Abstract
Cannabinoids have demonstrated utility in the management of cancer, obesity, and neurologic disease. More recently, their immunosuppressive and anti-inflammatory properties have been identified for the treatment of several dermatologic conditions. This review thus assesses the therapeutic potential of phytocannabinoids, endoocannabinoids, and chemically synthetic cannabinoids in the management of cutaneous disease. The PubMed® and Scopus® databases were subsequently reviewed in December 2017 using MeSH and keywords, such as cannabinoid, THC, dermatitis, pruritus, and skin cancer. The search yielded reports on the therapeutic role of cannabinoids in the management of skin cancer, acne vulgaris, pruritus, atopic and allergic contact dermatitis, and systemic sclerosis. While cannabinoids have exhibited efficacy in the treatment of inflammatory and neoplastic skin conditions, several reports suggest pro-inflammatory and pro-neoplastic properties. Further investigation is necessary to understand the complexities of cannabinoids and their therapeutic potential in dermatology.
Key Words:
acne, cannabinoid, cannabis, dermatitis, endocannabinoid, fibrosis, palmitoylethanolamide, inflammatory skin disease, pruritus, skin cancer, sclerosis, THC, tetrahydrocannabinol
Introduction
While the term “cannabis” often draws association to marijuana, cannabinoids represent a diverse class of hydrophobic compounds, deriving from plants (phytocannabinoids), animals (endocannabinoids), and chemical synthetics (Table 1).1 In mammalian tissue, two G protein-coupled cannabinoid receptors have been identified: cannabinoid receptor 1 (CB1R) in brain and neural cell lines and cannabinoid receptor 2 (CB2R) in the immune system.2,3 The cannabinoid receptors, transporters, and enzymes form the endocannabinoid system (ECS).4 Furthermore, phytocannabinoids, endoocannabinoids, and chemically synthetic cannabinoids bind to the CB1R/CB2R and induce cannabimimetic responses via ECS activation as shown in Figure 1.5
| Cannabinoid Class | Examples |
| Phytocannabinoids | Delta-9-tetrahydrocannabinol (Delta-9-THC), cannabichromene, cannabidiol, cannabigerol, cannabigerovarin |
| Endoocannabinoids | Arachidonoyl ethanolamide (AEA), 2-arachidonoyl glycerol (2-AG), N-palmitoyl ethanolamide (PEA) |
| Chemically synthetic cannabinoids | Ajulemic acid (AjA), JWH-015, WIN-55,212-2 |
| Table 1: Cannabinoid classes | |
The neuropathic properties of cannabinoids are well established and utilized in the treatment of obesity, cancer, spasticity, and tremor. More recently, the immunosuppressive and antiinflammatory effects of cannabinoids have been investigated in the treatment of inflammatory bowel disease, arthritis, vascular inflammation, and common dermatologic conditions.5-9 Herein, we provide a literature review to assess the therapeutic potential of cannabinoids as it relates to their role in skin growth control and homeostasis, pruritus, inflammation, and fibrosis.
Figure 1: Endocannabinoid system of the skin5
Adapted from figure 1 in Bíró T, et al. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci. 2009 Aug;30(8):411-20. Adapted with permission from the author, Bíró Tamás. License 4456340761996 granted by the Elsevier dated October 26, 2018.
Cannabinoids in Skin Growth Control and Homeostasis
Cannabinoids influence the homeostasis of keratinocytes, melanocytes, and sebocytes through CB1R/CB2R-dependent and -independent mechanisms.1,10,11 In the epidermis, CB1R activity in the stratum spinosum and stratum granulosum and CB2R in the basal layer may increase DNA methylation in human keratinocytes through a p38 MAP kinase to inhibit keratinocyte proliferation.8 In contrast, endocannabinoids inhibit keratinocyte proliferation independently of the CB1R/CB2R potentially through peroxisome proliferator-activated receptor gamma (PPAR-γ) and/or G-protein coupled receptor GPR55 activity.12
Non-Melanoma Skin Cancer (NMSC)
Given their role in keratinocyte homeostasis, cannabinoids influence basal and squamous cell carcinoma development.1 Following long-term exposure to ultraviolet B (UVB) light, tumorigenesis was significantly increased in CB1R/CB2R+/+ mice in comparison to CB1R/CB2R–/– mice, suggesting a receptor-dependent role of UV-induced skin carcinogenesis.13 In contrast, Gegotek et al.14 defended the anti-neoplastic properties of cannabinoids. The authors found a significant reduction in endocannabinoid receptors, anandamide (AEA), and 2-arachidonoylglycerol (2-AG) in keratinocytes and fibroblasts following UVA and UVB radiation. They determined that AEA exhibits nuclear factor kappa B (NFkB) inhibitory activity independently of CB1/CB2R, supporting pro-apoptotic properties of cannabinoids.14
Other reports, in comparison, have supported a CB1/CB2- dependent pathway as anti-neoplastic.15,16 WIN-55,212-2 (a mixed CB1/CB2 agonist) and JWH-133 (a CB2 agonist) decreased the viability of the skin tumor cells in mice with PDV.C57 epidermal tumor cells. The antitumoral activity resulted from an induction of apoptosis and impaired tumor vascularization with decreased expression of vascular endothelial growth factor (VEGF), placental growth factor, and angiopoietin 2.15
The paradoxical findings (i.e., cannabinoids exhibit both pro- and anti-neoplastic properties) may be explained by concentration-dependent effects.1 Nanomolar levels of endogenous cannabinoids associated with UVB and chemical carcinogens may stimulate NMSC tumorigenesis, while micromolar levels of exogenous cannabinoids may decrease NMSC growth. Data supports a similar concentration-dependent effect of cannabinoids on melanoma development.1
Melanoma Skin Cancer
Human melanomas express CB1R/CB2R and activation of these receptors is associated with decreased growth and increased apoptosis in mice.10 In vitro and in vivo, tetrahydrocannabinol (THC) induced autophagy, loss of cell viability, and apoptosis in melanoma A375, SK-MEL-28, and CHL-1 cell lines. Compared to temozolomide, THC and cannabidiol inhibited melanoma viability, proliferation, and tumor growth in mice with BRAF wild-type melanoma xenografts.16
Nonetheless, CB1R activation may promote tumor growth in melanoma. Compared to control, melanoma cells without CB1R showed reduced p-Akt and p-ERK expression, reduced colonyforming ability and cell migration, and increased cell cycle arrest at G1/S.17The influence of cannabinoids in the development of skin cancers is evidently complex. While most reports validate the anti-neoplastic properties of cannabinoids, the evidence remains equivocal.1,10,14-16 Given the immunomodulation properties of cannabinoids, further investigation of its effects on immunosurveillance is imperative to appreciating the principal therapeutic effects.4
Acne Vulgaris
Similarly, the regulatory function of cannabinoids on sebocytes has been implicated in acne vulgaris treatment.11,18,19 Sebocytes positively regulate sebaceous gland lipid homeostasis and negatively regulate sebocyte survival via CB2R.20 Specifically, cannabidiol inhibited the lipogenic actions of arachidonic acid, linoleic acid, and testosterone, and thus decreased sebocyte proliferation and lipogenesis.11 The principal investigator reinforced the sebostatic properties of cannabichromene and THC but noted pro-sebaceous activity of cannabigerol and cannabigerovarin.18 In a single-blinded, split-face study, 3% cannabis seed extract cream decreased skin sebum and erythema content, demonstrating a potential treatment for acne vulgaris and seborrhea.19
Cannabinoids in Pruritus
Activation of CB1R/CB2R in cutaneous nerve fiber bundles may decrease excitation of these nerve fibers and thus attenuate axon reflex flare responsible for the sensation of pruritus.21,22 Utilizing an acute allergic murine model, Schlosburg et al.23 established that systemic THC reduced scratching response induced by compound 48/80. Additional mice were treated with an inhibitor of fatty acid amide hydrolase (FAAH), the principal enzyme responsible for degradation of anandamide, which displayed equivalent scratch-reduction to loratadine and dexamethasone administration. The authors concluded that neuronal FAAH suppression reduces pruritus via CB1R activation, establishing the therapeutic role of cannabinoids in pruritus.23
WIN-55,212-2 has also exhibited anti-pruritic activity in murine models.24 Following intradermal serotonin injection, WIN- 55,212-2 displayed a significant and dose-dependent reduction in pruritus. Notably, reduced levels of monoamines in spinal tissue, secondary to artificial neurotoxic destruction, showed no impact on the anti-pruritic activity of WIN-55,212-2. These findings suggest that cannabinoid’s anti-pruritic properties act distinctly and independently from descending serotonergic and noradrenergic pathways.24
In human skin, peripheral administration of HU210, a cannabinoid receptor agonist, reduced histamine-induced itch in 18 participants.21 HU210 reduced vasodilation and neurogenic flare reaction with decline in neuropeptide (namely CGRP) release. However, co-administration of HU210 and histamine amplified protein extravasation significantly higher than histamine alone.21 Although cannabinoids exhibit predominant anti-pruritic properties, this additional finding indicates a more complex relationship between cannabinoid receptors and histamine.
The endocannabinoid palmitoylethanolamide (PEA) also exhibits anti-pruritic properties when applied topically. In an open-label application of a PEA-containing emollient (PEACE), 14 of 22 patients with prurigo nodularis, lichen simplex, and pruritus had an average itch reduction of 86.4%.25 Similarly, in an observational, prospective cohort study of 2456 patients with atopic dermatitis, the average itch on standard visual analogue scale (VAS) was reduced from 4.89 to 1.97 after 39 days of treatment with PEACE (P < 0.001). While the tolerance was assessed by physicians as very good or good in 66.3% and 25.7% of participants, 3.4% displayed poor tolerance with significant pruritus, burning, erythema, and/or miscellaneous events.26
Hemodialysis patients, likewise, demonstrated improved uremic pruritus following use of topical AEA and PEACE. After twicedaily application, 8 of 21 (38.1%) participants had resolved uremic pruritus as validated by both VAS and questionnaire method.27 Overall, these findings indicate a therapeutic role for cannabinoids in the management of itch but double-blinded, placebo-controlled studies are necessary to further determine their efficacy.8
Cannabinoids in Inflammation and Fibrosis
While pro-inflammatory properties have been identified, cannabinoids exert a largely anti-inflammatory effect by cannabinoid receptor-dependent and -independent mechanisms.5,6In mice modules, WIN-55,212,2 decreased tumor necrosis factor (TNF), interleukin (IL)-12, IL-1β and CXCL8 (IL-8), while THC decreased TNF and IL-6 when coadministered with lipopolysaccharides, but increased these cytokines when co-administered with Legionella pneumophila. Furthermore, cannabinoids suppress T helper type 1 (TH1)-cell immunity and promote TH2-cell immunity through cannabinoid type 2 receptor (CB2R) on B, T, and antigen-presenting cells.6 These potential anti-inflammatory properties have been indicated in the treatment of atopic dermatitis (AD), allergic contact dermatitis (ACD), and systemic sclerosis.
Atopic Dermatitis
Related to their anti-inflammatory and anti-pruritic effects, cannabinoids may function to treat AD.9 CB1R– mice displayed an increased response to fluorescein isothiocyanate-induced atopic-like dermatitis and decreased epidermal barrier repair. Specifically, IL-4, thymic stromal lymphopoietin (TSLP), and CCL8 cytokine were elevated in these mice, suggesting that CB1R maintains epidermal barrier homeostasis and attenuates type 2 CD4+ T helper cell response.28
Clinically, PEACE has demonstrated efficacy in the treatment of AD.26,29,30 In the aforementioned cohort study discussed in the section on pruritus, PEACE not only reduced pruritus but improved dryness, excoriation, lichenification, scaling, and erythema in 70% of patients with AD, as determined by physician assessment. Globally, AD symptoms improved substantially in 56.3% of participants and reduced weekly topical steroid use by 62%.26
In an investigator-blinded, split-body trial of 25 children and 18 adults with AD, Del Rosso29similarly demonstrated the therapeutic value of PEACE. The combination of PEACE and topical corticosteroid resulted in faster AD clearance when compared to moisturizer and topical corticosteroid. Additionally, PEACE prolonged the mean time to flare by 28 days compared to moisturizer.29 A similar split-body trial of 74 participants found that PEACE versus emollient alone prolonged time to AD flare by a median of 43 days and 29 days respectively. Mild stinging and burning was reported by 9 (12.2%) participants.30
In addition to topical application, dietary hempseed oil may improve AD. In a randomized, crossover study, daily consumption of 30 ml hempseed oil decreased skin dryness, itchiness, and use of dermal medications compared to consumption of olive oil. Symptomatic improvement may have resulted from the high concentration of polyunsaturated fatty acids in hempseed oil.31
As evidenced by several clinical studies, PEACE is efficacious in the treatment and further management of AD.26,29,30 Its therapeutic role has been suggested not to replace topical corticosteroids but rather to complement and reduce their use.26,29 Further research is necessary to understand the potentially synergistic mechanism of combination PEACE and topical steroids.
Allergic Contact Dermatitis
The anti-inflammatory properties of cannabinoids may also serve to treat ACD.9Specifically, CB1R/CB2R–/– mice had increased cutaneous contact hypersensitivity induced by 2,4-dintirofluorobenzene (DNFB). Additionally, THC decreased ear swelling and reduced Gr-1+ granulocytes following DNFB administration. Mice deficient in FAAH, furthermore, displayed decreased allergic response. These findings support that CB1R/ CB2R activation reduces inflammation in ACD. A notable exception, acute administration of a CB2R antagonist initially diminished inflammatory response, suggesting that CB2R antagonism may initially reduce acute inflammation but later propagate it.32
Further studies have similarly suggested a pro-inflammatory role of CB2R activation.33,34Following DNFB-induced ACD, mice deficient in CRB2 exhibited decreased ear swelling after 24 hours. Additionally, 2-AG activation of CB2R was associated with increase in ear weight in murine models and elevation of IL-8 and MCP-1 gene expression in human leukemia cell line HL-6.33 Ueda et al.34 further supported the pro-inflammatory activity of CB2R in mice.
Systemic Sclerosis
The therapeutic role of ECS has also been proposed for the management of systemic sclerosis.35,36 Ajulemic acid (AjA), a synthetic analogue of THC, significantly prevented bleomycininduced dermal fibrosis and modestly reduced its progression in three independent murine models. Moreover, co-treatment of AjA and a selective PPAR-γ antagonist entirely reversed the antifibrotic effects, illustrating that AjA activates PPAR-γ to reduce and further prevent fibrosis. Given its tolerated therapeutic dose, AjA offers a potential treatment for systemic sclerosis.37
In a randomized, placebo-controlled, double-blinded phase 2 clinical trial (NCT02465437) of 42 participants with diffuse cutaneous systemic sclerosis, lenabasum (AjA, JBT-101) significantly improved Combined Response Index Systemic Sclerosis (CRISS) scores by 33% in addition to the Modified Rodnan Skin Score, Systemic Sclerosis Skin Symptoms Questionnaire, and Health Assessment Questionnaire Disability Index.38,39 While one participant withdrew from the study due to dizziness, lenabasum established an acceptable safety profile without severe adverse events secondary to the study drug.39
Conclusion
These reports demonstrate the evident but complex role of cannabinoids and the endocannabinoid system in skin homeostasis and pathology. Clinical trials have supported the therapeutic role of cannabinoids in the management of acne vulgaris, pruritus, atopic dermatitis, and systemic sclerosis, as highlighted in Table 2.19,25,26,27,29,30,31,38,39 In vitroand in vivo studies have further indicated the potential therapeutic use of cannabinoids in skin cancer and allergic contact dermatitis.10,14,32 While the majority of evidence emphasizes the anti-inflammatory, anti-neoplastic activity of ECS, pro-inflammatory and proneoplastic properties have been documented.13,17,21,32,33,34,36 Further investigation is imperative to understand the influence of the cannabinoid type, delivery method, and concentration on pro- and anti-inflammatory mediators in skin homeostasis to ultimately define the therapeutic role of cannabinoids in clinical dermatology.
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