Planta Med 2022; 88(07): 492-506
DOI: 10.1055/a-1420-5780
Formulation and Delivery Systems of Natural Products
Reviews

Cannabis sativa and Skin Health: Dissecting the Role of Phytocannabinoids

Giulia Martinelli
Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy
,
Andrea Magnavacca
Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy
,
Marco Fumagalli
Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy
,
Mario DellʼAgli
Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy
,
Stefano Piazza
Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy
,
Enrico Sangiovanni
Department of Pharmacological and Biomolecular Sciences (DiSFeB), Università degli Studi di Milano, Milan, Italy
› Author Affiliations

Abstract

The use of Cannabis sativa is currently recognized to ease certain types of chronic pain, reduce chemotherapy-induced nausea, and improve anxiety. Nevertheless, few studies highlighted the therapeutic potential of C. sativa extracts and related phytocannabinoids for a variety of widespread skin disorders including acne, atopic dermatitis, psoriasis, pruritus, and pain. This review summarized the current evidence on the effects of phytocannabinoids at the cutaneous level through the collection of in vitro, in vivo, and clinical studies published on PubMed, Scopus, Embase, and Web of Science until October 2020. Phytocannabinoids have demonstrated potential anti-inflammatory, antioxidant, anti-aging, and anti-acne properties by various mechanisms involving either CB1/2-dependent and independent pathways. Not only classical immune cells, but also several skin-specific actors, such as keratinocytes, fibroblasts, melanocytes, and sebocytes, may represent a target for phytocannabinoids. Cannabidiol, the most investigated compound, revealed photoprotective, antioxidant, and anti-inflammatory mechanisms at the cutaneous level, while the possible impact on cell differentiation, especially in the case of psoriasis, would require further investigation. Animal models and pilot clinical studies supported the application of cannabidiol in inflammatory-based skin diseases. Also, one of the most promising applications of non-psychotropic phytocannabinoids is the treatment of seborrheic disorders, especially acne. In conclusion, the incomplete knowledge of the role of the endocannabinoid system in skin disorders emerged as an important limit for pharmacological investigations. Moreover, the limited studies conducted on C. sativa extracts suggested a higher potency than single phytocannabinoids, thus stimulating new research on phytocannabinoid interaction.



Publication History

Received: 27 November 2020

Accepted after revision: 09 March 2021

Article published online:
13 April 2021

© 2021. Thieme. All rights reserved.

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  • References

  • 1 Small E. Evolution and classification of Cannabis sativa (Marijuana, Hemp) in relation to human utilization. Bot Rev 2015; 81: 189-294
  • 2 Bonini SA, Premoli M, Tambaro S, Kumar A, Maccarinelli G, Memo M, Mastinu A. Cannabis sativa: A comprehensive ethnopharmacological review of a medicinal plant with a long history. J Ethnopharmacol 2018; 227: 300-315
  • 3 Goncalves J, Rosado T, Soares S, Simao AY, Caramelo D, Luis A, Fernandez N, Barroso M, Gallardo E, Duarte AP. Cannabis and its secondary metabolites: their use as therapeutic drugs, toxicological aspects, and analytical determination. Medicines (Basel) 2019; 6: 31
  • 4 Theroux Z, Cropley T. Cannabis and Dr. Piffard–a century ahead of the curve. JAMA Dermatol 2016; 152: 972
  • 5 Toth KF, Adam D, Biro T, Olah A. Cannabinoid signaling in the skin: therapeutic potential of the “c(ut)annabinoid” system. Molecules 2019; 24: 918
  • 6 Dhadwal G, Kirchhof MG. The risks and benefits of cannabis in the dermatology clinic. J Cutan Med Surg 2018; 22: 194-199
  • 7 Sheriff T, Lin MJ, Dubin D, Khorasani H. The potential role of cannabinoids in dermatology. J Dermatolog Treat 2020; 31: 839-845
  • 8 Rio CD, Millan E, Garcia V, Appendino G, DeMesa J, Munoz E. The endocannabinoid system of the skin. A potential approach for the treatment of skin disorders. Biochem Pharmacol 2018; 157: 122-133
  • 9 Biro T, Toth BI, Hasko 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: 411-420
  • 10 Lynn AB, Herkenham M. Localization of cannabinoid receptors and nonsaturable high-density cannabinoid binding sites in peripheral tissues of the rat: implications for receptor-mediated immune modulation by cannabinoids. J Pharmacol Exp Ther 1994; 268: 1612-1623
  • 11 Klein TW, Newton C, Larsen K, Lu L, Perkins I, Nong L, Friedman H. The cannabinoid system and immune modulation. J Leukoc Biol 2003; 74: 486-496
  • 12 Hurst DP, Schmeisser M, Reggio PH. Endogenous lipid activated G protein-coupled receptors: emerging structural features from crystallography and molecular dynamics simulations. Chem Phys Lipids 2013; 169: 46-56
  • 13 Kozak KR, Gupta RA, Moody JS, Ji C, Boeglin WE, DuBois RN, Brash AR, Marnett LJ. 15-Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. J Biol Chem 2002; 277: 23278-23286
  • 14 Hughes ML, Liu B, Halls ML, Wagstaff KM, Patil R, Velkov T, Jans DA, Bunnett NW, Scanlon MJ, Porter CJ. Fatty Acid-binding proteins 1 and 2 differentially modulate the activation of peroxisome proliferator-activated receptor α in a ligand-selective manner. J Biol Chem 2015; 290: 13895-13906
  • 15 Elmes MW, Kaczocha M, Berger WT, Leung K, Ralph BP, Wang LQ, Sweeney JM, Miyauchi JT, Tsirka SE, Ojima I, Deutsch DG. Fatty acid-binding proteins (FABPs) are intracellular carriers for delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem 2015; 290: 8711-8721
  • 16 Vara D, Morell C, Rodriguez-Henche N, Diaz-Laviada I. Involvement of PPAR gamma in the antitumoral action of cannabinoids on hepatocellular carcinoma. Cell Death Dis 2013; 4: 11
  • 17 Caterina MJ. TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation. ACS Chem Neurosci 2014; 5: 1107-1116
  • 18 De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, Stott CG, Di Marzo V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 2011; 163: 1479-1494
  • 19 De Petrocellis L, Orlando P, Moriello AS, Aviello G, Stott C, Izzo AA, Di Marzo V. Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf) 2012; 204: 255-266
  • 20 Ahrens J, Demir R, Leuwer M, de la Roche J, Krampfl K, Foadi N, Karst M, Haeseler G. The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-Beta glycine receptor function. Pharmacology 2009; 83: 217-222
  • 21 Xiong W, Cui T, Cheng K, Yang F, Chen SR, Willenbring D, Guan Y, Pan HL, Ren K, Xu Y, Zhang L. Cannabinoids suppress inflammatory and neuropathic pain by targeting α3 glycine receptors. J Exp Med 2012; 209: 1121-1134
  • 22 Denda M, Fuziwara S, Inoue K. Influx of calcium and chloride ions into epidermal keratinocytes regulates exocytosis of epidermal lamellar bodies and skin permeability barrier homeostasis. J Invest Dermatol 2003; 121: 362-367
  • 23 Inoue K, Takei K, Denda M. Functional glycine receptor in cultured human keratinocytes. Exp Dermatol 2015; 24: 307-309
  • 24 ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod 2017; 103: 1-36
  • 25 Turner SE, Williams CM, Iversen L, Whalley BJ. Molecular pharmacology of phytocannabinoids. Prog Chem Org Nat Prod 2017; 103: 61-101
  • 26 Hanus LO, Meyer SM, Munoz E, Taglialatela-Scafati O, Appendino G. Phytocannabinoids: a unified critical inventory. Nat Prod Rep 2016; 33: 1357-1392
  • 27 Martínez V, Iriondo De-Hond A, Borrelli F, Capasso R, Del Castillo MD, Abalo R. Cannabidiol and other non-psychoactive cannabinoids for prevention and treatment of gastrointestinal disorders: Useful nutraceuticals?. Int J Mol Sci 2020; 21: 3067
  • 28 Elsohly M, Gul W. Constituents of Cannabis sativa . In: Iversen L. ed. Handbook of Cannabis. Oxford, UK: Oxford University Press; 2014: 3-22
  • 29 Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009; 30: 515-527
  • 30 Pertwee RG, Ross RA, Craib SJ, Thomas A. (−)-Cannabidiol antagonizes cannabinoid receptor agonists and noradrenaline in the mouse vas deferens. Eur J Pharmacol 2002; 456: 99-106
  • 31 Thomas A, Baillie GL, Phillips AM, Razdan RK, Ross RA, Pertwee RG. Cannabidiol displays unexpectedly high potency as an antagonist of CB1 and CB2 receptor agonists in vitro. Br J Pharmacol 2007; 150: 613-623
  • 32 Morales P, Hurst DP, Reggio PH. Molecular Targets of the Phytocannabinoids: A complex Picture. In: Kinghorn AD, Falk H, Gibbons S, Kobayashi J. eds. Phytocannabinoids: Unraveling the complex Chemistry and Pharmacology of Cannabis sativa. Vol 103. Switzerland: Springer International Publishing; 2017: 103-131
  • 33 Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM. Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor. Br J Pharmacol 2015; 172: 4790-4805
  • 34 McPartland JM, Duncan M, Di Marzo V, Pertwee RG. Are cannabidiol and Δ(9) -tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 2015; 172: 737-753
  • 35 Morales P, Goya P, Jagerovic N, Hernandez-Folgado L. Allosteric modulators of the CB(1) cannabinoid receptor: a structural update review. Cannabis Cannabinoid Res 2016; 1: 22-30
  • 36 Sylantyev S, Jensen TP, Ross RA, Rusakov DA. Cannabinoid- and lysophosphatidylinositol-sensitive receptor GPR55 boosts neurotransmitter release at central synapses. Proc Natl Acad Sci U S A 2013; 110: 5193-5198
  • 37 Whyte LS, Ryberg E, Sims NA, Ridge SA, Mackie K, Greasley PJ, Ross RA, Rogers MJ. The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo. Proc Natl Acad Sci U S A 2009; 106: 16511-16516
  • 38 Ryberg E, Larsson N, Sjögren S, Hjorth S, Hermansson NO, Leonova J, Elebring T, Nilsson K, Drmota T, Greasley PJ. The orphan receptor GPR55 is a novel cannabinoid receptor. Br J Pharmacol 2007; 152: 1092-1101
  • 39 McHugh D, Page J, Dunn E, Bradshaw HB. Δ(9) -Tetrahydrocannabinol and N-arachidonyl glycine are full agonists at GPR18 receptors and induce migration in human endometrial HEC-1B cells. Br J Pharmacol 2012; 165: 2414-2424
  • 40 Gonca E, Darici F. The effect of cannabidiol on ischemia/reperfusion-induced ventricular arrhythmias: the role of adenosine A1 receptors. J Cardiovasc Pharmacol Ther 2015; 20: 76-83
  • 41 Carrier EJ, Auchampach JA, Hillard CJ. Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression. Proc Natl Acad Sci U S A 2006; 103: 7895-7900
  • 42 Xiong W, Cui T, Cheng K, Yang F, Chen SR, Willenbring D, Guan Y, Pan HL, Ren K, Xu Y, Zhang L. Cannabinoids suppress inflammatory and neuropathic pain by targeting alpha3 glycine receptors. J Exp Med 2012; 209: 1121-1134
  • 43 Russo EB, Burnett A, Hall B, Parker KK. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res 2005; 30: 1037-1043
  • 44 Yang KH, Galadari S, Isaev D, Petroianu G, Shippenberg TS, Oz M. The nonpsychoactive cannabinoid cannabidiol inhibits 5-hydroxytryptamine3A receptor-mediated currents in Xenopus laevis oocytes. J Pharmacol Exp Ther 2010; 333: 547-554
  • 45 Bisogno T, Hanus L, De Petrocellis L, Tchilibon S, Ponde DE, Brandi I, Moriello AS, Davis JB, Mechoulam R, Di Marzo V. Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide. Br J Pharmacol 2001; 134: 845-852
  • 46 Iannotti FA, Hill CL, Leo A, Alhusaini A, Soubrane C, Mazzarella E, Russo E, Whalley BJ, Di Marzo V, Stephens GJ. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 2014; 5: 1131-1141
  • 47 De Petrocellis L, Vellani V, Schiano-Moriello A, Marini P, Magherini PC, Orlando P, Di Marzo V. Plant-derived cannabinoids modulate the activity of transient receptor potential channels of ankyrin type-1 and melastatin type-8. J Pharmacol Exp Ther 2008; 325: 1007-1015
  • 48 Maione S, Piscitelli F, Gatta L, Vita D, De Petrocellis L, Palazzo E, de Novellis V, Di Marzo V. Non-psychoactive cannabinoids modulate the descending pathway of antinociception in anaesthetized rats through several mechanisms of action. Br J Pharmacol 2011; 162: 584-596
  • 49 Kathmann M, Flau K, Redmer A, Trankle C, Schlicker E. Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors. Naunyn Schmiedebergs Arch Pharmacol 2006; 372: 354-361
  • 50 Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci 2005; 78: 539-548
  • 51 Ahmed SA, Ross SA, Slade D, Radwan MM, Zulfiqar F, ElSohly MA. Cannabinoid ester constituents from high-potency Cannabis sativa . J Nat Prod 2008; 71: 536-542
  • 52 Radwan MM, Ross SA, Slade D, Ahmed SA, Zulfiqar F, Elsohly MA. Isolation and characterization of new Cannabis constituents from a high potency variety. Planta Med 2008; 74: 267-272
  • 53 Radwan MM, Elsohly MA, Slade D, Ahmed SA, Khan IA, Ross SA. Biologically active cannabinoids from high-potency Cannabis sativa . J Nat Prod 2009; 72: 906-911
  • 54 Navarro G, Varani K, Reyes-Resina I, Sánchez de Medina V, Rivas-Santisteban R, Sánchez-Carnerero Callado C, Vincenzi F, Casano S, Ferreiro-Vera C, Canela EI, Borea PA, Nadal X, Franco R. Cannabigerol action at cannabinoid CB1 and CB2 receptors and at CB1–CB2 heteroreceptor complexes. Front Pharmacol 2018; 9: 632
  • 55 De Petrocellis L, Ligresti A, Moriello AS, Allara M, Bisogno T, Petrosino S, Stott CG, Di Marzo V. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 2011; 163: 1479-1494
  • 56 Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha2-adrenoceptor agonist and moderately potent 5HT1A receptor antagonist. Br J Pharmacol 2010; 159: 129-141
  • 57 Gaoni Y, Mechoulam R. Cannabichromene, a new active principle in hashish. Chemical Communications (London) 1966; 20-21 doi:10.1039/C19660000020
  • 58 Udoh M, Santiago M, Devenish S, McGregor IS, Connor M. Cannabichromene is a cannabinoid CB2 receptor agonist. Br J Pharmacol 2019; 176: 4537-4547
  • 59 Patil AS, Mahajan UB, Agrawal YO, Patil KR, Patil CR, Ojha S, Sharma C, Goyal SN. Plant-derived natural therapeutics targeting cannabinoid receptors in metabolic syndrome and its complications: a review. Biomed Pharmacother 2020; 132: 110889
  • 60 Gohad P, McCoy J, Wambier C, Kovacevic M, Situm M, Stanimirovic A, Goren A. Novel cannabidiol sunscreen protects keratinocytes and melanocytes against ultraviolet B radiation. J Cosmet Dermatol 2020; DOI: 10.1111/jocd.13693.
  • 61 Jarocka-Karpowicz I, Biernacki M, Wronski A, Gegotek A, Skrzydlewska E. Cannabidiol effects on phospholipid metabolism in keratinocytes from patients with Psoriasis vulgaris. Biomolecules 2020; 10: 362
  • 62 Atalay S, Dobrzynska I, Gegotek A, Skrzydlewska E. Cannabidiol protects keratinocyte cell membranes following exposure to UVB and hydrogen peroxide. Redox Biol 2020; 36: 101613
  • 63 Jastrzab A, Gegotek A, Skrzydlewska E. Cannabidiol regulates the expression of keratinocyte proteins involved in the inflammation process through transcriptional regulation. Cells 2019; 8: 827
  • 64 Sangiovanni E, Fumagalli M, Pacchetti B, Piazza S, Magnavacca A, Khalilpour S, Melzi G, Martinelli G, DellʼAgli M. Cannabis sativa L. extract and cannabidiol inhibit in vitro mediators of skin inflammation and wound injury. Phytother Res 2019; 33: 2083-2093
  • 65 Casares L, Garcia V, Garrido-Rodriguez M, Millan E, Collado JA, Garcia-Martin A, Penarando J, Calzado MA, de la Vega L, Munoz E. Cannabidiol induces antioxidant pathways in keratinocytes by targeting BACH1. Redox Biol 2020; 28: 101321
  • 66 Styrczewska M, Kostyn A, Kulma A, Majkowska-Skrobek G, Augustyniak D, Prescha A, Czuj T, Szopa J. Flax Fiber hydrophobic extract inhibits human skin cells inflammation and causes remodeling of extracellular matrix and wound closure activation. Biomed Res Int 2015; 2015: 862391
  • 67 Gegotek A, Atalay S, Domingues P, Skrzydlewska E. The differences in the proteome profile of cannabidiol-treated skin fibroblasts following UVA or UVB irradiation in 2D and 3D cell cultures. Cells 2019; 8: 995
  • 68 Hwang YS, Kim YJ, Kim MO, Kang M, Oh SW, Nho YH, Park SH, Lee J. Cannabidiol upregulates melanogenesis through CB1 dependent pathway by activating p38 MAPK and p42/44 MAPK. Chem Biol Interact 2017; 273: 107-114
  • 69 Olah A, Markovics A, Szabo-Papp J, Szabo PT, Stott C, Zouboulis CC, Biro T. 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: 701-707
  • 70 Olah A, Toth BI, Borbiro I, Sugawara K, Szollosi AG, Czifra G, Pal B, Ambrus L, Kloepper J, Camera E, Ludovici M, Picardo M, Voets T, Zouboulis CC, Paus R, Biro T. Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. J Clin Invest 2014; 124: 3713-3724
  • 71 Touitou E, Fabin B, Dany S, Almog S. Transdermal delivery of tetrahydrocannabinol. Int J Pharmaceutics 1988; 43: 9-15
  • 72 Valiveti S, Hammell DC, Earles DC, Stinchcomb AL. In vitro/in vivo correlation studies for transdermal delta 8-THC development. J Pharm Sci 2004; 93: 1154-1164
  • 73 Stinchcomb AL, Valiveti S, Hammell DC, Ramsey DR. Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol. J Pharm Pharmacol 2004; 56: 291-297
  • 74 Gaffal E, Cron M, Glodde N, Tuting T. Anti-inflammatory activity of topical THC in DNFB-mediated mouse allergic contact dermatitis independent of CB1 and CB2 receptors. Allergy 2013; 68: 994-1000
  • 75 Glodde N, Jakobs M, Bald T, Tuting T, Gaffal E. Differential role of cannabinoids in the pathogenesis of skin cancer. Life Sci 2015; 138: 35-40
  • 76 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: 229-237
  • 77 Pucci M, Rapino C, Di Francesco A, Dainese E, DʼAddario C, Maccarrone M. Epigenetic control of skin differentiation genes by phytocannabinoids. Br J Pharmacol 2013; 170: 581-591
  • 78 Wilkinson JD, Williamson EM. Cannabinoids inhibit human keratinocyte proliferation through a non-CB1/CB2 mechanism and have a potential therapeutic value in the treatment of psoriasis. J Dermatol Sci 2007; 45: 87-92
  • 79 Petrosino S, Verde R, Vaia M, Allara 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: 652-663
  • 80 Kim JE, Kim JS, Cho DH, Park HJ. Molecular mechanisms of cutaneous inflammatory disorder: atopic dermatitis. Int J Mol Sci 2016; 17: 1234
  • 81 Reichelt J, Furstenberger G, Magin TM. Loss of keratin 10 leads to mitogen-activated protein kinase (MAPK) activation, increased keratinocyte turnover, and decreased tumor formation in mice. J Invest Dermatol 2004; 123: 973-981
  • 82 Formukong EA, Evans AT, Evans FJ. Analgesic and antiinflammatory activity of constituents of Cannabis sativa L. Inflammation 1988; 12: 361-371
  • 83 Tubaro A, Giangaspero A, Sosa S, Negri R, Grassi G, Casano S, Della Loggia R, Appendino G. Comparative topical anti-inflammatory activity of cannabinoids and cannabivarins. Fitoterapia 2010; 81: 816-819
  • 84 Lodzki M, Godin B, Rakou L, Mechoulam R, Gallily R, Touitou E. Cannabidiol-transdermal delivery and anti-inflammatory effect in a murine model. J Control Release 2003; 93: 377-387
  • 85 Bartner LR, McGrath S, Rao S, Hyatt LK, Wittenburg LA. Pharmacokinetics of cannabidiol administered by 3 delivery methods at 2 different dosages to healthy dogs. Can J Vet Res 2018; 82: 178-183
  • 86 Chelliah MP, Zinn Z, Khuu P, Teng JMC. Self-initiated use of topical cannabidiol oil for epidermolysis bullosa. Pediatr Dermatol 2018; 35: e224-e227
  • 87 Schrader NHB, Duipmans JC, Molenbuur B, Wolff AP, Jonkman MF. Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases. Br J Dermatol 2019; 180: 922-924
  • 88 Spleman L, Sinclair R, Freeman M, Davis M, Gebauer K. 1061 The safety of topical cannabidiol (CBD) for the treatment of acne. J Invest Dermatol 2018; 138: S180
  • 89 Callaway J, Schwab U, Harvima I, Halonen P, Mykkanen O, Hyvonen P, Jarvinen T. Efficacy of dietary hempseed oil in patients with atopic dermatitis. J Dermatolog Treat 2005; 16: 87-94
  • 90 Hill TDM, Cascio MG, Romano B, Duncan M, Pertwee RG, Williams CM, Whalley BJ, Hill AJ. Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol 2013; 170: 679-692
  • 91 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: 1389-1395
  • 92 Jin S, Lee MY. The ameliorative effect of hemp seed hexane extracts on the Propionibacterium acnes-induced inflammation and lipogenesis in sebocytes. PLoS One 2018; 13: e0202933