¹The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
²Georgetown University School of Medicine, Washington, DC, USA

Conflict of interest:
AJF is a consultant for Aclaris Therapeutics. ECM has no conflicts to declare for this work.

Abstract:
HP40 (Eskata™) is a stabilized, topical solution of 40% hydrogen peroxide (H₂O₂) packaged in an applicator pen that is US FDA-approved to treat seborrheic keratoses (SKs). By harnessing the oxidative capabilities of H₂O₂ , 1-2 treatments with HP40 produced a higher rate of clearance of four SKs per patient compared to vehicle in two phase 3 trials. The clearance rate was higher for the face than the trunk and extremities. Similarly, the risks of pigmentary changes and scarring from HP40 were lower for the face than other locations. Further, based on an ex vivo study, HP40 may be less cytotoxic to melanocytes than cryotherapy, but clinical trials comparing these therapies are needed. Limitations of HP40 are its low efficacy and requirement of multiple treatments, which can result in elevated costs. The application can also be time-consuming, though extenders or even staff members can apply it. Therefore, HP40 may be better reserved for the treatment of facial SKs.

Key Words:
efficacy, Eskata, hydrogen peroxide, safety, seborrheic keratoses, topical therapy

Introduction

Seborrheic keratoses (SKs) are benign epithelial tumors estimated to affect more than 83 million Americans.¹ Existing as at least nine variants, SKs present as round to oval macules or papules with variable surface textures that appear “stuck on” and can occur anywhere on the body, except the palms and soles.^2-4 The incidence and frequency of SKs per person increase with age.⁴ In one study of Korean males, the authors found that 79% of patients had SKs at age 40 (with 5.5 SKs per patient) compared to 94% of patients at age 50 (with 9.9 SKs per patient).⁵

In addition to increasing age, potential risk factors for SKs include ultraviolet light, as they occur with a higher prevalence on sun-exposed skin,^5,6 friction given they commonly occur in intertriginous areas,⁷ and genetic predisposition.^7,8 However, the true etiologic risk factors and pathogenesis of SKs are not fully known. Inhibition of apoptosis may occur in SKs, contributing to their formation.⁴Additionally, mutations in the fibroblast growth factor receptor⁸ and oncogenic phosphoinositide 3-kinase pathway⁹ may impact their development; however, these changes are not present in all SKs so additional genes are likely involved.⁸

While SKs do not require treatment, patients often request removal to relieve symptoms of irritated SKs or for cosmetic reasons.¹⁰ The most common treatment is cryotherapy with liquid nitrogen; surgical therapies are also used including electrodessication, curettage, shave excision, or laser therapy.^7,11

Among other side effects, these invasive methods can cause pain, bleeding, pigmentary changes, and scarring.^7,12-15 The risk of pigmentary changes is especially high in patients with skin of color.⁷ These side effects motivated the pursuit for efficacious topical therapies that minimize long-term adverse effects. Existing keratolytics (ammonium lactate, imiquimod, and tazarotene) and vitamin D analogs were examined to treat SKs, but these agents demonstrated limited efficacy in small clinical trials.^16-19

The first topical therapy to be US FDA-approved for the treatment of raised SKs is HP40 (Eskata™), a stabilized topical solution of 40% hydrogen peroxide (H₂O₂).²⁰ This therapy was approved in December 2017 based on the results of two phase 3 trials.²⁰ An earlier phase 2 dose-ranging trial additionally confirmed that HP40 was more efficacious than 32% H₂O₂ while still having a satisfactory side effect profile.^21, In this review, we will discuss the evidence for and limitations of HP40 based on these clinical trials as well as an ex vivo model of Fitzpatrick Skin Type (FST) V skin that examined HP40’s cytotoxicity.^20,22,23

Application and Mechanism

HP40 is applied by a healthcare professional with a single use pen that includes 0.7 mL of 40% H₂O₂ and can treat about seven SKs.²⁴ According to the manufacturer’s instructions, the tip of the pen is pressed to an SK and the solution is applied in a circular motion for about 20 seconds. This process is repeated up to three additional times per SK with 1 minute between each application. After 3 weeks, the SK can be re-treated if satisfactory clearance was not achieved.

The mechanism by which HP40 destroys keratinocytes is not fully elucidated, but is thought to involve H₂O₂‘s oxidizing power²¹ as both a direct oxidant and indirect oxidant through the formation of hydroxyl radicals.²⁵ When this oxidative stress overwhelms the antioxidant properties of the skin, H₂O₂ can lead to cellular destruction by damaging proteins, lipids, and nucleic acids.²⁵ Applied at a supra-physiologic concentration, a portion of the HP40 dose likely diffuses through the stratum corneum (SC) and into the epidermis.^20,21 Free radicals generated by H₂O₂ can then induce apoptosis or necrosis of seborrheic keratinocytes among other cell types (Figure 1). Given this mechanism, HP40 should not be applied to open or infected SKs; without an intact SC to act as a barrier, high concentration H₂O₂ can cause rapid death of adjacent cells (Figure 1).²⁶ Additionally, HP40 should not be applied within the orbital rim where contact with H₂O₂ can cause corneal injury.²⁴

Efficacy of HP40

In two phase 3 trials with a total of 937 patients, four raised SKs per patient were treated with either HP40 or vehicle using the previously described method (Application and Mechanism).²⁰ Three weeks later, residual SKs were re-treated. Pedunculated SKs or SKs in intertriginous areas, hair-bearing areas, or within 5 mm of the orbital rim were excluded. The therapeutic efficacy was assessed with a 4-point scale, Physician’s Lesion Assessment (PLA), developed by the manufacturer where 0 is clear, 1 is nearly clear, 2 is a thin SK with a depth of 1 mm or less, and 3 is a thick SK with a depth greater than 1 mm. The primary endpoint was complete clearance (0 on PLA) of all four SKs.²⁰

The treatment and control groups had similar demographic characteristics, with an average age of 68.7 years, and the completion rate was nearly 100% for each trial (99%, 98% per trial). At the end of the study (day 106), HP40 resulted in a significantly higher rate of complete clearance of all four SKs than vehicle; however, the rate of clearance of all four SKs with HP40 was low overall (4%, 8% per study for HP40 versus 0% for both studies for vehicle). Post hoc, the authors also calculated the mean per-patient percentage of clear/nearly clear SKs, which was higher for HP40 than vehicle (47%, 54% versus 10%, 5%, respectively).²⁰

To examine the efficacy of HP40 by location, the percentage of clear/nearly clear SKs at day 106 for each anatomic site was calculated in another study.²² A total of 1,868 SKs were treated in the HP40 group and 1,880 SKs were treated in the vehicle group; 59% of SKs were on the trunk, 30% on the face, and 11% on the extremities. The highest rate of clearance/near-clearance with HP40 treatment was observed for the face (65%), followed by the trunk (46%), and then the extremities (38%). The authors theorized that these efficacy differences may be due to variations in skin topography, such as varying water or lipid content or SC thickness. For instance, the thin SC of the face may allow enhanced penetration of HP40 compared to other anatomical sites. Another explanation proposed by the authors was that the high exposure of the face to ultraviolet radiation may impair its ability to respond to H₂O₂-induced oxidative stress.²²

Adverse Effects of HP40

In the phase 3 trials, 21% of the HP40 group and 19% of the vehicle group reported adverse effects; most were mild to moderate and all were limited to local skin reactions.²⁰ Three events related to HP40 were considered severe: application site pain, a burn from treatment, and a burning sensation. Ten minutes after HP40 application, erythema was observed in 91% of SKs and edema in 75% of SKs. By day 106, the percentage of HP40-treated SKs with erythema decreased to 10.1% and no SKs exhibited edema. Other symptoms at day 106 included scaling (8.0%), hyperpigmentation (7.8%), crusting (5.4%), hypopigmentation (3.0%), scarring (<1%), and erosion (<1%).²⁰ Examining skin reactions by anatomic location, Smith et al. found that SKs on the face showed the lowest rates of hyperpigmentation (2.3% versus 10.8% trunk, 6.9% extremities), hypopigmentation (1.9% versus 3.5% trunk, 3% extremities), and scarring (0% versus 0.6% trunk, 1% extremities).²²

While the risks of pigmentary changes and scarring at day 106 were low, especially for facial SKs, 98.8% of the study sample were FST I-IV, with only 7.3% having FST IV, so the effects on patients with FST IV or higher could not be adequately assessed.²⁰ A study by Kao et al. used an ex vivo model of human FST V skin to explore the toxicity of HP40 (1 and 2 μL) compared to cryotherapy (5- and 10-second cycles).²³ A colorimetric MTT assay was used to measure overall cytotoxicity and S100 stained-melanocytes were quantified to assess melanocyte toxicity. The authors found that HP40 was less cytotoxic overall and to melanocytes compared with cryotherapy, meaning that HP40 may cause less pigmentary changes in patients with dark skin.²³ However, clinical trials comparing the adverse effects of HP40 and cryotherapy are needed before conclusions can be drawn. Given hyperpigmentation was seen in 8% of HP40-treated SKs²⁰ and patients with darker skin are more prone to pigmentary changes,⁷ HP40 should be used cautiously in FST IV-VI patients until further research is done.

Limitations and Future Directions

HP40 was found to be superior to vehicle for the treatment of raised SKs, but its efficacy is limited overall, producing complete clearance of all four SKs in only 4% and 8% of patients per study.²⁰ As Bauman et al. discussed, patient satisfaction was not evaluated in the trials, and considering patients determine therapeutic success based on their appearances in the mirror rather than on physician-completed scales, superior results may have been observed with self-assessments.²⁰ Regardless, patients still often require repeat treatments to produce adequate SK clearance (97% of the trial participants required second treatments), which can be cost prohibitive and time intensive for patients.²⁰ HP40 is not covered by insurance and costs about $131 (US dollars) per treatment (as reported by The Medical Letter on Drugs and Therapeutics²⁴).

HP40 is also time consuming to apply for the dermatology clinic. In the clinical trials, treatment of four SKs took about 5 minutes and 20 seconds,²⁰ and this time would be almost doubled for the average of seven SKs that can be treated with each HP40 pen.²⁴ With four 20-second treatment cycles recommended per SK, this therapy is more time intensive than cryotherapy, which requires only 5 to 10 seconds of freezing for thin lesions.¹² Thicker SKs may require an additional freeze-thaw cycle with cryotherapy,¹² but this is still a shorter process than HP40 application. However, trained non-physician staff can also administer HP40, so practices can develop protocols to maximize application efficiency.

Patient Selection

When choosing a strategy for SK removal, it is important to consider the SK’s location as well as the patient’s skin type and treatment expectations. Based on the finding that HP40 is most efficacious for SKs on the face compared to the trunk and extremities, HP40 may be a good therapy to discuss with patients seeking treatment for SKs in cosmetically-sensitive areas like the face. While additional clinical studies are needed to explore this assertion, HP40 may destroy fewer melanocytes than cryotherapy, meaning that HP40 may be a potentially beneficial therapy for patients with dark skin who are susceptible to pigmentary changes with cryotherapy.⁷ On the contrary, because of the high cost of HP40 and need for repeat treatments, it is likely less useful for symptomatic SKs in non-cosmetically sensitive locations where patients desire rapid relief without as much concern about the cosmetic outcomes.

In terms of pregnancy and lactation risk, topical H₂O₂ is not systemically absorbed. Therefore, application of HP40 during pregnancy or while lactating should not result in exposure of the fetus or breastfeeding infant.²⁴

Conclusion

Given our current options for the treatment of SKs include only more invasive, non-topical therapies, HP40 fills a void in our therapeutic repertoire as the first FDA-approved topical therapy for SKs. However, this therapy has limited efficacy with 1-2 treatments, producing only about 50% clearance per patient.²⁰ Further, HP40 is expensive and can be time-intensive to apply. Nevertheless, considering HP40 produces higher clearance of SKs on the face than other anatomic locations²² and that it may be less cytotoxic to melanocytes than cryotherapy,²³ HP40 may be useful for the treatment of facial SKs. Given 92% of the phase 3 trial participants were FST I-III, further research is needed to explore the risk of pigmentary changes with HP40 in patients of FST IV or higher.

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¹The George Washington University School of Medicine and Health Sciences, Washington, DC, USA
²Department of Dermatology, The George Washington Medical Faculty Associates, Washington, DC, USA

Conflict of interest: 
Adam Friedman is currently developing a nanoparticle encapsulated cannabinoid with Zylo Therapeutics – this work is not referenced in the manuscript. Dustin Marks has no conflicts of interest to report for this work.
Funding: The George Washington Department of Dermatology received no funding in support of this manuscript.

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

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.

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.¹⁷ The 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.^5,6 In 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 Rosso²⁹ similarly 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.⁹ Specifically, 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.^33,34 Following 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 vitro and 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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