenous. Curr Treat Options Gastro 14, 461–477 (2016). https://doi.org/10.1007/s11938-016-0111-1

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11938-016-0111-1

Keywords

Navigation