Abstract Alcohol and marijuana (cannabinoids) are commonly abused drugs worldwide, and adolescent co-exposure/co-abuse of these two drugs is hallmarked by high levels of co-morbidity. Both chronic binge ethanol and cannabinoid consumption enhances the risk of acute lung injury (ALI) and both community and health care associated pneumonia (CAP and HAP, respectively), leading to increased morbidity and mortality. We have recently utilized a mouse model for adolescent intermittent ethanol (AIE) and cannabinoid (AIC) exposure to examine roles of binge exposure to adult-pulmonary inflammation, and our data suggests that that the prior polysubstance exposure leads to increased HMGB1 expression and microbial-induced pulmonary inflammation. Interestingly, our in vitro studies indicate that both alcohol and cannabinoids activate HMGB-1 expression from macrophage cells, and inhibiting cannabinoid receptors CB1R and CB2R on cells inhibits HMGB-1 expression, and is recapitulated in vivo using antagonists for CB1R. We aim to investigate CBR signaling as a potential therapeutic direction in response to alcohol and cannabinoid-dependent pulmonary inflammation.