Acne vulgaris (AV) is a globally occurring inflammatory skin disease manifesting in the pilosebaceous unit of human skin in the form of comedones, papules, and pustules that negatively affect self-esteem and work productivity. The etiopathogenesis of AV is complex, multifactorial, and not fully understood yet. The Cutibacterium acnes bacteria infestation, abnormal keratinization, and excessive lipid production are the main pillars of this disease. The higher colonization of C. acnes observed in inflammatory papules was believed, for decades, to be the main causative factor of AV. C. acnes, under normal aerobic conditions, act as a commensal to the skin, while oxygen deprivation triggers its virulency switching to a pathogenic behavior. C. acnestrapped inside anaerobic comedones environment release lipases with strong proinflammatory and chemoattractant activities that activate the local immune system resulting in inflammation.

Pilosebaceous unit governing cutaneous lipids level is called “the brain in the skin”due to its rich innervation among other skin appendages and its ability to synthetize by sebocytes and other follicular structures of a plethora of neuromediators. These neuromediators, both synthetized denovo and/or released from nerve fibres, regulate cutaneous steroidogenesis, androgen synthesis, and immune functions. The hyperproliferation and hyperactivity of sebocytes in the sebaceous gland during Acne Vulgaris result in excessive sebum production leading to comedones formation.

The nerve growth factor (NGF) plays crucial functions in human skin that are linked to tissue repair and regeneration by enabling reinnervation followed by accelerated cell migration and proliferation. The significantly higher expression of NGF was observed in inflammatory acne lesions, compared to healthy controls. It is proposed that NGF thus may be involved in impaired keratinocytes proliferation, neurogenic inflammation, and pain, all the hallmarks of acne. The cutaneous endocannabinoid system (ECS) regulates cell growth and differentiation, sebum production, and immune functions. The two main ECS representatives, anandamide (AEA) and 2-arachidonoylglycerol are produced by human sebocytes and modulate sebum production in receptor type-dependent fashion. Both ECS and Phytocannabinoids (plant-derived) have been shown to have a strong anti-acne activity that includes the normalization of impaired keratinocytes proliferation, attenuation of inflammatory responses, and homeostasis of SG lipogenesis.

Interestingly, cannabinoids reduce arachidonic acid-induced “acne-like” lipogenesis and facilitate the ‘beneficial’ triglycerides production with anti-inflammatory and microbiome-normalizing properties.

Acetylcholine (ACh) released from autonomic nerves or synthetized by skin cells acting via nicotinic receptor promote infundibular epithelial hyperplasia and follicular plugging leading to comedones formation during Acne Vulgaris.