Stirring the Pot: Cannabinoids and Atopic Dermatitis

Atopic dermatitis (AD) is one of the most prevalent skin diseases, affecting up to 20 percent of the population in the developed world and with a predilection for children.¹ AD has a significant disease burden, both taxing economically and decreasing the quality of life for patients.^2,3 Although the pathophysiology of AD has been increasingly understood, functional treatments have historically lagged behind discoveries regarding the disease’s basic scientific underpinnings.⁴ Recently, several new AD therapies have been launched, and the pipeline for new therapies is more robust than ever before.

While these pharmaceutical advancements are truly exciting for both patients and clinicians, there is perhaps a greater drive in AD than in other conditions for alternative, “natural,” and unconventional treatments to circumvent some of the common side effects of long-term use. One intriguing area of the intersection between scientific discovery and natural approaches lies within the science of cannabinoids. Topical cannabinoids for itch and pain are already being marketed on the Internet but are not yet available as prescription medications from physicians without a special license; and even then, the regulatory systems limit access to only certain states.

Infamous as the main chemical agent in marijuana, delta (9)-tetrahydrocannabinol (THC), has led to a lingering stigma around cannabis because of its psychoactive properties. Perhaps as a consequence of this stigmatization and hazy legal status, research in this area has been largely overlooked until recently. Cannabinoids are a remarkable and diverse group of compounds that hold significant therapeutic capabilities applicable to many areas of medicine, including dermatology.^5,6 Since the first human cannabinoid receptors were discovered in the twentieth century, a myriad of noteworthy applications for these promising derivatives of the Cannabis plant have been discovered. Of particular interest in dermatology are their application for inflammation, the immune system, and skin homeostasis.⁷

Cannabinoids and the Endocannabinoid System

Marijuana, derived from the plant Cannabis sativa is one of the oldest and most widely used drugs in the world.⁸ Of the more than 60 agents in marijuana and five major cannabinoids, including cannabidiol (CBD), cannabichromene (CBC), cannabigerol (CBG), delta (9)-tetrahydrocannabinol (THC), and cannabinol (CBN), only THC has intoxicating effects, and this one constituent has perpetuated the stigma and contributed to its illicit status in most states in the US. This status has also created considerable hurdles to research on the use of cannabinoids as approved medicines. However, the relatively recent discovery of cannabinoid receptors and their ligands throughout the human body has led to more open discussion on their role in physiological conditions and in various pathologies. Applications for cannabis have been explored in many conditions including anorexia, chronic pain, nausea, spasticity, atherosclerosis, autoimmune disorders, inflammatory bowel disease, multiple sclerosis, and tumorigenesis.⁹ Cannabinoids have sought a place in dermatological disorders as well, including use in acne, eczematous disorders, lichen simplex, melanoma and nonmelanoma skin cancer, melasma, prurigo, pruritus, psoriasis, scleroderma and systemic sclerosis, and seborrheic dermatitis.¹⁰

The endocannabinoid system consists of cannabinoid receptors (CBRs), their lipid ligands, and regulatory enzymes. Endocannabinoids, such as arachidonoyl ethanolamide (anandamide, AEA), 2-arachidonoyl glycerol (2-AG) and palmitoylethanolamide (PEA), are synthesized endogenously.^11,12 Phytocannabinoids, such as THC and CBD are naturally produced by plants, while synthetic cannabinoids are designed in laboratories.¹³ CBRs have been found in keratinocytes and on peripheral nerve fibers, and this distribution may play an important role in skin disease therapy.¹⁴ Early research demonstrated that cannabinoids act upon CBRs, but newer studies have demonstrated their wide array of associations with other channels and receptors, such as TRPV1, GPR55, PPAR-γ, PPAR-α, as well as their direct effects on keratinocytes independent of CBRs, opening up even more potential targets in dermatological disease treatments.^15,16

Atopic Dermatitis

AD is a disease that has become increasingly prevalent in the modern world. While it has been well-established that mutations in FLG, the gene that codes for the structural protein filaggrin disrupt the skin barrier in AD,¹⁷ and that Th2 cytokines drive inflammation,¹⁸ the story does not end there. New chemokines have been implicated in inflammatory pathways of AD. For example, thymic stromal lymphopoietin (TSLP) is a protein that is highly expressed by epithelial cells of patients with AD.¹⁹ TSLP incites the Th2 response via chemokines such as IL-4, -5, -13 and TNF-α. These chemokines, in turn, up-regulate TSLP, spawning a vicious cycle.²⁰ Chemokine ligand 8 (CCL8) is another prominent inflammatory mediator which instigates a Th2-type reaction. These and other mediators promote inflammation, skin barrier dysfunction, and pruritus in AD.

Cannabinoids in Pain, Pruritus, and Atopic Dermatitis

Pruritus is signaled by a complex interaction of mediators both in the skin and the central nervous system that leads to the “itchy” sensation. It can be so profound that it can disrupt sleep quality with frequent awakenings and reduced sleep quality, which result in increased tiredness throughout the day²¹ and decreased levels of cognitive performance.²²

Many features of AD contribute to pruritus, including dry skin, histamine release, and sensory nerve fiber hypertrophy. Dry skin exacerbates pruritus by causing the release of pruritogenic mediators from keratinocytes.²³ Th2 lymphocytes of patients with AD have up-regulated histamine receptors.²⁴ Sensory nerve fiber hypertrophy is induced by growth factors released by irritated keratinocytes.²⁵

Cannabinoids, however, are potently antipruritic and work against each of these defined mechanisms and others. CBR agonists, by stimulating CB1 and CB2 receptors on sensory nerve fibers in the skin, reduce pruritus by inhibiting the release of calcitonin gene-related peptide (CGRP), a ligand known contribute to flare-reactions in AD.^26,27 Synthetic cannabinoids have also been shown to reduce pruritus via anti-histaminergic properties.²⁸ Topical PEA reduces itch by desensitizing the TRPV1 channel, an important initiator of pruritus and an integrator of other sensory phenomena such as pain and heat.²⁹ Further supporting this understanding is the fact that inhibitors of the enzymes that degrade endocannabinoids have also been shown to mitigate pruritus.³⁰ Topical cannabinoids have even helped relieve uremic pruritus, though the mechanism is unclear.³¹

Cannabinoids also exhibit anti-inflammatory properties, another important characteristic relevant to AD. Applicable to the pathophysiology of AD, Gaffal et al demonstrated that topical THC suppresses allergic contact dermatitis in mice by activating CB1 receptors.³² Notably, THC was also shown to be able to bypass CBRs entirely and directly stimulate keratinocytes to decrease inflammation.

Confusingly, however, some studies have shown that the absence of cannabinoid receptors leads to a heightened inflammatory response, suggesting a more complex role of the endocannabinoid system in modulating cutaneous inflammation. Furthermore, the absence of CB1 receptors delays skin permeability barrier recovery after exposure to irritants and also results in decreased levels of filaggrin, loricrin, and involucrin.^33,34,35

While most authors seem to acknowledge the benefit of overall increased endocannabinoid tone on inflammation, pruritus, and pain, there is some debate over whether cannabinoids mitigate inflammation or actually worsen it. For example, Ueda et al. determined that a CB2 antagonist decreased inflammation in mice.³⁶ In a similar study, a CB2 agonist exacerbated inflammation in mice.³⁷ In an equally puzzling finding, CB2 receptor-deficient mice have shown speedier recovery from skin irritants.³⁸ Thus, there may be more complex modulatory roles beyond simply being anti-inflammatory, and these nuances require more research in order to be understood.

Despite the complexities of the underlying mechanisms, there are tantalizing reports of direct improvement of AD via topical cannabinoids and CBR agonists. Nam et al. showed that CB1 receptor agonists ameliorate AD in mouse models, possibly via mast cell down-regulation.³⁹ In another rodent study, CB1 receptor activity improved AD by reducing levels of TSLP and CCL8.³⁵ Kim et al. devised a compound structurally similar to anandamide, which enhanced epidermal barrier function and suppressed Th2-biased cytokine expression in mice as well by binding CB1 receptors.⁴⁰

Human trials have also shown promising outcomes for AD. In a trial for pediatric and adult patients, a PEA-containing cream significantly reduced mean time to the next flare.⁴¹ Similarly, in a pilot study, a topical cannabinoid emulsion resulted in clinical resolution and prevented relapse of mild atopic dermatitis in 80 percent of patients.⁴² In another trial, a PEA-containing cream improved severity of itch and loss of sleep by an average of 60 percent among subjects.⁴³ Twenty percent of subjects discontinued their topical immunomodulators, 38 percent ceased using their oral antihistamines, and 33.6 percent no longer felt the need to maintain their topical steroid regimen by the end of the study.

What Lies Ahead

Cannabinoids represent an exciting prospect for the future of AD therapy. They exhibit measurable antipruritic, antinociceptive, and anti-inflammatory properties, and their use in AD has already been demonstrated. While the studies are relatively few and the responses somewhat modest, the significant disease burden of AD warrants exploration of any promising therapeutic approach. More studies are required of cannabinoids, and their widely illegal status continues to make this even more challenging. With hope, more clinical data will help open doors for this compelling group of compounds.

Conflicts of interest statement: Helena Yardley, PhD is an employee of Franklin BioScience, the manufacturer of Altus products. Peter Lio, M.D. is on the advisory board of Franklin BioScience.

1. Palmer, C. N. A. et al. Common loss-of-function variants of the epidermal barrier protein filaggrin are a major predisposing factor for atopic dermatitis. Nat. Genet. 38, 441–446 (2006).

2. Eckert L, Gupta S, Amand C, Gadkari A, Mahajan P, Gelfand JM. Impact of atopic dermatitis on health-related quality of life and productivity in adults in the United States: An analysis using the National Health and Wellness Survey. J Am Acad Dermatol. 2017 Aug;77(2):274-279.e3. doi: 10.1016/j.jaad.2017.04.019.

3.Shrestha S, Miao R, Wang L, Chao J, Yuce H, Wei W. Burden of Atopic Dermatitis in the United States: Analysis of Healthcare Claims Data in the Commercial, Medicare, and Medi-Cal Databases. Adv Ther. 2017 Jul 13.

4.Williams HC. Epidemiology of human atopic dermatitis--seven areas of notable progress and seven areas of notable ignorance. Vet Dermatol. 2013 Feb;24(1):3-9.e1-2.

5. Fitzcharles, M.-A., Baerwald, C., Ablin, J. & Hauser, W. Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases (fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis): A systematic review of randomized controlled trials. Schmerz 30, 47–61 (2016).

6.Bíró, T., Tóth, B. I., Haskó, G., Paus, R. & Pacher, P. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol. Sci. 30, 411–420 (2009).

7. Matsuda, L. a, Lolait, S. J., Brownstein, M. J., Young, a C. & Bonner, T. I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 346, 561–564 (1990).

8. Russo, E. B. History of cannabis and its preparations in saga, science, and sobriquet. Chem. Biodivers. 4, 1614–1648 (2007).

9. Goldenberg M, Reid MW, IsHak WW, Danovitch I. The impact of cannabis and cannabinoids for medical conditions on health-related quality of life: A systematic review and meta-analysis. Drug Alcohol Depend. 2017 May 1;174:80-90.

10.Mounessa JS, Siegel JA, Dunnick CA, Dellavalle RP. The role of cannabinoids in dermatology. J Am Acad Dermatol. 2017 Jul;77(1):188-190.

11.Leonti M, Casu L, Raduner S, et al. Falcarinol is a covalent cannabinoid CB1 receptor antagonist and induces pro-allergic effects in skin. Biochem Pharmacol. 2010 Jun 15;79(12):1815-26.

12. Trusler AR, Clark AK, Sivamani RK, Shi VY. The Endocannabinoid System and Its Role in Eczematous Dermatoses. Dermatitis. 2017 Jan/Feb;28(1):22-32.

13.Kupczyk P, Reich A, Szepietowski JC. Cannabinoid system in the skin - a possible target for future therapies in dermatology. Exp Dermatol. 2009 Aug;18(8):669-79.

14. Ständer S, Schmelz M, Metze D, Luger T, Rukwied R. Distribution of cannabinoid receptor 1 (CB1) and 2 (CB2) on sensory nerve fibers and adnexal structures in human skin. J Dermatol Sci. 2005 Jun;38(3):177-88.

15. Gaffal E, Cron M, Glodde N, Tüting T. Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy. 2013 Aug;68(8):994-1000.

16. Steinhoff M, Bienenstock J, Schmelz M, Maurer M, Wei E, Bíró T. Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J Invest Dermatol. 2006 Aug;126(8):1705-18.

17. Dennin M, Lio PA. Filaggrin and childhood eczema. Arch Dis Child. 2017 Dec;102(12):1101-1102. doi: 10.1136/archdischild-2017-313010. Epub 2017 Jul 22.

18. Otsuka A, Nomura T, Rerknimitr P, et al. The interplay between genetic and environmental factors in the pathogenesis of atopic dermatitis. Immunol Rev. 2017 Jul;278(1):246-262.

19.Soumelis V, Reche PA, Kanzler H, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol. 2002 Jul;3(7):673-80.

20. Bogiatzi SI, Fernandez I, Bichet JC, et al. Cutting Edge: Proinflammatory and Th2 cytokines synergize to induce thymic stromal lymphopoietin production by human skin keratinocytes. J Immunol. 2007 Mar 15;178(6):3373-7.

21. Metz M, Wahn U, Gieler U, et al. Chronic pruritus associated with dermatologic disease in infancy and childhood: update from an interdisciplinary group of dermatologists and pediatricians. Pediatr Allergy Immunol. 2013;24(6):527-39.

22. Camfferman, D., Kennedy, J. D., Gold, M., Simpson, C., & Lushington, K. (2013). Sleep and neurocognitive functioning in children with eczema. International Journal of Psychophysiology, 89(2), 265–272. https://doi.org/10.1016/j.ijpsycho.2013.01.006

23. Steinhoff M, Bienenstock J, Schmelz M, Maurer M, Wei E, Bíró T. Neurophysiological, neuroimmunological, and neuroendocrine basis of pruritus. J Invest Dermatol. 2006 Aug;126(8):1705-18.

24.Gutzmer R, Mommert S, Gschwandtner M, et al. The histamine H4 receptor is functionally expressed on T(H)2 cells. J Allergy Clin Immunol. 2009 Mar;123(3):619-25.

25. Tobin D, Nabarro G, Baart de la Faille H, et al. Increased number of immunoreactive nerve fibers in atopic dermatitis. J Allergy Clin Immunol. 1992 Oct;90(4 Pt 1):613-22.

26. Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain. 1998 Mar;75(1):111-9.

27. Ellington HC, Cotter MA, Cameron NE, Ross RA. The effect of cannabinoids on capsaicin-evoked calcitonin gene-related peptide (CGRP) release from the isolated paw skin of diabetic and non-diabetic rats. Neuropharmacology. 2002 Jun;42(7):966-75.

28. Dvorak M, Watkinson A, McGlone F, Rukwied R. Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflamm Res. 2003 Jun;52(6):238-45.

29. Vaia M, Petrosino S, De Filippis D, et al. Palmitoylethanolamide reduces inflammation and itch in a mouse model of contact allergic dermatitis. Eur J Pharmacol. 2016 Nov 15;791:669-674.

30. Schlosburg JE, Boger DL, Cravatt BF, Lichtman AH. Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus. J Pharmacol Exp Ther. 2009 apr;329(1):314-23.

31. Szepietowski JC, Szepietowski T, Reich A. Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: a preliminary study. Acta Dermatovenerol Croat. 2005;13(2):97-103.

32. Gaffal E, Cron M, Glodde N, Tüting T. Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy. 2013 Aug;68(8):994-1000.

33.Gaffal E, Cron M, Glodde N, et al. Cannabinoid 1 receptors in keratinocytes modulate proinflammatory chemokine secretion and attenuate contact allergic inflammation. J Immunol. 2013 May 15;190(10):4929-36.

34. Roelandt T, Heughebaert C, Bredif S, et al. Cannabinoid receptors 1 and 2 oppositely regulate epidermal permeability barrier status and differentiation. Exp Dermatol. 2012 Sep;21(9):688-93.

35. Gaffal E, Glodde N, Jakobs M, et al. Cannabinoid 1 receptors in keratinocytes attenuate fluorescein isothiocyanate-induced mouse atopic-like dermatitis. Exp Dermatol. 2014 Jun;23(6):401-6.

36. Ueda Y, Miyagawa N, Wakitani K. Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice. Life Sci. 2007 Jan 9;80(5):414-9. Epub 2006 Sep 30.

37. Oka S, Yanagimoto S, Ikeda S, et al. Evidence for the involvement of the cannabinoid CB2 receptor and its endogenous ligand 2-arachidonoylglycerol in 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation in mouse ear. J Biol Chem. 2005 May 6;280(18):18488-97.

38. Roelandt T, Heughebaert C, Bredif S, et al. Cannabinoid receptors 1 and 2 oppositely regulate epidermal permeability barrier status and differentiation. Exp Dermatol. 2012 Sep;21(9):688-93.

39. Nam G, Jeong SK, Park BM, et al. Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model. Ann Dermatol. 2016 Feb;28(1):22-9.

40. Kim HJ, Kim B, Park BM, et al. Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model. Int J Dermatol. 2015 Oct;54(10):e401-8.

41. Del Rosso JQ. Use of a palmitoylethanolamide-containing nonsteroidal cream for treating atopic dermatitis: impact on the duration of response and time between flares. Cosmetic Dermatol. 2007 Apr; 20(4):208-211.

42. Pulvirenti N, Nasca MR, Micali G. Topical adelmidrol 2% emulsion, a novel aliamide, in the treatment of mild atopic dermatitis in pediatric subjects: a pilot study. Acta Dermatovenerol Croat. 2007;15(2):80-3.

43. Eberlein B, Eicke C, Reinhardt HW, Ring J. Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). J Eur Acad Dermatol Venereol. 2008 Jan;22(1):73-82.