Skin Deep: The Role of the Endocannabinoid System in Cutaneous Homeostasis

by Camille Charlier

We are excited to share the first of a three part series on CBD oil and the Skin by our new resident research writer, Camille Charlier.

Part I: Skin Deep – The Role of Endocannabinoid System in Cutaneous Homeostasis; Part II: The Skinny According to Science; and Part III: Cannabis: Plant, Industry, and Ideology. Look out for Part II next Wednesday, August 8th!

The secret to well-being, inside the body and out, is balance. In physiology it’s referred to as homeostasis — the tendency towards a relatively stable equilibrium between interdependent elements. Homeostasis is an active process, one that takes work. Any biological system is tightly regulated and requires constant adjustment to maintain. It’s a precarious tightrope act: When things wobble too far one way or another they topple and we’re faced with dysfunction and disease.

Skin health is no exception. The skin is regulated by an elaborate homeostatic complex responsible for coordinating inflammation, tissue proliferation, sebum production, and more: the endocannabinoid system (ECS). Indeed, this network is known to act globally to modulate such parameters as pain sensation, memory, and fertility, but only recently have researchers identified the existence of a functional cutaneous ECS. The skin’s role of protecting the internal milieu from the outside world presents a remarkable challenge in balance. Take a look at any common cutaneous disorder and evidence of dysregulation arises. Immune dysfunction, for example, plays a major role in pathologies of the skin such as acne vulgaris, allergic contact dermatitis, eczema, psoriasis, and rosacea (Dainichi et al., 2014).

It’s a sophisticated dance, and sometimes things get knocked off kilter. In light of our new understanding of the cutaneous ECS, however, treatments with cannabinoids, endogenous and otherwise, provide a novel approach to optimizing our hides. To understand what Cannabis and cutaneous salubrity (health) have in common, we’ll take a whirlwind tour of the anatomy of the skin, physiology of the endocannabinoid system, and methodology of the modern Cannabis industry. The age-old adage “it’s only skin deep” belies the stunning complexity of our soft human coverings. Perhaps it’s time to reconsider our idioms.

Skin: An Exposé

The skin is the largest organ in the human body, comprising as much as 15% of the total adult body weight. It is the principal barrier between the internal body and the external world; a deeply sensitive organ that protects against biological, chemical, mechanical, and ultraviolet threats. It serves an essential role in systemic thermoregulation and the prevention of excess water loss and is an important mediator of the interrelationship between the immune, neurologic, and endocrine systems.

Skin consists of three major layers, the epidermis, the dermis, and the subcutaneous tissue. The epidermis, outermost layer, is characterized by a constellation of cells known as keratinocytes. These cells synthesize the protective protein keratin, a fibrous intermediate alpha-helical filament and component of the cell’s cytoskeleton. Below the epidermis lies the dermis, a layer composed of the fibrillar structural protein collagen. Adjacent to this we find the lipocyte-containing subcutaneous tissue.

 

 

The epidermis is a remarkable structure, perpetually renewing itself and giving rise to hair follicles and sweat glands. It is itself composed of five layers, the deepest of which is called the basal layer. This is a hotspot of mitotic action, from whence cells arise to repopulate the outer layers. Basal cells engage in dynamic cycles of proliferation and migration, sending cells towards the surface of the skin to continually reconstitute the outer epidermis.

Epidermal stem cells are clonogenic in nature, which means that they are capable of proliferating interminably to give rise to a colony of cells. Under normal conditions the cells progress through their life cycle at a leisurely rate. In the case of a wound, however, the basal cells kick into high gear and increase the number of cycling epidermal cells via stimulation of stem cell division. Mechanical damage isn’t the only mechanism by which the rate of cell division can be altered — DNA damage caused by carcinogenic agents can also ramp up the cell proliferation machinery, resulting in hyperproliferation (Kolarsick, et al., 2011).

Embedded in the epidermis we find sebaceous glands, crucial regulators of human skin homeostasis, often associated with hair follicles in a structure known as the pilosebaceous unit. Sebaceous glands produce sebum, an oily secretion composed of triglycerides, cholesterol esters, squalene, free fatty acids, and wax esters. These lipids play an essential role in promoting integrity of the skin, from the mediation of inflammatory processes, to antioxidant delivery, to management of microbial populations. The cutaneous microbiota, an oft unappreciated microcosm, plays a critical role in skin fitness or distress. Sebum composition is a major factor in regulating the growth of the cutaneous commensal organisms — restricting undesired microbes while promoting the preferred populations. This behavior renders the sebaceous glands key instigators of cutaneous microbiota cross-talk essential for healthy skin homeostasis.

Sebaceous glands participate in the cutaneous endocrine and immune system, and serve as stem cell reservoirs. Dysfunction of the sebaceous gland contributes to myriad pathologies such as the ubiquitous acne and dry skin. Overproduction of sebum and pathological alterations of its chemical composition are key steps in the etiology of acne. On the flip side of the same coin, insufficient sebum production in adults may lead to dry skin, xerosis, skin aging, and atopic dermatitis (reviewed in Zákány et al., 2018).

The Endocannabinoid System — A Critical Cutaneous Regulator

The endocannabinoid system is a psychoneuroimmunological network responsible for promoting the activities ‘‘relax, eat, sleep, forget, and protect” (Di Marzo, 1998). Cannabis has been used medicinally and recreationally since time immemorial. Its effects are well recognized, but only as recently as 1992 did scientists establish conclusive experimental evidence for the existence of endogenous cannabinoids with the isolation of anandamide — named for the Sanskrit word meaning “bliss,” ananda. Due to this whimsical dub, anandamide is sometimes referred to as the “bliss molecule,” an endogenous fatty acid neurotransmitter that binds to the same receptors as Δ9-tetrahydrocannabinol (THC), the principal psychoactive constituent of Cannabis.

The ‘‘classic’’ endocannabinoid system is comprised of the G protein-coupled cannabinoid receptors CB1 and CB2, arachidonic acid-derived ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. CB1 receptors are predominantly expressed in the central nervous system, and in some peripheral organs and tissues such as the spleen, skeletal muscle, liver, pancreas, and adipose tissue. CB2 receptors are also expressed in the brain, though not as densely as CB1, as well as the peripheral nervous system, gastrointestinal system, and immune tissues of the spleen, tonsils, thymus gland, monocytes, macrophages, mast cells, B cells, and T cells.

Mammals are far from unique in their possession of such a system. Indeed, cannabimimetic metabolites and cannabinoid receptors are popular across the animal kingdom, and have endured over 500 million years of evolutionary emprise in organisms as ancient as the leech, sea urchin, and marine mollusc (reviewed in Di Marzo, 1998).

Everything from embryological development, neural plasticity, neuroprotection, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, hunger, and metabolism falls under the purview of the ECS. Importantly, this system can be acted upon not only by endogenous and phytocannabinoids, but also by pharmaceuticals, complementary/alternative clinical interventions, lifestyle modifications, and other ingested substances.

In 2014 McPartland et al. published an article entitled “The Care and Feeding of the Endocannabinoid System,” a literature review of clinical interventions that upregulate the ECS. They noted that pharmaceuticals including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants have all been found to influence the ECS, along with non-pharmaceutical clinical interventions such as massage and physical manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modifications (diet, weight control, exercise), and the use of psychoactive substances (alcohol, tobacco, coffee, Cannabis) have been found to modulate the eCB system as well (McPartland et al., 2014).

Macro detail of container with CBD oil (Credit: Istock by Getty Images)

The clinical relevance of these types of interventions becomes increasingly significant as our understanding of the endocannabinoid system deepens. Certainly, the ECS’s critical role in promoting a state of balance and vitality cannot be overstated. Dr. Ethan Russo, neurologist and medical researcher, writes in his article 2016 “Beyond Cannabis: Plants and the Endocannabinoid System” published in Trends in Pharmacological Sciences, “The ECS performs major regulatory homeostatic functions in the brain, skin, digestive tract, liver, cardiovascular system, genitourinary function, and even bone.” Russo has even proposed the existence of an “endocannabinoid deficiency syndrome,” which he theorizes may be the cause of such disorders as migraine, fibromyalgia, irritable bowel syndrome, and depression. Interestingly, the integrity of the system, or ‘endocannabinoid tone,’ is contingent upon a multitude of determinants. He explains:

Various lifestyle factors including diet and aerobic activity affect the overall ECS function or ‘endocannabinoid tone’, a function of the density of cannabinoid receptors, their functional status (upregulated or downregulated) and relative abundance or dearth of endocannabinoids.

Cannabis is not the only plant to act on the endocannabinoid system; other common plants and foods likewise contain phytocannabinoids that bind to CB1 and CB2 receptors. Just a few examples: Carrots, which contain falcarinol, a pesticide and fungicide that covalently binds CB1 and acts as an inverse agonist, kava kava (as Russo charmingly writes, “the ‘mystic pepper’, a convivial beverage of the South Pacific Islands”), and some liverworts which, according to our man, “spurred a spate of Internet ‘trip reports’ from amateur psychonauts variably documenting prominent psychoactive versus no effects after smoking these agents.”

It should be noted, however, that not all cannabinoids act via binding to CB1 and CB2 receptors. Non-intoxicating phytocannabinoid cannabidiol (CBD) acts on transient receptor potential vanilloid-1 (TRPV1), potentially “turning down the heat and pain” of sensation. Russo suggests that, due to its desensitizing properties at the receptor level, possible therapeutic targets for CBD and similar agents (capsaicin from chili peppers, black pepper, and ginger) would include neuropathic pain (causalgia, complex regional pain syndrome, migraine), burns, irritable bladder, interstitial cystitis, prostatitis, chronic pelvic pain, fibromyalgia, inflammatory bowel disease, irritable bowel syndrome, pancreatic pain, and numerous dermatological pruritic conditions (Russo, 2016).

 

For our current purposes, we’ll zero in on the role that the endocannabinoid system plays in skin health. As previously stated, the skin is an active physio-chemical barrier against constant environmental challenges including microbial threat, allergens, UV exposure, and chemical irritation, and cutaneous integrity arises via an elegantly orchestrated neuroimmunoendocrine homeostasis. Healthy skin requires the life-long regeneration and rejuvenation of cutaneous tissues and its associated mini-organs such as hair follicles and sebaceous glands. This process is contingent upon the exquisite balance of cell growth and proliferation, survival and programmed death (apoptosis), which is regulated by a host of growth and trophic factors, cytokines, and chemokines discharged from the skin cells. The mismanagement of cutaneous growth and immunoendocrine functions can result in pathological conditions such as hyperproliferative skin diseases (e.g. psoriasis and tumors), hair growth disorders (e.g. alopecia, effluvium, and hirsutism), acne vulgaris, and atopic dermatitis.

The endocannabinoid system is thought to manage skin cell proliferation, differentiation, and survival, the proper regulation of which is essential for functional cutaneous homeostasis. The ECS influences skin health in myriad ways, from modulating allergic response to mediating skin-derived sensory phenomena. When it comes to allergic inflammation of the skin, the ECS exerts a protective action. Studies found that mice lacking CB1 and CB2 receptors, or treated with antagonists for these receptors, demonstrated an exaggerated allergic inflammatory response. The ECS also mediates central and peripheral processing of skin-derived sensory phenomena such as pain and itch. Endocannabinoids and synthetic cannabinoid receptor agonists have been found to exert potent analgesic effects in humans and other animals via the activation of CB1 and CB2, and possibly by stimulating receptors such as TRPV1 at sensory nerve terminals and inflammatory cells (reviewed in Bíró, et al, 2009).

Various human skin cell compartments (epidermal keratinocytes, hair follicles, sebaceous and sweat glands) synthesize the endocannabinoids anandamide and 2-AG, along with enzymes that participate in their synthesis and metabolism. The potent role that these lipid mediators play in growth control of the human pilosebaceous unit renders them a topic of significant interest in cutaneous neuropharmacology. Indeed, CB1 and CB2 receptors, along with the ionotropic cannabinoid receptor TRPV1 were identified in situ and in vitro on manifold skin cells populations, from epidermal and hair follicle keratinocytes to sebaceous gland-derived sebocytes. Anandamide was found to inhibit proliferation and induce cell death in cultured human epidermal keratinocytes and in situ.

In other words, locally synthesized endocannabinoids prevent skin growth from spiraling out of control. A cutaneous ECS gone awry can therefore trigger and/or aggravating chronic hyperproliferative, pruritic, and pro-inflammatory skin diseases. In light of this, targeted manipulation of the endocannabinoid system offers a promising treatment approach for hyperproliferative dermatoses such as psoriasis and keratinocyte-derived skin tumors (Tóth, et al., 2011).

Human sebaceous glands are also capable of synthesizing the endocannabinoids anandamide and 2-AG, and express both CB1 receptors (primarily in differentiated cells) and CB2 receptors (mostly in proliferating basal layer sebocytes). Studies have shown that exogenous administration of anandamide and 2-AG dramatically increased lipid production via sebocytes, an intervention of particular interest in dry skin conditions (Zákány et al., 2018).


End of Part I.

Part II: The Skinny According to Science


References:

Bíró, Tamás, Balázs I. Tóth, György Haskó, Ralf Paus, and Pál Pacher. “The Endocannabinoid System of the Skin in Health and Disease: Novel Perspectives and Therapeutic Opportunities.” Trends in Pharmacological Sciences 30, no. 8 (August 2009): 411–20. https://doi.org/10.1016/j.tips.2009.05.004.

Dainichi, Teruki, Sho Hanakawa, and Kenji Kabashima. “Classification of Inflammatory Skin Diseases: A Proposal Based on the Disorders of the Three-Layered Defense Systems, Barrier, Innate Immunity and Acquired Immunity.,” November 2014. https://repository.kulib.kyoto-u.ac.jp/dspace/handle/2433/191232.

Di Marzo, V. “‘Endocannabinoids’ and Other Fatty Acid Derivatives with Cannabimimetic Properties: Biochemistry and Possible Physiopathological Relevance.” Biochimica Et Biophysica Acta 1392, no. 2–3 (June 15, 1998): 153–75.

Kolarsick, Paul A. J., Maria Ann Kolarsick, and Carolyn Goodwin. “Anatomy and Physiology of the Skin.” Journal of the Dermatology Nurses’ Association 3, no. 4 (August 2011): 203. https://doi.org/10.1097/JDN.0b013e3182274a98.

McPartland, John M., Geoffrey W. Guy, and Vincenzo Di Marzo. “Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions That Upregulate the Endocannabinoid System.” PLOS ONE 9, no. 3 (March 12, 2014): e89566. https://doi.org/10.1371/journal.pone.0089566.

Russo, Ethan B. “Beyond Cannabis: Plants and the Endocannabinoid System.” Trends in Pharmacological Sciences 37, no. 7 (July 1, 2016): 594–605. https://doi.org/10.1016/j.tips.2016.04.005.

Tóth, Balázs I., Nóra Dobrosi, Angéla Dajnoki, Gabriella Czifra, Attila Oláh, Attila G. Szöllosi, István Juhász, Koji Sugawara, Ralf Paus, and Tamás Bíró. “Endocannabinoids Modulate Human Epidermal Keratinocyte Proliferation and Survival via the Sequential Engagement of Cannabinoid Receptor-1 and Transient Receptor Potential Vanilloid-1.” The Journal of Investigative Dermatology 131, no. 5 (May 2011): 1095–1104. https://doi.org/10.1038/jid.2010.421.

Zákány, Nóra, Attila Oláh, Arnold Markovics, Erika Takács, Andrea Aranyász, Simon Nicolussi, Fabiana Piscitelli, et al. “Endocannabinoid Tone Regulates Human Sebocyte Biology.” The Journal of Investigative Dermatology, March 6, 2018. https://doi.org/10.1016/j.jid.2018.02.022.