ECS-targeted approaches in skin diseases. Modulations of the fine-tuned tone of the cutaneous endocannabinoid system (ECS) could have therapeutic values in the management of a large variety of human skin diseases. For example, suppression of the skin ECS tone (using e.g. CB antagonists and/or agents that attenuate the local production of endocannabinoids) could be used in the therapy of certain hair growth (e.g. forms of alopecia, effluvium) and sebaceous gland disorders (e.g. acne, seborrhea). Conversely, augmentation of the tone of the cutaneous ECS (using e.g. CB agonists and/or agents that stimulate the local production of endocannabinoids) could be beneficial in the treatment of various benign and malignant skin tumors, hyperproliferative skin diseases (e.g. psoriasis), excessive hair growth (e.g. hirsutism), different forms of dermatitis, dry skin conditions and sensory phenomena (e.g. pain, itch).

Functions of the cutaneous ECS. Prototypic endocannabinoids such as anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are produced locally in various cellular compartments of the skin (i.e. epidermis, sebaceous gland, hair follicle) (green arrows). These endocannabinoids, via binding to cannabinoid receptor subtypes 1 and/or 2 (CB₁/CB₂), constitutively control the proper and well-balanced cutaneous functions (e.g. sensation, growth, survival, immune competence and/or tolerance) (red arrows). For example, activation of CB₁ and CB₂ on epidermal keratinocytes by locally produced endocannabinoids results in the suppression of cellular proliferation, differentiation and the release of inflammatory mediators as well as the induction of apoptosis. Likewise, endocannabinoids, via CB₁/CB₂, inhibit inflammatory responses of resident and infiltrating immune cells. Furthermore, activation of CB₁ in the hair follicle by AEA attenuates hair shaft elongation and intrafollicular proliferation, whereas it stimulates apoptosis and the development of catagen regression. On another member of the pilosebaceous unit (i.e. on the sebaceous gland-derived sebocytes), locally released endocannabinoids markedly enhance lipid production and apoptosis via CB₂. Finally, skin-derived endocannabinoids inhibit various sensory phenomena (e.g. pain and itch) via CB₁ expressed on sensory afferent nerves.