Cannabidiol as a Novel Therapeutic for Skin Treatments

Júlia Scherer Santos¹ , Luana de Oliveira Costa¹ , Monique de Rezende Evangelista² , Laura Diogo Fernandes² , Eduarda Barbosa Scaldini Teixeira² , Ester Marques Rosa² , Fabricio Felippe dos Santos³ , Maurilio de Souza Cazarim^1,2* & Thaís Nogueira Barradas^1,2

¹Department of Pharmaceutical Sciences, School of Pharmacy, Federal University of Juiz de Fora, Brazil
²BscPharm, School of Pharmacy, Federal University of Juiz de Fora, Brazil
³Pharmaceutical Science Postgraduate Program, Federal University of Rio de Janeiro, Brazil

*Correspondence to: Dr. Maurilio de Souza Cazarim, Department of Pharmaceutical Sciences, School of Pharmacy & BscPharm, School of Pharmacy, Federal University of Juiz de Fora, Brazil.

Copyright © 2023 Dr. Maurilio de Souza Cazarim, et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Introduction
For thousands of years, Cannabis spp. has been employed with therapeutic purposes and as a source of phytocannabinoids. The two best-known phytocannabinoids are Δ9-tetrahydrocannabinol (Δ9-THC), and cannabidiol (CBD) [1]. The former is the main psychoative compound found in Cannabis while cannabidiol shows therapeutical potential for nervous system disorders. Beyond phytocannabinoids, endocannabinoids and synthetic cannabinoids also features therapeutic value [2,3]. Phytocannabinoids come from C. sativa, C. indica e C.ruderalis [3]. Diversely, endocannabinoids are cannabinoids of endogenous source. On the other hand, synthetic ones do not come from a natural source and they are not produced endogenously [2,3].

Biological effects of cannabinoids are due to their ability to modulate the endocannabinoid system (ECS), a complex molecular system found all over human organs. Currently, reports are directed towards understanding the modulation mechanisms of cannabinoids on the ECS [4]. As the endocannabinoid system is present in the skin, the understanding of the mechanisms and receptors involved in the skin ECS have been researched [5-7]. As a consequence, new skin treatments may be developed [4, 8-15]. Therefore, this report aims to highlight the potential of CBD to formulations designed to skin diseases treatment or cosmetic therapy. Furthermore, as ESC plays a fundamental role in cannabidiol effect, the main aspects and the most recent evidences regarding skin ECS will be discussed.

Endocannabinoid System of the Skin (ECS)
Endogenously, the human body produces several endocannabinoids, where anandamide and 2- arachidonoylglycerol (2-AG) are the most important ones [16]. These endogenous molecules are synthesized and metabolized by enzymes. In addition to endocannabinoids and enzymes, the ECS is composed of receptors, in which endocannabinoids and phytocannabinoids bind [4].

The cannabinoid receptor type 1 (CB1) and cannabinnoid receptor type 2 (CB2) are the oldest identified receptors, but several other receptors have already been identified such as the transient receptor potential channels (TRP), peroxisome proliferator-activated receptor (PPAR) [4], G protein-coupled receptores[16]. About TRP channels, there are the following subptypes: transient receptor potential vanilloid channels (TRPV), transient receptor potential ankyrin channels (TRPA), transient receptor potential melastatin channels (TRPM) [5]. TRPV channels are further divided into: TRPV1, TRPV2, TRVP3, TRPV-4 [17]. Regards to TRPA and TRPM, the most important are TRPA-1 and TRPM-8, respectively [5]. For PPAR and skin application, PPARγ is the principal [17]. TRPV channels, PPARγ as well as TRPA-1 and TRPM8 are secundary targets of cannabinoids [17].

Concerning endocannabinoid system, skin components have more than one ECS receptor. Table 1 shows the main ECS receptors and the skin site where they are found. For instance, the fibroblasts and keratinocytes express CB1, CB2, PPARy, TRPV1, TRPV2, TRPV3, TRPV4, TRPA1. On the other hand, for sebaceous gland the following receptores CB1, CB2, TRPV1 are found. In immune cells, CB1, CB2, TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, TRPM-8 are expressed. Hence, by knowing the receptors found in each skin component, cannabinoids can be topical applied to target one or several of these receptors [4].

CB: cannabinoid receptor, CB1: cannabinoid receptor type 1, CB2: cannabinoid receptor type 2, PPAR: peroxisome proliferator-activated receptor, PPARγ: peroxisome proliferator-activated receptor gamma, TRPV : transient receptor potential channel, TRPV1: transient receptor potential vanilloid type-1, TRPV2: receptor potential vanilloid type-2, TRPV3: receptor potential vanilloid type-3, TRPV4: receptor potential vanilloid type-4, TRPA: transient receptor potential ankyrin channel, TRPA1: transient receptor potential ankyrin type-1, TRPM: transient receptor potential melastin channel, TRPM-8: transient receptor potential melastatin type-8.

Skin Applications of Cannabidiol
Cannabinoids may be used to improve skin health either in the treatment of skin disorders [15,18] or as cosmeceutical [15]. Regarding skin disorders, they may be useful in the treatment of inflammatory diseases such as psoriasis and acne [18]. Besides, cannabinoids also shows ability to reduce melanoma and nonmelanoma skin cancer proliferation, and would then have a potential application to the treatment of these diseases [15]. As cosmeceuticals, phytocannabinoids improve skin healing [19] which is compromised in aged skin [20]. Therefore, an improved skin appearance can be achieved [19]. Moreover, cannabidiol features promising applications due to its anti-inflammatory and antioxidant effects [11].

Acne
As one of the most prevalent skin diseases, acne is an inflammatory disease causing increased sebum production [21] resulting in comedo and in inflammatory acne forms when there is Cutibacterium acnes [22]. Once traditional treatments are often associated with adverse effects, more effective new treatments need to be developed [22].

Cannabidiol have lipolytic an anti-inflammatory effect, which is essential for acne treatment [12]. Furthermore, Cannabis seed extract was able to reduce sebum production in a clinical study. In that report, isolated CBD was not used. Then, possibly the observed effects may be due to the association of cannabinoids found in Cannabis seed [23]. Nevertheless, there is a likely use of cannabinoids, including cannabidiol, in acne therapy.

Concerning mechanisms of action of cannabidiol in acne, its effect is possibly due to the activation of TRPV1[12,24], since it has low affinity to CB1 e CB2 [24]. Besides, CBD caused a upregulation of tribbles homolog 3 receptor, related to anti-inflammatory activity. The mechanisms, receptors and mediators involved in the CBD anti-acne activity [12] need to be better investigated in order to CBD-based acne treatments be more effective.

Skin Barrier Disorders
Stratum corneum is the outermost skin layer responsible for skin protection and to create the skin barrier. Disturbance of this barrier is related to dehydration of the skin and to atopic dermatitis and psoriasis [25,26]. Atopic dermatitis and psoriasis are complex diseases combining environmental and genetic factors [26] and they are related to systemic diseases [27,28]. Since patients affected by these diseases may have low life quality [29], alternatives to conventional treatments have been developed [27, 28, 30, 31].

The benefits of topical cannabidiol in atopic dermatitis have been shown both in clinical trials [32, 33] and in animal assays [14]. However, the number of volunteers in clinical trials is small [32, 33]. About animal assay, it is valuable in an initial development of CBD as drug candidate. However, further investigation in humans are necessary. Accordingly, additional studies need to be conducted to prove CBD efficaccy on atopic dermatitis.

The combination of CBD with other anti-inflammatory ingredients is also interesting. In this sense, aspartame associated with CBD had a greater anti-inflammatory activity than CBD alone, probably due to the synergistic anti-inflammatory effect of both CBD and aspartame [32]. Likewise, palmitoylethanolamide associated with CBD reduced inflammation. However, the results were not as satisfactory as the one obtained to mometasone, the traditional treatment. This denotes the need to better understand the effects of CBD and its associations in atopic dermatitis [14].

Apart from that, CBD topical use reduced the psoriasis severity [9]. Adverse effects were the same for the CBD-based product and for the control treatment [9], showing the probable safety of CBD use. Beyond that, reports aiming to detect oxidative stress markers [34, 35] showed that CBD inhibited reactive oxigen species [34] and lipid peroxidation [35]. Oxidative stress occur in psoriasis. Then, the reduction of free radicals and of other secundary molecules oxidative stress-related may be of interest in achieving successful psoriasis therapy. Nonetheless, additional researches are need to to prove CBD efficacy in psoriasis.

With respect to the probable CBD mechanisms on psoriasis, its action on CB1, CB2, G-protein coupled receptor 55 (GPR55) and PPARy is postulated [9]. Even though the CBD affinity to CB1 and CB2 is low, it is still able to bind in both receptors [36]. To atopic dermatitis, the probable mechanism of action is related to pruritus reduction through TRPV1, TRPV2, TRPV3, TRPV4, TRPA1[4], found in mast cells, keratinocytes and nerve endings. In addition, TRPM8 which is found mast cells and nerve endings, can be implicated as well [4].

Antiaging
Oppositely to stated so far, the view of aging as a solely physiological aspect is currently changing. Skin aging should be considered a disease, as other dysfunctions can occur as consequence of it. Among them, cancer may develop [37]. Therefore, the search for new anti-aging ingredients is essential to develop new more effective anti-aging products, which can prevent/avoid dysfunctions resulting from skin aging.

Beyond wrinkles [38], sun exposure increase the risk of developing skin cancer [39]. Cyclobutane pyrimidine dimers (CPD) are the main markers of ultraviolet B damage and of a possible skin cancer [40]. In keratinocytes, CBD reduced CPD content [41] and then it can be beneficial to prevent skin cancer, as reported previously [2, 42]. In addition, antioxidant ingredients are desired in anti-aging products[38]. In that regard, CBD promoted a photoprotective effect against UVB radiation [41] and against phospholipids upregulation or downregulation due to ultraviolet exposure [43]. Also, as photoaged skin is dehydrated, the increase of aquaporine-3 expression would be useful to improve skin hydration [44]. In that sense, the use of topical CBD is interesenting for this purpose [45]. Additionally, a topical product bearing retinol and CBD reduced wrinkles and skin laxity [46].

As to CBD mechanisms on the antiaging activity, it possibly involves the ones already described. However, as skin aging is complex and multifactorial [38], several mechanisms may be associated. Hence, TRP channels receptors are implicated in preventing skin dehydration [7]. Moreover, CBD antiaging effects is explained by its antioxidant ability, scavanging free radicals. In that case, the possible mechanism is through inhibition of BACH1 receptors on keratinocytes [47]. BTB and CNC homology (BACH1) is a transcrition factor related to free radicals production [48], which which makes this receptor a potential antiaging target for CBD.

Conclusion and Trends
Cannabidiol has potential applications in the treatment of skin disorders, mainly for those whose current treatments are side-effect related or the treatment efficacy is limited. Then, it may be a promise treatment for chronic skin diseases such as psoriasis and atopic dermatitis. Moreover, as cannabidiol can be used as a multifunctional ingredient, it may be interesting in increasing patient adherence to treatment, as the number of products required may be reduced.

Nevertheless, more researches on the mechanisms of action of canabidiol are needed in order to better establish its use in the treatment of skin diseases, as well as for new applications to be investigated. Further research addressing safety and possible adverse effects of topical cannabidiol should also be conducted.

Bibliography

1. Crippa, J. A., Guimarães, F. S., Campos, A. C., et al. (2018). Translational investigation of the therapeutic potential of cannabidiol (CBD): Toward a new age. Frontiers in Immunology, 9, 1-16.
2. Shao, K., Stewart, C. & Grant-Kels, J. M. (2021). Cannabis and the skin. Clinics in Dermatology, 39(5), 784-795.
3. Duggan, P. J. (2021). The Chemistry of Cannabis and Cannabinoids. Australian Journal of Chemistry, 74, 369-387.
4. Baswan, S. M., Klosner, A. E., Glynn, K., et al. (2020). Therapeutic potential of cannabidiol (CBD) for skin health and disorders. Clinical, Cosmetic and Investigational Dermatology, 13, 927-942.
5. Río C del, Millán, E., García, V., et al. (2018). The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders. Biochemical Pharmacology, 157, 122-133.
6. Bíró, T., Tóth, B. I., Haskó, G., et al. (2009). Novel perspectives and therapeutic opportunities Endocannabinoid system. Trends in Pharmacological Sciences, 30(8), 411-420.
7. Tóth, K. F., Ádám, D., Bíró, T., et al. (2019). Cannabinoid signaling in the skin: Therapeutic potential of the ‘c(ut)annabinoid’ system. Molecules, 24(5), 1-56.
8. Palmieri, B., Laurino, C. & Vadala, M. (2019). A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars. Clinica Terapeutica, 170(2), E93-E99.
9. Puaratanaarunkon, T., Sittisaksomjai, S., Sivapornpan, N., et al. (2022). Topical cannabidiol-based treatment for psoriasis: A dual-centre randomized placebo-controlled study. Journal of the European Academy of Dermatology and Venereology, 36(9), e718-e720.
10. Atalay, S., Gęgotek, A., Wroński, A., et al. (2021). Therapeutic application of cannabidiol on UVA and UVB irradiated rat skin. A proteomic study. Journal of Pharmaceutical and Biomedical Analysis, 192, 113656.
11. Atalay, S., Jarocka-karpowicz, I. & Skrzydlewskas, E. (2020). Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants, 9, 1-20.
12. Oláh, A., Tóth, B. I., Borbíró, I., et al. (2014). Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. Journal of Clinical Investigation, 124(9), 3713-3724.
13. Gupta, A. K. & Talukder, M. (2021). Cannabinoids for skin diseases and hair regrowth. Journal of Cosmetic Dermatology, 20(9), 2703-2711.
14. Rundle, C. W., Rietcheck, H. R., Maghfour, J., et al. (2022). Anti-inflammatory Effect of Cannabidiol and Palmitoylethanolamide Containing Topical Formulation on Skin in a 12-O-Tetradecanoylphorbol-13-Acetate-Induced Dermatitis Model in Mice. Dermatitis, 33(4), 277-281.
15. Sheriff, T., Lin, M. J., Dubin, D., et al. (2020). The potential role of cannabinoids in dermatology. Journal of Dermatological Treatment, 31(8), 839-845.
16. Rezende, B., Alencar, A. K. N., de Bem, G. F., et al. (2023). Endocannabinoid System: Chemical Characteristics and Biological Activity. Pharmaceuticals, 16(2), 2-20.
17. Mnekin, L. & Ripoll, L. (2021). Topical use of cannabis sativa l. Biochemicals. Cosmetics, 8(3), 1-17.
18. Scheau, C., Badarau, I. A., Mihai, L. G., et al. (2020). Cannabinoids in the pathophysiology of skin inflammation. Molecules, 25(3). Epub ahead of print 2020.
19. Gerasymchuk, M., Robinson, G. I., Groves, A., et al. (2022). Phytocannabinoids Stimulate Rejuvenation and Prevent Cellular Senescence in Human Dermal Fibroblasts. Cells, 11(23), 1-26.
20. Gosain, A. & DiPietro, L. A. (2004). Aging and Wound Healing. World Journal of Surgery, 28(3), 321-326.
21. Picardo, M. & Eichenfield, L. F. & Tan, J. (2017). Acne and Rosacea. Dermatology and Therapy, 7(Suppl 1), 43-52.
22. Santos, J. S. T. F. for AT. Nanocarriers‐Based Topical Formulations for Acne Treatment. In: Raj K. Keservani, Rajesh Kumar Kesharwani AKS (ed) Advances in Novel Formulations for Drug Delivery. Beverly: Scriever Publishing/Wiley, pp. 327-339.
23. Ali, A. & Akhtar, N. (2015). The safety and efficacy of 3% Cannabis seeds extract cream for reduction of human cheek skin sebum and erythema content. Pakistan Journal of Pharmaceutical Sciences, 28, 1389-1395.
24. Peyravian, N., Deo, S., Daunert, S., et al. (2022). The Anti-Inflammatory Effects of Cannabidiol (CBD) on Acne. Journal of Inflammation Research, 15, 2795-2801.
25. Bouwstra, J. A. & Ponec, M. (2006). The skin barrier in healthy and diseased state. Biochimica et Biophysica Acta - Biomembranes, 1758(12), 2080-2095.
26. Montero-Vilchez, T., Segura-Fernández-nogueras, M. V., Pérez-Rodríguez, I., et al. (2021). Skin barrier function in psoriasis and atopic dermatitis: Transepidermal water loss and temperature as useful tools to assess disease severity. Journal of Clinical Medicine, 10(2), 1-12.
27. Nomura, T. & Kabashima, K. (2016). Advances in atopic dermatitis in 2015. Journal of Allergy and Clinical Immunology, 138(6), 1548-1555.
28. Krueger, G. & Ellis, C. N. (2005). Psoriasis - Recent advances in understanding its pathogenesis and treatment. Journal of the American Academy of Dermatology, 53(1 Suppl 1), 94-100.
29. Bieber, T., Zhou, X., Chen, Y., et al. (2022). Advances in the pathogenesis of psoriasis: from keratinocyte perspective. Cell Death and Disease, 21, 21-40.
30. Souto, E. B., Dias-Ferreira, J., Oliveira, J., et al. (2019). Trends in atopic dermatitis-from standard pharmacotherapy to novel drug delivery systems. International Journal of Molecular Sciences, 20(22), 1-17.
31. Jyothi, S. L., Krishna, K. L., Ameena Shirin, V. K., et al. (2021). Drug delivery systems for the treatment of psoriasis: Current status and prospects. Journal of Drug Delivery Science and Technology, 62, 102364.
32. Gao, Y., Li, Y., Tan, Y., et al. (2022). Novel cannabidiol aspartame combination treatment (JW-100) significantly reduces ISGA score in atopic dermatitis: Results from a randomized double-blinded placebo-controlled interventional study. Journal of Cosmetic Dermatology, 21(4), 1647-1650.
33. Maghfour, J., Rundle, C. W., Rietcheck, H. R., et al. (2021). Assessing the effects of topical cannabidiol in patients with atopic dermatitis. Dermatology Online Journal, 27(2), 2-5.
34. Jarocka-Karpowicz, I., Biernacki, M., Wroński, A., et al. (2020). Cannabidiol effects on phospholipid metabolism in keratinocytes from patients with Psoriasis Vulgaris. Biomolecules, 10(3), 1-20.
35. Szachowicz-Petelska, B., Łuczaj, W., Wroński, A., et al. (2021). The differential effect of cannabidiol on the composition and physicochemical properties of keratinocyte and fibroblast membranes from psoriatic patients and healthy people. Membranes, 11(2), 1-17.
36. Pertwee, R. G. (2008). The diverse CB 1 and CB 2 receptor pharmacology of three plant cannabinoids: Δ 9-tetrahydrocannabinol, cannabidiol and Δ 9-tetrahydrocannabivarin. British Journal of Pharmacology, 153(2), 199-215.
37. Russell-Goldman, E. & Murphy, G. F. (2020). The Pathobiology of Skin Aging: New Insights into an Old Dilemma. American Journal of Pathology, 190(7), 1356-1369.
38. Zouboulis, C. C., Ganceviciene, R., Liakou, A. I., et al. (2019). Aesthetic aspects of skin aging, prevention, and local treatment. Clinics in Dermatology, 37(4), 365-372.
39. Lindqvist, P. G., Epstein, E. & Landin-Olsson, M. (2022). Sun Exposure - Hazards and Benefits. Anticancer Research, 42(4), 1671-1677.
40. Lawrence, K. P., Delinasios, G. J., Premi, S., et al. (2022). Perspectives on Cyclobutane Pyrimidine Dimers-Rise of the Dark Dimers†. Photochemistry and Photobiology, 98(3), 609-616.
41. Li, Y., Hao, D., Wei, D., et al. (2022). Photoprotective Effects of Cannabidiol against Ultraviolet-B-Induced DNA Damage and Autophagy in Human Keratinocyte Cells and Mouse Skin Tissue. Molecules, 27(19), 6740.
42. Burch, R., Mortuza, A., Blumenthal, E., et al. (2021). Effects of cannabidiol (CBD) on the inhibition of melanoma cells in vitro. Journal of Immunoassay and Immunochemistry, 42(3), 285-291.
43. Łuczaj, W., Domingues, M. D. R., Domingues, P., et al. (2020). Changes in lipid profile of keratinocytes from rat skin exposed to chronic uva or uvb radiation and topical application of cannabidiol. Antioxidants, 9(12), 1-15.
44. Ikarashi, N., Shiseki, M., Yoshida, R., et al. (2021). Cannabidiol application increases cutaneous aquaporin-3 and exerts a skin moisturizing effect. Pharmaceuticals, 14(9), 1-10.
45. Li, J., Tang, H., Hu, X., et al. (2010). Aquaporin-3 gene and protein expression in sun-protected human skin decreases with skin ageing. Australasian Journal of Dermatology, 51(2), 106-112.
46. Few, J., Lee, M. J., Semersky, A., et al. (2022). A Single-Center Study Evaluating the Effects of a Novel Retinol and Cannabidiol Combination Topical on Facial Skin. Aesthetic Surgery Journal Open Forum, 4, 1-9.
47. Casares, L., García, V., Garrido-Rodríguez, M., et al. (2020). Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biology, 28, 101321.
48. Zhang, X., Guo, J., Wei, X., et al. (2018). Bach1: Function, regulation, and involvement in disease. Oxidative Medicine and Cellular Longevity, 2018(1347969).