Revista de Odontologia da UNESP
Revista de Odontologia da UNESP
Review Article

Endocannabinoid system and periodontitis: mechanisms and therapeutic implications

Sistema endocanabinoide e periodontite: mecanismos e implicações terapêuticas

Lélio Fernando Ferreira SOARES; Luan Viana FARIA; Joni Augusto CIRELLI

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Introduction: Periodontitis is a major public health problem. Although the principle of periodontitis therapy is mainly focused on removing dental biofilm and associated factors, its physiopathology enrolls different molecular and inflammatory events related to the host immune system, as the participation of the endocannabinoid system.

Objective: This review aimed to explore and elucidate the mechanisms and roles of the endocannabinoid system on periodontitis physiopathology and its possibilities for future related therapies.

Material and method: An electronic search was carried out on the PubMed platform for studies involving the action of the endocannabinoid system on periodontitis.

Result: Nineteen clinical and preclinical studies were included in this narrative review.

Conclusion: Cannabinoid receptors type 1 and 2 are integral components of the endocannabinoid system, manifesting in various forms in the periodontal tissues. The actions and mechanisms through which cannabinoid receptors are activated in healthy or inflamed sites remain the focus of ongoing investigations. Moreover, phytocannabinoids and synthetic cannabinoids show therapeutic potential, with pre-clinical studies indicating benefits in reducing inflammation and facilitating tissue repair.


Cannabinoids, CB1 receptor, CB2 receptor, inflammation, periodontitis


Introdução: A periodontite é um importante problema de saúde pública. Embora o princípio da terapia da periodontite esteja focado principalmente na remoção do biofilme dental e dos fatores associados, sua fisiopatologia registra diferentes eventos moleculares e inflamatórios relacionados ao sistema imunológico do hospedeiro, como a participação do sistema endocanabinoide.

Objetivo: Esta revisão teve como objetivo explorar e elucidar os mecanismos e papéis do sistema endocanabinoide na fisiopatologia da periodontite e suas possibilidades para futuras terapias relacionadas.

Material e método: Realizou-se uma busca eletrônica na plataforma PubMed por estudos envolvendo a ação do sistema endocanabinoide sobre a periodontite.

Resultado: Dezenove estudos clínicos e pré-clínicos foram incluídos nesta revisão narrativa.

Conclusão: Os receptores canabinoides tipo 1 e 2 são componentes integrais do sistema endocanabinoide e manifestam-se de várias formas nos tecidos periodontais. As ações e mecanismos através dos quais os receptores canabinoides são ativados em locais saudáveis ou inflamados continuam a ser o foco de investigações em curso. Além disso, os fitocanabinoides e canabinoides sintéticos apresentam potencial como tratamentos, com estudos pré-clínicos indicando benefícios na redução da inflamação e na facilitação da reparação dos tecidos.


Canabinoides, receptor CB1 de canabinoide, receptor CB2 de canabinoide, inflamação, periodontite


1 Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M, Fine DH, et al. Periodontitis: Consensus report of workgroup 2 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Periodontol. 2018 Jun;89(Suppl 1):S173-82. PMid:29926951.

2 Chapple ILC, Mealey BL, Van Dyke TE, Bartold PM, Dommisch H, Eickholz P, et al. Periodontal health and gingival diseases and conditions on an intact and a reduced periodontium: Consensus report of workgroup 1 of the 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions. J Periodontol. 2018 Jun;89(Suppl 1):S74-84. PMid:29926944.

3 Sanz M, Herrera D, Kebschull M, Chapple I, Jepsen S, Berglundh T, et al. Treatment of stage I-III periodontitis-The EFP S3 level clinical practice guideline. J Clin Periodontol. 2020 Jul;47(Suppl 22):4-60. PMid:32383274.

4 Chapple IL, Van der Weijden F, Doerfer C, Herrera D, Shapira L, Polak D, et al. Primary prevention of periodontitis: managing gingivitis. J Clin Periodontol. 2015 Apr;42(Suppl 16):S71-6. PMid:25639826.

5 Herrera D, Sanz M, Kebschull M, Jepsen S, Sculean A, Berglundh T, et al. Treatment of stage IV periodontitis: the EFP S3 level clinical practice guideline. J Clin Periodontol. 2022 Jun;49(Suppl 24):4-71. PMid:35688447.

6 Billings M, Holtfreter B, Papapanou PN, Mitnik GL, Kocher T, Dye BA. Age-dependent distribution of periodontitis in two countries: findings from NHANES 2009 to 2014 and SHIP-TREND 2008 to 2012. J Clin Periodontol. 2018 Jun;45(Suppl 20):S130-48. PMid:29926501.

7 Pan W, Wang Q, Chen Q. The cytokine network involved in the host immune response to periodontitis. Int J Oral Sci. 2019 Nov;11(3):30. PMid:31685798.

8 Sanz M, Bäumer A, Buduneli N, Dommisch H, Farina R, Kononen E, et al. Effect of professional mechanical plaque removal on secondary prevention of periodontitis and the complications of gingival and periodontal preventive measures: consensus report of group 4 of the 11th European Workshop on Periodontology on effective prevention of periodontal and peri-implant diseases. J Clin Periodontol. 2015 Apr;42(Suppl 16):S214-20. PMid:25626357.

9 Meyle J, Dommisch H, Groeger S, Giacaman RA, Costalonga M, Herzberg M. The innate host response in caries and periodontitis. J Clin Periodontol. 2017 Dec;44(12):1215-25. PMid:28727164.

10 AlQranei MS, Chellaiah MA. Osteoclastogenesis in periodontal diseases: possible mediators and mechanisms. J Oral Biosci. 2020 Jun;62(2):123-30. PMid:32081710.

11 Souza JA, Rossa C Jr, Garlet GP, Nogueira AV, Cirelli JA. Modulation of host cell signaling pathways as a therapeutic approach in periodontal disease. J Appl Oral Sci. 2012 Mar-Apr;20(2):128-38. PMid:22666826.

12 Sedghi LM, Bacino M, Kapila YL. Periodontal disease: the good, the bad, and the unknown. Front Cell Infect Microbiol. 2021 Dec;11:766944. PMid:34950607.

13 Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, et al. The cannabinoid system and immune modulation. J Leukoc Biol. 2003 Oct;74(4):486-96. PMid:12960289.

14 Bellocchio L, Inchingolo AD, Inchingolo AM, Lorusso F, Malcangi G, Santacroce L, et al. Cannabinoids drugs and oral health-from recreational side-effects to medicinal purposes: a systematic review. Int J Mol Sci. 2021 Aug;22(15):8329. PMid:34361095.

15 Jirasek P, Jusku A, Simanek V, Frankova J, Storch J, Vacek J. Cannabidiol and periodontal inflammatory disease: a critical assessment. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2022 May;166(2):155-60. PMid:35332345.

16 Klein TW, Newton CA, Friedman H. Cannabinoids and the immune system. Pain Res Manag. 2001;6(2):95-101. PMid:11854771.

17 Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol. 2008 Jan;153(2):319-34. PMid:17994113.

18 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 Pharmacol. 1995 Jun;50(1):83-90. PMid:7605349.

19 Nakajima Y, Furuichi Y, Biswas KK, Hashiguchi T, Kawahara K, Yamaji K, et al. Endocannabinoid, anandamide in gingival tissue regulates the periodontal inflammation through NF-kappaB pathway inhibition. FEBS Lett. 2006 Jan;580(2):613-9. PMid:16406050.

20 Kozono S, Matsuyama T, Biwasa KK, Kawahara K, Nakajima Y, Yoshimoto T, et al. Involvement of the endocannabinoid system in periodontal healing. Biochem Biophys Res Commun. 2010 Apr;394(4):928-33. PMid:20233580.

21 Pellegrini G, Carmagnola D, Toma M, Rasperini G, Orioli M, Dellavia C. Involvement of the endocannabinoid system in current and recurrent periodontitis: a human study. J Periodontal Res. 2023 Apr;58(2):422-32. PMid:36727611.

22 Gullapalli S, Amrutkar D, Gupta S, Kandadi MR, Kumar H, Gandhi M, et al. Characterization of active and inactive states of CB1 receptor and the differential binding state modulation by cannabinoid agonists, antagonists and inverse agonists. Neuropharmacology. 2010 Jun;58(8):1215-9. PMid:20214912.

23 Weis WI, Kobilka BK. The molecular basis of g protein-coupled receptor activation. Annu Rev Biochem. 2018 Jun;87(1):897-919. PMid:29925258.

24 Gu Z, Singh S, Niyogi RG, Lamont GJ, Wang H, Lamont RJ, et al. Marijuana-derived cannabinoids trigger a CB2/PI3K axis of suppression of the innate response to oral pathogens. Front Immunol. 2019 Oct;10:2288. PMid:31681262.

25 Reich CG, Mihalik GR, Iskander AN, Seckler JC, Weiss MS. Adolescent chronic mild stress alters hippocampal CB1 receptor-mediated excitatory neurotransmission and plasticity. Neuroscience. 2013 Dec;253:444-54. PMid:24035826.

26 Ruehle S, Wager-Miller J, Straiker A, Farnsworth J, Murphy MN, Loch S, et al. Discovery and characterization of two novel CB1 receptor splice variants with modified N-termini in mouse. J Neurochem. 2017 Aug;142(4):521-33. PMid:28608535.

27 Qian H, Zhao Y, Peng Y, Han C, Li S, Huo N, et al. Activation of cannabinoid receptor CB2 regulates osteogenic and osteoclastogenic gene expression in human periodontal ligament cells. J Periodontal Res. 2010 Aug;45(4):504-11. PMid:20412420.

28 Napimoga MH, Benatti BB, Lima FO, Alves PM, Campos AC, Pena-Dos-Santos DR, et al. Cannabidiol decreases bone resorption by inhibiting RANK/RANKL expression and pro-inflammatory cytokines during experimental periodontitis in rats. Int Immunopharmacol. 2009 Feb;9(2):216-22. PMid:19070683.

29 Sharma R, Singh S, Whiting ZM, Molitor M, Vernall AJ, Grimsey NL. Novel Cannabinoid receptor 2 (CB2) low lipophilicity agonists produce distinct cAMP and arrestin signalling kinetics without bias. Int J Mol Sci. 2023 Mar;24(7):6406. PMid:37047385.

30 Liu C, Qi X, Alhabeil J, Lu H, Zhou Z. Activation of cannabinoid receptors promote periodontal cell adhesion and migration. J Clin Periodontol. 2019 Dec;46(12):1264-72. PMid:31461164.

31 Abidi AH, Presley CS, Dabbous M, Tipton DA, Mustafa SM, Moore BM 2nd. Anti-inflammatory activity of cannabinoid receptor 2 ligands in primary hPDL fibroblasts. Arch Oral Biol. 2018 Mar;87:79-85. PMid:29274621.

32 Abidi AH, Alghamdi SS, Dabbous MK, Tipton DA, Mustafa SM, Moore BM. Cannabinoid type-2 receptor agonist, inverse agonist, and anandamide regulation of inflammatory responses in IL-1β stimulated primary human periodontal ligament fibroblasts. J Periodontal Res. 2020 Oct;55(5):762-83. PMid:32562275.

33 Abidi AH, Abhyankar V, Alghamdi SS, Tipton DA, Dabbous M. Phytocannabinoids regulate inflammation in IL-1β-stimulated human gingival fibroblasts. J Periodontal Res. 2022 Dec;57(6):1127-38. PMid:36070347.

34 Ataei A, Rahim Rezaee SA, Moeintaghavi A, Ghanbari H, Azizi M. Evaluation of cannabinoid receptors type 1-2 in periodontitis patients. Clin Exp Dent Res. 2022 Oct;8(5):1040-4. PMid:35719011.

35 Konermann A, Jäger A, Held SAE, Brossart P, Schmöle A. In vivo and in vitro identification of endocannabinoid signaling in periodontal tissues and their potential role in local pathophysiology. Cell Mol Neurobiol. 2017 Nov;37(8):1511-20. PMid:28289947.

36 Alves LCV, Lisboa MRP, da Silveira HF, de Sousa LM, Gusmão JNFM, Dias DBS, et al. Electroacupuncture increases immunoexpression of CB1 and CB2 receptors in experimental model of inflammatory bone loss. Bone. 2019 Oct;127:59-66. PMid:31121356.

37 Ossola CA, Surkin PN, Pugnaloni A, Mohn CE, Elverdin JC, Fernandez-Solari J. Long-term treatment with methanandamide attenuates LPS-induced periodontitis in rats. Inflamm Res. 2012 Sep;61(9):941-8. PMid:22581275.

38 Rettori E, De Laurentiis A, Zorrilla Zubilete M, Rettori V, Elverdin JC. Anti-inflammatory effect of the endocannabinoid anandamide in experimental periodontitis and stress in the rat. Neuroimmunomodulation. 2012;19(5):293-303. PMid:22777139.

39 Özdemir B, Shi B, Bantleon HP, Moritz A, Rausch-Fan X, Andrukhov O. Endocannabinoids and inflammatory response in periodontal ligament cells. PLoS One. 2014 Sep;9(9):e107407. PMid:25226300.

40 Ossola CA, Surkin PN, Mohn CE, Elverdin JC, Fernández-Solari J. Anti-inflammatory and osteoprotective effects of Cannabinoid-2 receptor agonist HU-308 in a rat model of lipopolysaccharide-induced periodontitis. J Periodontol. 2016 Jun;87(6):725-34. PMid:26846967.

41 Yan W, Cao Y, Yang H, Han N, Zhu X, Fan Z, et al. CB1 enhanced the osteo/dentinogenic differentiation ability of periodontal ligament stem cells via p38 MAPK and JNK in an inflammatory environment. Cell Prolif. 2019 Nov;52(6):e12691. PMid:31599069.

42 Ossola CA, Rodas JA, Balcarcel NB, Astrauskas JI, Elverdin JC, Fernández-Solari J. Signs of alveolar bone damage in early stages of periodontitis and its prevention by stimulation of cannabinoid receptor 2. Model in rats. Acta Odontol Latinoam. 2020 Sep;33(2):143-52. PMid:32920617.

43 Zhang F, Özdemir B, Nguyen PQ, Andrukhov O, Rausch-Fan X. Methanandamide diminish the Porphyromonas gingivalis lipopolysaccharide induced response in human periodontal ligament cells. BMC Oral Health. 2020 Apr;20(1):107. PMid:32295577.

44 Wang Y, Liu Y, Sarker KP, Nakashima M, Serizawa T, Kishida A, et al. Polymyxin B binds to anandamide and inhibits its cytotoxic effect. FEBS Lett. 2000 Mar;470(2):151-5. PMid:10734225.

45 Kreitzer FR, Stella N. The therapeutic potential of novel cannabinoid receptors. Pharmacol Ther. 2009 May;122(2):83-96. PMid:19248809.

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