OBJECTIVE: The aim of this study is to understand the role of cannabinoid type 2 receptor (CB2R) during periodontal inflammation and to identify anti-inflammatory agents for the development of drugs to treat periodontitis (PD). BACKGROUND: Cannabinoid type 2 receptor is found in periodontal tissue at sites of inflammation/infection. Our previous study demonstrated anti-inflammatory responses in human periodontal ligament fibroblasts (hPDLFs) via CB2R ligands. METHODS: Anandamide (AEA), HU-308 (agonist), and SMM-189 (inverse agonist) were tested for effects on IL-1β-stimulated cytokines, chemokines, and angiogenic and vascular markers expressed by hPDLFs using Mesoscale Discovery V-Plex Kits. Signal transduction pathways (p-c-Jun, p-ERK, p-p-38, p-JNK, p-CREB, and p-NF-kB) were investigated using Cisbio HTRF kits. ACTOne and Tango™ -BLA functional assays were used to measure cyclic AMP (cAMP) and β-arrestin activity. RESULTS: IL-1β stimulated hPDLF production of 18/39 analytes, which were downregulated by the CB2R agonist and the inverse agonist. AEA exhibited pro-inflammatory and anti-inflammatory effects. IL-1β increased phosphoproteins within the first hour except p-JNK. 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 at 180 minutes. HU-308 affected both cAMP and β-arrestin pathway. SMM-189 only stimulated cAMP. CONCLUSION: The findings that CB2R agonist and inverse agonist may potentially regulate inflammation suggest that development of CB2R therapeutics could improve on current treatments for PD and other oral inflammatory pathologies.