Preserved Barrier Integrity and Altered Immune Profiles in Chronic Cannabis Users: Potential Roles of Δ9-Tetrahydrocannabinol

Abstract

Although cannabinoids such as delta-9-tetrahydrocannabinol (THC) are generally immunosuppressive in preclinical models, chronic cannabis use in humans is paradoxically associated with increased infection risk and systemic inflammation. In this study, we demonstrate that THC directly strengthens intestinal epithelial barrier function in vitro by increasing trans-epithelial electrical resistance in a concentration-dependent manner in Caco-2 monolayers. In a cross-sectional study of chronic cannabis users via smoking or snorting compared with non-using controls, plasma lipopolysaccharide (LPS), and microbial translocation-driven inflammatory cytokines (IL-23, MCP-1, IL-8) were significantly reduced, while some cytokines (IL-6, IL-1{beta}, TNF-, IL-10) remained unchanged. Concurrently, users exhibited elevated macrophage-derived chemokine (MDC) and homeostatic cytokines IL-15 and IL-21, markedly suppressed IL-7 and IL-4. Plasma IL-15 and MDC levels correlated with consumption intensity, and IL-23, IL-7, and IP-10 correlated with age of first use or during heaviest use. These findings suggest that habitual cannabis use may protect gut barrier integrity and reduce microbial translocation and associated inflammation, while simultaneously disrupting systemic immune homeostasis through selective cytokine dysregulation. This dual, dose-dependent immunomodulatory profile highlights the complex balance between potential benefits and risks in both recreational and therapeutic cannabis use.