Cannabidiol and the endocannabinoidome in atopic dermatitis

Abstract

Objective: To analyze the main pathophysiological mechanisms of atopic dermatitis from a neuroimmune perspective, emphasizing the integration of epidermal barrier dysfunction, chronic inflammation mediated by Th2 immune axes, and neurogenic pruritus pathways, while also discussing the regulatory role of the endocannabinoidome and the mechanistic basis of modulation by cannabidiol. Literature review: Atopic dermatitis results from the interplay between skin barrier dysfunction, immunological hyper-reactivity, and neuroimmune alterations that perpetuate chronic pruritus. Cytokines such as IL-4, IL-13, and IL-31 compromise the epidermal barrier and intensify inflammation, whereas neurogenic mediators amplify peripheral and central sensitization. The endocannabinoidome constitutes a regulatory axis comprising lipid mediators, metabolic enzymes, and multiple canonical and non-canonical receptors—including TRP, PPARγ, and GPR55—that participate in modulating inflammation, epidermal differentiation, and pruritogenic signaling. Cannabidiol indirectly regulates the endocannabinoidome through mechanisms such as negative allosteric modulation of CB1, functional interaction with CB2, and partial inhibition of FAAH, thereby positively influencing the inflammatory and neuroimmune processes involved in the disease. Final considerations: The endocannabinoidome is emerging as a relevant conceptual framework for understanding the integration of inflammation, the epidermal barrier, and pruritus. Cannabidiol demonstrates promising modulatory potential, although this is currently limited by scientific gaps requiring further rigorous investigation.