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Cannabinoids for the treatment of chronic pruritus: A review

Published:January 24, 2020DOI:https://doi.org/10.1016/j.jaad.2020.01.036
      Medical marijuana is becoming widely available to patients in the United States, and with recreational marijuana now legalized in many states, patient interest is on the rise. The endocannabinoid system plays an important role in skin homeostasis in addition to broader effects on neurogenic responses such as pruritus and nociception, inflammation, and immune reactions. Numerous studies of in vitro and animal models have provided insight into the possible mechanisms of cannabinoid modulation on pruritus, with the most evidence behind neuronal modulation of peripheral itch fibers and centrally acting cannabinoid receptors. In addition, human studies, although limited due to differences in the cannabinoids used, disease models, and delivery method, have consistently shown significant reductions in both scratching and symptoms in chronic pruritus. Clinical studies have shown a reduction in pruritus in several dermatologic (atopic dermatitis, psoriasis, asteatotic eczema, prurigo nodularis, and allergic contact dermatitis) and systemic (uremic pruritus and cholestatic pruritus) diseases. These preliminary human studies warrant controlled trials to confirm the benefit of cannabinoids for treatment of pruritus and to standardize treatment regimens and indications. In patients who have refractory chronic pruritus after standard therapies, cannabinoid formulations may be considered as an adjuvant therapy where it is legal.

      Key words

      Abbreviations used:

      2-AG (2-arachidonoylglycerol), AE (asteatotic eczema), CB1 (cannabinoid receptor 1), CB2 (cannabinoid receptor 2), CBD (cannabidiol), ECS (endocannabinoid system), GPCR (G-protein–coupled receptor), THC (Δ(9)-tetrahydrocannabinol), TRP (transient receptor potential), TRPA1 (TRP ankyrin 1), TRPM1 (TRP melastatin 1), TRPV1 (TRP vanilloid 1), TRPV2 (TRP vanilloid 2), TRPV3 (TRP vanilloid 3), TRPV4 (TRP vanilloid 4), PEA (palmitoylethanolamine)
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      References

        • Kini S.P.
        • DeLong L.K.
        • Veledar E.
        • et al.
        The impact of pruritus on quality of life: the skin equivalent of pain.
        Arch Dermatol. 2011; 147: 1152-1156
        • Ständer S.
        • Schafer I.
        • Phan N.Q.
        • et al.
        Prevalence of chronic pruritus in Germany: results of a cross-sectional study in a sample working population of 11,730.
        Dermatology. 2010; 221: 229-235
        • Sarikaya Solak S.
        • Kivanc Altunay I.
        • Mertoglu Caliskan E.
        Chronic pruritus in Turkish dermatology outpatients: prevalence, sociodemographic and clinical characteristics.
        G Ital Dermatol Venereol. 2016; 151: 178-185
        • Kopyciok M.E.R.
        • Ständer H.F.
        • Osada N.
        • Steinke S.
        • Ständer S.
        Prevalence and characteristics of pruritus: a one-week cross-sectional study in a German dermatology practice.
        Acta Derm Venereol. 2016; 96: 50-55
        • Ständer S.
        • Weisshaar E.
        • Raap U.
        Emerging drugs for the treatment of pruritus.
        Expert Opin Emerg Drugs. 2015; 20: 515-521
        • Yosipovitch G.
        • Bernhard J.D.
        Clinical practice. Chronic pruritus.
        N Engl J Med. 2013; 68: 1625-1634
        • Szepietowski J.C.
        • Reich A.
        • Szepietowski T.
        Emollients with endocannabinoids in the treatment of uremic pruritus: discussion of the therapeutic options.
        Ther Apher Dial. 2005; 9: 277-279
        • Yuan C.
        • Wang X.M.
        • Guichard A.
        • et al.
        N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients.
        Clin Interv Aging. 2014; 17: 1163-1169
        • Visse K.
        • Blome C.
        • Phan N.Q.
        • Augustin M.
        • Ständer S.
        Efficacy of body lotion containing N-palmitoylethanolamine in subjects with chronic pruritus due to dry skin: a dermatocosmetic study.
        Acta Derm Venereol. 2017; 97: 639-641
        • Dvorak M.
        • Watkinson A.
        • McGlone F.
        • Rukwied R.
        Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin.
        Inflamm Res. 2003; 52: 238-245
        • Gaoni Y.
        • Mechoulam R.
        The isolation and structure of Δ-tetrahydrocannabinol and other neutral cannabinoids from hashish.
        J Am Chem Soc. 1971; 93: 217-224
        • Mechoulam R.
        • Hanuš L.O.
        • Pertwee R.
        • Howlett A.C.
        Early phytocannabinoid chemistry to endocannabinoids and beyond.
        Nat Rev Neurosci. 2014; 15: 757-764
        • Barrie N.
        • Manolios N.
        The endocannabinoid system in pain and inflammation: its relevance to rheumatic disease.
        Eur J Rheumatol. 2017; 4: 210-218
        • Woodhams S.G.
        • Chapman V.
        • Finn D.P.
        • Hohmann A.G.
        • Neugebauer V.
        The cannabinoid system and pain.
        Neuropharmacology. 2017; 124: 105-120
        • Río C.
        • Millan E.
        • Garcia V.
        • Appendino G.
        • DeMesa J.
        • Muñoz E.
        The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders.
        Biochem Pharmacol. 2018; 157: 122-133
        • Caterina M.J.
        TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation.
        ACS Chem Neurosci. 2014; 5: 1107-1116
        • Baumann L.S.
        A primer on cannabis for cosmeceuticals: the endocannabinoid system.
        (MD Edge Dermatol. 2019. Available at:)
        • Kim H.J.
        • Kim B.
        • Park B.M.
        • et al.
        Topical cannabinoid receptor 1 agonist attenuates the cutaneous inflammatory responses in oxazolone-induced atopic dermatitis model.
        Int J Dermatol. 2015; 54: e401-e408
        • Nam G.
        • Jeong S.K.
        • Park B.M.
        • et al.
        Selective cannabinoid receptor-1 agonists regulate mast cell activation in an oxazolone-induced atopic dermatitis model.
        Ann Dermatol. 2016; 28: 22-29
        • Di Marzo V.
        • Piscitelli F.
        The endocannabinoid system and its modulation by phytocannabinoids.
        Neurotherapeutics. 2015; 12: 692-698
        • Sugawara K.
        • Zakany N.
        • Hundt T.
        • et al.
        Cannabinoid receptor 1 controls human mucosal-type mast cell degranulation and maturation in situ.
        J Allergy Clin Immunol. 2013; 132: 182-193
        • 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; 38: 177-188
        • Odan M.
        • Ishizuka N.
        • Hiramatsu Y.
        • et al.
        Discovery of S-777469: an orally available CB2 agonist as an antipruritic agent.
        Bioorg Med Chem Lett. 2012; 22: 2803-2806
        • Yun J.W.
        • Seo J.A.
        • Jang W.H.
        • et al.
        Antipruritic effects of TRPV1 antagonist in murine atopic dermatitis and itching models.
        J Invest Dermatol. 2011; 131: 1576-1579
        • Schlosburg J.E.
        • O'Neal S.T.
        • Conrad D.H.
        • Lichtman A.H.
        CB1 receptors mediate rimonabant-induced pruritic responses in mice: investigation of locus of action.
        Psychopharmacology (Berl). 2011; 216: 323-331
        • Clayton N.
        • Marshall F.H.
        • Bountra C.
        • O'Shaughnessy C.T.
        CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain.
        Pain. 2002; 96: 253-260
        • Schlosburg J.E.
        • Boger D.L.
        • Cravatt B.F.
        • Lichtman A.H.
        Endocannabinoid modulation of scratching response in an acute allergenic model: a new prospective neural therapeutic target for pruritus.
        J Pharmacol Exp Ther. 2009; 329: 314-323
        • Calignano A.
        • La Rana G.
        • Giuffrida A.
        • Piomelli D.
        Control of pain initiation by endogenous cannabinoids.
        Nature. 1998; 394: 277-281
        • Ellington H.C.
        • Cotter M.A.
        • Cameron N.E.
        • Ross R.A.
        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; 42: 966-975
        • Brodie M.J.
        • Ben-Menachem E.
        Cannabinoids for epilepsy: what do we know and where do we go?.
        Epilepsia. 2018; 59: 291-296
        • Hill K.P.
        Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review.
        JAMA. 2015; 313: 2474-2483
        • Potenzieri C.
        • Undem B.J.
        Basic mechanisms of itch.
        Clin Exp Allergy. 2012; 42: 8-19
        • Carstens E.
        • Akiyama T.
        Central mechanisms of itch.
        Curr Probl Dermatol. 2016; 50: 11-17
        • Haruna T.
        • Soga M.
        • Morioka Y.
        • et al.
        S-777469, a novel cannabinoid type 2 receptor agonist, suppresses itch-associated scratching behavior in rodents through inhibition of itch signal transmission.
        Pharmacology. 2015; 95: 95-103
        • Chiou L.C.
        • Hu S.S.J.
        • Ho Y.C.
        Targeting the cannabinoid system for pain relief?.
        Acta Anaesthesiol Taiwan. 2013; 51: 161-170
        • Bilir K.A.
        • Anli G.
        • Ozkan E.
        • Gunduz O.
        • Ulugol A.
        Involvement of spinal cannabinoid receptors in the antipruritic effects of WIN 55,212-2, a cannabinoid receptor agonist.
        Clin Exp Dermatol. 2018; 43: 553-558
        • Gingold A.R.
        • Bergasa N.V.
        The cannabinoid agonist WIN 55, 212-2 increases nociception threshold in cholestatic rats: implications for the treatment of the pruritus of cholestasis.
        Life Sci. 2003; 73: 2741-2747
        • Guindon J.
        • Hohmann A.G.
        Cannabinoid CB 2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain.
        Br J Pharmacol. 2008; 153: 319-334
        • Gouin O.
        • L’Herondelle K.
        • Lebonvallet N.
        • et al.
        TRPV1 and TRPA1 in cutaneous neurogenic and chronic inflammation: pro-inflammatory response induced by their activation and their sensitization.
        Protein Cell. 2017; 8: 644-661
        • Xie Z.
        • Hu H.
        TRP channels as drug targets to relieve itch.
        Pharmaceuticals (Basel). 2018; 11https://doi.org/10.3390/ph11040100
        • Muller C.
        • Morales P.
        • Reggio P.H.
        Cannabinoid ligands targeting TRP channels.
        Front Mol Neurosci. 2019; 11: 487
        • Patapoutian A.
        • Tate S.
        • Woolf C.J.
        Transient receptor potential channels: targeting pain at the source.
        Nat Rev Drug Discov. 2009; 8: 55-68
        • Imamachi N.
        • Park G.H.
        • Lee H.
        • et al.
        TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms.
        Proc Natl Acad Sci U S A. 2009; 106: 11330-11335
        • Shim W.S.
        • Tak M.H.
        • Lee M.H.
        • et al.
        TRPV1 Mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase.
        J Neurosci. 2007; 27: 2331-2337
        • Southall M.D.
        • Li T.
        • Gharibova L.S.
        • Pei Y.
        • Nicol G.D.
        • Travers J.B.
        Activation of epidermal vanilloid receptor-1 induces release of proinflammatory mediators in human keratinocytes.
        J Pharmacol Exp Ther. 2003; 304: 217-222
        • Davidson S.
        • Giesler G.J.
        The multiple pathways for itch and their interactions with pain.
        Trends Neurosci. 2010; 33: 550-558
        • Wilson S.R.
        • Gerhold K.A.
        • Bifolck-Fisher A.
        • et al.
        TRPA1 is required for histamine-independent, Mas-related G protein-coupled receptor-mediated itch.
        Nat Neurosci. 2011; 14: 595-602
        • Ambrosino P.
        • Soldovieri M.V.
        • Russo C.
        • Taglialatela M.
        Activation and desensitization of TRPV1 channels in sensory neurons by the PPARα agonist palmitoylethanolamide.
        Br J Pharmacol. 2013; 168: 1430-1444
        • Eagleston L.R.M.
        • Kalani N.K.
        • Patel R.R.
        • Flaten H.K.
        • Dunnick C.A.
        • Dellavalle R.P.
        Cannabinoids in dermatology: a scoping review.
        Dermatol Online J. 2018; 24
        • Brito R.
        • Sheth S.
        • Mukherjea D.
        • Rybak L.P.
        • Ramkumar V.
        TRPV1: a potential drug target for treating various diseases.
        Cells. 2014; 3: 517-545
        • Turcotte C.
        • Blanchet M.R.
        • Laviolette M.
        • Flamand N.
        The CB2 receptor and its role as a regulator of inflammation.
        Cell Mol Life Sci. 2016; 73: 4449-4470
        • Small-Howard A.L.
        • Shimoda L.M.N.
        • Adra C.N.
        • Turner H.
        Anti-inflammatory potential of CB1-mediated cAMP elevation in mast cells.
        Biochem J. 2005; 388: 465-473
        • Sugawara K.
        • Biro T.
        • Tsuruta D.
        • et al.
        Endocannabinoids limit excessive mast cell maturation and activation in human skin.
        J Allergy Clin Immunol. 2012; 129: 726-738.e8
        • Szepietowski J.C.
        • 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: 97-103
        • Neff G.W.
        • O'Brien C.B.
        • Reddy K.R.
        • et al.
        Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease.
        Am J Gastroenterol. 2002; 97: 2117-2119
        • Eberlein B.
        • Eicke C.
        • Reinhardt H.W.
        • Ring J.
        Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study).
        J Eur Acad Dermatol Venereol. 2008; 22: 73-82
        • Ständer S.
        • Reinhardt H.W.
        • Luger T.A.
        Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus.
        Hautarzt. 2006; 57 ([in German]): 801-807
        • Pulvirenti N.
        • Nasca M.R.
        • 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: 80-83
        • Zucker I.
        • Yosipovitch G.
        • David M.
        • Gafter U.
        • Boner G.
        Prevalence and characterization of uremic pruritus in patients undergoing hemodialysis: uremic pruritus is still a major problem for patients with end-stage renal disease.
        J Am Acad Dermatol. 2003; 49: 842-846
        • Weisshaar E.
        Epidemiology of itch.
        Curr Probl Dermatol. 2016; 50: 5-10
        • Bruni N.
        • Della Pepa C.
        • Oliaro-Bosso S.
        • Pessione E.
        • Gastaldi D.
        • Dosio F.
        Cannabinoid delivery systems for pain and inflammation treatment.
        Molecules. 2018; 23https://doi.org/10.3390/molecules23102478
        • Wilsey B.
        • Marcotte T.
        • Tsodikov A.
        • et al.
        A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain.
        J Pain. 2008; 9: 506-521
        • Singh D.
        • Lippmann S.
        Vaping medical marijuana.
        Postgrad Med. 2018; 130: 183-185
        • Schier J.G.
        • Meiman J.G.
        • Layden J.
        • et al.
        Severe pulmonary disease associated with electronic-cigarette-product use—interim guidance.
        MMWR Morb Mortal Wkly Rep. 2019; 68: 787-790
        • Decuyper II,
        • Van Gasse A.L.
        • Cop N.
        • et al.
        Cannabis sativa allergy: looking through the fog.
        Allergy. 2017; 72: 201-206
        • Spradley J.M.
        • Davoodi A.
        • Gee L.B.
        • Carstens M.I.
        • Carstens E.
        Differences in peripheral endocannabinoid modulation of scratching behavior in facial vs. spinally-innervated skin.
        Neuropharmacology. 2012; 63: 743-749
        • ProCon.org
        Number of Legal Medical Marijuana Patients.
        (Available at:)
        • Lim M.
        • Kirchhof M.
        Dermatology-related uses of medical cannabis promoted by dispensaries in Canada, Europe, and the United States.
        J Cutan Med Surg. 2019; 23: 178-184