The role of the endocannabinoid system in dermatological diseases

In an extract from the handbook, Principles of Clinical Cannabinology, Viola Brugnatelli and Fabio Turco explore the cutaneous Endocannabinoid System and its potential applications in treating various dermatological conditions.

The skin, the body’s largest organ, serves not only as a protective barrier but also plays crucial roles in neuroendocrine and immunological functions. Dermatological diseases, affecting a significant portion of the population, can have far-reaching consequences for both physical and mental health.

The Skin and the Endocannabinoid System

The historical use of Cannabis Sativa L. for medicinal purposes, including topical applications, dates back to ancient civilizations such as China, Egypt, and the Arab world of the Middle Ages. Archaeological evidence supports the use of cannabis preparations to treat wounds, ulcers, skin diseases, and even as a bandage for preserving the dead.

In the early 20th century, before the prohibitionist wave against cannabis, tinctures and ointments containing cannabis were commonly sold in pharmacies for medicinal use. Despite the historical anecdotal data supporting the topical use of cannabis, the scientific understanding of the Endocannabinoid System (ECS) in the skin was only recently discovered.

Components and Functions of the ECS in the Skin

The ECS is present in the skin, acting as a regulator of various functions, given its role as a general regulator of the human body’s homeostasis.

Various elements of the ECS have been identified in the skin, including: 

• endocannabinoids like Anandamide and 2-arachidonoylglycerol (2-AG), 
• receptors such as CB1, CB2, and TRPV1, 
• enzymes involved in the biosynthesis and degradation of endocannabinoids, such as FAAH and MAGL, are present in the skin. 

These components are found on different skin cells, including epidermal keratinocytes, melanocytes, mast cells, fibroblasts, sebocytes, sweat glands, and certain types of hair follicles.

The ECS in the skin serves as a regulator for various functions, including: 

• cell growth, 
• proliferation, 
• apoptosis (programmed cell death).

The ECS plays a role in inflammatory and immune responses, the transmission of sensory stimuli to the central nervous system, and the synthesis of lipids and other epidermal components. The comprehensive localization of SEC components on diverse skin cells indicates its involvement in maintaining skin homeostasis and responding to environmental signals.

Understanding the presence and functionality of the ECS in the skin opens up avenues for exploring its role in dermatological conditions. While the historical use of cannabis for skin issues was based on anecdotal evidence, the current knowledge of SEC provides a scientific basis for further research into the potential therapeutic applications in various dermatological conditions of cannabinoids, such as: 

• cannabis extracts, 
• palmitoylethanolamine (PEA), 
• cannabidiol (CBD), 
• tetrahydrocannabinol (THC) and analogs, 

Use of Medical Cannabis in Dermatology

The use of Medical Cannabis in dermatology presents a broad spectrum of potentially beneficial applications, although much of the available data is pre-clinical, with a scarcity of randomized, controlled clinical trials in this area. Examining some of the most intriguing applications reveals promising insights into the treatment of various dermatological conditions.

Acne Vulgaris

Contrary to the misconception that acne is a natural characteristic of youth, it is a genuine inflammatory disease often caused by sebaceous gland inflammation, leading to overproduction of sebum and skin issues. While existing remedies lack proven scientific evidence, the ECS shows promise. Human studies indicate the presence of endocannabinoids in sebaceous glands, suggesting that targeting CB2 receptors could be useful. Additionally, cannabinoids like CBD have demonstrated efficacy in inhibiting sebum production.

Eczema/Dermatitis

Dermatitis, or eczema, is a non-infectious inflammatory skin reaction characterized by itching, erythema, blisters, or scab formation. Different types, such as contact dermatitis, asteatotic eczema, and atopic eczema, affect about 3.5% of the world’s population. Modulating the SEC has shown positive results, with studies revealing CB2 receptor involvement in contact dermatitis. Clinical trials with cannabinoid-like substances, such as PEA, have demonstrated effectiveness in improving hydration and reducing symptoms.

Psoriasis

Psoriasis, an immune-mediated genetic disease affecting the skin or joints, involves hyperproliferation of epidermal cells and overproduction of inflammatory cytokines. Current treatments, while effective, come with considerable side effects. Cannabinoids show promise in treating psoriasis, with mechanisms including anti-proliferative effects on keratinocytes and inhibition of immune cell action. CB2 receptors, PPARγ receptors (affected by PEA), and phytocannabinoids demonstrate validity in pre-clinical studies.

Itching

Cannabinoids present a promising application in relieving itching, a sensory experience causing a reflex to scratch. Both CB1 and CB2 receptors, along with TRPV1, are implicated in this sensation. Capsaicin, found in chili peppers, has been effective in reducing itching, and PEA-based emollient creams show efficacy in combating itching associated with various pathological conditions. Synthetic THC analogs, such as Dronabinol, have demonstrated success in treating cholestatic pruritus.

Systemic Sclerosis

Systemic sclerosis, a rare autoimmune disease, involves dysfunction of connective tissue cells, leading to skin thickening. Recent data suggest that modulating the ECS may be beneficial, with selective CB2 receptor agonists showing potential in mitigating the clinical course of the disease.

Skin Tumors

Skin cancer, including melanoma, is a frequent occurrence, especially in individuals with high sun exposure. Cannabinoids, acting on CB1 and CB2 receptors, demonstrate interference with cell migration, growth inhibition, impaired vascularization, and induction of apoptosis in tumorigenic epidermal cells. Nabiximols (a THC:CBD 1:1 formulation) has shown effectiveness in inhibiting melanoma cancer cell viability and growth.

Concluding remarks

Dermatological diseases, while not always perceived as the most severe, affect a significant portion of the population, with nearly 35% of primary care patients experiencing acute or chronic skin conditions. Despite their prevalence, many skin diseases, especially inflammatory ones, are often treated with over-the-counter products whose efficacy remains unproven.

The emerging field of applying the studies on the cutaneous ECS to dermatology presents a promising avenue. While research in this area is relatively limited, pre-clinical data highlights the effectiveness of cannabis extracts, PEA, CBD, and THC analogs in various dermatological conditions. Focusing on ECS modulation in topical preparations could offer reduced side effects. Patients with serious conditions such as psoriasis, systemic sclerosis, and skin cancer may benefit from ECS-based formulations. However, the lack of extensive clinical studies poses a challenge, emphasizing the need to overcome obstacles, including legislative ones, to enhance clinical data and conclusively demonstrate the efficacy of cannabis-derived treatments for dermatological issues.

Cannabis in dermatology and beyond

To gain a deeper understanding of the role of Medical Cannabis in dermatological diseases and to explore all the references to the cited studies, the handbook Principle of Clinical Cannabinology by experts Viola Brugnatelli and Fabio Turco, serves as a comprehensive resource.

The handbook transcends theoretical discussions by incorporating case studies and practical evidence from experienced prescribers. By shedding light on the challenges and successes associated with the incorporation of Medical Cannabis into dermatological treatment regimens, it offers valuable insights into real-world applications.

Furthermore, the resource extends its relevance to encompass insights into the application of Medical Cannabis in various pathological conditions, providing a holistic perspective on its potential therapeutic benefits.