Cannabinoids: Potential Role in Inflammatory and Neoplastic Skin Diseases

Abstract

The endocannabinoid system is a complex and nearly ubiquitous network of endogenous ligands, enzymes, and receptors that can also be stimulated by exogenous compounds such as those derived from the marijuana plant, Cannabis sativa. Recent data have shown that the endocannabinoid system is fully functional in the skin and is responsible for maintaining many aspects of skin homeostasis, such as proliferation, differentiation, and release of inflammatory mediators. Because of its role in regulating these key processes, the endocannabinoid system has been studied for its modulating effects on both inflammatory disorders of the skin and skin cancer. Although legal restrictions on marijuana as a Schedule I drug in the USA have made studying cannabinoid compounds unfavorable, an increasing number of studies and clinical trials have focused on the therapeutic uses of cannabinoids. This review seeks to summarize the current, and rapidly expanding field of research on the broad potential uses of cannabinoids in inflammatory and neoplastic diseases of the skin.

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References

  1. 1.

    US Drug Enforcement Administration. Drug scheduling. 2018. https://www.dea.gov/druginfo/ds.shtml. Accessed 11 Jul 2018.

  2. 2.

    Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry. 2012;38:4–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    US Food and Drug Administration. FDA and Marijuana: Questions and Answers. 2018. https://www.fda.gov/newsevents/publichealthfocus/ucm421168.htm. Accessed 9 Sep 2018.

  4. 4.

    US Food and Drug Administration. FDA approves first drug comprised of an active ingredient derived from marijuana to treat rare, severe forms of epilepsy. 2018. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm611046.htm. Accessed 11 Jul 2018.

  5. 5.

    Klein TW. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005;5:400–11.

    Article  CAS  PubMed  Google Scholar 

  6. 6.

    Khan MI, Sobocińska AA, Brodaczewska KK, Zielniok K, Gajewska M, Kieda C, et al. Involvement of the CB2 cannabinoid receptor in cell growth inhibition and G0/G1 cell cycle arrest via the cannabinoid agonist WIN 55,212-2 in renal cell carcinoma. BMC Cancer. 2018;18:583.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Pacher P, Bátkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Bíró T, Tóth BI, Haskó G, Paus R, Pacher P. The endocannabinoid system of the skin in health and disease: novel perspectives and therapeutic opportunities. Trends Pharmacol Sci. 2009;30:411–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Devane WA, Dysarz FA, Johnson MR, Melvin LS, Howlett AC. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–13.

    CAS  PubMed  Google Scholar 

  10. 10.

    Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365:61–5.

    Article  CAS  PubMed  Google Scholar 

  11. 11.

    Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci. 2012;367:3353–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Schlicker E, Kathmann M. Modulation of transmitter release via presynaptic cannabinoid receptors. Trends Pharmacol Sci. 2001;22:565–72.

    Article  CAS  PubMed  Google Scholar 

  13. 13.

    Christie MJ, Vaughan CW. Neurobiology: cannabinoids act backwards. Nature. 2001;410:527–30.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Szabo B, Siemes S, Wallmichrath I. Inhibition of GABAergic neurotransmission in the ventral tegmental area by cannabinoids. Eur J Neurosci. 2002;15:2057–61.

    Article  PubMed  Google Scholar 

  15. 15.

    Rodríguez-Muñoz M, Sánchez-Blázquez P, Merlos M, Garzón-Niño J. Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction. Oncotarget. 2016;7:55840–62.

    Article  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Pisanti S, Picardi P, D’Alessandro A, Laezza C, Bifulco M. The endocannabinoid signaling system in cancer. Trends Pharmacol Sci. 2013;34:273–82.

    Article  CAS  PubMed  Google Scholar 

  17. 17.

    Pisanti S, Malfitano AM, Grimaldi C, Santoro A, Gazzerro P, Laezza C, et al. Use of cannabinoid receptor agonists in cancer therapy as palliative and curative agents. Best Pract Res Clin Endocrinol Metab. 2009;23:117–31.

    Article  CAS  PubMed  Google Scholar 

  18. 18.

    Mackie K. Cannabinoid receptors: where they are and what they do. J Neuroendocrinol. 2008;20(Suppl 1):10–4.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Caterina MJ. TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation. ACS Chem Neurosci. 2014;5:1107–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Cabral GA, Griffin-Thomas L. Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation. Expert Rev Mol Med. 2009;11:e3.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Marzo VD, Petrocellis LD, Fezza F, Ligresti A, Bisogno T. Anandamide receptors. Prostaglandins Leukot Essent Fatty Acids. 2002;66:377–91.

    Article  PubMed  Google Scholar 

  22. 22.

    Pistis M, O’Sullivan SE. The role of nuclear hormone receptors in cannabinoid function. Adv Pharmacol. 2017;80:291–328.

    Article  PubMed  CAS  Google Scholar 

  23. 23.

    Sertznig P, Reichrath J. Peroxisome proliferator-activated receptors (PPARs) in dermatology: challenge and promise. Dermatoendocrinol. 2011;3:130–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    O’Sullivan SE. An update on PPAR activation by cannabinoids. Br J Pharmacol. 2016;173:1899–910.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Sertznig P, Seifert M, Tilgen W, Reichrath J. Peroxisome proliferator-activated receptors (PPARs) and the human skin: importance of PPARs in skin physiology and dermatologic diseases. Am J Clin Dermatol. 2008;9:15–31.

    Article  PubMed  Google Scholar 

  26. 26.

    Gupta M, Mahajan VK, Mehta KS, Chauhan PS, Rawat R. Peroxisome proliferator-activated receptors (PPARs) and PPAR agonists: the “future” in dermatology therapeutics? Arch Dermatol Res. 2015;307:767–80.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, et al. The concise guide to PHARMACOLOGY 2013/14: G protein-coupled receptors. Br J Pharmacol. 2013;170:1459–581.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Zubrzycki M, Liebold A, Janecka A, Zubrzycka M. A new face of endocannabinoids in pharmacotherapy. Part I: protective role of endocannabinoids in hypertension and myocardial infarction. J Physiol Pharmacol. 2014;65:171–81.

    CAS  PubMed  Google Scholar 

  29. 29.

    Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson N-O, Leonova J, et al. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol. 2007;152:1092–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Adinolfi B, Romanini A, Vanni A, Martinotti E, Chicca A, Fogli S, et al. Anticancer activity of anandamide in human cutaneous melanoma cells. Eur J Pharmacol. 2013;718:154–9.

    Article  CAS  PubMed  Google Scholar 

  31. 31.

    Munawar N, Oriowo MA, Masocha W. Antihyperalgesic activities of endocannabinoids in a mouse model of antiretroviral-induced neuropathic pain. Front Pharmacol. 2017;8:136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Cantarella G, Scollo M, Lempereur L, Saccani-Jotti G, Basile F, Bernardini R. Endocannabinoids inhibit release of nerve growth factor by inflammation-activated mast cells. Biochem Pharmacol. 2011;82:380–8.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Pincelli C. Nerve growth factor and keratinocytes: a role in psoriasis. Eur J Dermatol. 2000;10:85–90.

    CAS  PubMed  Google Scholar 

  34. 34.

    Zygmunt PM, Petersson J, Andersson DA, Chuang H, Sørgård M, Di Marzo V, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature. 1999;400:452–7.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Ständer S, Moormann C, Schumacher M, Buddenkotte J, Artuc M, Shpacovitch V, et al. Expression of vanilloid receptor subtype 1 in cutaneous sensory nerve fibers, mast cells, and epithelial cells of appendage structures. Exp Dermatol. 2004;13:129–39.

    Article  PubMed  Google Scholar 

  36. 36.

    Tóth BI, Benko S, Szöllosi AG, Kovács L, Rajnavölgyi E, Bíró T. Transient receptor potential vanilloid-1 signaling inhibits differentiation and activation of human dendritic cells. FEBS Lett. 2009;583:1619–24.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Denda M, Fuziwara S, Inoue K, Denda S, Akamatsu H, Tomitaka A, et al. Immunoreactivity of VR1 on epidermal keratinocyte of human skin. Biochem Biophys Res Commun. 2001;285:1250–2.

    Article  CAS  PubMed  Google Scholar 

  38. 38.

    Bodó E, Bíró T, Telek A, Czifra G, Griger Z, Tóth BI, et al. A hot new twist to hair biology: involvement of vanilloid receptor-1 (VR1/TRPV1) signaling in human hair growth control. Am J Pathol. 2005;166:985–98.

    Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Denda M, Sokabe T, Fukumi-Tominaga T, Tominaga M. Effects of skin surface temperature on epidermal permeability barrier homeostasis. J Investig Dermatol. 2007;127:654–9.

    Article  CAS  PubMed  Google Scholar 

  40. 40.

    Sulk M, Seeliger S, Aubert J, Schwab VD, Cevikbas F, Rivier M, et al. Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. J Investig Dermatol. 2012;132:1253–62.

    Article  CAS  PubMed  Google Scholar 

  41. 41.

    Lee YM, Kang SM, Lee SR, Kong KH, Lee JY, Kim EJ, et al. Inhibitory effects of TRPV1 blocker on UV-induced responses in the hairless mice. Arch Dermatol Res. 2011;303:727–36.

    Article  CAS  PubMed  Google Scholar 

  42. 42.

    Tóth BI, Dobrosi N, Dajnoki A, Czifra G, Oláh A, Szöllosi AG, et al. Endocannabinoids modulate human epidermal keratinocyte proliferation and survival via the sequential engagement of cannabinoid receptor-1 and transient receptor potential vanilloid-1. J Investig Dermatol. 2011;131:1095–104.

    Article  CAS  PubMed  Google Scholar 

  43. 43.

    Fioravanti B, De Felice M, Stucky CL, Medler KA, Luo M-C, Gardell LR, et al. Constitutive activity at the cannabinoid CB1 receptor is required for behavioral response to noxious chemical stimulation of TRPV1: antinociceptive actions of CB1 inverse agonists. J Neurosci. 2008;28:11593–602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873–84.

    Article  CAS  PubMed  Google Scholar 

  45. 45.

    Sugiura T, Kobayashi Y, Oka S, Waku K. Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins Leukot Essent Fatty Acids. 2002;66:173–92.

    Article  CAS  PubMed  Google Scholar 

  46. 46.

    Zurier RB, Burstein SH. Cannabinoids, inflammation, and fibrosis. FASEB J. 2016;30:3682–9.

    Article  CAS  PubMed  Google Scholar 

  47. 47.

    Gaffuri A-L, Ladarre D, Lenkei Z. Type-1 cannabinoid receptor signaling in neuronal development. Pharmacology. 2012;90:19–39.

    Article  CAS  PubMed  Google Scholar 

  48. 48.

    Mechoulam R, Hanuš LO, Pertwee R, Howlett AC. Early phytocannabinoid chemistry to endocannabinoids and beyond. Nat Rev Neurosci. 2014;15:757–64.

    Article  CAS  PubMed  Google Scholar 

  49. 49.

    Bisogno T, Melck D, Bobrov MY, Gretskaya NM, Bezuglov VV, De Petrocellis L, et al. N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J. 2000;351(Pt 3):817–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Ross RA. Anandamide and vanilloid TRPV1 receptors. Br J Pharmacol. 2003;140:790–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Oláh A, Ambrus L, Nicolussi S, Gertsch J, Tubak V, Kemény L, et al. Inhibition of fatty acid amide hydrolase exerts cutaneous anti-inflammatory effects both in vitro and in vivo. Exp Dermatol. 2016;25:328–30.

    Article  PubMed  Google Scholar 

  52. 52.

    Guida F, Luongo L, Boccella S, Giordano ME, Romano R, Bellini G, et al. Palmitoylethanolamide induces microglia changes associated with increased migration and phagocytic activity: involvement of the CB2 receptor. Sci Rep. 2017;7:375.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Costa B, Comelli F, Bettoni I, Colleoni M, Giagnoni G. The endogenous fatty acid amide, palmitoylethanolamide, has anti-allodynic and anti-hyperalgesic effects in a murine model of neuropathic pain: involvement of CB1, TRPV1 and PPARγ receptors and neurotrophic factors. Pain. 2008;139:541–50.

    Article  CAS  PubMed  Google Scholar 

  54. 54.

    Morales P, Hurst DP, Reggio PH. Molecular targets of the phytocannabinoids: a complex picture. Prog Chem Org Nat Prod. 2017;103:103–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Khilnani G, Khilnani AK. Inverse agonism and its therapeutic significance. Indian J Pharmacol. 2011;43:492–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Pucci M, Rapino C, Di Francesco A, Dainese E, D’Addario C, Maccarrone M. Epigenetic control of skin differentiation genes by phytocannabinoids. Br J Pharmacol. 2013;170:581–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Oláh A, Tóth BI, Borbíró I, Sugawara K, Szöllõsi AG, Czifra G, et al. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J Clin Investig. 2014;124:3713–24.

    Article  CAS  PubMed  Google Scholar 

  58. 58.

    Tepper MA, Zurier RB, Burstein SH. Ultrapure ajulemic acid has improved CB2 selectivity with reduced CB1 activity. Bioorg Med Chem. 2014;22:3245–51.

    Article  CAS  PubMed  Google Scholar 

  59. 59.

    Burstein S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J. 2005;7:E143–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Hillard CJ, Liu Q. Endocannabinoid signaling in the etiology and treatment of major depressive illness. Curr Pharm Des. 2014;20:3795–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Mahajan R, Handa S. Pathophysiology of psoriasis. Indian J Dermatol Venereol Leprol. 2013;79(Suppl 7):S1–9.

    PubMed  Google Scholar 

  62. 62.

    Johnson-Huang LM, McNutt NS, Krueger JG, Lowes MA. Cytokine-producing dendritic cells in the pathogenesis of inflammatory skin diseases. J Clin Immunol. 2009;29:247–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Ogawa E, Sato Y, Minagawa A, Okuyama R. Pathogenesis of psoriasis and development of treatment. J Dermatol. 2018;45:264–72.

    Article  CAS  PubMed  Google Scholar 

  64. 64.

    Maccarrone M, Di Rienzo M, Battista N, Gasperi V, Guerrieri P, Rossi A, et al. The endocannabinoid system in human keratinocytes: evidence that anandamide inhibits epidermal differentiation through CB1 receptor-dependent inhibition of protein kinase C, activating protein-1, and transglutaminase. J Biol Chem. 2003;278:33896–903.

    Article  CAS  PubMed  Google Scholar 

  65. 65.

    Gutzmer R, Mommert S, Gschwandtner M, Zwingmann K, Stark H, Werfel T. The histamine H4 receptor is functionally expressed on T(H)2 cells. J Allergy Clin Immunol. 2009;123:619–25.

    Article  CAS  PubMed  Google Scholar 

  66. 66.

    Tobin D, Nabarro G, de la Faille HB, van Vloten WA, van der Putte SC, Schuurman HJ. Increased number of immunoreactive nerve fibers in atopic dermatitis. J Allergy Clin Immunol. 1992;90:613–22.

    Article  CAS  PubMed  Google Scholar 

  67. 67.

    Trusler AR, Clark AK, Sivamani RK, Shi VY. The endocannabinoid system and its role in eczematous dermatoses. Dermatitis. 2017;28:22–32.

    Article  CAS  PubMed  Google Scholar 

  68. 68.

    Shalaby M, Yardley H, Lio PA. Stirring the pot: cannabinoids and atopic dermatitis. Pract Dermatol. 2018;68–70. http://practicaldermatology.com/2018/01/stirring-the-pot-cannabinoids-and-atopic-dermatitis/. Accessed 11 Jul 2018.

  69. 69.

    Engel MA, Izydorczyk I, Mueller-Tribbensee SM, Becker C, Neurath MF, Reeh PW. Inhibitory CB1 and activating/desensitizing TRPV1-mediated cannabinoid actions on CGRP release in rodent skin. Neuropeptides. 2011;45:229–37.

    Article  CAS  PubMed  Google Scholar 

  70. 70.

    Gaffal E, Glodde N, Jakobs M, Bald T, Tüting T. Cannabinoid 1 receptors in keratinocytes attenuate fluorescein isothiocyanate-induced mouse atopic-like dermatitis. Exp Dermatol. 2014;23:401–6.

    Article  CAS  PubMed  Google Scholar 

  71. 71.

    Nam G, Jeong SK, Park BM, Lee SH, Kim HJ, Hong S-P, et al. Selective cannabinoid receptor-1 agonists regulate mast cell activation in an oxazolone-induced atopic dermatitis model. Ann Dermatol. 2016;28:22–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Kim HJ, Kim B, Park BM, Jeon JE, Lee SH, Mann S, et al. Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model. Int J Dermatol. 2015;54:e401–8.

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    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;20(4):208–11.

    Google Scholar 

  74. 74.

    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;15:80–3.

    CAS  PubMed  Google Scholar 

  75. 75.

    Hesselink JMK. Evolution in pharmacologic thinking around the natural analgesic palmitoylethanolamide: from nonspecific resistance to PPAR-α agonist and effective nutraceutical. J Pain Res. 2013;6:625–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Ständer S, Reinhardt HW, Luger TA. Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus. Hautarzt. 2006;57:801–7.

    Article  PubMed  Google Scholar 

  77. 77.

    Vaia M, Petrosino S, De Filippis D, Negro L, Guarino A, Carnuccio R, et al. Palmitoylethanolamide reduces inflammation and itch in a mouse model of contact allergic dermatitis. Eur J Pharmacol. 2016;791:669–74.

    Article  CAS  PubMed  Google Scholar 

  78. 78.

    Jakasa I, Thyssen JP, Kezic S. The role of skin barrier in occupational contact dermatitis. Experimental Dermatol. 2018;27(8). https://onlinelibrary.wiley.com/doi/abs/10.1111/exd.13704. Accessed 11 Jul 2018.

  79. 79.

    Petrosino S, Verde R, Vaia M, Allarà M, Iuvone T, Di Marzo V. Anti-inflammatory properties of cannabidiol, a nonpsychotropic cannabinoid, in experimental allergic contact dermatitis. J Pharmacol Exp Ther. 2018;365:652–63.

    Article  CAS  PubMed  Google Scholar 

  80. 80.

    Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt J, Petrosino S, et al. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science. 2007;316:1494–7.

    Article  CAS  PubMed  Google Scholar 

  81. 81.

    Kim JS, Bashir MM, Werth VP. Gottron’s papules exhibit dermal accumulation of CD44 variant 7 (CD44v7) and its binding partner osteopontin: a unique molecular signature. J Investig Dermatol. 2012;132:1825–32.

    Article  CAS  PubMed  Google Scholar 

  82. 82.

    Nabatian AS, Bashir MM, Wysocka M, Sharma M, Werth VP. Tumor necrosis factor α release in peripheral blood mononuclear cells of cutaneous lupus and dermatomyositis patients. Arthritis Res Ther. 2012;14:R1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Pachman LM, Liotta-Davis MR, Hong DK, Kinsella TR, Mendez EP, Kinder JM, et al. TNFalpha-308A allele in juvenile dermatomyositis: association with increased production of tumor necrosis factor alpha, disease duration, and pathologic calcifications. Arthritis Rheum. 2000;43:2368–77.

    Article  CAS  PubMed  Google Scholar 

  84. 84.

    Robinson ES, Alves P, Bashir MM, Zeidi M, Feng R, Werth VP. Cannabinoid reduces inflammatory cytokines, tumor necrosis factor-α, and type i interferons in dermatomyositis in vitro. J Investig Dermatol. 2017;137:2445–7.

    Article  CAS  PubMed  Google Scholar 

  85. 85.

    Safety, Tolerability, and Efficacy of JBT-101 in Subjects With Dermatomyositis—full text view—ClinicalTrials.gov [Internet]. 2018. https://clinicaltrials.gov/ct2/show/NCT02466243. Accessed 13 Jul 2018.

  86. 86.

    A Phase 2 Study of Safety and Efficacy of Anabasum (JBT-101), a Cannabinoid Receptor Type 2 Agonist, in Refractory Skin-Predominant Dermatomyositis. ACR Meeting Abstracts. 2017. https://acrabstracts.org/abstract/a-phase-2-study-of-safety-and-efficacy-of-anabasum-jbt-101-a-cannabinoid-receptor-type-2-agonist-in-refractory-skin-predominant-dermatomyositis/. Accessed 9 Sept 2018.

  87. 87.

    del Río C, Navarrete C, Collado JA, Bellido ML, Gómez-Cañas M, Pazos MR, et al. The cannabinoid quinol VCE-004.8 alleviates bleomycin-induced scleroderma and exerts potent antifibrotic effects through peroxisome proliferator-activated receptor-γ and CB2 pathways. Sci Rep. 2016;6:21703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Garcia-Gonzalez E, Selvi E, Balistreri E, Lorenzini S, Maggio R, Natale M-R, et al. Cannabinoids inhibit fibrogenesis in diffuse systemic sclerosis fibroblasts. Rheumatology (Oxford). 2009;48:1050–6.

    Article  CAS  Google Scholar 

  89. 89.

    Servettaz A, Kavian N, Nicco C, Deveaux V, Chéreau C, Wang A, et al. Targeting the cannabinoid pathway limits the development of fibrosis and autoimmunity in a mouse model of systemic sclerosis. Am J Pathol. 2010;177:187–96.

    Article  PubMed  PubMed Central  Google Scholar 

  90. 90.

    A Phase 2 Study of Safety and Efficacy of Anabasum (JBT-101), a Cannabinoid Receptor Type 2 Agonist, in Diffuse Cutaneous Systemic Sclerosis. ACR Meeting Abstracts. 2017. https://acrabstracts.org/abstract/a-phase-2-study-of-safety-and-efficacy-of-anabasum-jbt-101-a-cannabinoid-receptor-type-2-agonist-in-diffuse-cutaneous-systemic-sclerosis/. Accessed 11 Jul 2018.

  91. 91.

    Trial to evaluate efficacy and safety of lenabasum in diffuse cutaneous systemic sclerosis—full text view—ClinicalTrials.gov. 2018. https://clinicaltrials.gov/ct2/show/NCT03398837. Accessed 13 Jul 2018.

  92. 92.

    Clark GW, Pope SM, Jaboori KA. Diagnosis and treatment of seborrheic dermatitis. Am Fam Physician. 2015;91:185–90.

    PubMed  Google Scholar 

  93. 93.

    Ali A, Akhtar N. The safety and efficacy of 3% Cannabis seeds extract cream for reduction of human cheek skin sebum and erythema content. Pak J Pharm Sci. 2015;28:1389–95.

    CAS  PubMed  Google Scholar 

  94. 94.

    A study of tolerability and efficacy of cannabidiol on tremor in Parkinson’s disease—full text view—ClinicalTrials.gov. 2017. https://clinicaltrials.gov/ct2/show/NCT02818777. Accessed 9 Sept 2018.

  95. 95.

    Arsic Arsenijevic VS, Milobratovic D, Barac AM, Vekic B, Marinkovic J, Kostic VS. A laboratory-based study on patients with Parkinson’s disease and seborrheic dermatitis: the presence and density of Malassezia yeasts, their different species and enzymes production. BMC Dermatol. 2014;14:5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Heineman K. Marijuana may help solve skin rash sting. Inside science. 2018. https://www.insidescience.org/video/marijuana-may-help-solve-skin-rash-sting. Accessed 9 Sept 2018.

  97. 97.

    Chelliah MP, Zinn Z, Khuu P, Teng JMC. Self-initiated use of topical cannabidiol oil for epidermolysis bullosa. Pediatr Dermatol. 2018;35:e224–7.

    Article  PubMed  Google Scholar 

  98. 98.

    National Center for Advancing Translational Science. Genetic and Rare Diseases Information Center (GARD). Epidermolysis bullosa. 2018. https://rarediseases.info.nih.gov/diseases/6359/epidermolysis-bullosa. Accessed 28 Oct 2018.

  99. 99.

    Ramot Y, Sugawara K, Zákány N, Tóth BI, Bíró T, Paus R. A novel control of human keratin expression: cannabinoid receptor 1-mediated signaling down-regulates the expression of keratins K6 and K16 in human keratinocytes in vitro and in situ. PeerJ. 2013;1:e40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Ramot Y, Oláh A, Paus R. Cover image: neuroendocrine treatment of inherited keratin disorders by cannabinoids? Br J Dermatol. 2018;178:1469.

    Article  CAS  PubMed  Google Scholar 

  101. 101.

    Schräder NHB, Duipmans JC, Molenbuur B, Wolff A, Jonkman MF. Combined THC and CBD to treat pain in epidermolysis bullosa: a report of three cases. Br J Dermatol. 2018. http://onlinelibrary.wiley.com/doi/abs/10.1111/bjd.17341. Accessed 28 Oct 2018.

  102. 102.

    Villarreal CDV, Alanis JCS, Pérez JCJ, Candiani JO. Cutaneous graft-versus-host disease after hematopoietic stem cell transplant—a review. An Bras Dermatol. 2016;91:336–43.

    Article  PubMed  PubMed Central  Google Scholar 

  103. 103.

    Yeshurun M, Shpilberg O, Herscovici C, Shargian L, Dreyer J, Peck A, et al. Cannabidiol for the prevention of graft-versus-host-disease after allogeneic hematopoietic cell transplantation: results of a phase II study. Biol Blood Marrow Transplant. 2015;21:1770–5.

    Article  CAS  PubMed  Google Scholar 

  104. 104.

    Sido JM, Nagarkatti PS, Nagarkatti M. Δ9-Tetrahydrocannabinol attenuates allogeneic host-versus-graft response and delays skin graft rejection through activation of cannabinoid receptor 1 and induction of myeloid-derived suppressor cells. J Leukoc Biol. 2015;98:435–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. 105.

    Robinson RH, Meissler JJ, Breslow-Deckman JM, Gaughan J, Adler MW, Eisenstein TK. Cannabinoids inhibit T-cells via cannabinoid receptor 2 in an in vitro assay for graft rejection, the mixed lymphocyte reaction. J Neuroimmune Pharmacol. 2013;8:1239–50.

    Article  PubMed  Google Scholar 

  106. 106.

    Szöllősi AG, Oláh A, Bíró T, Tóth BI. Recent advances in the endocrinology of the sebaceous gland. Dermatoendocrinol. 2018;9. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5821152/. Accessed 29 Oct 2018.

  107. 107.

    Dobrosi N, Tóth BI, Nagy G, Dózsa A, Géczy T, Nagy L, et al. Endocannabinoids enhance lipid synthesis and apoptosis of human sebocytes via cannabinoid receptor-2-mediated signaling. FASEB J. 2008;22:3685–95.

    Article  CAS  PubMed  Google Scholar 

  108. 108.

    Oláh A, Markovics A, Szabó-Papp J, Szabó PT, Stott C, Zouboulis CC, et al. Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment. Exp Dermatol. 2016;25:701–7.

    Article  CAS  PubMed  Google Scholar 

  109. 109.

    Ahn C, Negus D, Huang W. Pyoderma gangrenosum: a review of pathogenesis and treatment. Expert Rev Clin Immunol. 2018;14:225–33.

    Article  CAS  PubMed  Google Scholar 

  110. 110.

    Wall LB, Stern PJ. Pyoderma gangrenosum. J Hand Surg. 2012;37:1083–5.

    Article  Google Scholar 

  111. 111.

    Besur SV, Tadakamalla A, Talluri SK. Pyoderma gangrenosum. QJM. 2012;105:1219–20.

    Article  PubMed  Google Scholar 

  112. 112.

    Maida V, Corban J. Topical medical cannabis: a new treatment for wound pain-three cases of pyoderma gangrenosum. J Pain Symptom Manag. 2017;54:732–6.

    Article  Google Scholar 

  113. 113.

    Johnson DR, Stebulis JA, Rossetti RG, Burstein SH, Zurier RB. Suppression of fibroblast metalloproteinases by ajulemic acid, a nonpsychoactive cannabinoid acid. J Cell Biochem. 2007;100:184–90.

    Article  CAS  PubMed  Google Scholar 

  114. 114.

    Soliman E, Ladin D, Van Dross R. Cannabinoids as therapeutics for non-melanoma and melanoma skin cancer. J Dermatol Clin Res. 2016;4:1069.

    Google Scholar 

  115. 115.

    Liu Y, Sheikh MS. Melanoma: molecular pathogenesis and therapeutic management. Mol Cell Pharmacol. 2014;6:228.

    PubMed  PubMed Central  Google Scholar 

  116. 116.

    Blázquez C, Carracedo A, Barrado L, Real PJ, Fernández-Luna JL, Velasco G, et al. Cannabinoid receptors as novel targets for the treatment of melanoma. FASEB J. 2006;20:2633–5.

    Article  CAS  PubMed  Google Scholar 

  117. 117.

    Glodde N, Jakobs M, Bald T, Tüting T, Gaffal E. Differential role of cannabinoids in the pathogenesis of skin cancer. Life Sci. 2015;138:35–40.

    Article  CAS  PubMed  Google Scholar 

  118. 118.

    Carpi S, Fogli S, Polini B, Montagnani V, Podestà A, Breschi MC, et al. Tumor-promoting effects of cannabinoid receptor type 1 in human melanoma cells. Toxicol In Vitro. 2017;40:272–9.

    Article  CAS  PubMed  Google Scholar 

  119. 119.

    Pucci M, Pasquariello N, Battista N, Di Tommaso M, Rapino C, Fezza F, et al. Endocannabinoids stimulate human melanogenesis via type-1 cannabinoid receptor. J Biol Chem. 2012;287:15466–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. 120.

    Zheng D, Bode AM, Zhao Q, Cho Y-Y, Zhu F, Ma W-Y, et al. The cannabinoid receptors are required for ultraviolet-induced inflammation and skin cancer development. Cancer Res. 2008;68:3992–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. 121.

    Casanova ML, Blázquez C, Martínez-Palacio J, Villanueva C, Fernández-Aceñero MJ, Huffman JW, et al. Inhibition of skin tumor growth and angiogenesis in vivo by activation of cannabinoid receptors. J Clin Investig. 2003;111:43–50.

    Article  CAS  PubMed  Google Scholar 

  122. 122.

    Gęgotek A, Biernacki M, Ambrożewicz E, Surażyński A, Wroński A, Skrzydlewska E. The cross-talk between electrophiles, antioxidant defence and the endocannabinoid system in fibroblasts and keratinocytes after UVA and UVB irradiation. J Dermatol Sci. 2016;81:107–17.

    Article  CAS  PubMed  Google Scholar 

  123. 123.

    Whiting PF, Wolff RF, Deshpande S. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA. 2015;313(24):2456–73.

    Article  CAS  PubMed  Google Scholar 

  124. 124.

    Nayak AP, Green BJ, Sussman G, Berlin N, Lata H, Chandra S, et al. Characterization of Cannabis sativa allergens. Ann Allergy Asthma Immunol. 2013;111(32–37):e4.

    Google Scholar 

  125. 125.

    Foster E, Nguyen C, Norris P. Contact buzz: allergic contact dermatitis to cannabis. Dermatitis. 2018;29:223–4.

    Article  PubMed  Google Scholar 

  126. 126.

    Can cannabis help your eczema? What you need to know. National Eczema Association. 2017. https://nationaleczema.org/can-marijuana-help/. Accessed 8 Sept 2018.

  127. 127.

    A Phase I, Double Blind, Randomized, Placebo Controlled, Maximal Dose Study to Determine the Safety, Tolerability of Topical Cream Containing MGC (Medical Grade Cannabis) in Healthy Volunteers. ClinicalTrials.gov. 2016. https://clinicaltrials.gov/ct2/show/NCT02976779. Accessed 13 Jul 2018.

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Correspondence to Adam Friedman.

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Rose Milando and Adam Friedman have no conflicts of interest that are directly relevant to the content of this article.

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The George Washington Department of Dermatology received no funding in support of this manuscript.

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Milando, R., Friedman, A. Cannabinoids: Potential Role in Inflammatory and Neoplastic Skin Diseases. Am J Clin Dermatol 20, 167–180 (2019). https://doi.org/10.1007/s40257-018-0410-5

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