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Activities:
Anti-inflammatory, antioxidant, antimicrobial, antitumor, antispasmodic, antiviral, immunomodulatory1–3
Important Chemical Components:
Glycyrrhiza glabra: glycyrrhizin, also known as glycyrrhizic acid or glycyrrhizinic acid (a triterpenoid saponin glycoside), 18β-glycyrrhetinic acid, polysaccharides, and various polyphenols (such as the isoflavone formononetin and the prenylated isoflavonoid glabridin as well as liquiritin, isoliquiritin, isoliquiritigenin, and liquiritigenin)4,5
Glycyrrhiza inflata: phenols, namely licochalcone A, lico-chalcone B, licochalcone C, licochalcone D, licochalcone E, echinatin, and isoliquiritigenin5,6
Glycyrrhiza uralensis: phenylflavonoids, such as dehydroglyasperin C, dehydroglyasperin D, isoangustone A; glycyrrhetinic acid; and the benzofuran courmarin glycyrol7
Origin Classification:
This ingredient is natural. Many organic choices exist.
Personal Care Category:
Anti-inflammatory, antiaging, skin lightening
Recommended for the following Baumann Skin Types:
DSNT, DSPT, DSNT, DSNW, OSNT, OSNW, OSPT, and OSPW. This ingredient is an optimal choice for sensitive pigmented types.
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Licorice (also spelled as “liquorice”) is best known in its popular confectionery form of black or red candy. Although it is not often thought of as a plant, it is derived from the roots and rhizomes of multiple Glycyrrhiza species and has been used in systemic and topical herbal medications for approximately 4,000 years (Table 67-1). In fact, licorice is one of the oldest and most popular herbs used in traditional Chinese medicine (TCM), second only to ginseng.8–10 Members of the Fabaceae or Leguminosae family (better known as the legume, pea, or bean family), Glycyrrhiza glabra (also known as Liquiritiae officinalis) and G. inflata are the species that have displayed the most therapeutic actions among the 18 known Glycyrrhiza species, with G. glabra the most used since antiquity. G. inflata is actually the Chinese licorice root, while G. glabra grows around the Mediterranean Sea, the Middle East, and central and southern Russia.11 The Roman physician of Greek extraction Pedanius Dioscorides, who practiced in the 1st century CE, is credited with bestowing the botanical name of the plant based on the Greek glukos (sweet) and riza (root).7,12,13 The Latin name “Liquiritiae” is a corruption of the Greek “Glycyrrhiza.”12
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G. glabra is a perennial herb that originated on the land surrounding the Mediterranean Sea as well as central and southern Russia and the Middle East.11 Licorice is now cultivated throughout much of Asia, Europe, and the Middle East, though, and is also used globally as a pharmacologic agent,14 particularly as an effective anti-inflammatory product.15 In addition to anti-inflammatory potency, licorice root is believed to possess antiviral, antiulcer, and anticarcinogenic properties.10 In China, licorice root has served as a folk elixir and antidote, and long been used as a demulcent (an agent that provides a soothing film over a mucous membrane).11 One of its active components, glycyrrhetinic acid, has traditionally been used in Asian and European herbal medicine to treat skin and pulmonary diseases, hepatitis, and peptic ulcers.2,16,17 A panel from the University of Würzburg, the World Wildlife Fund, and TRAFFIC chose licorice (G. glabra) as “medicinal plant of the year” for 2012 in recognition of its important roles in human health.18
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Licorice has been used for medicinal and dietary purposes for thousands of years, with such use dating back to ancient Egypt, Greece, and Rome in the West and to the times of the Han Dynasty (300–200 BCE) in ancient China.3 Asthma, dry cough, and lung disorders were described by the Roman naturalist Theophrastus (circa 372–287 BCE) as indications for licorice root.12,19 Gastric ulcer and various forms of inflammation have also been targets of licorice root in traditional medicine.6
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The radices of G. uralensis and herbal preparations containing Glycyrrhiza spp. have been used for thousands of years as an herbal medicine for the treatment of viral-induced cough, viral hepatitis, and viral skin diseases like ulcers in China.20 At least six Glycyrrhiza species, mainly G. uralensis and G. inflata, are used in Chinese licorice gan-cao, or “sweet herb” (and known as kanzo in Japan).19,21 G. inflata has a wide range of pharmaceutical and dietary applications and is related to G. glabra.22
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In contemporary times, licorice remains one of the most frequently used herbs in TCM.3,7 Licorice was introduced into Japan from China in the 8th century,3 and is also an important herb in Kampo (the Japanese adaptation of TCM) and Ayurvedic medicine.23,24 During the past 75 years, a glycyrrhizin formulation called Stronger Neo-Minophagen C™ (SNMC) has been used in the clinical setting in Japan as an antiallergic and antihepatitis treatment.3 In 1946, the Dutch physician Revers recommended licorice extracts to treat gastric ulcer, but side effects led to its swift removal from the market.3 In the United Kingdom, a licorice preparation was used to treat peptic ulcers.3 The modern scientific investigation into the pharmacologic properties of licorice species began in earnest in the 1950s and quickly revealed a broad range of biologic activity.24 The long history of traditional uses of licorice root and its extensive study over the last several decades make licorice one of the most widely researched plants for medicinal purposes.
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More than 400 compounds have been isolated from Glycyrrhiza species.25 Of the six major Glycyrrhiza species, G. glabra, G. uralensis, and G. inflata produce glycyrrhizin as a major saponin; G. echinata, G. macedonica, and G. pallidiflora produce macedonoside C as a major saponin. G. uralensis and G. inflata are closely related,26 but G. inflata is more often used medically and in the diet. G. glabra, G. inflata, and G. uralensis are the three species of licorice most often used medically, and are the focus of this discussion.
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Extracts from this more Western species of licorice, sometimes referred to as European licorice, are increasingly found in anti-inflammatory products.5,14 Glycyrrhizin, the primary water-soluble constituent of licorice, has been shown to confer numerous pharmacological benefits, though various derivatives also possess such properties.11 A sweet-tasting triterpene saponin exhibiting poor blood solubility as compared with other saponins, glycyrrhizin is typically present in the root in 5 to 10 percent concentrations,14,27 and is the source of the plant’s sweetness.28 In addition to the triterpenoid glycyrrhizin, and its aglycone form glycyrrhizic acid, licorice root contains polysaccharides and various polyphenols, such as the isoflavone formononetin, to which antioxidant characteristics have been ascribed.10
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Glabridin, which is the main component in the hydrophobic fraction of licorice extract, was also found to exhibit inhibitory effects on melanogenesis and inflammation when evaluated using cultured murine melanoma cells and guinea pig skin.29 A prenylated isoflavonoid of G. glabra roots, glabridin was first described in 1976 and has since been characterized as exhibiting broad biologic activity, including antioxidant, anti-inflammatory, antiatherogenic, energy metabolism regulating, estrogenic, neuroprotective, antiosteoporotic, and skin whitening. Its anti-inflammatory, antiatherogenic, estrogenic, and energy-regulating capacities are currently thought to be most prominent.5
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The primary active ingredient isolated and extracted from Chinese licorice roots is licochalcone A, also known as 3-a, a-dimethylallyl-4,4ʹ-dihydroxy-6-methoxychalcone, an oxygenated or reversely-constructed chalcone or “retrochalcone.”22,30,31 Licochalcone A has been shown to exhibit antiparasitic and antibacterial properties as well as antitumorigenic activity.31–33 This extract has also demonstrated anti-inflammatory activity against arachidonic acid- and 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced mouse ear edema and been reported to manifest in vivo antitumor properties in mouse skin papilloma initiated by 7,12-dimethylbenz(a)anthracene (DMBA) and promoted by TPA.31 Chalcones exhibit activity against oxidative stress. A study assessing their radical-scavenging activity revealed that licochalcones B and D potently delay superoxide anion production.34
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Noting that the herbal formulation PC-SPES, which contains licorice root, has been shown to possess potent estrogenic activity in vitro, in animals, and in patients with prostate cancer, researchers investigated whether the flavonoid licochalcone A shared these characteristics. Through a range of assays, they determined that licochalcone A is a phytoestrogen, demonstrates antitumor activity, enhancing the effects of paclitaxel and vinblastine, and can affect the apoptotic protein bcl-2 in human cell lines derived from several cancers.33
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In 2010, Cho et al. studied the capacity of the recently isolated licochalcone E to influence the synthesis of interleukin (IL)-12p40, a subunit of IL-12 and IL-23, and found that the G. inflata extract inhibited IL-12p40 expression and attenuated symptoms induced by oxazolone in a chronic allergic contact dermatitis model. They concluded that licochalcone E displays potential for use in treating cutaneous inflammation.35
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Glycyrrhiza Uralensis
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Li et al. used a calcineurin inhibitory test in 2010 to identify glycyrol, a benzofuran coumarin isolate, as an effective immunosuppressant in G. uralensis. Various assays revealed that glycyrol exerted immunosuppressive activity by blocking calcineurin activity, thus inhibiting the synthesis of IL-2 and regulating T lymphocytes. The investigators concluded that glycyrol shows promise as an immunomodulatory agent.36 Previously, glycyrol had been shown to exert in vitro anti-inflammatory effects.37
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Licorice is used broadly as a natural sweetening agent in food as well as tobacco products.7,25 Notably, glycyrrhizin is 50-fold sweeter than sugar.19 Indeed, in the United States, it is used more often as a flavoring and sweetening agent in food products than for salutary purposes,10 though licorice candy is typically flavored with anise oil, not licorice. Glycyrrhizin can be found in the confection, though, in concentrations ranging from 1 to 25 percent, with a minimum of 4 percent found in good quality licorice.19 Licorice is also widely available in supplement form.24
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Various herbal product companies provide licorice oral supplements as well as some topical preparations that contain licorice extract amid a cocktail of other botanical ingredients. Licorice extract is widely used as an anti-inflammatory in Europe and has been reported to be effective as an antiviral medication for chronic hepatitis.27 The use of oral licorice is approved by the German Commission E for bronchitis and chronic gastritis.
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G. glabra has also been shown to effectively protect against or treat oral mucositis engendered by radiation and chemotherapy for head and neck malignancies.38
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Modern research has shown that licorice extracts are comparably effective to corticosteroids in treating dermatitis, eczema, and psoriasis.39 Licorice extracts are also among the compounds known to be effective in topical creams intended to repair the skin barrier.40
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G. glabra has been used for a wide range of medical indications. Among the cutaneous indications, the extract has been used to treat dermatitis, eczema, pruritus, cysts,41 and skin irritation.42 In the modern pharmacopoeia, licorice is incorporated into cosmetics for acne patients as well as the treatment of sunburn.42
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Anti-inflammatory Uses
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The topical anti-inflammatory properties and antiulcer capacity of licorice root have been attributed mainly to glycyrrhetic acid, the biologically active metabolite of glycyrrhizic acid,27,43,44 which has been used successfully to treat inflammation without secondary infection.45 It has been reported to have anti-inflammatory activity in subacute and chronic dermatoses, and therefore has been used to treat eczema, pruritus, contact dermatitis, seborrheic dermatitis, and psoriasis.41 In a series of animal studies in 1988, glyderinine, a derivative of glycyrrhizic acid isolated from G. glabra, was shown by Azimov et al. to exhibit anti-inflammatory effects as well as analgesic and antipyretic properties. The researchers concluded that glyderinine is an appropriate ointment for treating skin diseases.46
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Studies have shown that glycyrrhetic acid is able to exert a cortisone-like effect, thus inhibiting proinflammatory prostaglandins and leukotrienes.47 Licorice (glycyrrhetic acid) has not been demonstrated to be superior to topical corticosteroids in treating acute inflammation, such as atopic dermatitis.41 The combination of corticosteroids with glycyrrhetic acid has been proven to be effective, however. One study displayed effective potentiation of hydrocortisone activity in skin by the addition of 2 percent glycyrrhetic acid.48
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A 2002 study assessing the effects of five different chalcones, including licochalcone A, revealed that four of the five tested chalcones, including licochalcone A, inhibited the production of proinflammatory cytokines from monocytes and T cells. The investigators concluded that licochalcone A and some of its synthetic analogs may have immunomodulatory effects, potentially rendering them suitable agents for the treatment of infectious and other inflammatory diseases.32
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Furuhashi et al., in 2005, studied the in vitro anti-inflammatory effects of licochalcone A on the formation of chemical mediators [e.g., prostaglandin E2 (PGE2) and cytokines) by IL-1β in human skin fibroblasts and compared it to the effects of other compounds. The steroid dexamethasone was found to inhibit PGE2, prostaglandin F(2α) [PGF(2α)], IL-6, and IL-8 production, and potently blocked cyclooxygenase (COX)-2 mRNA and protein expression, whereas licochalcone A, in response to IL-1β, hindered PGF(2α) generation and PGE2 synthesis, but had no effect on increased levels of COX-2 mRNA and protein in cells or IL-6, and IL-8 production. The investigators concluded that the licorice isolate engenders anti-inflammatory activity by suppressing COX-2-dependent PGE2 synthesis with a response to IL-1β that is markedly divergent from that of dexamethasone.49
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In 2008, Kwon et al. reported on the dynamic anti-inflammatory properties of licochalcone A as demonstrated in vitro and in animal models. The G. inflata extract inhibited the generation of nitric oxide (NO), PGE2, inflammatory cytokines such as IL-1 and IL-6, as well as the expression of inducible NO synthase (iNOS) and COX-2 induced by lipopolysaccharide (LPS) in RAW264.7 cells in vitro. In addition, the investigators speculated that licochalcone A may have suppressed inflammatory cytokine and NO synthesis in the process of protecting BALB/c mice from LPS-induced endotoxin shock in an animal model. They concluded that licochalcone A might be considered for use in treating various inflammatory conditions.50
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Studies by Furusawa et al. in 2009 revealed that the anti-inflammatory activity of G. inflata could be attributed to potent suppression of nuclear factor (NF)-κB exerted by licochalcones A, B, and D.6
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Funakoshi-Tago et al. have shown in mice that licochalcone A potently suppresses tumor necrosis factor-α-induced NF-κB activation and that the fixed structure of licochalcone A is pivotal in imparting its anti-inflammatory properties. They also noted, in 2010, that licochalcone A demonstrates great promise in vivo as an anti-inflammatory agent.51
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In 2013, Lee et al. demonstrated that topically applied licochalcone E displayed strong anti-inflammatory properties in a TPA-induced mouse ear edema model and similar effects when the G. inflata extract was administered in vitro in an LPS-stimulated RAW 264.7 murine macrophage model. They found that licochalcone E inhibited AKT and p38 mitogen activated protein kinase (MAPK), thus suppressing NF-κB and activator protein (AP)-1 transcriptional activity, which in turn facilitates the decline of proinflammatory cytokines.52
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Also that year, Fu et al. isolated six flavonoids from G. inflata and G. uralensis, with all six compounds [5-(1,1-dimethylallyl)-3, 4,4ʹ-trihydroxy-2-methoxychalcone, licochalcones A and B, echinatin, glycycoumarin, and glyurallin B] found to possess varying degrees of antioxidant and anti-inflammatory characteristics.25
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In a 2003 study of antiacne activity displayed by Asian herbal extracts, Name et al. found that G. glabra showed significant antibacterial activity against Propionibacterium acnes without inducing noteworthy resistance. The investigators suggested that a formulation combining three herbal extracts, including G. glabra, Angelica dahurica, and Coptis chinensis, may be suitable for preventing and treating acne.53
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Ten years later, Angelova-Fischer et al. conducted a nine-week, randomized, double-blind, vehicle-controlled study with 60 volunteers with mild-to-moderately severe acne to evaluate and provide proof-of-concept for a formulation containing licochalcone A, L-carnitine and 1,2-decanediol. After one week for standardization of the cleansing procedure, the participants (40 females and 20 males between the ages of 14 and 40 years old) were randomized to apply either the test formulation or vehicle to the face twice daily for eight weeks. At the end of the study, the mean total lesion count and papular lesions were decreased in the active formulation group compared to baseline. Significant reductions in pustules, sebum levels, and P. acnes were recorded in the active formulation subjects along with improvements in Dermatology Life Quality Index (DLQI), whereas no significant improvements were observed in the vehicle group. Evidence of acne improvement associated with the licochalcone A-containing formulation was noted in both physician and patient assessments.54
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G. glabra is one among various plant constituents demonstrated to be effective in treating atopic dermatitis.55,56 In a 2003 double-blind study over two weeks, investigators evaluated the effect of 1 and 2 percent topical licorice extract preparations on atopic dermatitis in two 30-patient groups. Results indicated that the 2 percent licorice topical gel was more effective in reducing erythema, edema, and pruritus. Significantly, the authors also concluded that licorice extract was effective in treating atopic dermatitis.41
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In 2011, Udompataikul and Srisatwaja conducted a six-week, randomized, controlled, investigator-blinded comparative pilot study of the effects of moisturizers containing licochalcone A or hydrocortisone on children with atopic dermatitis (mean age, 5.8 years). Twenty-six patients completed the protocol, which included twice-daily application of licochalcone A on one side of the body and hydrocortisone on the other side. The response rate to both treatments was found to be 73.33 percent, with no significant differences in scoring atopic dermatitis (SCORAD) score reductions from treatment. Edema and erythema resolved more rapidly with hydrocortisone, but the relapse rate associated with hydrocortisone was higher; in both cases, the differences were not significant. The investigators concluded that licochalcone A lotion, which was found to be equally effective as hydrocortisone lotion, is an option to treat mild-to-moderate childhood atopic dermatitis in the maintenance as well as acute phases.57
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In 2013, Wananukul et al. led a four-week, prospective, multicenter, randomized, double-blind, split-side study in 55 children (three months to 14 years of age) with mild-to-moderate atopic dermatitis to compare the efficacy of a licochalcone A-containing moisturizer and 1 percent hydrocortisone. Simultaneous treatment with either the licochalcone A preparation or 1 percent hydrocortisone on opposite sides of the lesion were administered twice daily. The SCORAD declined significantly for both treatments from baseline, with no statistically significant differences between the treatments. Transepidermal water loss was found to be significantly decreased from baseline on the side that received licochalcone A treatment. The investigators also reported that continuing treatment with licochalcone A for four weeks maintained clinical and skin barrier benefits.58
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Licorice extracts are included among the array of topical tyrosinase inhibitors used to lighten hyperpigmented areas of the skin.59–61 Glabridin, found in concentrations between 10 and 40 percent in commercial depigmenting agents, is thought to be the chief ingredient in licorice to provide skin-lightening activity.61 Draelos has noted that the status of licorice extracts as the safest of options among skin-lightening agents while eliciting the fewest side effects accounts for its popularity for this purpose.62,63
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In a study of 20 women between the ages of 18 and 40 with a clinical diagnosis of bilateral and symmetrical idiopathic epidermal melasma, liquiritin cream was applied on one side of the face and a vehicle cream on the other twice daily for four weeks. Liquiritin is a flavonoid component of licorice that, along with other ingredients, contributes to the natural yellow pigment. Individuals with dermal melasma, melasma with pregnancy, and those receiving hormone replacement therapy were excluded from the study. Topical sunscreen use was encouraged during the treatment period while sun exposure was discouraged. Sixteen patients (80 percent) were characterized as exhibiting excellent responses from liquiritin, with no discernible differences between the normal skin and previously pigmented areas. Two patients (10 percent) showed a good response on the liquiritin side, and two patients (10 percent) had fair responses from liquiritin, with moderate pigmentation, while moderate improvement was seen in only 20 percent on the vehicle side.64
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Nerya et al. found in 2003 that in addition to glabridin, glabrene, and isoliquiritigenin (2ʹ,4ʹ,4-trihydroxychalcone), constituents of licorice root extract contributed significantly and dose-dependently in the observed potent tyrosinase-inhibiting activity displayed by the plant.65
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In a 2010 single-blind, 60-day study with 56 women between 18 to 60 years old, Costa et al. found that a formulation combining belides, emblica, and licorice was as effective as hydroquinone 2 percent in ameliorating the effects of melasma (see Chapter 38, Emblica Extract). There were no statistically significant differences between the groups and the herbal combination was associated with fewer adverse effects.66
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In 2008, Adhikari et al. screened 52 crude drugs traditionally used in Nepal to treat hyperpigmentation for inhibitory activity against mushroom tyrosinase, finding that methanolic extracts of G. glabra manifested the greatest inhibitory activity, with kojic acid used as a positive control.67 Licorice extract is frequently combined with other skin-lightening ingredients (see Chapter 32, Overview of the Pigmentation Process). Vitamin C is often combined with licorice extracts or soy when deployed for skin-lightening purposes [see Chapter 40, Vitamin C (Ascorbic Acid), and Chapter 45, Soy].68
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Cassano et al. conducted a pilot, randomized, open-label, parallel-group trial in 40 patients in 2010 to assess the effects of an emollient cream containing milk proteins and G. glabra extracts in the treatment of palmar and/or plantar psoriasis treated with topical corticotherapy. Twenty patients were treated only with mometasone furoate ointment for four weeks and 20 patients received the same corticosteroid in combination with the licorice-containing emollient, which was applied twice daily during the four-week study period. Statistically significant decreases in the severity of all clinical signs of psoriasis were seen in all patients, all of whom completed the study. In the group treated with the test emollient, significantly greater reductions in desquamation, affected surface area, and subjective symptoms were reported as compared with the corticosteroid-only treatment group. The investigators concluded that their findings support the adjuvant use of this new emollient combining G. glabra extracts and milk proteins for psoriasis management.69
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The topical application of Tuhuai, a Chinese herbal medicine that includes licorice, has also been found by Man et al. to exhibit antiproliferative and anti-inflammatory activity in murine models of inflammatory dermatoses. The investigators suggest the herbal formulation may offer an effective, relatively safe, and inexpensive option to treat inflammatory disorders such as psoriasis.70
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Sensitive Skin/Rosacea
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In 2006, Weber et al. assessed the cutaneous compatibility and efficacy of a skin care regimen containing licochalcone A in 62 patients with mild-to-moderate rosacea over eight weeks. The regimen was well tolerated and effective in reducing erythema, as indicated by clinical evaluations, subject response, and photographic review. Responses to quality-of-life questionnaires revealed subjective improvements, and average erythema scores at four and eight weeks indicated significant improvements. The investigators concluded that licochalcone A use is suitable for patients with sensitive facial skin, as characterized by rosacea, and that the tested licochalcone A-containing regimen was compatible with daily metronidazole application.71
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That same year, Kolbe et al. showed in prospective, randomized, vehicle-controlled clinical trials that licochalcone A displays significant anti-irritative efficacy in cosmetic formulations and is thus well suited for sensitive or irritated skin. They also showed in vitro that licochalcone A-rich extracts of G. inflata as well as synthetic licochalcone A potently inhibit proinflammatory responses.72 Licorice extract is a popular ingredient in over-the-counter skin care products designed to treat rosacea, although few studies supporting its use in rosacea are published.
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Most, if not all, pharmacopoeias around the world recognize and include licorice extract.12 The United States Food and Drug Administration (FDA) bestowed generally recognized as safe (GRAS) status upon licorice in 1983.28 The dietary ingredient licorice flavonoid oil, in which glabridin is a primary bioactive flavonoid, has been found to be safe when used once daily up to 1,200 mg/day.73
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The rare side effects from the oral administration of licorice are dose-dependent and occur more frequently in women and with the use of oral contraceptives.74 At doses of less than 10 mg of glycycrrhizin daily, side effects are thought to be nominal.75 Chronic use of high doses of glycyrrhizin or glycyrrhetinic acid can result in adverse effects such as edema, hypertension, and hypokalemia. Chemical modifications to licorice formulations have been made to enhance therapeutic benefits while reducing the risk of side effects.3 Oral licorice is contraindicated in pregnancy according to the German Commission E, though doses up to 3 g daily are thought to be safe; hypertension, cardiac or renal histories, various liver conditions, hypokalemia, and edema are also contraindications.24,27,75
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The Cosmetic Ingredient Review (CIR) Expert Panel suggested that acute, short-term, subchronic, or chronic toxicity is minimal and deemed the use of all licorice constituents safe for skin care in the current usage and concentration practices.17
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The CIR Expert Panel noted that the chemicals isolated from the licorice plant may have pesticide and toxic metal residues, and advised that polychlorobiphenyl (PCB)/pesticide contamination should be no higher than 40 parts per million. They further cautioned that toxic metal levels should be limited to 3 mg/kg of arsenic, 1 mg/kg of lead, and 0.002 percent heavy metals.17
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In 2003, Yamamoto et al. acknowledged that cultivation of G. uralensis had emerged to compensate for the waning supply of wild Glycyrrhiza plants in China incurred by collection restrictions spurred by over-collection of wild plants.21,76 Six years later, Gao et al. reported on the ramifications of using G. uralensis seeds flown on a recoverable satellite for 18 days. After their return to earth, the seeds were planted and grown to maturity. Analysis of the content of the roots of the seeds flown in space revealed glycyrrhizic acid as 2.19 times higher than a control group and liquiritin content as 1.18 times that of the control. The investigators suggested that extraterrestrial breeding warrants attention as an approach to future breeding of what is considered an endangered medicinal plant.76
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FORMULATION CONSIDERATIONS
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The licorice derivatives glycyrrhizin and glycyrrhetinic acid occasionally cause edema, hypertension, and hypokalemia when used orally in patients treated over a long period and with higher doses. Topical use has not been associated with these side effects. Chemical modifications to the myriad compounds have enhanced the anti-inflammatory activities of the various forms of licorice extract,3 and several products have been formulated with the intent to increase penetration of the active compounds.
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Hao et al. demonstrated in 2010 that glycyrrhetinic acid, a metabolite of glycyrrhizic acid, could better penetrate the skin when combined with organic bases (triethanolamine or triethylamine) in nonaqueous solvent comprising isopropyl myristate and alcohols (ethanol, butanol, octanol, and dodecanol). Specifically, they found that an ion pair between glycyrrhizic acid and an organic base enhanced the solubility of the extract in the stratum corneum as well as its partition into the viable skin, thus fostering the penetration of the licorice component into the skin.77
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Marianecci et al. found in 2012 that using niosomes composed of surfactants (Tween 85 and Span 20) loaded with ammonium glycyrrhizinate is potentially effective for treating various inflammatory disorders, as the delivery system was shown to exhibit good skin tolerability and no toxicity while enhancing the drug anti-inflammatory activity in mice. Skin erythema chemically induced in a human model was also found to be improved by the ammonium glycyrrhizinate-infused vesicles.39
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Early in 2014, Mostafa et al. reported on the formulation of a stable, cost-effective, easy-to-use transdermal microemulsion system (ME3) for G. glabra delivery that delivers 13-fold higher ex vivo antioxidant capacity than the licorice extract solution itself.78
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No topical products with licorice extract as the primary active ingredient are FDA approved for the treatment of melasma, rosacea, acne, or other inflammatory skin disorders.27 Glycyrrhetinic acid is used in many cosmeceuticals at concentrations of up to 2 percent and glycyrrhizic acid, up to 0.1 percent.17 Studies have not been performed to investigate how other agents affect efficacy and penetration when used in combination with various forms of licorice extract.
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SIGNIFICANT BACKGROUND
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In some of the earlier research on licorice extract, the use of topical ointments containing active isomers of glycyrrhetic acid reportedly showed anti-inflammatory activity in subacute and chronic dermatoses, such as contact dermatitis, seborrheic dermatitis, and psoriasis. Topical corticosteroids were more effective than the glycyrrhetic acid formulation in treating acute atopic dermatitis.79 But glycyrrhetic acid has been characterized as exerting a cortisone-like effect, rendering it viable as an anti-inflammatory agent, and has inhibited proinflammatory prostaglandins and leukotrienes.47,80 Combining glycyrrhetic acid with corticosteroids has also been shown to be effective. Results from topical corticosteroid application were significantly improved with the addition of 2 percent glycyrrhetic acid in one study.48
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Assays of physical stability and antioxidant activity of topical preparations containing various plant extracts performed by Di Mambro and Fonseca in 2005 revealed that G. glabra and Ginkgo biloba are suitable for incorporation into topical formulations intended to protect skin from the deleterious effects of free radical and reactive oxygen species.81
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In 2011, Veratti et al. investigated the potential protective properties of glycyrrhizin, 18β-glycyrrhetinic acid, and glabridin against UVB-induced damage in human keratinocyte cultures. They found that 18β-glycyrrhetinic acid and glabridin exhibit strong antioxidant activity by blocking oxidative DNA fragmentation as well as the induction of apoptosis in human keratinocytes.82
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Also during that year, Li et al. employed novel techniques to screen and characterize 35 radical scavengers in G. inflata, G. glabra, G. pallidflora, and G. uralensis, with 21 identified as flavonoids.9
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The phenolic compounds licochalcone A-D and echinatin, retrochalcones isolated from G. inflata roots, have exhibited activity against an array of oxidative stresses. A study assessing their inhibitory capacity on lipid peroxidation and radical scavenging activity, specifically, revealed that licochalcones B and D potently hindered superoxide anion production in the xanthine/xanthine oxidase system, protected red cells from oxidative hemolysis, and displayed potent scavenging activity.34 These retrochalcones have also demonstrated antimicrobial activity. Specifically, licochalcones A and C have been shown to exert potent activity against some Gram-positive bacteria and hamper oxygen consumption in vulnerable bacterial cells.83
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Antibacterial Activity
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In a study evaluating the in vitro activities of licochalcone A against some food contaminant microorganisms, the licorice derivative exhibited activity against all Gram-positive bacteria tested, particularly all Bacillus spp. tested, but was ineffective against tested Gram-negative bacteria and eukaryotes at 50 μg/mL. This study demonstrated the potential viability of licochalcone A as an integral constituent in antibacterial products designed to preserve food high in salts and proteases.22
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Flavonoid extracts of several species of licorice plant have been shown to exhibit antiulcer activity for peptic ulcers. Inhibitory activity against Helicobacter pylori growth has also been observed in vitro among glabridin and glabrene (components of G. glabra), licochalcone A (G. inflata), as well as licoricidin and licoisoflavone B (G. uralensis). Among these licorice constituents, anti-H. pylori activity was also identified against a clarithromycin- and amoxicillin-resistant strain.23
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In 2013, Long et al. showed that high concentrations of 18β-glycyrrhetinic acid, a constituent of the root of several Glycyrrhiza species, were bactericidal to methicillin-resistant Staphylococcus aureus (MRSA). In addition, both in vitro and in vivo, the licorice component, at sublethal doses, decreased virulent gene expression in S. aureus.84
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Chemopreventive/Photoprotective Activity
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Oral feeding of licorice extract to Sencar mice was shown in 1991 to protect against skin tumorigenesis caused by DMBA initiation and TPA promotion. Tumors developed in much less time in mice not fed the licorice preparation; treated mice also had significantly fewer tumors during and at the end of the study. Researchers concluded that the considerable antitumorigenic activity of licorice extract might ultimately be proved useful in protecting against some forms of human cancer.11 Since the time that this study was published, the polyphenols in licorice have been shown to induce apoptosis in cancer cells, as licorice constituents have exhibited significant antimutagenic, anticarcinogenic, and tumor-suppressive capacity in animal models.10 In fact, the National Cancer Institute has formally recognized the chemopreventive worth of licorice root and its primary constituent glycyrrhizin.82,85
++
In 2005, Rossi et al. assessed the effect of glycyrrhizin and its aglycone metabolite 18β-glycyrrhetinic acid on UVB-irradiated human melanoma cells, finding that glycyrrhizin has the potential to confer photoprotection, though it is ineffective on metastatic cells.86
++
Also that year, Agarwal et al. reported that 18β-glycyrrhetinic acid inhibits TPA-mediated oxidative stress and tumor promotion in murine skin, attenuating the activity of ornithine decarboxylase, incorporation of [3H]-thymidine in DNA, and induction of oxidative stress. The licorice component also suppressed DMBA/TPA-induced skin tumor formation in mice. The researchers concluded that the antioxidant glycyrrhetinic acid may be a viable chemopreventive agent.87
++
In 2007, Rahman et al. investigated the chemopreventive effects of glycyrrhizin on TPA-induced cutaneous oxidative stress and tumor protection in Swiss albino mice. Pretreatment of animals with the licorice compound prior to TPA yielded significant reductions in cutaneous microsomal lipid peroxidation and restoration of cutaneous glutathione and its dependent enzymes. The investigators suggested that glycyrrhizin provided substantial protection to mice from pernicious TPA-induced effects.88
++
Cherng et al. showed in 2011 that oral administration of glycyrrhizic acid to SKH-1 hairless mice prior to UVB exposure (180 mJ/cm2 per exposure) mitigates UVB-induced tumorigenesis through downregulation of cell proliferation controls (i.e., thymine dimer-positive cells, proliferative cell nuclear antigen expression, apoptosis, and transcription factor NF-κB) and inflammatory responses (i.e., COX-2, PGE2, and NO) and upregulation of p53 and p21/Cip1 to preclude damage while mediating repair to DNA.1
++
Afnan et al. conducted an in vitro study in 2012 of the effects of glycyrrhizic acid against UVB-induced photoaging in human dermal fibroblasts, finding that treatment with the licorice extract diminished reactive oxygen species, NF-κB, cytochrome c, and caspase 3 levels and hindered hyaluronidase. The investigators speculated, though, that the botanical ingredient significantly suppressed photoaging primarily through inhibiting matrix metalloproteinase-1 activation and altering NF-κB signaling. They concluded that glycyrrhizic acid appears to have potential as a key ingredient in natural and safe products intended to protect against UVB-induced damage.4
++
A G. inflata extract containing licochalcone A was included in a formulation with urea, lactate, and polidocanol that was tested by Schweiger et al. in 2013 in 30 volunteers with dry and itchy scalp conditions. Participants applied the leave-on tonic three times each week for four weeks on one side of the scalp. Investigators found that scalp moisture was significantly enhanced after treatment with the tonic, while pruritus was significantly diminished. A substantial decrease in key proinflammatory markers was also confirmed through scalp wash-up analyses. The investigators concluded that the formulation containing anti-inflammatory licochalcone A, urea, lactate, and polidocanol displayed great efficacy in normalizing scalp lipid disturbances and, more importantly, relieving scalp dryness, itching, and microinflammation.89
+++
Infantile Seborrheic Dermatitis
++
In 2012, Wananukul et al. conducted a two-week, prospective, randomized, double-blind, split-side comparison study of a 0.025 percent licochalcone-containing moisturizer and 1 percent hydrocortisone in 75 infants (72 of whom completed the study) with infantile seborrheic dermatitis. Patients were treated twice daily on opposite sides of the lesion. A significantly higher clearance rate (42 percent vs. 32 percent) was recorded in the licochalcone group at days 3 to 4, with the products appearing equally effective at days 6 to 7 and 14.90
+++
Other Biologic Activity
++
Shin et al. conducted in vitro and in vivo investigations of the antiallergic effects of G. glabra and its constituents in 2007, reporting that glycyrrhizin, 18β-glycyrrhetinic acid, and liquiritigenin are primarily responsible for imparting antiallergic activity that can alleviate the symptoms of immunoglobulin E-mediated allergic conditions such as dermatitis and asthma.91
++
Pellati et al. showed in vitro in 2009 that 18β-glycyrrhetinic acid substantially stemmed, in a pH-dependent manner, the growth of clinical isolates of Candida albicans strains from patients with recurrent vulvovaginal candidiasis. The researchers suggested that the constituent of Glycyrrhiza species has potential as a topical therapeutic option for patients with the condition.92
++
Peng et al. showed in 2011 that glycyrrhetinic acid extracted from G. uralensis induced the dose-dependent expression of Toll-like receptor 4 in Ana-1 murine macrophages and activated its downstream signaling pathway, which is involved in the regulation of the innate immune reaction to encroaching pathogens.16
++
Kato et al. studied the extracts of 25 plants used in Kampo medicine in 2012 to identify anti-UV and anti-HIV activity. Of the plants tested, licorice displayed the second highest anti-UV activity (gardenia fruit was first) and was one of only six plants to display some anti-HIV activity.93
++
In 2013, Wang et al. extracted the radices of G. uralensis with hot water and reported antiviral activity against enterovirus 71 and coxackievirus A16, validating the use of the botanical extract against the etiological sources of hand, foot, and mouth disease, with glycyrrhizic acid identified as the primary antiviral component of G. uralensis.20
++
Licorice root has been used in traditional medicine in the East and West for well over two millennia. In addition, it has been evaluated in a vast range of modern scientific studies, and licorice extracts have been included in the cosmeceutical as well as medical realm. The reputed anti-inflammatory and depigmenting properties of licorice root are particularly intriguing. The great challenge in producing cosmeceutical products – harnessing the identified strengths of a given ingredient and bottling it, delivering health benefits in a topical formulation – applies here as in most cases discussed in this text. The wealth of evidence points to the benefits of several species of licorice plant, indicating that such benefits have been reaped in oral and topical preparations of the extract. Given the relative wealth of history and research supporting its use, licorice root is likely to be incorporated into an increasing number of products. Several medical applications have been derived from various species of licorice, particularly G. glabra, G. inflata, and G. uralensis. Overall, there appears to be ample reason for optimism regarding the role of licorice extracts in dermatology.
++
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