Article Data

  • Views 1905
  • Dowloads 143


Open Access

Targeting the Endocannabinoid System to Treat Sepsis


1,Department of Pharmacology Dalhousie University

2,Department of Anaesthesia Pain Management and Perioperative Medicine and Department of Microbiology and Immunology Dalhousie University

DOI: 10.22514/SV81.052013.1 Vol.8,Issue 1,May 2013 pp.9-14

Published: 01 May 2013

*Corresponding Author(s): CHRISTIAN LEHMANN E-mail:


The endocannabinoid system represents a potential therapeutic target in sepsis due to the presence of cannabinoid receptors (CB2) on immune cells. In this review we discuss how various targets within the endocannabinoid system can be manipulated to treat the immune consequences of sepsis. One of the targets outlined are the endocannabinoid receptors and modulation of their activity through pharmacological agonists and antagonists. Another therapeutic target covered in this review is the modulation of the endocannabinoid degradative enzyme’s activity. Modulation of degradative enzyme activity can change the levels of endogenous cannabinoids thereby altering immune activity. Overall, activation of the CB2 receptors causes immunosuppression and can be beneficial during the hyperactivated immune state of sepsis, while suppression of the CB2 receptors may be beneficial during a hypoimmune septic state. 


sepsis, endocannabi-noid system, inflammation, immune modulation

Cite and Share

JOEL SARDINHA,CHRISTIAN LEHMANN,MELANIE KELLY. Targeting the Endocannabinoid System to Treat Sepsis. Signa Vitae. 2013. 8(1);9-14.


1. Vincent JL, Rello J, Marshall J, Silva E, Anzueto A, Martin CD, et al. International study of the prevalence and outcomes of infection in intensive care units. JAMA 2009;302:2323-9.

2. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med 2001;29:1303-10.

3. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med 2003;348(16):1546-54.

4. United Nations. (2009). World Population Ageing . Department of Economic and Social Affairs.

5. Kleinpell R, Graves B, Ackerman M. Incidence, Pathogenesis, and Management of Sepsis. An Overview. AACN Adv Crit Care 2006;17(4):385-93.

6. Gaoni Y, Mechoulam R. Isolation, structure, and partial synthesis of an active constituent of hashish. J Am Chem Soc 1964;86:1646-47.

7. Jonsson K.O., Holt S., Fowler C.J. The endocannabinoid system: Curr Pharmacol Res Ther Opp. Basic Clin Pharmacol Toxicol, 2006;98:124-134.

8. Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev 2002;54(2):161-202.

9. Pertwee RG, Howlett AC, Abood ME, Alexander SPH, Di Marzo V, Elphick MR, et al. International Union of Basic and Clinical Pharmacology.

LXXIX. Cannabinoid receptors and their ligands: beyond CB1 and CB2. Pharmacol Rev 2010;62(4):588-631.

10. Di Marzo V. Endocannabinoid signaling in the brain: biosynthetic mechanisms in the limelight. Nat Neurosci 2011;14(1):9-15.

11. Luchicchi A, Pistis M. Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features, and emerging specificities of the two major endocannabinoids. Mol Neurobiol 2012;46(2):374-92.

12. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346:561-4.

13. Pertwee RG, Ross RA. Cannabinoid receptors and their ligands. Prostag Leukotr Ess 2002;66:101-21.

14. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature 1993;365:61-5.

15. Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol 2005;5(5):400-11.

16. Galiègue S, Mary S, Marchand J, Dussossoy D, Carrière D, Carayon P, et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem 1995;232:54–61.

17. Rang H, Dale M, Ritter J, Moore P. Pharmacology. 5th ed. Edinburgh: Churchill Livingstone; 2003.

18. Cohn J. The immunopathogenesis of sepsis. Nature 2002;420:885-91.

19. Pacher P, Mechoulam R. Is lipid signaling through cannabinoid 2 receptors part of a protective system? Prog Lipid Res 2011;50:193-211.

20. Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev 2006 Sep;58(3):389-462.

21. Yao B, Mackie K. Endocannabinoid receptor pharmacology. Curr Top Behav Neurosci 2009;1:37-63.

22. Alexander SP, Kendall DA. The life cycle of the endocannabinoids: formation and inactivation. Curr Top Behav Neurosci 2009;1:3-35.

23. Atwood BK, Straiker A, Mackie K. CB2: therapeutic target-in-waiting. Prog Neuropsychopharmacol Biol Psychiatry 2012 Jul 2;38(1):16-20.

24. Luchicchi A, Pistis M. Anandamide and 2-arachidonoylglycerol: pharmacological properties, functional features, and emerging specificities of the two major endocannabinoids. Mol Neurobiol 2012;46(2):374-92.

25. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992;258:1946-49.

26. Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharm 1995;50:83-90.

27. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodu-latory fatty-acid amides. Nature 1996;384-7.

28. Ahn K, McKinney MK, Cravatt BF. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev 2008;108:1687-1707.

29. Hotchkiss RS, Coopersmith CM, McDunn JE, Ferguson TA. The sepsis seesaw: Tilting toward immunosuppression. Nature 2009;15(5):496-7.

30. Bosier B, Muccioli GG, Hermans E, Lambert DM. Functionally selective cannabinoid receptor signalling: therapeutic implications and opportunities. Biochem Pharmacol 2010;80:1-12.

31. Godlewski G, Malinowska B, Schlicker E. Presynaptic cannabinoid CB(1) receptors are involved in the inhibition of the neurogenic vaso-pressor response during septic shock in pithed rats. Br J Pharmacol 2004;142:701-8.

32. Bátkai S, Pacher P, Járai Z, Wagner JA, Kunos G. Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mecha-nism not involving CB1 or CB2 receptors. Am J Physiol-Heart C 2004;287:595-600.

33. Kelly M, Dong A, Toguri T, Zhou J, Cerny V, Whynot S, et al. Cannabinoid 2 receptor modulation in the iris microcirculation during expe-rimental endotoxemia. 2010; Presented: British Pharmacology Society annual meeting, London, UK. Abstract [Internet] Available from:

34. Lehmann C, Kianian M, Zhou J, Kuster I, Kuschnereit R, Whynot S, et al. Cannabinoid receptor 2 activation reduces intestinal leukocyte recruitment and systemic inflammatory mediator release in acute experimental sepsis. Crit Care 2012;16:R47.

35. Orliac ML, Peroni R, Celuch SM, Adler-Graschinsky E. Potentiation of anandamide effects in mesenteric beds isolated from endotoxemic rats. J Pharmacol Exp Ther 2003;304:179-84.

36. Tschop J, Kasten KR, Nogueiras R, Goetzman HS, Cave CM, England LG, et al. The cannabinoid receptor 2 is critical for the host response to sepsis. J Immunol 2009;183:499-505.

37. Csóka B, Németh ZH, Mukhopadhyay P, Spolarics Z, Rajesh M, Federici S, et al. CB2 cannabinoid receptors contribute to bacterial invasion and mortality in polymicrobial sepsis. PLoS One 2009;4(7):6409.

38. Blankman JL, Simon GM, Cravatt BF. A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglyce-rol. Chem Biol 2007;14:1347-56.

39. Long JZ, Cravatt BF. The metabolic serine hydrolases and their functions in mammalian physiology and disease. Chem Rev 2011;111(10):6022-63.

40.Maccarrone M, De Petrocellis L, Bari M, Fezza F, Salvati S, Di Marzo V, et al. Lipopolysaccharide downregulates fatty acid amide hydrolase expression and increases anandamide levels in human peripheral lymphocytes. Arch Biochem Biophys 2001;393:321-8. 

41.Tanaka M, Yanagihara I, Takahashi H, Hamaguchi M, Nakahira K, Sakata I. The mRNA    expression of fatty acid amide hydrolase in human whole blood correlates with sepsis. J Endotoxin Res 2007;13:35-8.

42. Cravatt BF, Demarest K, Patricelli MP, Bracey MH, Giang DK, Martin BR, et al. Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase. Proc Natl Acad Sci USA 2001;98:9371-6.

43. Saario SM, Laitinen JT. Therapeutic Potential of Endocannabinoid Hydrolysing Enzyme Inhibitors. Basic Clin Pharmacol Toxicol 2007;101(5):287-93.

44. Kianian M, Al-Banna NA, Kelly MEM, Lehmann C. Inhibition of endocannabinoid degradation in experimental endotoxemia reduces leu-kocyte adhesion and improves capillary perfusion in the gut. J Basic Clin Physiol Pharmacol 2013;24(1):27-33.

Abstracted / indexed in

Science Citation Index Expanded (SciSearch) Created as SCI in 1964, Science Citation Index Expanded now indexes over 9,200 of the world’s most impactful journals across 178 scientific disciplines. More than 53 million records and 1.18 billion cited references date back from 1900 to present.

Journal Citation Reports/Science Edition Journal Citation Reports/Science Edition aims to evaluate a journal’s value from multiple perspectives including the journal impact factor, descriptive data about a journal’s open access content as well as contributing authors, and provide readers a transparent and publisher-neutral data & statistics information about the journal.

Chemical Abstracts Service Source Index The CAS Source Index (CASSI) Search Tool is an online resource that can quickly identify or confirm journal titles and abbreviations for publications indexed by CAS since 1907, including serial and non-serial scientific and technical publications.

Index Copernicus The Index Copernicus International (ICI) Journals database’s is an international indexation database of scientific journals. It covered international scientific journals which divided into general information, contents of individual issues, detailed bibliography (references) sections for every publication, as well as full texts of publications in the form of attached files (optional). For now, there are more than 58,000 scientific journals registered at ICI.

Geneva Foundation for Medical Education and Research The Geneva Foundation for Medical Education and Research (GFMER) is a non-profit organization established in 2002 and it works in close collaboration with the World Health Organization (WHO). The overall objectives of the Foundation are to promote and develop health education and research programs.

Scopus: CiteScore 1.0 (2022) Scopus is Elsevier's abstract and citation database launched in 2004. Scopus covers nearly 36,377 titles (22,794 active titles and 13,583 Inactive titles) from approximately 11,678 publishers, of which 34,346 are peer-reviewed journals in top-level subject fields: life sciences, social sciences, physical sciences and health sciences.

Embase Embase (often styled EMBASE for Excerpta Medica dataBASE), produced by Elsevier, is a biomedical and pharmacological database of published literature designed to support information managers and pharmacovigilance in complying with the regulatory requirements of a licensed drug.

Submission Turnaround Time