The Phytocannabinoid (–)-Cannabidiol Operates as a Complex, Differential Modulator of Human Hair Growth: Anti-Inflammatory Submicromolar versus Hair Growth Inhibitory Micromolar Effects

  • Author Footnotes
    7 These authors contributed equally as first authors.
    Imre L. Szabó
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    7 These authors contributed equally as first authors.
    Affiliations
    Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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  • Author Footnotes
    7 These authors contributed equally as first authors.
    Erika Lisztes
    Footnotes
    7 These authors contributed equally as first authors.
    Affiliations
    Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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  • Gabriella Béke
    Affiliations
    Department of Dermatology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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  • Kinga Fanni Tóth
    Affiliations
    Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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  • Ralf Paus
    Affiliations
    Centre for Dermatology Research, University of Manchester, MAHSC and NIHR Manchester Biomedical Research Centre, Manchester, United Kingdom

    Dr Phillip Frost Department of Dermatology & Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA
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  • Author Footnotes
    7 These authors contributed equally as first authors.
    ,
    Author Footnotes
    8 These authors contributed equally as senior authors.
    Attila Oláh
    Correspondence
    Corresponding authors.
    Footnotes
    7 These authors contributed equally as first authors.
    8 These authors contributed equally as senior authors.
    Affiliations
    Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
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    7 These authors contributed equally as first authors.
    ,
    Author Footnotes
    8 These authors contributed equally as senior authors.
    Tamás Bíró
    Correspondence
    Corresponding authors.
    Footnotes
    7 These authors contributed equally as first authors.
    8 These authors contributed equally as senior authors.
    Affiliations
    Department of Immunology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

    Hungarian Center of Excellence for Molecular Medicine, Szeged, Hungary
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  • Author Footnotes
    7 These authors contributed equally as first authors.
    8 These authors contributed equally as senior authors.

      Graphical abstract

      Abbreviations:

      CBD ( (–)-cannabidiol), HF ( hair follicle), TLR ( toll-like receptor), TRPV4 ( transient receptor potential vanilloid-4)
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      References

        • Armstrong J.L.
        • Hill D.S.
        • McKee C.S.
        • Hernandez-Tiedra S.
        • Lorente M.
        • Lopez-Valero I.
        • et al.
        Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death.
        J Invest Dermatol. 2015; 135: 1629-1637
        • Chelliah M.P.
        • Zinn Z.
        • Khuu P.
        • Teng J.M.C.
        Self-initiated use of topical cannabidiol oil for epidermolysis bullosa.
        Pediatr Dermatol. 2018; 35: e224-e227
        • Crippa J.A.
        • Guimarães F.S.
        • Campos A.C.
        • Zuardi A.W.
        Translational investigation of the therapeutic potential of cannabidiol (CBD): toward a new age.
        Front Immunol. 2018; 9: 2009
        • Esposito G.
        • Filippis D.D.
        • Cirillo C.
        • Iuvone T.
        • Capoccia E.
        • Scuderi C.
        • et al.
        Cannabidiol in inflammatory bowel diseases: a brief overview.
        Phytother Res. 2013; 27: 633-636
        • Everaerts W.
        • Zhen X.
        • Ghosh D.
        • Vriens J.
        • Gevaert T.
        • Gilbert J.P.
        • et al.
        Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis.
        Proc Natl Acad Sci USA. 2010; 107: 19084-19089
        • Ghai G.
        • Francis J.E.
        • Williams M.
        • Dotson R.A.
        • Hopkins M.F.
        • Cote D.T.
        • et al.
        Pharmacological characterization of CGS 15943A: a novel nonxanthine adenosine antagonist.
        J Pharmacol Exp Ther. 1987; 242: 784-790
        • Hoffmann R.
        • Happle R.
        • Paus R.
        Elements of the interleukin-1 signaling system show hair cycle-dependent gene expression in murine skin.
        Eur J Dermatol. 1998; 8: 475-477
        • Iino M.
        • Ehama R.
        • Nakazawa Y.
        • Iwabuchi T.
        • Ogo M.
        • Tajima M.
        • et al.
        Adenosine stimulates fibroblast growth factor-7 gene expression via adenosine A2b receptor signaling in dermal papilla cells.
        J Invest Dermatol. 2007; 127: 1318-1325
        • Klotz K.N.
        Adenosine receptors and their ligands.
        Naunyn Schmiedebergs Arch Pharmacol. 2000; 362: 382-391
        • Langan E.A.
        • Philpott M.P.
        • Kloepper J.E.
        • Paus R.
        Human hair follicle organ culture: theory, application and perspectives.
        Exp Dermatol. 2015; 24: 903-911
        • Maccarrone M.
        • Bab I.
        • Bíró T.
        • Cabral G.A.
        • Dey S.K.
        • Di Marzo V.
        • et al.
        Endocannabinoid signaling at the periphery: 50 years after THC.
        Trends Pharmacol Sci. 2015; 36: 277-296
        • Oh J.W.
        • Kloepper J.
        • Langan E.A.
        • Kim Y.
        • Yeo J.
        • Kim M.J.
        • et al.
        A guide to studying human hair follicle cycling in vivo.
        J Invest Dermatol. 2016; 136: 34-44
        • Oláh A.
        • Bíró T.
        Targeting cutaneous Cannabinoid Signaling in Inflammation - A “High”-way to Heal?.
        EBioMedicine. 2017; 16: 3-5
        • Oláh A.
        • Szekanecz Z.
        • Bíró T.
        Targeting Cannabinoid Signaling in the Immune System: “High”-ly Exciting Questions, Possibilities, and Challenges.
        Front Immunol. 2017; 8: 1487
        • Oláh A.
        • Tóth B.I.
        • Borbíró I.
        • Sugawara K.
        • Szöllõsi A.G.
        • Czifra G.
        • et al.
        Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes.
        J Clin Invest. 2014; 124: 3713-3724
        • Oura H.
        • Iino M.
        • Nakazawa Y.
        • Tajima M.
        • Ideta R.
        • Nakaya Y.
        • et al.
        Adenosine increases anagen hair growth and thick hairs in Japanese women with female pattern hair loss: a pilot, double-blind, randomized, placebo-controlled trial.
        J Dermatol. 2008; 35: 763-767
        • Paus R.
        • Cotsarelis G.
        The biology of hair follicles.
        N Engl J Med. 1999; 341: 491-497
        • Paus R.
        • Langan E.A.
        • Vidali S.
        • Ramot Y.
        • Andersen B.
        Neuroendocrinology of the hair follicle: principles and clinical perspectives.
        Trends Mol Med. 2014; 20: 559-570
        • Pertwee R.G.
        The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta 9-tetrahydrocannabinol, cannabidiol and delta 9-tetrahydrocannabivarin.
        Br J Pharmacol. 2008; 153: 199-215
        • Philpott M.P.
        • Sanders D.A.
        • Bowen J.
        • Kealey T.
        Effects of interleukins, colony-stimulating factor and tumour necrosis factor on human hair follicle growth in vitro: a possible role for interleukin-1 and tumour necrosis factor-alpha in alopecia areata.
        Br J Dermatol. 1996; 135: 942-948
        • Pisanti S.
        • Malfitano A.M.
        • Ciaglia E.
        • Lamberti A.
        • Ranieri R.
        • Cuomo G.
        • et al.
        Cannabidiol: state of the art and new challenges for therapeutic applications.
        Pharmacol Ther. 2017; 175: 133-150
        • Ramot Y.
        • Alam M.
        • Oláh A.
        • Bíró T.
        • Ponce L.
        • Chéret J.
        • et al.
        Peroxisome proliferator-activated receptor-γ-mediated signaling regulates mitochondrial energy metabolism in human hair follicle epithelium.
        J Invest Dermatol. 2018; 138: 1656-1659
        • Rückert R.
        • Lindner G.
        • Bulfone-Paus S.
        • Paus R.
        High-dose proinflammatory cytokines induce apoptosis of hair bulb keratinocytes in vivo.
        Br J Dermatol. 2000; 143: 1036-1039
        • Shin J.M.
        • Choi D.K.
        • Sohn K.C.
        • Kim S.Y.
        • Min Ha J.
        • Ho Lee Y.
        • et al.
        Double-stranded RNA induces inflammation via the NF-κB pathway and inflammasome activation in the outer root sheath cells of hair follicles.
        Sci Rep. 2017; 7: 44127
        • Szabó I.L.
        • Herczeg-Lisztes E.
        • Szegedi A.
        • Nemes B.
        • Paus R.
        • Bíró T.
        • et al.
        TRPV4 is expressed in human hair follicles and inhibits hair growth in vitro.
        J Invest Dermatol. 2019; 139: 1385-1388
        • Telek A.
        • Bíró T.
        • Bodó E.
        • Tóth B.I.
        • Borbíró I.
        • Kunos G.
        • et al.
        Inhibition of human hair follicle growth by endo- and exocannabinoids.
        FASEB J. 2007; 21: 3534-3541
        • Tóth K.F.
        • Ádám D.
        • Bíró T.
        • Oláh A.
        Cannabinoid Signaling in the Skin: therapeutic Potential of the “C(ut)annabinoid” System.
        Molecules. 2019; 24: E918
        • Williams M.
        • Francis J.
        • Ghai G.
        • Braunwalder A.
        • Psychoyos S.
        • Stone G.A.
        • et al.
        Biochemical characterization of the triazoloquinazoline, CGS 15943, a novel, non-xanthine adenosine antagonist.
        J Pharmacol Exp Ther. 1987; 241: 415-420

      Supplementary References

        • Armstrong J.L.
        • Hill D.S.
        • McKee C.S.
        • Hernandez-Tiedra S.
        • Lorente M.
        • Lopez-Valero I.
        • et al.
        Exploiting cannabinoid-induced cytotoxic autophagy to drive melanoma cell death.
        J Invest Dermatol. 2015; 135: 1629-1637
        • Bíró T.
        • Bodó E.
        • Telek A.
        • Géczy T.
        • Tychsen B.
        • Kovács L.
        • et al.
        Hair cycle control by vanilloid receptor-1 (TRPV1): evidence from TRPV1 knockout mice.
        J Invest Dermatol. 2006; 126: 1909-1912
        • Bodó E.
        • Bíró T.
        • Telek A.
        • Czifra G.
        • Griger Z.
        • Tóth B.I.
        • 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: 985-998
        • Borbíró I.
        • Lisztes E.
        • Tóth B.I.
        • Czifra G.
        • Oláh A.
        • Szöllosi A.G.
        • et al.
        Activation of transient receptor potential vanilloid-3 inhibits human hair growth.
        J Invest Dermatol. 2011; 131: 1605-1614
        • Esposito G.
        • Filippis D.D.
        • Cirillo C.
        • Iuvone T.
        • Capoccia E.
        • Scuderi C.
        • et al.
        Cannabidiol in inflammatory bowel diseases: a brief overview.
        Phytother Res. 2013; 27: 633-636
        • Ghai G.
        • Francis J.E.
        • Williams M.
        • Dotson R.A.
        • Hopkins M.F.
        • Cote D.T.
        • et al.
        Pharmacological characterization of CGS 15943A: a novel nonxanthine adenosine antagonist.
        J Pharmacol Exp Ther. 1987; 242: 784-790
        • Green D.R.
        • Reed J.C.
        Mitochondria and apoptosis.
        Science. 1998; 281: 1309-1312
        • Harada N.
        • Okajima K.
        • Arai M.
        • Kurihara H.
        • Nakagata N.
        Administration of capsaicin and isoflavone promotes hair growth by increasing insulin-like growth factor-I production in mice and in humans with alopecia.
        Growth Horm IGF Res. 2007; 17: 408-415
        • Iino M.
        • Ehama R.
        • Nakazawa Y.
        • Iwabuchi T.
        • Ogo M.
        • Tajima M.
        • et al.
        Adenosine stimulates fibroblast growth factor-7 gene expression via adenosine A2b receptor signaling in dermal papilla cells.
        J Invest Dermatol. 2007; 127: 1318-1325
        • Kloepper J.E.
        • Sugawara K.
        • Al-Nuaimi Y.
        • Gáspár E.
        • van Beek N.V.
        • Paus R.
        Methods in hair research: how to objectively distinguish between anagen and catagen in human hair follicle organ culture.
        Exp Dermatol. 2010; 19: 305-312
        • Klotz K.N.
        Adenosine receptors and their ligands.
        Naunyn Schmiedebergs Arch Pharmacol. 2000; 362: 382-391
        • Langan E.A.
        • Philpott M.P.
        • Kloepper J.E.
        • Paus R.
        Human hair follicle organ culture: theory, application and perspectives.
        Exp Dermatol. 2015; 24: 903-911
        • Oláh A.
        • Gherardini J.
        • Bertolini M.
        • Chéret J.
        • Ponce L.
        • Kloepper J.
        • et al.
        The thyroid hormone analogue KB2115 (eprotirome) prolongs human hair growth (Anagen) ex vivo.
        J Invest Dermatol. 2016; 136: 1711-1714
        • Oláh A.
        • Tóth B.I.
        • Borbíró I.
        • Sugawara K.
        • Szöllõsi A.G.
        • Czifra G.
        • et al.
        Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes.
        J Clin Invest. 2014; 124: 3713-3724
        • Ramot Y.
        • Alam M.
        • Oláh A.
        • Bíró T.
        • Ponce L.
        • Chéret J.
        • et al.
        Peroxisome proliferator-activated receptor-γ-mediated signaling regulates mitochondrial energy metabolism in human hair follicle epithelium.
        J Invest Dermatol. 2018; 138: 1656-1659
        • Szabó I.L.
        • Herczeg-Lisztes E.
        • Szegedi A.
        • Nemes B.
        • Paus R.
        • Bíró T.
        • et al.
        TRPV4 is expressed in human hair follicles and inhibits hair growth in vitro.
        J Invest Dermatol. 2019; 139: 1385-1388