Advertisement

Cannabinoids for the Treatment of Dermatologic Conditions

  • Author Footnotes
    6 These authors contributed equally to this work.
    Torunn E. Sivesind
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
    Search for articles by this author
  • Author Footnotes
    6 These authors contributed equally to this work.
    Jalal Maghfour
    Footnotes
    6 These authors contributed equally to this work.
    Affiliations
    Department of Dermatology and Skin Care, Henry Ford Health System, Detroit, Michigan, USA
    Search for articles by this author
  • Hope Rietcheck
    Affiliations
    Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
    Search for articles by this author
  • Kevin Kamel
    Affiliations
    School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
    Search for articles by this author
  • Ali S. Malik
    Affiliations
    Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA
    Search for articles by this author
  • Robert P. Dellavalle
    Correspondence
    Correspondence: Robert P. Dellavalle, Dermatology Service, Rocky Mountain Regional VA Medical Center, U.S. Department of Veterans Affairs, Colorado School of Public Health, Room E1-342, 1700 North Wheeling Street, Aurora, Colorado 80045, USA.
    Affiliations
    Department of Dermatology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

    Rocky Mountain Regional VA Medical Center, U.S. Department of Veterans Affairs, Aurora, Colorado, USA
    Search for articles by this author
  • Author Footnotes
    6 These authors contributed equally to this work.
Open AccessPublished:January 12, 2022DOI:https://doi.org/10.1016/j.xjidi.2022.100095
      In recent years, cannabinoid (CB) products have gained popularity among the public. The anti-inflammatory properties of CBs have piqued the interest of researchers and clinicians because they represent promising avenues for the treatment of autoimmune and inflammatory skin disorders that may be refractory to conventional therapy. The objective of this study was to review the existing literature regarding CBs for dermatologic conditions. A primary literature search was conducted in October 2020, using the PubMed and Embase databases, for all articles published from 1965 to October 2020. Review articles, studies using animal models, and nondermatologic and pharmacologic studies were excluded. From 248 nonduplicated studies, 26 articles were included. There were 13 articles on systemic CBs and 14 reports on topical CBs. Selective CB receptor type 2 agonists were found to be effective in treating diffuse cutaneous systemic sclerosis and dermatomyositis. Dronabinol showed efficacy for trichotillomania. Sublingual cannabidiol and Δ-9-tetrahydrocannabinol were successful in treating the pain associated with epidermolysis bullosa. Available evidence suggests that CBs may be effective for the treatment of various inflammatory skin disorders. Although promising, additional research is necessary to evaluate efficacy and to determine dosing, safety, and long-term treatment guidelines.

      Abbreviations:

      Δ9-THC (delta-9-tetrahydrocannabinol), 2-AG (2-arachidonoylglycerol), ACR-CRISS (American College of Rheumatology-combined response index in diffuse cutaneous systemic sclerosis), AEA (anandamide), CB (cannabinoid), CB1R (cannabinoid receptor 1), CB2R (cannabinoid receptor 2), CBD (cannabidiol), CDASI (cutaneous dermatomyositis disease area and severity index), DM (dermatomyositis), ECS (endocannabinoid system), KC (keratinocyte), MRSS (modified Rodnan skin thickness score), N-PEA (N-palmitoylethanolamide), QOLHEQ (Quality of Life Hand Eczema Questionnaire), RCT (randomized controlled trial), SSc (systemic sclerosis), VAS (Visual Analog Score)

      Introduction

      For many centuries, at least as early as BC 500, cannabis has been widely used as an herbal medicine for the treatment of insomnia and gastrointestinal disorders, as an anesthetic agent, and for religious practices (
      • Zuardi A.
      History of cannabis as a medicine: a review.
      ). In the 19th century, investigation into the pharmacokinetics of the active constituents of cannabis, the cannabinoids (CBs), began to shed light on their potential application in modern medicine (
      • Zuardi A.
      History of cannabis as a medicine: a review.
      ). In recent years, there has been an increase in both preclinical and clinical studies exploring the use of CBs for the treatment of dermatologic conditions (
      • Eberlein B.
      • Eicke C.
      • Reinhardt H.W.
      • Ring J.
      Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study).
      ;
      • Ständer S.
      • Reinhardt H.W.
      • Luger T.A.
      Topische Cannabinoidagonisten. Eine effektive, neue Möglichkeit zur Behandlung von chronischem Pruritus [Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus].
      ;
      • Yuan C.
      • Wang X.-M.
      • Guichard A.
      • Tan Y.M.
      • Qian C.-Y.
      • Yang L.-J.
      • et al.
      N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients.
      ).
      Given the increasing availability and popularity of CB-containing skincare products and the increase in clinical studies regarding the role of CBs in the treatment of dermatologic conditions, we aimed to review the existing evidence on the use of CBs for the treatment of dermatologic conditions. To orient the reader, we first provide an overview of CB classes, biological pathways, and mechanistic details as follows.
      CBs represent a diverse class of chemicals that share structural and biologic similarities with the psychoactive compound delta-9-tetrahydrocannabinol (Δ9-THC), which is derived from Cannabis sativa (
      • 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.
      ).
      There are three main classes of CBs: phytocannabinoids (derived from the C. sativa plant), endocannabinoids (endogenously produced in humans), and synthetic CBs (synthesized in a laboratory) (
      • 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.
      ). An introduction to representative CBs from each class, along with their respective mechanisms, is provided in Table 1.
      Table 1Biological Activity of Select CB Compounds
      CompoundCB ClassMechanism of Action
      Receptor types.
      Selected Biologic Effects of Interest
      2-ArachidonylglycerolEndocannabinoid (structure: eicosanoid
      Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:4‒15.
      )
      Agonist of CB1R (primary location: CNS) and primary endogenous agonist of CB2R (PNS and immune cells)
      Baggelaar MP, Maccarrone M, van der Stelt M. 2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain. Prog Lipid Res 2018;71:1‒17.
      ; additional affinity for GABAa, TRPV1, PPAR-γ, GPR55
      Regulation of circulatory system; emotion; cognition; pain; inflammation (immune cells and neuroinflammation)
      Anandamide (N-arachidonoylethanolamine, AEA)Endocannabinoid (structure: eicosanoid
      Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:4‒15.
      )
      Partial agonist of CB1R (primary location: CNS) and CB2R (primary location: periphery)
      Scherma M, Masia P, Satta V, Fratta W, Fadda P, Tanda G. Brain activity of anandamide: a rewarding bliss? Acta Pharmacol Sin 2019;40:309‒323.
      ; activator of TRPV1 cation channel
      Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:4‒15.
      Reward pathways; thermoregulation; nociception
      CBDPhytocannabinoid (structure: classical CB
      Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:4‒15.
      )
      Low affinity for CB1R/CB2R; can act as an antagonist of CB1R/CB2R agonists and inverse agonist of multiple GPRs; 5-HT1a partial agonist at low concentration (inverse agonist at higher concentrations); an allosteric modulator of μ and δ opioid receptors; possible PPAR-γ agonistEpilepsy; movement disorders; inflammation; pain; anxiety
      DronabinolSynthetic CB (structure: synthetic analog of THC)Agonist of CB1R and CB2R; complex CNS effects, including central sympathomimetic action; possible agonism of CB1R receptors in vomiting center of the medulla
      Prescribers’ Digital Reference. Dronabinol mechanism of action. https://www.pdr.net/drug-summary/Marinol-dronabinol-2726#14 (accessed on September 2021).
      ; possible CB receptor‒mediated effects in neural tissue; CB1R receptor agonism in hypothalamus stimulating appetite
      Prescribers’ Digital Reference. Dronabinol mechanism of action. https://www.pdr.net/drug-summary/Marinol-dronabinol-2726#14 (accessed on September 2021).
      Appetite; nausea/emesis; sleep apnea; cannabis withdrawal
      NabiloneSynthetic CB (structure: synthetic analog of Δ9-THC)Agonist of CB1R and CB2R; possible agonism of CB1R receptors in vomiting center of the medulla
      Prescribers’ Digital Reference. Nabilone mechanism of action. https://www.pdr.net/drug-summary/Cesamet-nabilone-692#0 (accessed on September 2021).
      Chemotherapy-induced nausea/emesis; neuropathic pain
      N-PEAEndocannabinoid-like (structure: fatty acid amide)Agonist of nuclear PPAR-α; agonist of GPR-55; indirect activator of CB1R/CB2R and TRPV1
      Petrosino S, Di Marzo V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations Br J Pharmacol 2017;174:1349‒65.
      Pain (particularly neuropathic); inflammation; mast cell degranulation
      Δ9-THCPhytocannabinoid (structure: classical CB
      Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:4‒15.
      )
      Partial agonist of CB1R (action in CNS, PNS, and enteric nervous system) and CB2R (PNS)Neurological disorders; movement disorders; pain; appetite; inflammation
      Abbreviations: Δ9-THC, delta-9-tetrahydrocannabinol; 5-HT, 5-hydroxytryptamine; AEA, anandamide; CB, cannabinoid; CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; CBD, cannabidiol; GPR, G-protein-coupled receptor; N-PEA, N-palmitoylethanolamide; PNS, peripheral nervous system; PPAR-γ, peroxisome proliferator‒activated receptor-γ.
      CB1R plays role in anxiety, pain, metabolism, addiction, inflammation; CB2R plays role in inflammation. GPR is a family of transmembrane receptors with signal transduction through cAMP or phosphatidylinositol pathways. γ-Aminobutyric acid (GABA)a plays a role in mood, sedation, memory, convulsion, and muscle tone. PPAR-γ plays a role in inflammation.
      Serotonin, (5HT1a) plays a role in mood, vascular tone, pain, emesis, and thermoregulation. TRPV1 plays a role in neuropathic pain.
      1 Receptor types.
      2 Console-Bram L, Marcu J, Abood ME. Cannabinoid receptors: nomenclature and pharmacological principles. Prog Neuropsychopharmacol Biol Psychiatry 2012;38:4‒15.
      3 Baggelaar MP, Maccarrone M, van der Stelt M. 2-Arachidonoylglycerol: A signaling lipid with manifold actions in the brain. Prog Lipid Res 2018;71:1‒17.
      4 Scherma M, Masia P, Satta V, Fratta W, Fadda P, Tanda G. Brain activity of anandamide: a rewarding bliss? Acta Pharmacol Sin 2019;40:309‒323.
      5 Prescribers’ Digital Reference. Dronabinol mechanism of action. https://www.pdr.net/drug-summary/Marinol-dronabinol-2726#14 (accessed on September 2021).
      6 Prescribers’ Digital Reference. Nabilone mechanism of action. https://www.pdr.net/drug-summary/Cesamet-nabilone-692#0 (accessed on September 2021).
      7 Petrosino S, Di Marzo V. The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations Br J Pharmacol 2017;174:1349‒65.
      Phytocannabinoids include over 100 compounds; the most notable of these are Δ9-THC and cannabidiol (CBD) (
      • 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.
      ). The most clinically relevant endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG) (
      • 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.
      ), whereas the endogenous fatty acid amide N-palmitoylethanolamide (N-PEA) is also recognized as an important component of the endocannabinoid system (ECS), acting through multiple pathways (
      • Petrosino S.
      • Di Marzo V.
      The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations.
      ). Endocannabinoids have been shown to attenuate the production of proinflammatory cytokines and regulate keratinocyte (KC) expression (
      • 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.
      ). Therefore, it is not surprising that malfunctioning of the ECS has been implicated in a variety of pathologic skin conditions as well as in cutaneous wounds.
      Synthetic CBs, first produced in the 20th century, include dronabinol and nabilone, which are approved by the United States Food and Drug Administration for the treatment of acquired immunodeficiency syndrome‒induced anorexia and for chemotherapy-induced nausea and vomiting (
      • Taylor B.N.
      • Mueller M.
      • Sauls R.S.
      Cannaboinoid antiemetic therapy.
      ).
      The physiologic effects of CBs are mediated through CB receptor 1 (CB1R) and CB receptor 2 (CB2R), which are members of the large family of G protein-coupled receptors. Both CB1R and CB2R are expressed on cutaneous nerve fibers, mast cells, and KCs (
      • 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.
      ). CB1Rs are the predominant CB type in the CNS and appear at lower concentrations in the peripheral nervous system; in the enteric nervous system; as well as in the heart, liver, and muscle tissues (
      • Nikan M.
      • Nabavi S.M.
      • Manayi A.
      Ligands for cannabinoid receptors, promising anticancer agents.
      ). CB2R is notable for its presence in the immune system, with expression among cells of the hematopoietic lineage and organs of the immune system, such as the spleen and thymus (
      • Basu S.
      • Ray A.
      • Dittel B.N.
      Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses.
      ).
      With regard to binding effects, CB1Rs are primarily responsible for memory, mood, and modulation of pain sensation through the release of neurotransmitters (
      • Nikan M.
      • Nabavi S.M.
      • Manayi A.
      Ligands for cannabinoid receptors, promising anticancer agents.
      ). It is thought that CB2Rs are largely responsible for the anti-inflammatory and immunomodulatory effects of CBs (
      • Nikan M.
      • Nabavi S.M.
      • Manayi A.
      Ligands for cannabinoid receptors, promising anticancer agents.
      ). CB2R stimulation in KCs has been shown to promote the release of analgesic opioid peptides, which can modulate pain at a local level as well as systemically (through the CNS) (
      • Caterina M.J.
      TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation.
      ).
      CBs can interact with transient receptor potential channels, also known as ionotropic CB receptors, which have been shown to modulate pain and itch perception (
      • Caterina M.J.
      TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation.
      ). Transient receptor potential channels are abundant on cutaneous peripheral neurons.

      Skin Health and the ECS

      The ECS is an integral component of skin homeostasis, comprising CB1R and CB2R, the endogenous CBs 2-AG and AEA, lipid mediators such as N-PEA, and hydrolytic enzymes such as fatty acid amide hydrolase (
      • 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.
      ). N-PEA itself has a low binding affinity for CB1Rs and CB2Rs but is able to activate CB receptors indirectly and enhance the effects of endogenous CB compounds such as AEA. N-PEA serves as an alternative substrate to fatty acid amide hydrolase; this in turn potentiates the physiologic effects of AEA. This is known as the entourage effect (
      • Ho W.S.
      • Barrett D.A.
      • Randall M.D.
      ‘Entourage’ effects of N -palmitoylethanolamide and N -oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors.
      ). Downstream signaling mediated by AEA leads to the activation of peroxisome proliferator‒activated receptor-α. The signaling response is characterized by the inhibition of proinflammatory cytokines, including IL-2; the induction, proliferation, and differentiation of KCs; and increased synthesis of lipids, including fatty acids and ceramides, which play an important role in maintaining skin barrier function and integrity (
      • Kreitzer F.R.
      • Stella N.
      The therapeutic potential of novel cannabinoid receptors.
      ).
      Transcription factors such as NF-κB are essential to the pathogenesis of inflammatory skin disorders; NF-κB has been shown to activate downstream molecular signaling pathway, resulting in the upregulation of proinflammatory mediators such as IL-8, matrix metalloproteinase, and VEGF (
      • Hoesel B.
      • Schmid J.A.
      The complexity of NF-κB signaling in inflammation and cancer.
      ). Results of an in vitro model of human KC cell lines show that CBD is able to inhibit NF-κB transcription and subsequently inactivate the inflammatory cascade (
      • Motwani M.P.
      • Bennett F.
      • Norris P.C.
      • Maini A.A.
      • George M.J.
      • Newson J.
      • et al.
      Potent anti-inflammatory and pro-resolving effects of Anabasum in a human model of self-resolving acute inflammation.
      ).

      Mechanistic Action of Topical CBS

      Topical Δ9-THC and CBD have been shown to suppress the levels of proinflammatory cytokines, including IL such as IL-6 and IL-17, whereas pretreatment with CBD has resulted in an upregulation of IL-10, an anti-inflammatory cytokine (
      • Kozela E.
      • Juknat A.
      • Kaushansky N.
      • Rimmerman N.
      • Ben-Nun A.
      • Vogel Z.
      Cannabinoids decrease the th17 inflammatory autoimmune phenotype.
      ). These immune-modulating effects appear to be mediated independently of CB signaling pathways.

      Mechanistic Action of Oral CBS

      Recent studies have illustrated several mechanisms through which oral CBs exert their effects. For example, systemic sclerosis (SSc) fibroblasts are known to possess increased numbers of CB2R, through which oral CB2R agonists act to reduce TGFβ and collagen production and limit the fibrosis characteristic of SSc (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.
      • Hsu V.
      • et al.
      Safety and efficacy of Lenabasum in a Phase II, randomized, placebo-controlled trial in adults with systemic sclerosis.
      ). Modulation of the ECS system by CB2R agonists stimulates the resolution of innate immune responses by activating the production of proresolving lipid mediators, such as lipoxin-A4 and B4 and resolvin-D1 and D3. Activation of CB2Rs present in lymphoid tissue has been shown to inhibit cytokine release from immune cells and, therefore, decrease inflammation (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.
      • Hsu V.
      • et al.
      Safety and efficacy of Lenabasum in a Phase II, randomized, placebo-controlled trial in adults with systemic sclerosis.
      ). The marked anti-inflammatory action of CB2R agonists is due in part to inhibition of leukotriene B4, a neutrophil chemoattractant, and allows for effective clearance of inflammatory stimuli by inhibiting antiphagocytic prostanoids, including prostaglandin E2, thromboxane B2, and prostaglandin F2α (
      • Motwani M.P.
      • Bennett F.
      • Norris P.C.
      • Maini A.A.
      • George M.J.
      • Newson J.
      • et al.
      Potent anti-inflammatory and pro-resolving effects of Anabasum in a human model of self-resolving acute inflammation.
      ).
      Oral CB2R agonists have also been shown to modulate the immune system in patients with dermatomyositis (DM). A recent study showed a reduction in the production of proinflammatory cytokines, including TNF-α, IFN-α, and IFN-β, among those treated with ajulemic acid/lenabasum, a CB2R agonist (
      • Robinson E.S.
      • Alves P.
      • Bashir M.M.
      • Zeidi M.
      • Feng R.
      • Werth V.P.
      Cannabinoid reduces inflammatory cytokines, tumor necrosis factor-α, and Type I interferons in dermatomyositis in vitro.
      ).
      A summary figure illustrating the mechanistic actions and therapeutic effects of CBs as they relate to skin health and the immune system is provided in Figure 1.
      Figure thumbnail gr1
      Figure 1Cannabinoid mechanisms of action. Proposed mechanisms of action of cannabinoids on the immune and cutaneous neuroendocrine system. CB, cannabinoid; CBR, cannabinoid receptor; CB1R, cannabinoid receptor 1; CB2R, cannabinoid receptor 2; CBD, cannabidiol; MMP-9, matrix metalloproteinase 9; PG, prostaglandin; THC, tetrahydrocannabinol; TRP, transient receptor potential; TXB2, thromboxane B2.
      A systematic review was conducted, adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.A.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
      ) as illustrated in Figure 2. A search in the Embase and PubMed databases for all peer-reviewed articles in the English language was performed in October 2020, using the following search terms: dermatology, dermatologic conditions, cutaneous, skin, psoriasis, pruritus, and oral, topical, cannabinoids.
      Figure thumbnail gr2
      Figure 2PRISMA flow diagram. The search process is depicted using a flow diagram adapted from the PRISMA guidelines. PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses.
      The resulting articles were screened on the basis of eligibility criteria. Only articles written in English and discussing the study of CB-based products in humans for treating skin conditions were included. Review articles, studies regarding pharmacology, and in vitro or in vivo studies were excluded. Study design and outcome data were extracted from each included article and are summarized in Tables 2 and 3.
      Table 2Summary of studies investigating oral cannabinoids
      Condition, SourceLevel of EvidenceStudy Design, Number of ParticipantsCannabinoid Treatment RegimenResultsAdverse Events
      Diffuse cutaneous SSc
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Furst D.
      • et al.
      OP0126 A phase 2 study of safety and efficacy of anabasum (JBT-101) in systemic sclerosis [abstract].
      ,
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Hsu V.
      • et al.
      Safety and efficacy of anabasum (JBT-101) in diffuse cutaneous systemic sclerosis (dcSSc) subjects treated in an open-label extension of trial jbt101-ssc-001.
      1RCT, n = 42Oral lenabasum 5 mg or 20 mg q.d. or 20 mg b.i.d. for 4 wks, then 20 mg b.i.d. for 8 wks; or PBO .Significant Improvement in ACR-CRISS scores, (including MRSS, PtGA, and PGA) compared with those of the PBO (over 16 wks), P = 0.044.n = 5 (14%), mild fatigue; n = 4 (11%), mild/moderate URI; dizziness occurred in two (6%) subjects.
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Furst D.
      • et al.
      OP0126 A phase 2 study of safety and efficacy of anabasum (JBT-101) in systemic sclerosis [abstract].
      ,
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Hsu V.
      • et al.
      Safety and efficacy of anabasum (JBT-101) in diffuse cutaneous systemic sclerosis (dcSSc) subjects treated in an open-label extension of trial jbt101-ssc-001.
      2OLE, n = 36Oral lenabasum (20 mg b.i.d.)Skin induration improved; no withdrawals due to medicationAEs: ≥10% subjects had mild fatigue (14%) and mild/moderate URI (11% of subjects); dizziness in 6%.
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.
      • Domsic R.
      • Hsu V.
      • et al.
      OP0006 Safety and efficacy of lenabasum (JBT-101) in diffuse cutaneous systemic sclerosis subjects treated for one year in an open-label extension of trial jbt101-ssc-001 [abstract].
      2OLE, n = 19Oral lenabasum (20 mg b.i.d.)Improvements from study start were ACR-CRISS score = 0.33, MRSS = -8.6 (1.5), HAQ-DI = ‒0.14 (0.11), PGA = ‒0.9 (0.5), and 5-D itch = ‒2.3 (0.8). FVC% predicted was stable from study start.One subject had a life-threatening AE, 3 (8%) had severe AEs, 21 (58%) moderate, and 8 (22%) mild AEs. Seven (19%) had AEs related to lenabasum; AEs include URI, UTI, diarrhea, and skin ulcers.
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.
      • Domsic R.
      • Hsu V.
      • et al.
      OP0325 safety and efficacy of lenabasum in an open-label extension of a phase 2 study in diffuse cutaneous systemic sclerosis subjects (DCSSC) [abstract].
      2OLE, n = 36Oral lenabasum (20 mg b.i.d.), assessed at 4 weeks, then every 8 weeksCompared with the study start, ACR-CRISS median score: 0.99 (0.43 IQR) at wk 76 and MRSS declined by mean (SD) = ‒10.7 (7.2) points. FVC% predicted decreased by 2.5% from the study start.At week 92, 97% of subjects had at least 1 AE. 7 (19%) had at least 1 AE considered (fatigue), which was related to lenabasum
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.
      • Hsu V.
      • et al.
      Safety and efficacy of Lenabasum in a Phase II, randomized, placebo-controlled trial in adults with systemic sclerosis.
      1RCT, n = 42Oral lenabasum, dose 5 mg or 20 mg once a day, or 20 mg b.i.d. for 4 weeks, then 20 mg b.i.d. for 8 weeks, or PBOMedian ACR-CRISS score at wk 16 was 0.33 versus 0.00 in PBO. PtGA treatment differences: 1.2 (0.67) (P = 0.04, P = 0.08 at wk 16). SSPRO treatment effect (SE) = ‒16 (6.0) (P = 0.005, P = 0.01 at wk 12); 5-D itch was ‒1.8 (1.0) (P = 0.04, P = 0.08 at wk 12). HAQ-DI at 12 weeks: ‒0.32 (0.12) (P = 0.006, P = 0.01).Lenabasum versus PBO: AEs 63% versus 60%. In lenabasum group, dizziness and nausea were most common. No evidence of toxicity.
      • Nogueira A.R.
      • Shoenfeld Y.
      • Amital H.
      Cannabis sativa as a Potential Treatment for Systemic Sclerosis.
      5Case report, n = 1Inhaled cannabis (30 g/day)Improvement in all symptoms and total resolution of Raynaud's phenomenon and dyspnea.No AEs reported
      • Cocchiara E.
      • Spinella A.
      • Magnani L.
      • Lumetti F.
      • Palermo A.
      • Balocchi G.
      • et al.
      AB0645 cannabinoids in the treatment of pain related to systemic sclerosis skin ulcers: our experience [abstract].
      3Cohort study, n = 25CBD (10%) orally b.i.d. and topical application.Significant reduction in pain VAS and HAQ-DI at 2 months.No AEs reported
      Dermatomyositis (skin predominant)
      • Werth V.P.
      • Hejazi E.
      • Pena S.
      • Haber J.S.
      • Feng R.
      • Patel B.
      • et al.
      605 Study of safety and efficacy of lenabasum, a cannabinoid receptor type 2 agonist, in refractory skin-predominant dermatomyositis.
      1RCT, n = 22Oral lenabasum in escalating doses for12 weeks.Mean reduction in CDASI activity by ≥5 points at all visits after 4 weeks (P = 0.02); Greater improvement than PBO in PROM of global skin disease and overall disease assessments, skin symptoms
      Skin symptoms included: pain interfering with activities, fatigue, photosensitivity and itch.
      (P ≤ 0.1) at visits after wk 4.
      No AEs reported
      • Werth V.
      • Pearson D.
      • Owaka J.
      • Feng R.
      • Concha J.
      • Patel B.
      • et al.
      op 0241 safety and efficacy of lenabasum in an open-label extension of a phase 2 study of lenabasum in refractory skin-predominant dermatomyositis (dm) subjects [abstract].
      2OLE, n = 22Oral lenabasum (20 mg b.i.d.)At week 28, decrease in CDASI score by 15 points. Physician overall disease VAS = ‒2.6 (1.90) points, 82.3% of subjects achieving at least 1 point and 20% improvement. Significant improvement in Skindex 29.≥1 mild AEs in five subjects (25%)

      Two subjects (10%) experienced DM flare
      Trichotillomania
      • Grant J.E.
      • Odlaug B.L.
      • Chamberlain S.R.
      • Kim S.W.
      Dronabinol, a cannabinoid agonist, reduces hair pulling in trichotillomania: a pilot study.
      3Pilot study, n = 14Oral dronabinol (2.5‒15 mg/day)MGH-HPS scores decreased from a mean of 16.5 ± 4.4 at baseline to 8.7 ± 5.5 at study endpoint (mean effective dose = 11.1 ± 4); NIMH-Trichotillomania severity: 11.21 decreased to 4.36 (P < 0.001)No AEs reported
      Epidermolysis bullosa
      • Schräder N.H.B.
      • Duipmans J.C.
      • Molenbuur B.
      • Wolff A.P.
      • Jonkman M.F.
      Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases.
      4Case Series, n = 3Sublingual THC/CBD (20 mg/mg, CBD; 13 mg/mg,THC)Improved pain control and decreased pruritus with CBD/THC oil. VAS reduction from 9/10 to 3/10 at 1 month for one subject; 40% reduction in pain reported in one subject; VAS reduction from 9/10 to 1‒4/10 at 1 month in one subject.Increased appetite (n = 1), drug‒drug interaction with opioid in one patient (reduced reaction time, altered sense of time)
      Pruritus (various causes)
      • Neff G.W.
      • O’Brien C.B.
      • Reddy K.R.
      • Bergasa N.V.
      • Regev A.
      • Molina E.
      • et al.
      Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease.
      4Case series, n = 35 mg Dronabinol nightlyResolution of pruritus in three of three patients after 4‒6 hs of dronabinol doseDisturbance in coordination, resolved with a decrease in dronabinol (by 2.5 mg)
      • Dvorak M.
      • Watkinson A.
      • McGlone F.
      • Rukwied R.
      Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin.
      3Pilot study, n = 12HU210 (through a skin patch or microdialysis)Resolution of pruritus. Skin blood flow and neurogenic-mediated flare responses were reduced (P < 0.003 and P < 0.03)AEs not reported
      Abbreviations: ACR-CRISS, American College of Rheumatology-Combined Response Index in diffuse cutaneous Systemic Sclerosis; AE, adverse event; b.i.d., twice a day; CBD, cannabidiol; CDASI, Cutaneous Dermatomyositis Disease Area and Severity Index; DM, dermatomyositis; EB, epidermolysis bullosa; HAQ-DI, Health Assessment Questionnaire-Disability Index; IQR, interquartile range; MGH-HPS, Massachusetts General Hospital Hair Pulling Scale; MRSS, Modified Rodnan Skin thickness Score; NIMH, National Institute of Mental Health; OLE, open label extension; PBO, placebo; PGA, Physician Global Assessment; PROM, patient reported outcome measure; ptGA, patient Global-Assessment; q.d., every day; RCT, randomized controlled trial; SSc, systemic sclerosis; SSPRO, Scleroderma Skin Patient-Reported Outcome; THC, Δ9-tetrahydrocannabinol; URI, upper respiratory infection; UTI, urinary tract infection; VAS, Visual Analog Score.
      1 Skin symptoms included: pain interfering with activities, fatigue, photosensitivity and itch.
      Table 3Summary of Studies Investigating Topical Cannabinoids
      Condition, SourceLevel of EvidenceStudy DesignCannabinoid Treatment RegimenResultsAdverse Events
      Atopic dermatitis
      • Yuan C.
      • Wang X.-M.
      • Guichard A.
      • Tan Y.M.
      • Qian C.-Y.
      • Yang L.-J.
      • et al.
      N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients.
      1RCT, n = 60Topical N-PEA/AEAReduction in skin scaling, dryness, and itching (P < 0.05)AEs not reported
      • Palmieri B.
      • Laurino C.
      • Vadalà M.
      A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars.
      3Retrospective cohort, n = 5Topical CBD, twice daily, for 3 monthsHydration increased (P < 0.01); TEWL improved (P < 0.001); improvement in SCORAD index scoreAEs not reported
      • Eberlein B.
      • Eicke C.
      • Reinhardt H.W.
      • Ring J.
      Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study).
      3Cohort, n = 2,456Topical N-PEA, b.i.d. for 6 wksSignificant reduction in dryness, excoriations, lichenification, scaling, erythema, and pruritus (P < 0.001).Pruritus, burning, and erythema
      • 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.
      3Cohort study, n = 20Topical adelmidrol16 (80%) experienced complete resolution of AD symptomsAEs not reported
      • Maghfour J.
      • Rietcheck H.R.
      • Rundle C.W.
      • Runion T.M.
      • Jafri Z.A.
      • Dercon S.
      • et al.
      An observational study of the application of a topical cannabinoid gel on sensitive dry skin.
      )
      3Cohort study, n = 16Topical CBD, b.i.d. for 2 wksReduction in POEM: (16 ± 1.35) to (8.25 ± 1.80), P < 0.0007. QOLHEQ from a mean score of 20.9 ± 2.06 to 8.375 ± 1.609 (P < 0.004)AEs not reported
      Pruritus (various causes)
      • 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.
      3OLE, n = 21Topical AEA/N-PEAReduction in xerosis in 80% of Pts; decrease in pruritus (P < 0.001); n = 8 experienced resolution of itchAEs not reported
      • 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.
      3Cohort, n= 100Topical N-PEA, twice daily, for 2 wksPruritus VAS decreased after 2-wk treatment (P < 0.001).12 subjects experienced the following AEs: pruritus, stinging, scaling, and erythema)
      • Ständer S.
      • Reinhardt H.W.
      • Luger T.A.
      Topische Cannabinoidagonisten. Eine effektive, neue Möglichkeit zur Behandlung von chronischem Pruritus [Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus].
      3Observational, n = 7Topical N-PEA, daily, 2 wks for 6 monthsImprovement in pruritus, unspecified. No changes in the intensity of pruritus due to aquagenic and/or cholestasisAEs not reported
      Prurigo nodularis
      • Ständer S.
      • Reinhardt H.W.
      • Luger T.A.
      Topische Cannabinoidagonisten. Eine effektive, neue Möglichkeit zur Behandlung von chronischem Pruritus [Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus].
      3Observational, n = 13Topical N-PEA, daily for 7.6 wksReduction in pruritus in nine subjectsAEs not reported
      Lichen simplex chronicus
      • Ständer S.
      • Reinhardt H.W.
      • Luger T.A.
      Topische Cannabinoidagonisten. Eine effektive, neue Möglichkeit zur Behandlung von chronischem Pruritus [Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus].
      3Observational, n = 2Topical N-PEA, daily for 3

      wks
      (VAS: 8.5 vs. 0; P < 0.05) in both PtsAEs not reported
      Psoriasis vulgaris
      • Friedman A.J.
      • Momeni K.
      • Kogan M.
      Topical cannabinoids for the management of psoriasis vulgaris: report of a case and review of the literature.
      5Case report, n = 1THC soap infused with hemp 5 mg/mL, hair oil with THC distillate dissolved oil 5 mg/mLLesion clearance after 2 wks. At 2 months, Pt started using product as maintenance therapy (once a wks)AEs not reported
      • Palmieri B.
      • Laurino C.
      • Vadalà M.
      A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars.
      3Retrospective cohort, n = 5Topical CBD ointment, b.i.d. for 3 monthsA decrease in the number of psoriasis plaques. Improved PASI at day 90 (P < 0.001).AEs not reported
      Scalp psoriasis and seborrheic dermatitis
      • Vincenzi C.
      • Tosti A.
      Efficacy and tolerability of a shampoo containing broad-spectrum cannabidiol in the treatment of scalp inflammation in patients with mild to moderate scalp psoriasis or seborrheic dermatitis.
      3Observational study, n = 500.075% CBD in shampoo, dailyReduction in arborizing vessel/twisted capillary inflammation and scaling by day 14 in both scalp psoriasis and seborrheic dermatitis.AEs not reported
      Epidermolysis bullosa
      • Chelliah M.P.
      • Zinn Z.
      • Khuu P.
      • Teng J.M.C.
      Self-initiated use of topical cannabidiol oil for epidermolysis bullosa.
      4Case Series, n = 3Topical CBD, dailyDecreased pain, faster AEs not reported

      wound healing
      Wounds (pyoderma gangrenosum, calciphylaxis)
      • Maida V.
      • Corban J.
      Topical medical cannabis: A new treatment for wound pain-three cases of pyoderma gangrenosum.
      4Case series, n = 3, Pyoderma GangrenosumTHC 7 mg/ml + CBD 9 mg/ml). Route: 0.5-1mL to wound bed.Daily pain score decreased (P <0.05) (n = 2). All cases had pain reduction of 30% or greater. Average daily opioid dose was reducedOnset of analgesia 3‒5 min after application of topical CBD/THC
      • Maida V.
      • Shi R.B.
      • Fazzari F.G.T.
      • Zomparelli L.
      Promoting wound healing of uremic calciphylaxis leg ulcers using topical cannabis-based medicines.
      2Multicohort open-label trial, n = 33, calciphylaxisTopical THC and CBDWound closure in up to 90% of cases in nonuremic Pts.AEs not reported
      Abbreviations: AD, atopic dermatitis; AE, adverse event; AEA, anandamide; b.i.d., twice a day; CBD, cannabidiol; N-PEA, N-palmitoylethanolamide; PG, pyoderma gangrenosum; Pt, Patient; sig, significant; POEM, patient-oriented eczema measure; QOLHEQ, Quality of Life Hand Eczema Questionnaire; RCT, randomized controlled trial; SCORAD, scoring atopic dermatitis; TEWL, transepidermal water loss; THC, tetrahydrocannabinol; VAS, Visual Analog Score.
      The search criteria identified 270 published articles from 1965 to October 2020. After duplicates were removed, two reviewers (TES and JM) independently screened articles on the basis of title, abstract, and full-text review to determine eligibility. One article (
      • Maghfour J.
      • Rietcheck H.R.
      • Rundle C.W.
      • Runion T.M.
      • Jafri Z.A.
      • Dercon S.
      • et al.
      An observational study of the application of a topical cannabinoid gel on sensitive dry skin.
      ) known to the authors from previous research was also included, with 26 reports eligible for inclusion in this review. Of these, 12 were clinical trials (randomized, open label); six were cohort studies, including one retrospective study; six were case reports or case series; and two were pilot studies. Retrieved articles included assessments of both topical and oral CBs.
      There were 13 reports that assessed the effects of systemic CBs (oral, inhalation, or sublingual preparations), of which seven were clinical trials; there were two pilot studies, two case series, one case report, and one experimental study (see Table 2).
      There were 13 articles assessing the utility of topical CBs (shown in Table 3). Of these, four were randomized controlled trials (RCTs), five were cohort studies, and four were case reports or case series. Only one article investigated the effects of both topical and oral CBs.

      Efficacy of Oral CBS

      Diffuse cutaneous SSc

      Current dermatologic literature regarding the use of oral CBs is focused on the treatment of diffuse cutaneous systemic sclerosis. The strongest evidence of safety and efficacy is derived from two RCTs and three open-label extension trials—in these trials, selective CB2R agonists (ajulemic acid; trade name lenabasum, formerly anabasum) were investigated.
      Lenabasum is a nonpsychoactive synthetic CB that is a CB2R agonist. Its therapeutic effects occur through the modulation of the immune system and resolution of fibrosis, through two putative molecular mechanisms (
      • Burstein S.
      Molecular mechanisms for the inflammation-resolving actions of Lenabasum.
      ). After CB2R and phospholipase A2 activation, free arachidonic acid enters one of two pathways: the cyclooxygenase-2– or lipoxygenase-mediated pathway (
      • Burstein S.
      Molecular mechanisms for the inflammation-resolving actions of Lenabasum.
      ). The cyclooxygenase-2 pathway facilitates caspase production and ultimately apoptosis and resolution of chronic inflammation, whereas the lipoxygenase pathway produces lipoxin A4 and other proresolving mediators (
      • Burstein S.
      Molecular mechanisms for the inflammation-resolving actions of Lenabasum.
      ).
      Lenabasum was investigated for the treatment of SSc in 42 participants on immunosuppressive therapy, who received either placebo or oral lenabasum for a total duration of 84 days (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Furst D.
      • et al.
      OP0126 A phase 2 study of safety and efficacy of anabasum (JBT-101) in systemic sclerosis [abstract].
      ,
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Hsu V.
      • et al.
      Safety and efficacy of anabasum (JBT-101) in diffuse cutaneous systemic sclerosis (dcSSc) subjects treated in an open-label extension of trial jbt101-ssc-001.
      : “A phase 2 study…”). After discontinuation of therapy or placebo, all participants were followed from days 85 to 113. Therapeutic dosage was based on randomization and consisted of the following: 5 mg lenabasum daily, 20 mg lenabasum daily, or 20 mg lenabasum twice a day for days 1 to 28, followed by 20 mg twice daily on days 29 to 84, or placebo on days 1 to 84. In the overall disease assessment, the treated group experienced a greater improvement than the placebo group (American College of Rheumatology-combined response index in diffuse cutaneous systemic sclerosis [ACR-CRISS] score: 33 vs. 1% at week 16 in the lenabasum and placebo groups, respectively, P = 0.044). There was also a greater reduction in skin thickness and pruritus observed in the lenabasum group. In an open-label extension (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Furst D.
      • et al.
      OP0126 A phase 2 study of safety and efficacy of anabasum (JBT-101) in systemic sclerosis [abstract].
      ,
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Hsu V.
      • et al.
      Safety and efficacy of anabasum (JBT-101) in diffuse cutaneous systemic sclerosis (dcSSc) subjects treated in an open-label extension of trial jbt101-ssc-001.
      : “Safety and efficacy…”), all participants received lenabasum for a median duration of 194 days, and at 10 weeks, modified Rodnan skin thickness score (MRSS) decreased by 3.2 compared with that at the baseline (P = 0.0001).
      In a double-blind placebo-controlled RCT (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.
      • Hsu V.
      • et al.
      Safety and efficacy of Lenabasum in a Phase II, randomized, placebo-controlled trial in adults with systemic sclerosis.
      ), the safety and efficacy of oral Lenabasum were explored in 42 subjects (aged 18–69 years) with diffuse cutaneous SSc. This included 32 female participants (9 in the placebo group and 23 in the treatment group). During the initial 4 weeks, participants in the treated group received one of the following: 5 mg or 20 mg of lenabasum once daily. For the remaining treatment period (8 weeks), all subjects in the lenabasum-treated group received a dose of 20 mg twice daily. The control group (n = 12) received placebo throughout the entire study duration (n = 12 weeks). All participants were assessed at weeks 4, 8, 12, and 16.
      All participants, including the control group, were receiving background immunosuppressive medications (mycophenolate, etanercept, or hydroxychloroquine). All treated subjects experienced an overall improvement as assessed by the ACR-CRISS score. The ACR-CRISS is a validated outcome measure for SSc. It is composed of five core sets of measures, including MRSS, percent predicted forced vital capacity, the health assessment questionnaire disability index, and the patient and clinical global assessments. A score of 0.6 or higher indicates the likelihood that a patient improved with treatment (
      • Khanna D.
      • Berrocal V.J.
      • Giannini E.H.
      • Seibold J.R.
      • Merkel P.A.
      • Mayes M.D.
      • et al.
      The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis.
      ). At week 16, the ACR-CRISS score for the treated group was 0.33 (interquartile range: 0.01–0.82), compared with 0.00 (interquartile range: 0.000–0.16) in the placebo group (P = 0.04). Participants also experienced improvement in the following domains: scleroderma skin patient-reported outcome (P < 0.005), MRSS (mean ± SEM: −2.6 ± 1.9 at week 16, P < 0.05), and 5-D itch score (mean ± SEM: −1.8 ± 1.0 at week 12, P = 0.04).
      Two open-label trials (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.
      • Domsic R.
      • Hsu V.
      • et al.
      OP0006 Safety and efficacy of lenabasum (JBT-101) in diffuse cutaneous systemic sclerosis subjects treated for one year in an open-label extension of trial jbt101-ssc-001 [abstract].
      ,
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.
      • Domsic R.
      • Hsu V.
      • et al.
      OP0325 safety and efficacy of lenabasum in an open-label extension of a phase 2 study in diffuse cutaneous systemic sclerosis subjects (DCSSC) [abstract].
      ) further explored the safety and efficacy of oral lenabasum among participants who had completed the phase II trial. A total of 25 subjects remained on lenabasum for 52 weeks, with additional improvement in ACR-CRISS score (56%) compared with that at the baseline (before therapy initiation) (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Furst D.
      • et al.
      OP0126 A phase 2 study of safety and efficacy of anabasum (JBT-101) in systemic sclerosis [abstract].
      ,
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Hsu V.
      • et al.
      Safety and efficacy of anabasum (JBT-101) in diffuse cutaneous systemic sclerosis (dcSSc) subjects treated in an open-label extension of trial jbt101-ssc-001.
      : “Safety and efficacy…”). A reduction in skin thickness (MRSS = −8.6) and decrease in pruritus (5-D itch scale = −2.3) were also observed. In another open-label study (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.
      • Domsic R.
      • Hsu V.
      • et al.
      OP0325 safety and efficacy of lenabasum in an open-label extension of a phase 2 study in diffuse cutaneous systemic sclerosis subjects (DCSSC) [abstract].
      ), participants who remained on lenabasum for >18 months continued to experience clinical improvement in ACR-CRISS score (0.99) and skin thickness reduction (MRSS = −10.2).
      It is important to note that although lenabasum appeared to show great promise for the treatment of scleroderma, on the basis of the results of phase II trials and open-label extension studies, it has failed phase III testing, owing to its inability to meet the primary efficacy endpoint of significant ACR-CRISS improvement compared with placebo (
      • Terry M.
      Corbus’ Lenabasum fails Phase III trial for systemic sclerosis. BioSpace.
      ). Notably, ACR-CRISS was the primary outcome measure in the successful phase II trial of lenabasum. However, posthoc analysis of the phase III data showed that participants who received background immunosuppression and were treated with 20 mg lenabasum twice daily had a smaller decline in forced vital capacity at 1 year than those who were treated with placebo (nominal P = 0.048). Treatment with lenabasum was also associated with a greater likelihood of a stable forced vital capacity percentage predicted (64% lenabasum vs. 35% placebo).
      Both inhaled cannabis and oral formulations of CBD oil have resulted in improvement in the symptoms of SSc. In a study (
      • Cocchiara E.
      • Spinella A.
      • Magnani L.
      • Lumetti F.
      • Palermo A.
      • Balocchi G.
      • et al.
      AB0645 cannabinoids in the treatment of pain related to systemic sclerosis skin ulcers: our experience [abstract].
      ) on subjects with SSc (n = 25; 22 female) that assessed both oral ingestion of 10% CBD oil (five drops twice daily) and local application of CBD oil to cutaneous ulcers, there was a significant improvement in pain, Visual Analog Score (VAS) improved from 94.8 at baseline to 40.9 after treatment (P < 0.0001), and the health assessment questionnaire disability index decreased from 1.1 to 0.46 after a 2-month course of therapy.
      In a previous study (
      • Nogueira A.R.
      • Shoenfeld Y.
      • Amital H.
      Cannabis sativa as a Potential Treatment for Systemic Sclerosis.
      ), a patient with SSc who smoked 30 g of C. sativa daily experienced an improvement in dyspnea, Raynaud’s phenomenon, and pain. However, there were no specific metrics measured in this study.

      DM

      The role of lenabasum was investigated in a study of 22 participants with DM: 11 subjects received 20 mg oral lenabasum twice daily, whereas the remaining half of participants were in the placebo group for a total duration of 16 weeks (
      • Werth V.P.
      • Hejazi E.
      • Pena S.
      • Haber J.S.
      • Feng R.
      • Patel B.
      • et al.
      605 Study of safety and efficacy of lenabasum, a cannabinoid receptor type 2 agonist, in refractory skin-predominant dermatomyositis.
      ). Compared with placebo, a five-point reduction in cutaneous disease activity severity index score (CDASI) was observed at 16 weeks (P < 0.05). Patient-reported metrics of global skin disease, including photosensitivity and itch, were significantly improved at week 4. Treated participants also experienced an improvement in fatigue, sleep, and functional activity.
      Of the 22 participants in the study, 20 were eligible for an open-label extension (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.
      • Domsic R.
      • Hsu V.
      • et al.
      OP0325 safety and efficacy of lenabasum in an open-label extension of a phase 2 study in diffuse cutaneous systemic sclerosis subjects (DCSSC) [abstract].
      ,
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Furst D.
      • et al.
      OP0126 A phase 2 study of safety and efficacy of anabasum (JBT-101) in systemic sclerosis [abstract].
      ,
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.M.
      • Domsic R.T.
      • Hsu V.
      • et al.
      Safety and efficacy of anabasum (JBT-101) in diffuse cutaneous systemic sclerosis (dcSSc) subjects treated in an open-label extension of trial jbt101-ssc-001.
      ;
      • Werth V.
      • Pearson D.
      • Owaka J.
      • Feng R.
      • Concha J.
      • Patel B.
      • et al.
      op 0241 safety and efficacy of lenabasum in an open-label extension of a phase 2 study of lenabasum in refractory skin-predominant dermatomyositis (dm) subjects [abstract].
      ), in which all subjects received oral lenabasum for 28 weeks. A 15.4-point reduction in CDASI, a reduction in VAS results for itch and pain, and QOL improvement measured through Skindex-29 were noted after treatment completion. There were two serious adverse events reported (fatigue and metastatic prostate cancer), which were considered unrelated to lenabasum; no serious events related to lenabasum were reported, and no subjects discontinued the open-label extension owing to adverse events related to the drug (
      • Spiera R.
      • Hummers L.
      • Chung L.
      • Frech T.
      • Domsic R.
      • Hsu V.
      • et al.
      OP0325 safety and efficacy of lenabasum in an open-label extension of a phase 2 study in diffuse cutaneous systemic sclerosis subjects (DCSSC) [abstract].
      ). With regard to DM, lenabasum also failed to meet its primary endpoint in phase III: total improvement score at week 28. Of note, regulatory mandates prompted the change from CDASI to total improvement score as the primary outcome for the phase III trial, whereas the validated CDASI scale was downgraded to a secondary endpoint. Nonetheless, posthoc analysis of phase III data revealed that participants with skin predominant DM (minimal muscle activity) experienced a significant improvement in CDASI score (P = 0.016) ().

      Trichotillomania

      The effect of oral dronabinol was investigated in 14 female patients (mean age = 33.3 years) with trichotillomania for a period of 12 weeks (
      • Grant J.E.
      • Odlaug B.L.
      • Chamberlain S.R.
      • Kim S.W.
      Dronabinol, a cannabinoid agonist, reduces hair pulling in trichotillomania: a pilot study.
      ). The mean effective dose of dronabinol was 11.6 mg (range: 2.5−15 mg). At the end of the study, there was an improvement in the Massachusetts General Hospital Hair Pulling Scale from 16.5 ± 4.4 at baseline to 8.7 ± 5.5 (P = 0.001).

      Epidermolysis bullosa

      Phytocannabinoids (Δ9-THC and CBD) were explored as a therapeutic option among three patients with epidermolysis bullosa (aged 36−61 years) (
      • Schräder N.H.B.
      • Duipmans J.C.
      • Molenbuur B.
      • Wolff A.P.
      • Jonkman M.F.
      Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases.
      ). Sublingual delivery of Δ9-THC (13 mg/ml) and CBD (20 mg/ml) was provided to all participants. The main outcome measured was an improvement in pain and pruritus; improvement was noted after only 1 month of treatment.
      In one patient, after 2 years of treatment with the sublingual CB regimen, the addition of topically applied Δ9-THC−CBD oil (1 mg CBD with 0.65 mg Δ9-THC) enabled the cessation of topical morphine and amitriptyline; the patient also continued on the sublingual CB regimen. A patient with recessive dystrophic epidermolysis bullosa (generalized severe) continued to experience severe pain despite being on a regimen of multiple opioids; after 1 week of sublingual CBD−Δ9-THC combination oil, the patient reported a 40% reduction in pain (
      • Schräder N.H.B.
      • Duipmans J.C.
      • Molenbuur B.
      • Wolff A.P.
      • Jonkman M.F.
      Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases.
      ).

      Pruritus secondary to systemic diseases

      In this review, one report (
      • Neff G.W.
      • O’Brien C.B.
      • Reddy K.R.
      • Bergasa N.V.
      • Regev A.
      • Molina E.
      • et al.
      Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease.
      ) assessed the efficacy of oral Δ9-THC for the treatment of recalcitrant pruritus secondary to cholestatic liver disease. All three patients in the report were unresponsive to doxepin, naltrexone, cholestyramine, UV therapy, and plasmapheresis; they experienced severe and debilitating pruritus that resulted in impaired QOL, depression, and suicidal ideation. Patients were started on 5 mg of Δ9-THC at bedtime and experienced a decrease in pruritus, along with improvements in sleep and functional activities, with treatment effects lasting from 4 to 6 hours. One patient developed disturbance in coordination, which improved after a dose reduction to 2.5 mg at night (
      • Neff G.W.
      • O’Brien C.B.
      • Reddy K.R.
      • Bergasa N.V.
      • Regev A.
      • Molina E.
      • et al.
      Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease.
      ).

      Histamine-induced pruritus

      In an experimental study (
      • Dvorak M.
      • Watkinson A.
      • McGlone F.
      • Rukwied R.
      Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin.
      ), pruritus was induced in 18 participants and was successfully treated with peripheral administration (dermal patch) of HU210, a CB2R agonist. Skin blood flow and neurogenic-mediated flare responses were the major outcome measures; both were reduced from baseline (P < 0.003 and P < 0.03, respectively).

      Efficacy of Topical CBS

      The effectiveness of topical CBD, N-PEA, and Δ9-THC was reported for the following conditions: chronic and uremic pruritus, postinflammatory scars, ulcers secondary to pyoderma gangrenosum and calciphylaxis (uremic and nonuremic types), epidermolysis bullosa, psoriasis vulgaris, and dermatitis (atopic, asteatotic, and seborrheic).

      Atopic dermatitis

      The efficacy of topical CBs for dermatitis treatment was reported six times (
      • Cocchiara E.
      • Spinella A.
      • Magnani L.
      • Lumetti F.
      • Palermo A.
      • Balocchi G.
      • et al.
      AB0645 cannabinoids in the treatment of pain related to systemic sclerosis skin ulcers: our experience [abstract].
      ;
      • Eberlein B.
      • Eicke C.
      • Reinhardt H.W.
      • Ring J.
      Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study).
      ;
      • Maghfour J.
      • Rietcheck H.R.
      • Rundle C.W.
      • Runion T.M.
      • Jafri Z.A.
      • Dercon S.
      • et al.
      An observational study of the application of a topical cannabinoid gel on sensitive dry skin.
      ;
      • Palmieri B.
      • Laurino C.
      • Vadalà M.
      A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars.
      ;
      • 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.
      ;
      • Yuan C.
      • Wang X.-M.
      • Guichard A.
      • Tan Y.M.
      • Qian C.-Y.
      • Yang L.-J.
      • et al.
      N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients.
      ). A total of 60 female participants with asteatotic eczema experienced an improvement in scaling, dryness, and itch (P < 0.05) after the use of topical N-PEA and AEA (
      • Yuan C.
      • Wang X.-M.
      • Guichard A.
      • Tan Y.M.
      • Qian C.-Y.
      • Yang L.-J.
      • et al.
      N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: results of a randomized, double-blind, controlled study in 60 patients.
      ). Similar findings were reported among 21 subjects (
      • Maghfour J.
      • Rietcheck H.R.
      • Rundle C.W.
      • Runion T.M.
      • Jafri Z.A.
      • Dercon S.
      • et al.
      An observational study of the application of a topical cannabinoid gel on sensitive dry skin.
      ;
      • Palmieri B.
      • Laurino C.
      • Vadalà M.
      A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars.
      ) with atopic dermatitis when treated with a 1% CBD infusion gel and ointment. There was an improvement in transepidermal water loss (P < 0.001) and PASI score (P < 0.001) after a treatment period of 3 months (
      • Palmieri B.
      • Laurino C.
      • Vadalà M.
      A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars.
      ) and in the patient-oriented eczema measure score from 16 to 8.1 (P < 0.007) (
      • Maghfour J.
      • Rietcheck H.R.
      • Rundle C.W.
      • Runion T.M.
      • Jafri Z.A.
      • Dercon S.
      • et al.
      An observational study of the application of a topical cannabinoid gel on sensitive dry skin.
      ) at 2 weeks. In the same study (
      • Maghfour J.
      • Rietcheck H.R.
      • Rundle C.W.
      • Runion T.M.
      • Jafri Z.A.
      • Dercon S.
      • et al.
      An observational study of the application of a topical cannabinoid gel on sensitive dry skin.
      ) in which authors assessed the emotional burden of atopic dermatitis using the Quality of Life Hand Eczema Questionnaire (QOLHEQ), a significant reduction in the emotional domain of the QOLHEQ was noted after treatment completion (20.9 ± 2.06 vs. 8.37 ± 1.609, P < 0.004)
      Topical adelmidrol, an analog of N-PEA, appeared effective for the treatment of pediatric atopic dermatitis (
      • 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.
      ). After a treatment course of 4 weeks, all participants experienced a significant improvement in pruritus and erythema; 16 (80%) experienced clinical resolution.
      • Eberlein B.
      • Eicke C.
      • Reinhardt H.W.
      • Ring J.
      Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study).
      assessed the efficacy of topical N-PEA in a large dataset of 2,456 patients (aged 21.2 ± 17.8 years; 65% female). Participants from various geographic locations received topical N-PEA with a mean treatment duration of 38 days. All subjects experienced symptom improvement of at least 70% in the following domains: dryness, excoriation, lichenification, scaling, erythema, and pruritus (P < 0.01).

      Psoriasis vulgaris

      Six patients with psoriasis (
      • Friedman A.J.
      • Momeni K.
      • Kogan M.
      Topical cannabinoids for the management of psoriasis vulgaris: report of a case and review of the literature.
      ;
      • Palmieri B.
      • Laurino C.
      • Vadalà M.
      A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars.
      ) were treated with topical CBD (n = 5) or Δ9-THC (n = 1). All patients had a resolution of psoriasis plaques. Patients treated with topical CBD had an overall improvement in PASI score on day 90 (P < 0.001).

      Scalp psoriasis and seborrheic dermatitis

      • Vincenzi C.
      • Tosti A.
      Efficacy and tolerability of a shampoo containing broad-spectrum cannabidiol in the treatment of scalp inflammation in patients with mild to moderate scalp psoriasis or seborrheic dermatitis.
      investigated CBD oil (0.075%) as a treatment for scalp psoriasis (n = 22) and scalp seborrheic dermatitis (n = 28). Efficacy was assessed using trichoscopy at baseline and on day 14. There was a reduction in arborizing vessel/twisted capillary inflammation and scaling by day 14 (2.3 vs. 0.5, P < 0.001). Symptoms of itching and burning were also reduced from 6.9 to 1.3 for scalp psoriasis and from 4.5 to 1.0 for seborrheic dermatitis (both with P < 0.0001).

      Calciphylaxis

      In a multicohort open-label trial (
      • Maida V.
      • Shi R.B.
      • Fazzari F.G.T.
      • Zomparelli L.
      Promoting wound healing of uremic calciphylaxis leg ulcers using topical cannabis-based medicines.
      ), 32 participants with calciphylaxis, not caused by uremia, received topical CBD (3.75 mg/ml) and minimal Δ9-THC (<1 mg per day), which was applied to wound beds and periwound tissues. Wound closure was achieved in 90% of cases after 1 year of treatment. There was only one patient in the trial with uremic calciphylaxis located on the bilateral lower legs; this patient experienced an increase in granulation tissue (58% on the left and 78% on the right leg wound) with an overall reduction in wound size by 9% on the left and 5% on the right. No localized or systemic effects were reported; however, the patient expired owing to coexisting heart disease.

      Pyoderma gangrenosum

      Topical combined CBD–Δ9-THC appears to be effective for pain relief in patients with pyoderma gangrenosum. Three patients achieved symptomatic relief of pain (P < 0.05), with an overall pain reduction of 30% (
      • Maida V.
      • Corban J.
      Topical medical cannabis: A new treatment for wound pain-three cases of pyoderma gangrenosum.
      ).

      Idiopathic pruritus

      Topical N-PEA solution was assessed as a therapy for chronic pruritus secondary to xerosis in 100 participants (mean age = 56 years; range = 18–83 years; 56 female subjects) (
      • 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.
      ). After 2 weeks of twice-daily use, there was a significant improvement in VAS-measured pruritus (P < 0.001). However, in both the treated and control groups, 13 individuals reported worsening of pruritus, stinging, scaling, and erythema.

      Pruritus secondary to systemic disease

      Uremic pruritus secondary to renal disease can be debilitating and often represents a therapeutic challenge. In a trial conducted by
      • 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.
      , 21 subjects were instructed to apply topical N-PEA/AEA cream twice a day. After a 3-week course of treatment, there was a significant reduction in pruritus (P < 0.0001); eight subjects (38.1%) had complete resolution of pruritus (
      • 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.
      ).
      Topical N-PEA was also explored for pruritus secondary to the following conditions: cholestasis due to hepatitis C (n = 1), pruritus due to limited scleroderma (CREST [calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia] syndrome) (n = 1), and aquagenic pruritus (n = 2) (
      • Ständer S.
      • Reinhardt H.W.
      • Luger T.A.
      Topische Cannabinoidagonisten. Eine effektive, neue Möglichkeit zur Behandlung von chronischem Pruritus [Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus].
      ). Subjects were instructed to apply the N-PEA test product on a daily basis, with treatment ranging from 2 weeks to 6 months. No improvement was noted among patients with cholestasis or aquagenic pruritus.

      Prurigo nodularis and lichen simplex chronicus

      Prurigo nodularis and lichen simplex are chronic skin conditions in which pruritus is the hallmark symptom. In a study on these conditions (Stӓnder et al., 2006), topical N-PEA was used for an average of 7.6 weeks among participants with prurigo nodularis (n = 13, VAS: 6.6 for baseline vs. 3.3 after treatment). However, four (30.7%) subjects were unresponsive to topical N-PEA. Two patients with lichen simplex chronicus were instructed to apply topical N-PEA for a 3-week course; subjects achieved a significant improvement in pruritus (VAS = 8.5 at baseline, VAS = 0 at end of treatment) (Stӓnder et al., 2006).

      Epidermolysis bullosa

      Topical CBD was investigated in two reports (
      • Chelliah M.P.
      • Zinn Z.
      • Khuu P.
      • Teng J.M.C.
      Self-initiated use of topical cannabidiol oil for epidermolysis bullosa.
      ;
      • Eberlein B.
      • Eicke C.
      • Reinhardt H.W.
      • Ring J.
      Adjuvant treatment of atopic eczema: assessment of an emollient containing N-palmitoylethanolamine (ATOPA study).
      ) with six pediatric patients (aged 6 months to 10 years). All patients experienced a reduction in blisters by at least 50%, with improved wound healing and decreased use of opioid analgesics.

      Adverse Effects of Topical CBS

      Topical CBs have shown a significantly lower side effect profile than oral CBs. For topical CBs, adverse events were reported in nine subjects receiving topical N-PEA who experienced at least one of the following: stinging, erythema, and/or burning after application.

      Adverse Effects of Oral CBS

      All patients treated with lenabasum experienced at least one adverse event, including mild fatigue, dizziness, and upper respiratory tract infection. DM flare was reported in two participants. One patient experienced a disturbance in coordination after administration of oral 5 mg dronabinol, which resolved with a 50% dose reduction.
      This systematic review sought to examine the present use of CB-based products in dermatology. Analysis of the included research revealed that the application of CBs has been studied for 13 different dermatologic conditions, with systemic sclerosis and DM investigated most extensively.
      Current evidence highlights the use of topical CBs in the treatment of pruritus, reduction of erythema, and enhanced wound healing. These clinical effects rely on CBs ability to inhibit the production of proinflammatory cytokines and modulate the immune system.
      Findings from the available published data, although relatively scarce, highlight the promising results of CBs for the treatment of various dermatologic conditions. Despite the expanding body of evidence relating to the applicability and efficacy of CBs, there continue to be significant knowledge gaps. This review confirmed that existing evidence from high-quality studies (particularly RCTs) remains limited. Further clinical studies pertaining to the therapeutic dosage and long-term safety of both topical and oral CBs are highly warranted. Physicians who prescribe CBs should be aware of the systemic effects reported in the literature and bear in mind that long-term safety data exist primarily for the selective CB2R agonists only.
      In addition, clinical trials investigating autoimmune skin conditions such as scleroderma and DM should be mindful of the necessity for ongoing immunosuppression in potential study participants and ethical implications related to the fact that systemic disease negates the possibility of a placebo-only group. Such trials should be designed with an eye toward including outcomes that allow for tapering of prednisone and the inclusion of participants who are on stable background doses of immunosuppressive medications.

      Limitations

      A significant limitation of our review is the small number of RCTs available for inclusion, resulting in a greater proportion of lower-level evidence obtained from case reports or case series. Selection bias may also have affected this review because positive outcomes are more likely to be published.
      In conclusion, both oral and topical CBs appear to be promising therapies for the treatment of various inflammatory and autoimmune skin disorders. Despite limited studies, the compilation of current evidence from the published literature supports the utility of topical and systemic CBs for the treatment of primary inflammatory skin disorders such as DM, diffuse cutaneous systemic sclerosis, atopic dermatitis, leg ulcers, and epidermolysis bullosa. In addition, thoughtfully designed RCTs are warranted to provide the necessary evidence base to support the use of CBs for the treatment of these dermatologic conditions. Studies should aim to control for confounders that may affect outcomes, such as the use of ongoing immunosuppressive agents and the potential anxiolytic properties of CBs, which could influence patient-reported outcomes. The minimal side effect profiles associated with CBs, particularly with topicals, are an important attribute and further encourage additional studies to support the application of CBs in dermatology practice.

      ORCIDs

      Author Contributions

      Conceptualization: TES, RPD; Data Curation: TES, JM, HR; Investigation: TES, JM, HR; Methodology: TES, JM, HR; Supervision: RPD; Validation: TES, JM, HR; Writing - Original Draft Preparation: TES, JM; Writing - Review and Editing: TES, JM, KK, ASM, RPD

      Conflict of Interest

      RPD is editor in chief of the Journal of Medical Internet Research (JMIR) Dermatology, a joint coordinating editor for Cochrane Skin, a dermatology section editor for UpToDate, a social media editor for the Journal of the American Academy of Dermatology, and a podcast editor for the Journal of Investigative Dermatology. He is a coordinating editor representative on Cochrane Council. TES is an editorial board member-at-large for JMIR Dermatology. The remaining authors state no conflict of interest.

      Acknowledgments

      RPD receives editorial stipends (American Academy of Dermatology and Journal of Investigative Dermatology), royalties (UpToDate), and expense reimbursement from Cochrane Skin. TES, United States receives fellowship funding (Pfizer Global Medical Grant [58858477] Dermatology Fellowship 2020, principal investigator: RPD) and fees for serving as a medical advisor and investigator for Antedotum. The remaining authors have no disclosures to report. No funding was received for this work.

      References

        • Basu S.
        • Ray A.
        • Dittel B.N.
        Cannabinoid receptor 2 is critical for the homing and retention of marginal zone B lineage cells and for efficient T-independent immune responses.
        J Immunol. 2011; 187: 5720-5732
        • Burstein S.
        Molecular mechanisms for the inflammation-resolving actions of Lenabasum.
        Mol Pharmacol. 2021; 99: 125-132
        • Caterina M.J.
        TRP channel cannabinoid receptors in skin sensation, homeostasis, and inflammation.
        ACS Chem Neurosci. 2014; 5: 1107-1116
        • 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
        • Cocchiara E.
        • Spinella A.
        • Magnani L.
        • Lumetti F.
        • Palermo A.
        • Balocchi G.
        • et al.
        AB0645 cannabinoids in the treatment of pain related to systemic sclerosis skin ulcers: our experience [abstract].
        Ann Rheum Dis. 2019; 78: 1784
        • Dvorak M.
        • Watkinson A.
        • McGlone F.
        • Rukwied R.
        Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin.
        Inflamm Res Off J Eur Histamine Res Soc Al. Inflamm Res. 2003; 52: 238-245
        • 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
        • 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
        • Friedman A.J.
        • Momeni K.
        • Kogan M.
        Topical cannabinoids for the management of psoriasis vulgaris: report of a case and review of the literature.
        J Drugs Dermatol. 2020; 19: 795
        • Global newswire
        Corbus pharmaceuticals announces topline results from DETERMINE phase 3 study of Lenabasum for treatment of dermatomyositis.
        (accessed September 2021)
        • Grant J.E.
        • Odlaug B.L.
        • Chamberlain S.R.
        • Kim S.W.
        Dronabinol, a cannabinoid agonist, reduces hair pulling in trichotillomania: a pilot study.
        Psychopharmacol (Berlin). 2011; 218: 493-502
        • Ho W.S.
        • Barrett D.A.
        • Randall M.D.
        ‘Entourage’ effects of N -palmitoylethanolamide and N -oleoylethanolamide on vasorelaxation to anandamide occur through TRPV1 receptors.
        Br J Pharmacol. 2008; 155: 837-846
        • Hoesel B.
        • Schmid J.A.
        The complexity of NF-κB signaling in inflammation and cancer.
        Mol Cancer. 2013; 12: 86
        • Khanna D.
        • Berrocal V.J.
        • Giannini E.H.
        • Seibold J.R.
        • Merkel P.A.
        • Mayes M.D.
        • et al.
        The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis.
        Arthritis Rheumatol. 2016; 68: 299-311
        • Kozela E.
        • Juknat A.
        • Kaushansky N.
        • Rimmerman N.
        • Ben-Nun A.
        • Vogel Z.
        Cannabinoids decrease the th17 inflammatory autoimmune phenotype.
        J Neuroimmune Pharmacol. 2013; 8: 1265-1276
        • Kreitzer F.R.
        • Stella N.
        The therapeutic potential of novel cannabinoid receptors.
        Pharmacol Ther. 2009; 122: 83-96
        • Liberati A.
        • Altman D.G.
        • Tetzlaff J.
        • Mulrow C.
        • Gøtzsche P.C.
        • Ioannidis J.P.A.
        • et al.
        The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration.
        BMJ. 2009; 339: b2700
        • Maghfour J.
        • Rietcheck H.R.
        • Rundle C.W.
        • Runion T.M.
        • Jafri Z.A.
        • Dercon S.
        • et al.
        An observational study of the application of a topical cannabinoid gel on sensitive dry skin.
        J Drugs Dermatol. 2020; 19: 1204-1208
        • Maida V.
        • Corban J.
        Topical medical cannabis: A new treatment for wound pain-three cases of pyoderma gangrenosum.
        J Pain Symptom Manage. 2017; 54: 732-736
        • Maida V.
        • Shi R.B.
        • Fazzari F.G.T.
        • Zomparelli L.
        Promoting wound healing of uremic calciphylaxis leg ulcers using topical cannabis-based medicines.
        Dermatol Ther. 2020; 33: e14419
        • Motwani M.P.
        • Bennett F.
        • Norris P.C.
        • Maini A.A.
        • George M.J.
        • Newson J.
        • et al.
        Potent anti-inflammatory and pro-resolving effects of Anabasum in a human model of self-resolving acute inflammation.
        Clin Pharmacol Ther. 2018; 104: 675-686
        • Neff G.W.
        • O’Brien C.B.
        • Reddy K.R.
        • Bergasa N.V.
        • Regev A.
        • Molina E.
        • et al.
        Preliminary observation with dronabinol in patients with intractable pruritus secondary to cholestatic liver disease.
        Am J Gastroenterol. 2002; 97: 2117-2119
        • Nikan M.
        • Nabavi S.M.
        • Manayi A.
        Ligands for cannabinoid receptors, promising anticancer agents.
        Life Sci. 2016; 146: 124-130
        • Nogueira A.R.
        • Shoenfeld Y.
        • Amital H.
        Cannabis sativa as a Potential Treatment for Systemic Sclerosis.
        Isr Med Assoc J. 2019; 21: 217-218
        • Palmieri B.
        • Laurino C.
        • Vadalà M.
        A therapeutic effect of cbd-enriched ointment in inflammatory skin diseases and cutaneous scars.
        Clin Ter. 2019; 170: e93-e99
        • Petrosino S.
        • Di Marzo V.
        The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations.
        Br J Pharmacol. 2017; 174: 1349-1365
        • 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 ADC. 2007; 15: 80-83
        • Robinson E.S.
        • Alves P.
        • Bashir M.M.
        • Zeidi M.
        • Feng R.
        • Werth V.P.
        Cannabinoid reduces inflammatory cytokines, tumor necrosis factor-α, and Type I interferons in dermatomyositis in vitro.
        J Invest Dermatol. 2017; 137: 2445-2447
        • Schräder N.H.B.
        • Duipmans J.C.
        • Molenbuur B.
        • Wolff A.P.
        • Jonkman M.F.
        Combined tetrahydrocannabinol and cannabidiol to treat pain in epidermolysis bullosa: a report of three cases.
        Br J Dermatol. 2019; 180: 922-924
        • Spiera R.
        • Hummers L.
        • Chung L.
        • Frech T.
        • Domsic R.
        • Hsu V.
        • et al.
        OP0006 Safety and efficacy of lenabasum (JBT-101) in diffuse cutaneous systemic sclerosis subjects treated for one year in an open-label extension of trial jbt101-ssc-001 [abstract].
        Ann Rheum Dis. 2018; 77: 52
        • Spiera R.
        • Hummers L.
        • Chung L.
        • Frech T.
        • Domsic R.
        • Hsu V.
        • et al.
        OP0325 safety and efficacy of lenabasum in an open-label extension of a phase 2 study in diffuse cutaneous systemic sclerosis subjects (DCSSC) [abstract].
        Ann Rheum Dis. 2019; 78: 245-246
        • Spiera R.
        • Hummers L.
        • Chung L.
        • Frech T.M.
        • Domsic R.
        • Hsu V.
        • et al.
        Safety and efficacy of Lenabasum in a Phase II, randomized, placebo-controlled trial in adults with systemic sclerosis.
        Arthritis Rheumatol. 2020; 72: 1350-1360
        • Spiera R.
        • Hummers L.
        • Chung L.
        • Frech T.M.
        • Domsic R.T.
        • Furst D.
        • et al.
        OP0126 A phase 2 study of safety and efficacy of anabasum (JBT-101) in systemic sclerosis [abstract].
        Ann Rheum Dis. 2017; 76: 105
        • Spiera R.
        • Hummers L.
        • Chung L.
        • Frech T.M.
        • Domsic R.T.
        • Hsu V.
        • et al.
        Safety and efficacy of anabasum (JBT-101) in diffuse cutaneous systemic sclerosis (dcSSc) subjects treated in an open-label extension of trial jbt101-ssc-001.
        Arthritis Rheumatol. 2017; 79
        • Ständer S.
        • Reinhardt H.W.
        • Luger T.A.
        Topische Cannabinoidagonisten. Eine effektive, neue Möglichkeit zur Behandlung von chronischem Pruritus [Topical cannabinoid agonists. An effective new possibility for treating chronic pruritus].
        Hautarzt Z Dermatol Venerol Verwandte Geb. 2006; 57: 801-807
        • 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
        • 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 ADC. 2005; 13: 97-103
        • Taylor B.N.
        • Mueller M.
        • Sauls R.S.
        Cannaboinoid antiemetic therapy.
        in: StatPearls [Internet]. StatPearls Publishing, Treasure Island, FL2020
        • Terry M.
        Corbus’ Lenabasum fails Phase III trial for systemic sclerosis. BioSpace.
        (2020)
        • Vincenzi C.
        • Tosti A.
        Efficacy and tolerability of a shampoo containing broad-spectrum cannabidiol in the treatment of scalp inflammation in patients with mild to moderate scalp psoriasis or seborrheic dermatitis.
        Skin Appendage Disord. 2020; 6: 355-361
        • 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
        • Werth V.P.
        • Hejazi E.
        • Pena S.
        • Haber J.S.
        • Feng R.
        • Patel B.
        • et al.
        605 Study of safety and efficacy of lenabasum, a cannabinoid receptor type 2 agonist, in refractory skin-predominant dermatomyositis.
        J Invest Dermatol. 2018; 138: S103
        • Werth V.
        • Pearson D.
        • Owaka J.
        • Feng R.
        • Concha J.
        • Patel B.
        • et al.
        op 0241 safety and efficacy of lenabasum in an open-label extension of a phase 2 study of lenabasum in refractory skin-predominant dermatomyositis (dm) subjects [abstract].
        Ann Rheum Dis. 2019; 78: 199-200
        • Yuan C.
        • Wang X.-M.
        • Guichard A.
        • Tan Y.M.
        • Qian C.-Y.
        • Yang L.-J.
        • 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; 9: 1163-1169
        • Zuardi A.
        History of cannabis as a medicine: a review.
        Rev Bras Psiquiatr. 2006; 28: 153-157