Combination of CBD with minor cannabinoid CBDV suppresses CXCR4 via CB2 receptor and alleviates colitis in mice

Cannabis extracts, particularly those rich in cannabinoids like cannabidiol (CBD), have shown potential anti-inflammatory properties and are being examined in managing conditions involving inflammation. One proposed mechanism is their modulation of chemokine expression and function in immune cells. C-X-C chemokine receptor type 4 (CXCR4) plays a pivotal role in immune cell trafficking and is implicated in the pathogenesis of inflammatory bowel disease (IBD). Given emerging evidence that cannabinoids can influence chemokine signaling, we explored whether they could downregulate CXCR4 in immune cells. In this study, we show that the combination of CBD and cannabidivarin (CBDV) at a 20:1 ratio significantly reduces CXCR4 expression in MOLT-4 cells, murine splenocytes and human peripheral blood mononuclear cells. This reduction in CXCR4 expression correlated with impaired chemotactic responses and suppressed actin polymerization, effects that were abrogated by CB2 receptor inhibition. In vivo, the CBD:CBDV combination ameliorated disease severity in a murine model of DSS-induced colitis, improving disease activity index, colon length, and histological outcomes. These therapeutic benefits were absent in CB2 knockout mice, confirming CB2 dependence. Our findings support a CB2-mediated mechanism by which the CBD:CBDV combination downregulates CXCR4, providing a mechanistic basis for the entourage effect and highlighting the significance of CBDV as a modulator of the CBD effect. Overall, this study implicates cannabinoid combinations as a promising therapeutic strategy for treating IBD.