Cannabinoids: Potential Role in Inflammatory and Neoplastic Skin Diseases

Rose Milando; Adam Friedman

Disclosures

Am J Clin Dermatol. 2019;20(2):167-180. 

In This Article

Cannabinoids and Chronic Inflammatory Diseases of the Skin

Inflammatory skin conditions result from a number of aberrant responses of immune cells and immune signaling in the skin. Epidermal keratinocytes, lymphocytes, and dendritic cells have been found to be the key players in the skin's immune response, regulating the release of cytokines and chemokines, growth factors, and transcription factors.[61,62] Because of its role in regulating the inflammatory response of keratinocytes and dermal immune cells, the endocannabinoid system offers potential targets for management of many inflammatory skin conditions.

Psoriasis

Psoriasis is characterized by dysregulation of the skin immune system that causes marked proliferation and keratinization of epidermal cells. Overactivation of Th1 and Th17 inflammatory responses in psoriasis produces cytokines such as interleukin (IL)-17 and IL-22 that set off cascades of events resulting in increased keratinocyte proliferation, expression of keratins 6 and 16, and inflammatory cell infiltration.[63]

Activation of the endocannabinoid system in the skin reduces inflammation through a number of mechanisms, such as shifting the pro-inflammatory Th1 response to an anti-inflammatory Th2 response via CB2r activation.[20] The endocannabinoid system also plays a role in regulating keratinocyte proliferation and differentiation, which are pathologically increased in psoriasis. For example, CB1r activation by cannabinoids such as AEA inhibits keratinocyte differentiation and decreases production of keratin K6, a marker of keratinocyte hyperproliferation.[64] The potential therapeutic effects of cannabinoids in psoriasis also include activation of non-cannabinoid receptors such as GPR55, which reduces inflammation caused by NGF, and PPARα and PPARγ, which reduces epidermal hyperplasia via suppressed proliferation of keratinocytes.[25,32]

Atopic Dermatitis

In AD, histamine receptors are upregulated by Th2 lymphocytes, and irritated keratinocytes release growth factors causing hypertrophy of sensory nerve fibers.[65,66] Because cannabinoids exert both anti-inflammatory and antipruritic effects, they represent possible therapies for the treatment of AD.[67] Cannabinoids stimulate CB1r and CB2r on sensory nerve fibers and inhibit calcitonin gene-related peptide (CGRP), a mediator of pruritus and flares in AD.[68,69] CB1r activation also works to maintain epidermal barrier homeostasis, diminish Th2 inflammatory response, and downregulate mast cell activation.[70–72]

Use of topical PEA and cannabinoid emulsions increased the time between flares and reduced relapses in human trials of patients with AD[73,74] (Table 1). PEA exerts its anti-inflammatory effects via direct binding to PPARα and via interaction with the endocannabinoid system.[52,75] PEA is thought to play a role in decreasing symptoms of pruritus[76] and ACD, eczematous dermatitis, and AD by limiting mast cell infiltration and angiogenesis.[70,77]

Contact Dermatitis

ACD is a T cell-mediated type IV delayed hypersensitivity reaction that occurs after a patient is sensitized to an allergen. The resulting release of pro-inflammatory cytokines causes the eczematous skin reaction seen in ACD.[78] By regulating the levels of these cytokines, the endocannabinoid system is able to modulate inflammation in experimental models of ACD.[79] In an in vitro experimental model of ACD, administration of cannabidiol increased levels of AEA and decreased release of pro-inflammatory cytokines and chemokines monocyte chemoattractant protein (MCP)-2, IL-6, IL-8, and tumor necrosis factor (TNF)-α via CB2r and TRPV1.[79] In a mouse model of ACD, CB1r- and CB2r-deficient mice displayed an intensified allergic response, whereas the allergic response was diminished in FAAH-deficient mice, further suggesting that activation of the endocannabinoid system works to attenuate inflammation in this disease model.[80] Although these data were produced from experimental models, the results indicate that activation of the endocannabinoid system is a therapeutic avenue to explore for patients with ACD.

Dermatomyositis

Dermatomyositis is a chronic inflammatory condition affecting the connective tissue in muscles and the skin. The predominant inflammatory cytokines produced in dermatomyositis are TNF-α and type 1 interferons.[81–83] In a study analyzing peripheral blood samples from 18 patients with dermatomyositis, treatment with AJA significantly reduced the levels of pro-inflammatory cytokines TNF-α and type 1 interferons.[84] A recently completed phase II clinical trial (ClinicalTrials.gov identifier: NCT02466243) found that subjects with refractory dermatomyositis who received escalating doses of AJA showed statistically significant improvement in Cutaneous Dematomyositis Disease Area and Severity Index (CDASI) scores by 4 weeks.[85,86] This study and others will hopefully lead to the production of FDA-approved cannabinoid therapies for this inflammatory condition.

Scleroderma

Scleroderma, or systemic sclerosis, is a group of diseases characterized by inflammation and vascular injury in the early stages and fibrosis in the skin and numerous internal organs in later stages.[87] The endocannabinoid system's role in modulating skin immunity, inflammation, cell death, and vasomotor response suggests it could be utilized to regulate inflammation and fibrosis formation in scleroderma.[88] In a mouse model of chemically induced scleroderma, synthetic cannabinoid receptor agonists WIN-55,212 and JWH-113 caused a decrease in dermal thickness and collagen deposition and slowed the rate of fibroblast proliferation.[89] Similarly, in another mouse model, activation of both CB2r and PPARγ resulted in reduced collagen accumulation in blood vessels, decreased dermal thickness, and prevention of macrophage infiltration and mast cell degranulation.[87] In a recently completed clinical trial (ClinicalTrials.gov identifier: NCT02465437), the 42 subjects with systemic sclerosis who received JBT-101 (AJA) had greater improvement in Combined Response Index Systemic Sclerosis (CRISS) scores than did controls (p = 0.044).[90] Recently, the FDA approved a phase III clinical trial assessing AJA efficacy and safety in systemic sclerosis (ClinicalTrials.gov identifier: NCT03398837).[91] The advancement of these clinical trials suggests that cannabinoids such as AJA may represent viable treatment options for patients with systemic sclerosis.

Seborrheic Dermatitis

Seborrheic dermatitis is a condition characterized by scaling, erythema, and pruritus, thought to be triggered by an inflammatory reaction to Malassezia yeast species.[92] To assess the use of cannabinoids in acne and seborrheic dermatitis, Ali and Akhtar[93] treated 11 patients with a 3% Cannabis seeds cream and found a significant reduction in erythema and sebum production compared with control. A current clinical trial assessing the efficacy of cannabidiol in treating tremor in Parkinson's disease (ClinicalTrials.gov identifier: NCT02818777) is also currently assessing the efficacy of cannabidiol in treating seborrheic dermatitis.[94–96] Because seborrheic dermatitis can cause significant patient discomfort and impact quality of life, cannabinoids offer an exciting new direction in treatment options.

Epidermolysis Bullosa

Epidermolysis bullosa (EB) is a group of genetic blistering disorders characterized by fragile skin that is susceptible to painful blistering and erosion after minor trauma.[97] EB subtypes are defined by specific mutations in genes encoding for several structural and attachment proteins such as keratins, laminins, and collagens.[98] Cannabinoids show therapeutic promise in EB for their ability to modulate levels of keratins and to dampen the inflammatory response that contributes to the pain and pruritus seen in EB.[99–101] In one observational study of three patients with EB who self-initiated cannabidiol treatment (including oil, cream, and spray), all three patients reported significant reduction of pain and blistering and increased wound healing.[97] Another study followed three patients with EB who were prescribed increasing doses of a sublingual preparation of cannabidiol 20 mg/mL and THC 13 mg/mL.[101] Similarly, all three patients reported treatment-related amelioration of pain and pruritus symptoms.[101] Albeit limited, these reports on the role of cannabinoid treatment in EB highlight an intriguing new area of research that will benefit from expansion into clinical trials.

Cutaneous Graft-versus-host Disease

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplants. In patients with GVHD, cutaneous GVHD is a common early manifestation of disease process.[102] The morbilliform eruption seen in cutaneous GVHD is a result of activated donor T-cell lymphocytes attacking and destroying recipient keratinocytes.[102] Because of their ability to modulate lymphocyte proliferation and cytokine release, cannabinoids have been proposed as therapeutic agents to help prevent GVHD presentation in the skin. In a prospective study of 48 patients receiving hematopoietic cell transplantation from either 10/10 human leukocyte antigen (HLA)-matched or 1-antigen-mismatched related or unrelated donors, patients received oral 2.5% cannabidiol solution 125 g in olive oil twice daily alongside a standard GVHD prophylaxis regimen.[103] Although there was no significant difference in overall risk for developing GVHD in the experimental subjects, this study showed that skin involvement occurred significantly less often in patients treated with cannabidiol than in controls.[103] In a mouse model of GVHD, daily intraperitoneal THC treatment significantly increased the survival of allogeneic skin grafts in a CB1r-dependent fashion, although a separate in vitro model suggested a CB2rdependent mechanism of skin graft survival.[104,105] These studies and others point toward a possible therapeutic indication for cannabinoids in regulating and protecting the skin environment in GVHD, although the mechanisms need further elucidation.

Acne

Acne is a common skin condition that involves inflammation and overproduction of sebum in sebaceous glands. The endocannabinoid system exerts anti-inflammatory properties and can regulate key functions such as growth, proliferation, and differentiation of a number of cell types in the skin, including sebocytes.[106,107] As such, numerous studies have investigated the role of the endocannabinoid system in acne. In a 2014 study, Oláh et al.[57] found that cannabidiol suppressed cell proliferation and reduced production of sebum and pro-inflammatory cytokine elevation caused by "pro-acne agents" via TRPV activation in an in vitro study using SZ95 sebocytes. In a 2016 study, Oláh et al.[57] expanded their previous study to include an evaluation of the role of additional phytocannabinoids such as cannabichromene (CBC), cannabidivarin (CBDV), and Δ9-tetrahydrocannabivarin (THVC) in an experimental in vitro acne model using SZ95 sebocytes.[108] They found that all tested phytocannabinoids exerted anti-inflammatory actions, whereas CBC, CBDV, and THCV were able to reduce acne-like lipogenesis caused by arachidonic acid, and THCV was able to suppress sebocyte proliferation.[108] In the human study referenced above for seborrheic dermatitis, Ali and Akhtar[93] found a significant reduction in sebum production in 11 patients with a 3% Cannabis seeds cream compared with control. Cannabinoids should be considered as possible therapeutic agents in future clinical trials for treating the underlying mechanisms of inflammation and increased sebum production in acne.

Pyoderma Gangrenosum

Pyoderma gangrenosum (PG) is a rare dermatosis thought to be associated with dysregulated neutrophilic and T-cell immune function, which classically leads to painful ulceration.[109,110] The treatment options for PG generally consist of local wound care, systemic corticosteroids or immunosuppression, and opioids for pain management.[110,111] In a prospective case study of three patients with PG, topical THC + cannabidiol oil (either THC 5 mg/mL + cannabidiol 6 mg/mL or THC 7 mg/mL + cannabidiol 9 mg/mL) was applied to the patients' wound beds daily.[112] Two of the three patients reported statistically significant analgesia and subsequent reduction of daily opioids.[112] However, the molecular mechanism underlying this analgesic effect of cannabinoid treatment was not explored, and additional literature on the subject is limited. Hopefully, further research and clinical trials can expand on this promising area.

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