Atopic Dermatitis (AD), commonly called “eczema, is a disease of the skin characterized by dry skin, severe itching, inflammation, abnormal skin barrier function, and secondary infection. Often familial, most patients with severe AD have at least one abnormal gene for filaggrin, essential for maintaining skin hydration. AD usually onsets in childhood and its severity usually decreases with age, however, it may persist into adulthood and be very debilitating. Typically, the lesions will come and go, usually in the same areas of the skin. The lesions are inflammatory, and scratching causes the inflammation to worsen and often leads to secondary infection. Scratching is uncontrollable in most individuals but even those who can control the scratching while awake, scratch during the night. The itch in AD is does not appear to be caused by one factor, however, recent research has shown that mast cells in the skin in AD patients release compounds that: 1) stimulate nerves in the skin causing the itch sensation and 2) trigger inflammatory reactions in the skin. This scratching of the skin causes these mast cells to release more of these compounds causing the scratching and inflammation to increase leading to the development of the typical lesions seen in AD flare-ups. Recent evidence suggests prevention of the itch (and subsequent scratching) may eliminate all the signs and symptoms of the disease. This seems to be true even though the abnormalities in skin barrier function remain active. Typical anti-itch medications, including antihistamines, may provide some temporary relief but do not eliminate the itch and scratching completely. Creams and topical steroids have been shown to be helpful in treating and preventing AD, but relapses are common, and the side effects of chronic steroid use can great significant health problems.
The itching and subsequent scratching worsens the dermatitis in AD and causes the level of IgE (allergy antibodies) to increase, causing the skin to be more sensitive and react more violently to anything that person may be allergic to.1,2 Scratching causes mast cell activation which causes the release of inflammatory compounds and the opening of Transient Receptor Protein channels on the sensory nerves. When sensory nerve TRP channels open, the nerve does 2 things: 1) it sends the “itch” message to the spinal cord, 2) it releases compounds that cause inflammation, and 3) it causes the nerve to make more TRP channels.3-6 The increase in TRP channels causes more itching and inflammation, further increasing the severity of the disease. The reason that histamine doesn’t work well in AD patients is that activation of the TRP channels is what causes the majority of and the persistent itching in AD rather than histamine.7,8 Many of the TRP channels on the nerves are associated with and controlled by cannabinoid receptors.9,10 As severity of the disease increases, the TRP channels and their associated cannabinoid receptors increase together. 11 When cannabinoids bind to these receptors, they can modify the TRP channels making it harder for the nerve to be stimulated, which effectively controls the “itch” sensation.12,13 Studies have shown that CB1 receptor synthetic stimulators decrease the mast cell activation and CB2 receptor synthetic antagonists suppress the itch. 12,13 In addition to the effects of cannabinoid binding to CB1-2 receptors, CBD-like compounds that bind to G-protein coupled orphan receptors GRP55 and GRP119 inhibit itching in patients with chronic itching diseases.14 CBD has other anti-inflammatory effects which may help control the inflammation found in AD.15
Recent research has found that the itching in AD is caused by compounds that stimulate receptors in the “itch” nerves of the skin and that cannabinoids can suppress this itch. This suggests that cannabinoids may have the potential to reduce the signs and symptoms of the atopic dermatitis.
- Mihara K. et al. Vital role of the itch-scratch response in development of spontaneous dermatitis in NC/Nga mice. Br J Dermatol 2004 Aug;151(2):335-45.
- Hashimoto Y, et al. Itch-associated scratching contributes to the development of dermatitis and hyperimmunoglobulinaemia E in NC/Nga mice. Exp Dermatol. 2011 Oct;20(10):820-5.
- Wilson S, et al. TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch. Nat Neurosci 2011 May; 14(5): 595-602.
- Lui B, etal. TRPA1 controls inflammation and pruritogen responses in allergic contact dermatitis. FASEB J. 2013 Sep; 27(9): 3549–3563.
- Feng J, etal. Sensory TRP channels contribute differentially to skin inflammation and persistent itch. Nature Comm 2017;8:980.
- Sugimoto M, et al. Putative mechanism of the itch-scratch circle: repeated scratching decreases the cutaneous level of prostaglandin D2, a mediator that inhibits itching. Prostaglandins Leukot Essent Fatty Acids. 2007 Feb;76(2):93-101.
- Wilson S, et al. The Ion Channel TRPA1 Is Required for Chronic Itch. J Neurosci 2013 May; 33(22): 9283-9294
- Oh MH, et al. TRPA1-Dependent Pruruitus in IL-13-induced Chronic Atopic Dermatitis. J Immunol 2013 Dec 1; 191(11): 5371-5382.
- Ankopian AN, etal Role of ionotropic cannabinoid receptors in peripheral antinociception and antihyperalgesia. Trends Pharmacol Sci 2009; 30(2):79-84.
- Ru F, et al. Mechanisms of pruritogen-induced activation of itch nerves in isolated mouse skin. J Physiol 2017; 595(11):3651-3666.
- Ueda Y, et al. Involvement of cannabinoid CB2 receptors in the IgE-mediated triphasic cutaneous reaction in mice. Life Sci. 2007 Jan 9;80(5):414-9.
- Nam G, et al. Selective Cannabinoid Receptor-1 Agonists Regulate Mast Cell Activation in an Oxazolone-Induced Atopic Dermatitis Model. Ann Dermatol 2016: 28(1): 22-29.
- Maekawa T, et al. The cannabinoid CB2 receptor inverse agonist JTE-907 suppresses spontaneous itch-associated responses of NC mice, a model of atopic dermatitis. Eur J Pharmacol. 2006 Aug 7;542(1-3):179-83. Petrosino S, et al. Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis. J Pharmacol Exp Ther. 2018 Jun;365(3):652-663.
- Ständer S, et al. Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus. 2006 Sep;57(9):801-7.
- Biro 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): 411-420.