The skin is a vital organ that is not only an external defence barrier but also an agent implied in body functioning. When we talk about the endocannabinoid system (ECS) in the skin we mean that regulates many of its functions. As a result, cannabinoids can influence skin biology, as scientific research supports, and their use is now being considered to treat or alleviate the symptoms of various skin disorders.
The endocannabinoid system in the skin
What is the role of skin?
Not only is the skin a protective barrier against environmental influences that detects exterior signals and sends them to the nervous system and the immune system, but it is also a neuroendocrinoimmuno organ, which produces several hormones and is a thermoregulator.
That defence system includes physicochemical, immunological and microbiological barriers and works due to successful cooperation and communication between immune cells and other cell types (keratinocytes, fibroblasts, melanocytes, sebocytes, adipocytes…). Those cells express receptors which are meant to recognize pathogenic agents and produce several anti-microbial peptides and lipids, as well as pro- and anti-inflammatory cytokines and chemokines that regulate local immune responses.
What is the endocannabinoid system?
The endocannabinoid system is a signalling network, made of endogenous ligands – also called endocannabinoids such as anandamide (AEA). The receptors – mainly type 1 and type 2 cannabinoid receptor (CB1 and CB2), and related enzymatic complex responsible for synthesis, uptake and release, transport and degradation of endocannabinoids. Phytocannabinoids, such as cannabidiol (CBD) and tetrahydrocannabinol (THC), are cannabinoids naturally present in Cannabis Sativa L. that can influence the endocannabinoid system. Cannabinoids can activate, antagonize or inhibit various cellular target, such as cannabinoid receptors, some transient receptor potential ion channel, nuclear receptors, enzymes, and transporters.
While THC is a partial CB1 agonist, CBD is an inverse agonist/antagonist, depending on the context:
The cannabinoid signalling
Some studies showed that disrupting the ECS could affect skin biology since it is an important contributor to cutaneous homeostasis. In fact, the ECS is expressed by various cells of the skin such as keratinocytes (which represent 90% of the epidermis cells and synthetize keratin), melanocytes (which are located in the epidermis and synthetize melanin), mast cells, fibroblasts, sebocytes (epithelial cells localized in the sebaceous gland and produce sebum), sweat gland cells, and some hair follicles.  Understanding which mechanisms are involved is key to be able to purposely act on the ECS to treat skin disorders.
Taking advantage of the ECS to treat skin conditions
Since the ECS influences the activity of skin cells, could be useful to treat skin cancers. In fact, CB1 and CB2 appear in melanoma and non-melanoma skin cancers. In the case of non-melanoma skin cancers, which develop in the epidermis, studies reached paradoxical findings: when combined with long-term ultraviolet V (UBV) light and chemical carcinogens, some studies put forward the anti-neoplastic effects of high levels of cannabinoids, mediated by either CB1/CB2-independent or dependent mechanisms, while others demonstrated the pro-neoplastic properties of low levels of cannabinoids. In the case of melanoma skin cancers, a study on mice models reported that THC would not only decrease angiogenesis, tumour growth and metastasis, but also increase apoptosis within tumours.
Pruritus & inflammation
Several studies have demonstrated the anti-pruritus effects of cannabinoids, via inhibition ofTRPV1 in cutaneous nerve fibre bundles would decrease their excitation and consequently reducing the axon reflex that induces pruritus. Additionally, inhibiting FAAH, the main enzyme responsible for the degradation of AEA, which inhibits the ion channel TRPV1 (expressed mainly in pain sensorial receptors nociceptive neurons), also reduces pruritus sensation. Finally, topical application of palmitoylethanolamide (PEA), which activates AEA also resulted in anti-pruritus action.
Furthermore, cannabinoids exert anti-inflammatory properties mediated by various complex mechanisms that often involve CB1 and CB2 receptors, chemokines and interactions between the endocannabinoid system and the immune system. For instance, CBD has been shown to suppress the migration, the proliferation and the maturation of the cells involved in inflammatory responses.
The anti-inflammatory properties of cannabinoids, together with their anti-pruritus properties, could be very useful to treat skin disorders such as allergic contact dermatitis and atopic dermatitis as well as systemic sclerosis. Indeed, in model fibrotic dermal tissues, a study showed that the activation of CB2 resulted in a modulation of the immune response which prevent not only fibrosis but also tissues leucocyte infiltration.
One could also take advantage of cannabinoids to treat psoriasis. Psoriasis is a disease characterized by a disfunction of keratinocytes that excessively multiply. Cannabinoids, especially THC, may inhibit keratinocyte proliferation. In a study, activating CB1 has resulted in a downregulation of keratin (K6 and K16) expression. Plus, other studies suggested that cannabinoids could inhibit antigen processing and prevent the release of inflammatory cytokines, which are substances produced by the immune system to regulate cells proliferation.
Cannabinoids also exert skin rejuvenation and anti-ageing properties, since the endocannabinoid system in the skin controls the proliferation, differentiation and survival of basal cell. A study showed that deleting CB1 receptors in mice delayed ageing.
Cannabinoids can also impact Acne Vulgaris by regulating sebocytes. First, a study showed that antagonization of CB2 receptors expressed on sebocytes resulted in a suppression of basal lipid production. Second, CBD has been found to inhibit sebocytes proliferation by activating ion channel TRPV4. It also inhibited lipogenic actions of arachidonic, linoleic acids and testosterone, which resulted in a decrease in sebum production. CBD also reportedly inhibits human keratinocyte proliferation.
Acne is caused by an increased sebum production and alteration of its composition, such as desaturation of fatty acids, the presence of lipoperoxides or a decrease in vitamin E. Those dysfunction lead to hyperkeratinisation and then to comedo formation. In closed comedos (white spots), bacteria overgrowth induces an inflammatory response from the sebaceous glands, spurred by the alterations in the sebum composition. The inflammation itself leads to an increase in sebum production which creates a vicious circle. An in vitro study showed that other cannabinoids than CBD are interesting when it comes to treat acne. For instance, “Canabigerol (CBG) and Cannabigerovarina (CBGV) may have potential for dry-skin diseases, while Cannabicromeno (CBC), Cannabidivarin (CBDV) and especially Tetrahydrocannabivarin (THCV) show promise to become highly efficient”.
Focus on the antioxidative properties of CBD
The skin is barrier constantly exposed to environmental influences lead to the generation of reactive oxygen species (ROS). High ROS levels causes oxidative stress which damages cells and can lead to chronic inflammation as well as to skin diseases, skin disorder and skin aging. To prevent high levels of ROS, healthy skin exerts various defence mechanisms such as antioxidant and detoxification systems. CBD induces the expression of HMOX1, a protein with antioxidant properties in keratinocytes.
The endocannabinoid system in the skin appears to be a potent lever to treat or at least alleviates the symptoms of various skin disorders. Since it is a complex mechanism, further studies are needed to fully understand how disrupting the ECS impacts the skin biology to eventually be able to take full advantage of cannabinoids in dermatology.
 Tóth, K. F., Ádám, D., Bíró, T., & Oláh, A. (2019). Cannabinoid Signaling in the Skin: Therapeutic Potential of the “C(ut)annabinoid” System. Molecules (Basel, Switzerland), 24(5), 918. doi:10.3390/molecules24050918
 Sheriff, T., Lin, M. J., Dubin, D., & Khorasani, H. (2019). The potential role of cannabinoids in dermatology. Journal of Dermatological Treatment, 1–7. doi:10.1080/09546634.2019.1675854
 Oláh, A., Markovics, A., Szabó-Papp, J., Szabó, P. T., Stott, C., Zouboulis, C. C., & Bíró, T. (2016). Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment. Experimental Dermatology, 25(9), 701–707. doi:10.1111/exd.13042
 Casares, Laura et al. “Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1.” Redox biology vol. 28 (2020): 101321. doi:10.1016/j.redox.2019.101321