Nakajima et al.1919 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. http://dx.doi.org/10.1016/j.febslet.2005.12.079. PMid:16406050. http://dx.doi.org/10.1016/j.febslet.2005...
(2006) |
In vitro
|
CB1 and CB2 |
HGF |
- |
AEA |
AEA significantly reduced the production of IL-6, IL-8, and MCP-1 induced by P. gingivalis LPS in HGFs, attenuated by AM251 and SR144528. AEA blocked LPS-triggered NF-kB activation. |
Kozono et al.2020 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. http://dx.doi.org/10.1016/j.bbrc.2010.03.080. PMid:20233580. http://dx.doi.org/10.1016/j.bbrc.2010.03...
(2010) |
In vitro, In vivo and Clinical cross-sectional |
CB1 and CB2 |
HGF |
Oral wounds / rats |
AEA; CP55940; 2-AG |
Upregulation of the expression of CB1/CB2 receptors in wound-healing model. Proliferation of HGFs by AEA were attenuated by AM251 and AM630. CP55940 induced phosphorylation of ERK 1/2, p38MAPK, and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MEK, p38MAPK, and PI3-K. Increase in AEA levels in the gingival crevicular fluid after periodontal surgery in human patients with periodontitis. |
Qian et al.2727 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. http://dx.doi.org/10.1111/j.1600-0765.2009.01265.x. PMid:20412420. http://dx.doi.org/10.1111/j.1600-0765.20...
(2010) |
In vitro
|
CB2 |
hPDL |
- |
HU-308 |
HU-308 enhanced the mRNA levels of osteogenic genes. Expression of the OPG was up-regulated, whereas RANKL expression was downregulated. Accelerated mineralization was observed in hPDL cells with HU-308. |
Ossola et al.3737 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. http://dx.doi.org/10.1007/s00011-012-0485-z. PMid:22581275. http://dx.doi.org/10.1007/s00011-012-048...
(2012) |
In vivo
|
CB1 |
- |
LPS-induced periodontitis / rats |
Meth-AEA |
Topical Meth-AEA significantly diminished alveolar bone loss. Reduction of biological mediators of periodontal disease augmented by LPS. |
Rettori et al.3838 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. http://dx.doi.org/10.1159/000339113. PMid:22777139. http://dx.doi.org/10.1159/000339113...
(2012) |
In vivo
|
CB1 and CB2 |
- |
Ligature-induced periodontitis + immobilization stress / rats |
AEA |
Local injection of AEA decreased corticosterone plasma levels and the content of the cytokines TNF-α and IL-1β in gingival tissue in periodontitis-stress groups. AEA-induced inhibitions were mediated by CB1 and CB2. |
Özdemir et al.3939 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. http://dx.doi.org/10.1371/journal.pone.0107407. PMid:25226300. http://dx.doi.org/10.1371/journal.pone.0...
(2014) |
In vitro
|
CB1 and CB2 |
hPDL |
- |
AEA; 2-AG |
hPDL viability was significantly increased by AEA in the presence of P. gingivalis LPS. In P.gingivalis LPS stimulated hPDL, AEA down-regulated gene-expression and protein production of IL-6, IL-8, and MCP-1. |
Ossola et al.4040 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. http://dx.doi.org/10.1902/jop.2016.150612. PMid:26846967. http://dx.doi.org/10.1902/jop.2016.15061...
(2016) |
In vivo
|
CB2 |
- |
LPS-induced periodontitis / rats |
HU-308 |
HU-308 attenuated alveolar bone loss resulted by LPS-induced periodontitis, and reduction of inflammatory mediators augmented in LPS-injected rats (iNOS, TNF-α, and PGE2). |
Konermann et al.3535 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. http://dx.doi.org/10.1007/s10571-017-0482-4. PMid:28289947. http://dx.doi.org/10.1007/s10571-017-048...
(2017) |
In vitro, In vivo and Clinical cross-sectional |
CB1 and CB2 |
hPDL |
Mechanically-induced root resorptions |
- |
CB1 expression was significantly higher in healthy PDL structures compared to CB2. Bacterial inflammation affected a decrease in CB1, but an increase in CB2. |
Abidi et al.3131 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. http://dx.doi.org/10.1016/j.archoralbio.2017.12.005. PMid:29274621. http://dx.doi.org/10.1016/j.archoralbio....
(2018) |
In vitro
|
CB2 |
hPDLF |
- |
AEA, HU-308 |
LPS, TNF-α, and IL-1β increased IL-6 and MCP-1 production, which were inhibited by AEA, SMM-189, and HU-308. AEA alone significantly increased IL-6, but not MCP-1 levels. |
Alves et al.3636 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. http://dx.doi.org/10.1016/j.bone.2019.05.015. PMid:31121356. http://dx.doi.org/10.1016/j.bone.2019.05...
(2019) |
In vivo
|
CB1 and CB2 |
- |
Ligature-induced periodontitis / rats |
Electroacupuncture |
Increased bone loss in the furcation of experimental periodontitis (EP) and experimental periodontitis-electroacupuncture (EA) - sham groups. Enhanced CB2 immunolabeling was observed in the periodontal tissues in the EP-EA group when compared to the EP and EP-EA-sham groups. |
Gu et al.2424 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. http://dx.doi.org/10.3389/fimmu.2019.02288. PMid:31681262. http://dx.doi.org/10.3389/fimmu.2019.022...
(2019) |
In vitro and In vivo
|
CB2 |
TIGK; CD14+ human monocytes |
Gavage Infection Model / knockout CB2−/− mice |
CBD; CBN; THC |
CBD, CBN, and THC each suppressed P. gingivalis-induced IL-12 p40, IL-6, IL-8, and TNF release while enhancing the anti-inflammatory cytokine, IL-10, from human innate cells. Similar phenomena were observed in F. alocis- and T. denticola-exposed human monocytes and human gingival keratinocytes. |
Liu et al.3030 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. http://dx.doi.org/10.1111/jcpe.13190. PMid:31461164. http://dx.doi.org/10.1111/jcpe.13190...
(2019) |
In vitro and in vivo
|
CB1 and CB2 |
hPDLF |
Periodontal tissue biopsies / mice |
THC |
Both CB1 and CB2 were expressed in periodontal tissues but with different expression patterns. THC promoted periodontal cell wound healing by inducing hPDLF cell adhesion and migration. The effect of cannabinoids on periodontal fibroblast cell adhesion and migration was mainly dependent on the CB2. |
Yan et al.4141 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. http://dx.doi.org/10.1111/cpr.12691. PMid:31599069. http://dx.doi.org/10.1111/cpr.12691...
(2019) |
In vitro
|
CB1 |
PDLSC |
- |
R‐1 Meth |
CB1 overexpression or R‐1 Meth promoted the osteo/dentinogenic differentiation of PDLSCs. Deletion of CB1 or the application of AM251 repressed the osteo/dentinogenic differentiation of PDLSCs. The activation of CB1 enhanced the TNF‐α‐ and INF‐γ‐impaired osteo/dentinogenic differentiation potential in PDLSCs. CB1 activated p38 MAPK and JNK signaling and repressed PPAR‐γ and Erk1/2 signaling. |
Abidi et al.3232 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. http://dx.doi.org/10.1111/jre.12765. PMid:32562275. http://dx.doi.org/10.1111/jre.12765...
(2020) |
In vitro
|
CB2 |
hPDLF |
- |
AEA, HU-308 |
AEA exhibited pro-inflammatory and anti-inflammatory effects. CB2R ligands attenuated p-p38 and p-NFĸB, but a late rise in p-38 was seen with HU-308. As p-ERK levels declined, a significant increase in p-ERK was observed later in the time course by synthetic CB2R ligands. P-JNK was significantly affected by SMM-189 only, while p-CREB was elevated significantly by CB2R ligands. HU-308 affected both cAMP and β-arrestin pathway. SMM-189 only stimulated cAMP. |
Ossola et al.4242 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. http://dx.doi.org/10.54589/aol.33/2/143. PMid:32920617. http://dx.doi.org/10.54589/aol.33/2/143...
(2020) |
In vivo
|
CB2 |
- |
LPS-induced periodontitis / rats |
HU-308 |
Rats subjected to experimental periodontitis showed higher bone resorption areas, number of osteoclasts and gingival content of prostaglandin E2 than controls, while HU 308 prevented, the deleterious effects. |
Zhang et al.4343 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. http://dx.doi.org/10.1186/s12903-020-01087-6. PMid:32295577. http://dx.doi.org/10.1186/s12903-020-010...
(2020) |
In vitro
|
CB1 and CB2 |
hPDL |
- |
Meth-AEA |
Meth-AEA significantly inhibited P. gingivalis LPS-induced production of IL-6, IL-8, and MCP-1. |
Abidi et al.3333 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. http://dx.doi.org/10.1111/jre.13050. PMid:36070347. http://dx.doi.org/10.1111/jre.13050...
(2022) |
In vitro
|
CB1 and CB2 |
HGF |
- |
CBVN; CBG; CBD |
In IL-1β-stimulated HGFs, PGE2 production was significantly suppressed by CBG and CBVN. CBD and CBG elevated PGE2. IL-β-stimulated HGF with pCBs significantly reduced INF-ɣ, TNF-α, and IL-2. Suppression of IL-4 was seen with CBD and CBVN, while only CBVN exerted suppression of IL-13. pCBs significantly increased IL-6, IL-10, and IL-12 levels, while none of the pCBs reduced the expression of IL-8 in IL-1β-stimulated HGF. |
Ataei et al.3434 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. http://dx.doi.org/10.1002/cre2.608. PMid:35719011. http://dx.doi.org/10.1002/cre2.608...
(2022) |
Clinical cross-sectional |
CB1 and CB2 |
- |
- |
- |
Expression of CB2 in periodontitis patients was significantly lower than in healthy patients. Expression of CB1 was not significantly different in periodontitis or healthy patients. |
Pellegrini et al.2121 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. http://dx.doi.org/10.1111/jre.13103. PMid:36727611. http://dx.doi.org/10.1111/jre.13103...
(2023) |
Clinical cross-sectional |
CB1 and CB2 |
- |
- |
- |
The number of CBs in inflamed sites of recurrent periodontitis was significantly higher than in those with non-recurrent disease and in healthy subjects, but less activated. Levels of AEA in inflamed sites of non-recurrent patients were higher than in inflamed recurrent sites and in healthy sites. After periodontal therapy, levels of AEA were significantly lower in both periodontal groups. In recurrent sites, AEA was lower than in non-recurrent and healthy subjects. |