The first records of medicinal use of cannabis are found in a Chinese pharmacopeia by Chen Nung, circa 2700 BC, in which cannabis was recommended for fatigue, rheumatism, and malaria. In addition, its seeds, rich in γ-linolenic acid, were recommended for treating eczema, psoriasis, and inflammatory diseases.

The skin is the largest organ of the human body and the first barrier between the external environment and the interior of the body, protecting it against pathogens and chemical, biological, and/or radiation damage. Besides its protective function, the skin also plays an important role in immune, neurological, and endocrine responses, being composed of an intricate multicellular communication network, where the skin and its pilosebaceous units function as neuroimmunoendocrine organs, responding to external stimuli in a complex and delicate process that is essential for maintaining skin homeostasis.

The Skin’s Endocannabinoid System

In 2009, a study with researchers from Germany, the United States, England, and Hungary identified the presence of CB1 and CB2 sites – receptors modulated by the endocannabinoid system – in the skin. The epidermal SEC possibly mediates the actions of endocannabinoids (anadamide and 2-AG) in the skin, and when disturbed, can cause disorders such as dermatitis, acne, and pruritus. CB1 and CB2 receptors have been found in epidermal keratinocytes, melanocytes, dermal cells, mast cells, sweat glands, hair follicles, and cutaneous nerve fibers. Other receptors have also been identified in various skin cells. In addition, FAAH and MAGL enzymes have been identified in sebocytes, melanocytes, fibroblasts and immunocytes.

Figure 1: The localization of the endocannabinoid system in the skin. A, hair follicle; B, sebaceous gland; C, sweat gland; D, nerve; E, blood vessels; F, keratinocytes; G, Langerhans cell (immunocyte); H, melanocytes. The figure shows the location of the two main endocannabinoids, 2-arachidoylglycerol (2-AG) and anandamide (AEA), and of several receptors, including the main CB1 and CB2, TRPs and PPARs. Figure adapted from Martins et. al 2022.

From this, it is understood that the function of the endocannabinoid system in the skin is to control and balance cell growth, differentiation and survival, and to produce appropriate immune responses. Thus, specific manipulation of the endocannabinoid system may be beneficial in a variety of dermatological diseases.

State of the Science

Conditions Studied

• Acne
• Kaposi’s Sarcoma
• Head and Neck Squamous Cell Carcinoma
• Melanoma
• Skin Cancer (Non-Melanoma)
• Night sweats and excessive sweating
• Allergic Contact Dermatitis
• Eczema
• Toenail fungus
• Fungal Infections
• Abnormal Hair Growth
• Hair loss
• Herpes
• Leishmaniasis
• Wound Healing
• Psoriasis
• Seborrhea
• Skin and Subcutaneous Tissue Disorders
• Systemic Sclerosis/Scleroderma
• Pruritus
• Fibrosis of the Skin and Scar Conditions
• Hidradenitis Suppurativa/ Acne inversa
• Pyoderma Gangrenosum
• Burn injury
• Edema
• Sunburn
• Epidermolysis bullosa
• Zoster
• Longevity

Cannabinoid-based products have potential promising applications in skin care, both in the topical treatment of skin diseases and in the cosmetics industry, acting on conditions such as pruritus, inflammatory diseases and even skin cancers . Studies suggest that cannabinoids and cannabinoid receptor modulators may have therapeutic action in various inflammatory skin diseases, due to their antiproliferative, immunomodulatory, and anti-inflammatory properties. A significant body of laboratory studies and animal models already exists. Increasing the volume of rigorous clinical studies will allow us to deepen our understanding of the cutaneous cannabinoid system and further explore these therapeutic possibilities. In general, the use of topical and oral cannabinoid-based products (CBD, CBG, THC, for example) has been shown to be quite safe. In difficult to control conditions where more conventional approaches often fail, cannabis enters as a very attractive alternative.

Below we briefly review some conditions that fit this profile.

Psoriasis

Psoriasis is a chronic skin condition characterized by inflammation and excessive proliferation of keratinocytes. The endocannabinoid system present in the skin plays a crucial role in maintaining its homeostasis. Skin affected by psoriasis contains fewer CB1 and CB2 receptor sites, indicating dysfunction of the ECS as a possible contributing factor. Targeted activation of receptor sites such as CB1, CB2, GPR55, PPAR-gamma by phytocannabinoids such as THC, CBN, CBD or CBG , endocannabinoids such as anandamide, as well as targeting their degradation enzymes can produce therapeutic effects that include anti-inflammatory actions (by reducing pro-inflammatory cytokines), inhibition of keratinocyte proliferation, or negative regulation of mast cell activation (common in psoriasis), for example. In addition, cannabinoids appear to inhibit antigen processing, interaction between macrophages and T lymphocytes, and the release of pro-inflammatory cytokines characteristic of psoriasis. Modulation of the NRIP1 gene and targeting of angiogenesis are also potential mechanisms by which cannabinoids may exert their therapeutic effects in psoriasis.

Clinical studies have demonstrated the efficacy of topical formulations containing cannabinoids, especially CBD and CBG, in improving symptoms. These effects have been shown to be dose-dependent, with T lymphocyte rebalancing and direct inhibition of keratinocyte proliferation. 

There are several case studies reporting rapid improvement of symptoms with effective maintenance with the use of cannabinoid-containing products.

A 2019 retrospective study in Italy, for example, using a topical application of CBD-enriched ointment twice daily with five psoriasis patients reported objective improvements in hydration, elasticity, and transcutaneous water loss, indicating therapeutic potential. 

In general, cannabinoids have potential as therapeutic agents for psoriasis due to their antiproliferative, anti-inflammatory, and antiangiogenic properties. As current antipsoriatic drugs can have adverse side effects, the search for safer alternatives or complementary treatments is essential. Additionally, many studies show that cannabis produces therapeutic effects that can mitigate common psoriasis comorbidities, such as itching, pain, anxiety, and depression.

Acne

Some initial studies indicate that CBD may have anti-inflammatory and oil-reducing effects and may be beneficial for treating acne. Cannabinoids interact with multiple receptor sites in human skin and therefore may present multiple novel and simultaneous targets for acne treatment. These cellular receptors have been shown to balance skin growth, regulate sebum production, and induce systemic and localized anti-inflammatory effects. 

In terms of local action, CBD shows combined effect as sebostatic, antibacterial, antiproliferative, and anti-inflammatory. In systemic terms, CBD has known therapeutic potential in reducing certain mood disorders commonly associated with acne, such as anxiety or depression.

Pruritus, or itching, is a common symptom in inflammatory skin diseases and can significantly impair the quality of life of those affected. Current antipruritic treatments often have low efficacy rates, highlighting the need for new therapeutic options.

The endocannabinoid system plays a crucial role in processing sensory manifestations in the skin, including pain and itching. Because cannabinoid receptors are found on sensory nerve endings and inflammatory cells, cannabinoid agonists and endocannabinoids become potential treatment options for pruritus, especially in patients who have not responded well to other treatments. Activation of CB1 and/or CB2, as well as other receptors such as TRPV1, has shown powerful analgesic and antipruritic effects in humans and animals. Clinical studies have demonstrated the reduction of pruritus in various dermatological and systemic diseases, including atopic dermatitis, psoriasis, uremic pruritus, and cholestatic pruritus. Formulations containing cannabinoids that stimulate CB2 or increase local production of endocannabinoids have been suggested to relieve dry skin and pruritus. 

Epidermolysis bullosa

Although the scientific literature currently available on the use of cannabinoid-based therapeutics in treating the signs and symptoms of epidermolysis bullosa is limited to reviews and meta-analyses of case studies, all trials suggest similar benefits, such as reduced pain, blistering, pruritus, wound healing, and reduced use of opioids and other analgesics. In such a difficult-to-manage condition, cannabis may emerge as a viable option with few or no side effects.

A meta-analysis published in 2021 evaluated 71 cases and found that the use of cannabinoid-based therapeutics improved the overall symptoms of epidermolysis bullosa (95%), pain (94%), pruritus (91%) and wound healing (81%). Most participants (79%) reported decreased use of other analgesics.   

Herpes

Exploration of the involvement of the endocannabinoid system (ECS) in the pathologies of various herpes infections is in the clinical stages. As recently as 1980, researchers found that THC was able to prevent the replication of HIV 1 and 2 in Petri dishes. A possible mechanism for these antiviral effects was elucidated by the results of a later study, which found that the endocannabinoids anandamide and 2-AG stimulated the release of antimicrobial effectors by neutrophils against HSV-1 (2013). However, in humans, the ideal outcome is likely to be more complex. It is worth noting that common terpenes found in cannabis have also demonstrated antimicrobial effects against HSV-1 virus, such as eucalyptol, pinene, terpineol, ß-caryophyllene, and perillyl alcohol (a precursor to limonene).

In conclusion, advances in research on the use of cannabis in dermatology offer a promising horizon for the treatment of various skin conditions. With its antiproliferative, immunomodulatory, and anti-inflammatory therapeutic properties, cannabis and cannabinoid-based products have the potential to transform the approach to skin care. As our knowledge of the cutaneous cannabinoid system expands, we are getting closer to unlocking the benefits of this amazing plant. With further research and discovery, cannabis has the potential to revolutionize dermatology, providing effective treatments and improving the quality of life for patients.

References

1. Avila, C. et al. (2020) ‘Cannabinoids for the treatment of chronic pruritus: A review’, Journal of the American Academy of Dermatology. Mosby Inc, 82(5), pp. 1205-1212. doi: 10.1016/j.jaad.2020.01.036.
2. Bíró, T. et al. (2009) ‘Novel perspectives and therapeutic opportunities Endocannabinoid system’, Trends in Pharmacological Sciences, 30(8), pp. 411-420. doi: 10.1016/j.tips.2009.05.004.The.
3. Cohen, G. et al. (2023) ‘Development of an effective acne treatment based on CBD and herbal extracts: Preliminary in Vitro, Ex Vivo, and Clinical Evaluation’, Evidence-based Complementary and Alternative Medicine, 2023. doi: 10.1155/2023/4474255.
4. Ferreira, B. P. et al. (2023) ‘Skin applications of cannabidiol: sources, effects, delivery systems, marketed formulations and safety’, Phytochemistry Reviews 2023. Springer, pp. 1-48. doi: 10.1007/S11101-023-09860-5.
5. Luz-Veiga, M. et al. (2023) ‘Cannabidiol and Cannabigerol Exert Antimicrobial Activity without Compromising Skin Microbiota’, International Journal of Molecular Sciences 2023, Vol. 24, Page 2389. Multidisciplinary Digital Publishing Institute, 24(3), p. 2389. doi: 10.3390/IJMS24032389.
6. Marks, D. H. and Friedman, A. (2018) ‘The therapeutic potential of cannabinoids in dermatology’, Skin Therapy Letter. NLM (Medline), 23(6), pp. 1-5.
7. Martinez, A. E. (2019) ‘Time to drop the stigma: cannabinoids are drugs that can relieve pain in people with epidermolysis bullosa.’, The British Journal of Dermatology. England, 180(4), pp. 711-712. doi: 10.1111/bjd.17619.
8. Martins, A. M. et al. (2022) ‘Cannabis-Based Products for the Treatment of Skin Inflammatory Diseases: A Timely Review.’, Pharmaceuticals (Basel, Switzerland). MDPI, 15(2). doi: 10.3390/ph15020210.
9. Mounessa, J. S. et al. (2017) “The role of cannabinoids in dermatology,” Journal of the American Academy of Dermatology. Mosby Inc, 77(1), pp. 188-190. doi: 10.1016/j.jaad.2017.02.056.
10. Oláh, A. et al. (2014) “Cannabidiol exerts sebostatic and anti-inflammatory effects on human sebocytes,” Journal of Clinical Investigation, 124(9), pp. 3713-3724. doi: 10.1172/JCI64628.
11. Pagano, C. et al. (2022) “Cannabinoids: Therapeutic Use in Clinical Practice”, International Journal of Molecular Sciences, 23(6), pp. 1-20. doi: 10.3390/ijms23063344.
12. Palmieri, B., Laurino, C. and Vadalà, M. (2019) “A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and skin scars.”, La Clinica terapeutica. Italy, 170(2), pp. e93-e99. doi: 10.7417/CT.2019.2116.
13. Peyravian, N. et al. (2022) “The anti-inflammatory effects of cannabidiol (CBD) on acne,” Journal of Inflammation Research. Dove Medical Press, 15, pp. 2795-2801. doi: 10.2147/JIR.S355489.
14. Ramer, R. and Hinz, B. (2022) “Cannabinoid Compounds as a Pharmacotherapeutic Option for the Treatment of Non-Cancer Skin Diseases,” Cells. MDPI, 11(24). doi: 10.3390/cells11244102.
15. Río, C. Del et al. (2018) ‘The endocannabinoid system of the skin. A potential approach for the treatment of skin diseases’, Biochemical Pharmacology. England, 157, pp. 122-133. doi: 10.1016/j.bcp.2018.08.022.
16. Schräder, N. H. B. et al. (2021) “Cannabinoid use and effects in patients with epidermolysis bullosa: an international cross-sectional survey study,” Orphanet Journal of Rare Diseases. BioMed Central, 16(1), pp. 1-13. doi: 10.1186/s13023-021-02010-0.
17. Shao, K., Stewart, C. and Grant-Kels, J. M. (2021) “Cannabis and the skin”, Clinics in dermatology. United States, 39(5), pp. 784-795. doi: 10.1016/j.clindermatol.2021.05.006.
18. Sheriff, T. et al. (2020) “The potential role of cannabinoids in dermatology”, Journal of Dermatological Treatment. Taylor and Francis Ltd, 31(8), pp. 839-845. doi: 10.1080/09546634.2019.1675854.
19. Tortolani, D. et al. (2023) ‘Rare phytocannabinoids exert anti-inflammatory effects on human keratinocytes through the endocannabinoid system and MAPK signaling pathway’, International Journal of Molecular Sciences. MDPI, 24(3). doi: 10.3390/ijms24032721.
20. Wroński, A. et al. (2023) ‘Phytocannabinoids in the pharmacotherapy of psoriasis’, Molecules, 28 (3), pp. 1-21. doi: 10.3390 / molecules28031192.