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 Table of Contents  
REVIEW ARTICLES
Year : 2023  |  Volume : 9  |  Issue : 1  |  Page : 5-12

Newer botanicals in melasma: A review


Department of Dermatology, Venereology & Leprosy, Bharati Vidyapeeth (DTU) Medical College, Pune, Maharashtra, India

Date of Submission01-Feb-2023
Date of Decision01-Jul-2023
Date of Acceptance17-Jul-2023
Date of Web Publication24-Aug-2023

Correspondence Address:
Vidyadhar R Sardesai
Department of Dermatology, Venereology & Leprosy, Bharati Vidyapeeth (DTU) Medical College, Pune 411043, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_3_23

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  Abstract 

Melasma is a common acquired pigmentary disorder predominantly affecting women of childbearing age and Fitzpatrick skin types IV–VI. It negatively impacts the quality of life due to its chronic and relapsing nature. It occurs due to a complex interplay between genetics, hormonal influences, inflammation, oxidative stress, and chronic photodamage. Therefore, a multimodality approach is essential for its treatment. It encompasses photoprotection, topical and oral therapy, and various procedures such as chemical peels, microneedling, lasers, and light treatment. The gold-standard treatment remains topical modified Kligman’s formula, consisting of hydroquinone, corticosteroid, and retinoid, in different concentrations. However, it may cause various adverse effects due to its unsupervised and chronic use. Therefore, novel treatment modalities should not only focus on reducing melanin synthesis and other influencing factors but also have a high safety profile. Among them, botanicals or plant-based extracts have gained massive popularity in the recent past. These compounds have been investigated extensively for their therapeutic activity against pigmentation, efficacy, and safety. Currently, they act as adjuncts to existing topicals. However, there is a paucity of data for their use as monotherapy. This review focuses on newer as well as existing botanicals for the treatment of melasma. Data extraction was done by searching words like botanicals, plant extracts, melasma, and depigmenting agents in databases: Pubmed, Google Scholar, Scopus, and others over the last 20 years.

Keywords: Botanicals, melasma, pigmentation


How to cite this article:
Sawarthia S, Sardesai VR, Lunge SB, Chandwani BH. Newer botanicals in melasma: A review. Indian J Drugs Dermatol 2023;9:5-12

How to cite this URL:
Sawarthia S, Sardesai VR, Lunge SB, Chandwani BH. Newer botanicals in melasma: A review. Indian J Drugs Dermatol [serial online] 2023 [cited 2023 Sep 23];9:5-12. Available from: https://www.ijdd.in/text.asp?2023/9/1/5/384290




  Key Messages: Top


Multiple plant-based products or botanicals are being researched extensively and added as adjuncts to the existing depigmenting formulas used for treating melasma. This article emphasizes newer botanicals that could be a potential treatment of choice for melasma.


  Introduction Top


Melasma is one of the most common yet challenging pigmentary disorders to treat. It is prevalent among women of childbearing ages and Fitzpatrick skin types IV–VI. The etiopathogenesis of melasma is complex, and factors such as genetic predisposition, ultraviolet (UV) radiation exposure, and hormonal influences play a significant role. The chronicity and relapsing nature of the condition require a multimodality approach to its treatment. Despite the availability of multiple topical and oral treatments, topical hydroquinone or its combination with corticosteroid and retinoid remains the gold standard. However, these topical preparations may cause various side effects when used over a prolonged period. Moreover, the so-called triple combination creams are available as over-the-counter preparations in India, and their unsupervised usage is more detrimental than beneficial. Therefore, a novel yet safe topical treatment for melasma is the need of the hour.

Multiple plant-based products or botanicals are being researched extensively and added as adjuncts to the existing formulas. However, further studies are obligatory to study their mechanism of action, efficacy, and safety before being recommended as a monotherapy. This article emphasizes newer botanicals that could be a potential treatment of choice for melasma.

Topical formulations

Aloesin

Aloesin is a compound derived from aloe vera. A study on in vitro reconstituted human skin equivalents showed a statistically significant dose-dependent reduction in tyrosinase activity and melanin content with aloesin.[1] It acts as a competitive inhibitor of tyrosinase with L-tyrosine as substrate.[2] It has potent antioxidant and anti-inflammatory properties.

In a randomized controlled trial, subjects were assigned to four groups: control, aloesin-treated, arbutin-treated, and both aloesin- and arbutin-treated. Aloesin showed a reduction in pigmentation by 34%, arbutin by 43.5%, and cotreatment by 63.3%.[3] In another comparative study, tea polyphenols showed a more concentration-dependent suppression effect on tyrosinase activity than aloesin, although aloesin had much lower toxicity.[4] Therefore, it acts as a safe and promising pigmentation-altering agent.

Mulberry extract

Mulberry extract, obtained from Morus alba, has a potent tyrosinase inhibitory activity, low cytotoxicity, and good radical scavenging activity.[5] Mulberroside F is the active compound isolated from dried M. alba leaves. It exhibited tyrosinase activity stronger and superoxide scavenging activity weaker than Kojic acid.[6] It has also been established that betulinic acid in mulberry is responsible for its anti-inflammatory and antityrosinase activity.[7]

In a randomized placebo-controlled trial, patients treated with 75% of mulberry extract oil showed significant improvement in Melasma Area and Severity Index (MASI) at the end of 8 weeks.[8] Severity assessment with Mexameter reading and melasma quality of life scale (MelasQOL) also improved with mild itching as the only adverse effect.

Ellagic acid

Ellagic acid (EA) is a natural compound found in medicinal plants and food such as strawberries, grapes, pomegranate, cherries, walnuts, and green tea.[9] It is not a tyrosinase inhibitor but an alternative substrate of the enzyme, oxidized by the enzyme, producing reactive o-quinones.[10] Nonetheless, its antioxidant action reduces the o-quinones, thus inhibiting melanogenesis. In addition, it also acts as a copper iron chelator from the tyrosinase enzyme’s active site.[11]

In a double-blinded clinical study, a topical containing 0.5% EA and 0.1% salicylic acid validated comparable tolerance and efficacy to a standard 4% hydroquinone.[12] Another study compared results with the application of synthetic arbutin (1%), synthetic EA (1%), and plant extract containing EA in 30 patients. All three groups showed a statistically significant decrease (P = 0.05) in the level of melanin. Therefore, formulation with plant extracts containing EA can be considered an alternative to synthetic EA.[13]

Coffeeberry extract

Coffeeberry extract is harvested from the coffee plant Coffee arabica. It is known to have antioxidant properties. However, limited research has been conducted to prove its depigmenting action. A study led by McDaniel et al.[14] showed improvement in hyperpigmentation following six weeks of coffeeberry extract application in 30 patients.

Licorice extract (Glycyrrhiza glabra)

Around 300 flavonoids have been isolated from licorice to date.[15] Glabrene and isoliquiritigenin derived from licorice root extracts inhibit mono and diphenolase tyrosinase activities.[16] Topical liquiritin reduced the surge in reactive oxygen species, pro-inflammatory factors, and matrix metalloproteins caused by UVB irradiation in rats.[17] Another potential derivative, glabridin 0.5%, inhibits melanogenesis and reduces inflammation in UVB-irradiated guinea pig skin.[18]

A total of 80% of patients with epidermal melasma at the end of 4 weeks had an excellent response with topical liquiritin.[19] Moreover, topical 4% liquiritin is appreciably more effective than topical 2% liquiritin, and 2% liquiritin is more effective than 4% hydroquinone.[20] In a monoblind clinical study, combination of licorice 7%, emblica, and belides in melasma patients showed statistically significant (P < 0.001) results. Moreover, there was no difference (P > 0.05) when compared with hydroquinone 2%.[21] In a recent study, an innovative preparation of dissolving microneedles containing tranexamic acid (TXA) and licorice extract had a synergistic therapy in melasma in guinea pigs.[22] Licorice is still being researched extensively as a potential depigmenting compound.

Orchid extract

The extracts from epiphytic orchid, Dendrobium crepidatum, has antioxidant and cytotoxic properties due to tetracosane, triacontane, stigmasterol, and some phenol derivatives.[23] Root extract of Phalaenopsis species and leaf of Prosthechea karwinskii also inhibits reactive oxygen species (ROS) and exerts anti-inflammatory activity.[24] A single open 8-week trial compared orchid extracts with vitamin C in 48 Japanese females with melasma and lentigo senilis. The efficacy was significant and clinically similar to the vitamin C derivative.[25]

Grapeseed extract

Resveratrol (RES) is an active polyphenol of grape seed extract (GSE). It also contains proanthocyanidin (PA), which is a potent oral antioxidant. It reduces UVB-induced production of ROS in normal human dermal fibroblasts.[26] Phenolic acids, phytosterols, flavonoids, tocopherols, carotenoids, and tocotrienols are other active compounds of GSE.[27] Resveratryl triglycolate is a novel hybrid compound derived by the esterification of RES with glycolic acid (GA). It decreases melanin synthesis efficiently by inhibiting the catalytic activity of tyrosinase.[28] There are limited studies on the depigmenting effect of topical GSE.

Silymarin

Silymarin is a polyphenol extracted from the Silybum marianum plant (milk thistle), and its active compound is silybin.[29] It functions as a free radical scavenger and lipid peroxidation inhibitor. A mouse melanocyte cell line (Mel-Ab) inhibited melanin synthesis by reducing protein expression of tyrosinase without cytotoxicity.[30]

Ninety-six adults with melasma showed significant improvement in pigmentation with topical silymarin without side effects.[31] In another study, it exhibited moderate benefit in melasma with potency significantly less than 50% GA but superior to intradermal TXA.[32] Likewise, 99 patients received topical silymarin (0.7% or 1.4%) versus 4% hydroquinone cream. MASI scores were reduced in both groups with no significant difference and no adverse effects with silymarin.[33] In a more recent study, 50 females were randomly divided into two groups: group A (6 sessions of low fluence Q-switched neodymium-doped yttrium aluminium garnet (Nd:YAG) 1064-nm laser) and group B (topical silymarin 1.4% for 3 months). There was no statistically significant difference in modified Melasma Area and Severity Index (mMASI) score and dermoscopic assessment between both groups with no recorded side effects.[34]

Arbutin

Arbutin is a compound, in which one molecule of D-glucose is bound to hydroquinone.[35] It is found in wheat, pear, bearberry, blueberry, and cranberry.[36] It competitively inhibits the tyrosinase activity of cultured human melanocytes at noncytotoxic concentrations.[37] Deoxyarbutin (dA) is a novel compound that inhibits mushroom tyrosinase in vitro with a Ki (inhibition constant), 10-fold lower than hydroquinone (HQ) and 350-fold lower than arbutin.[38] Moreover, its second-generation derivatives inhibit tyrosine hydroxylase and dihydroxyphenylalanine (DOPA) oxidase, thereby deterring melanogenesis.[39]

A novel formulation containing nicotinamide (4%), arbutin (3%), bisabolol (1%), and retinaldehyde (0.05%) showed a significant reduction in MASI score at day 30 (P < 0.0001) and day 60 (P < 0.0001).[40] Thirty-five refractory melasma cases were treated with 10 weekly laser Q-switched Nd:YAG and topical 7% alpha arbutin solution. At 6 months, 30% showed (>81%) reduction and 36.7% showed (51%–80%) reduction, suggesting an effective treatment for melasma.[41] A total of 75.86% of melasma patients showed a lightening effect with an aqueous extract of leaves of Serratula quinquefolia (β-arbutin) at 8 weeks.[42] A study comparing results in three groups applying synthetic arbutin (1%), synthetic EA (1%), and plant extract containing EA, respectively, in 30 patients showed a statistically significant decrease (P = 0.05) in the level of melanin.[14] A total of 2% dA and 4% hydroquinone showed comparable depigmenting efficacy in 59 melasma patients with no side effects.[43]

Soybean

Soybean seeds consist of protein proteinase inhibitors: soybean trypsin inhibitor (STI) and Bowman-Birk protease inhibitor (BBI).[44] It interferes with keratinocyte receptor protease-activated receptor-2 (PAR-2) activation and inhibits melanosome transfer.[44] Equol, a soy-derived isoflavonoid, stimulates collagen types I and III and increases the expression of skin antioxidants.[45] In patients with facial hypermelanosis, soy extract and azelaic acid led to significant skin lightening in 3 weeks, in contrast to GA, which showed a varying effect.[46] A pilot study on 50 Asian women with solar lentigines showed a modest skin-lightening effect with a stabilized soy extract.[47] Soy moisturizer containing STI and BBI was significantly more effective in improving pigmentation and overall texture than the vehicle.[48]

Gentisic acid

It is a phenolic acid derived from various plant species (Gentiana spp. roots, Citrus spp., Vitis vinifera, Pterocarpus santalinus, Helianthus tuberosus, Hibiscus rosa-sinensis, Olea europaea, and Sesamum indicum) and fruits (avocados, batoko plum, kiwi fruits, apple, bitter melon, blackberries, pears, and mushrooms).[49] Its methyl ester is structurally similar to hydroquinone. It inhibits tyrosinase through copper chelation.[50] Though, it is less cytotoxic and mutagenic than HQ. It also acts as a free radical scavenger.[51] However, sufficient clinical trials are lacking to demonstrate its practical usage as a depigmenting agent.

Cinnamic acid

It is a phenylpropanoid naturally occurring in plants: Cinnamomum cassia Blume and Panax ginseng.[52] It is mainly used in fragrances. Other functions include UV protection, antioxidant, antimicrobial, skin lightening, and anti-aging properties.[53] In a study, four cinnamamides exhibited higher tyrosinase inhibition than kojic acid.[54] 4-hydroxycinnamic acid is widely tested in vitro and in vivo, as a depigmenting agent.[53] One hundred ppm of cinnamic acid resulted in a significant reduction of melanin production in melan-a cells.[52] Another study demonstrated a significantly higher inhibition rate (P < 0.05) than hydroquinone.[55]

Green tea extract

Green tea extract (Camellia sinensis) is one of the most extensively studied compounds. It contains four major polyphenolic catechins: epigallocatechin (EGC), epicatechin (EC), EGC gallate, and EC gallate.[56] They are structurally similar to tyrosine or DOPA and, thus, act as alternative competitive tyrosinase substrates, which convert without pigment production.[57] In a study, Camellia sinensis water extracts inhibited melanin accumulation and synthesis, which were superior to Arbutin.[56] It also possesses antioxidant, anti-inflammatory, photo-protective, and anticarcinogenic properties.[58] However, there is a paucity of data regarding its application in melasma.

Curcumin (Sabiwhite)

Curcumin is a component of turmeric derived from the rhizome of Curcuma longa.[59] It exhibits anti-inflammatory, antimicrobial, antioxidant, and antineoplastic properties.[60] It inhibits tyrosinase and melanogenesis through activation of protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β), extracellular signal-regulated kinase (ERK), or p38 mitogen-activated protein kinase (MAPK) signaling pathways.[61] Poor stability and solubility of curcumin have limited its use. A study compared four novel chemically modified curcumin (CMC) derivatives to the parent compound curcumin (PC). Results showed that CMC2.24 had the highest tyrosinase inhibitor activity than PC and kojic acid.[62]

Hydroxycoumarin

7-hydroxycoumarin or umbelliferone is a phenolic compound belonging to the Apiaceae plant family: carrot and coriander.[63] It acts as a free radical scavenger and a photoprotective agent.[64] 3-hydroxycoumarin gel formulation for 2 h favored local inhibition of tyrosinase activity with minimal systemic absorption.[65] Geranyloxycoumarin derivatives exhibited better tyrosinase inhibiting activity than hydroxycoumarin derivatives, suggesting that it has better potential as a depigmenting agent.[66]

Alpha bisabolol (Alpha Melight)

It is derived from German chamomile and Myoporum crassifolium. It inhibits alpha-melanocyte-stimulating hormone (MSH)-induced melanogenesis.[67] In a study done on 28 females with pigmented skin, a lightening effect was seen in a majority of the treatment group at the end of 8 weeks.[68] However, the results were not statistically significant.

Aloe vera extract

The extract derived from Aloe vera Linne or Aloe barbadensis Miller offers limited protection against photodamage at a cellular level in both UV and visible spectra. An randomized controlled trial (RCT) done in 180 pregnant females with melasma showed a 32% improvement in MASI scores in the liposomal aloe vera gel extract group compared with 10% in the control group at the end of 5 weeks.[69] In an animal study, aloe vera leaf extract containing the active ingredient aloin induced powerful, dose-dependent melanin aggregating effects leading to skin lightening via alpha-adrenergic receptor stimulation.[70] However, there is a paucity of studies to justify its role in melasma.

Boswellia

Boswellic acids (BAs) are pentacyclic triterpenes isolated from gum resins of Boswellia serrata. They exert anti-inflammatory and immunomodulatory activity. In a randomized study, 0.5% BA cream applied by 15 females exhibited significant improvement in Dover’s global score for photoaging without adverse effects.[71] However, the efficacy of Boswellia in melasma is debatable.

Marine algae extract

They are potential matrix metalloproteinases (MMP) and tyrosinase inhibitors. Cha et al.[72] evaluated 43 native marine algae and found that few extracts demonstrated potent tyrosinase inhibitory activity similar to kojic acid without any adverse effects.

Rumex extract

It is derived from a flowering plant, Rumex occidentalis. It is known to inhibit the tyrosinase enzyme. In an RCT, 3% R. occidentalis cream showed a higher decline in MASI and mexameter readings than 4% HQ cream at the end of 8 weeks.[73] Twice-daily application of a cream containing GA and R. occidentalis in 27 patients of melasma showed statistically significant improvement at the end of 24 weeks as visualized colorimetrically.[74] In another study, 71 Indian women showed a significant skin-lightening effect from a product containing 1% dioic acid and 2% R. occidentalis extract.[75]

Pterostilbene (PteroWhite)

Pterostilbene (Pterocarpus marsupium) is a natural analog of RES found in blueberries and grapes. It induces antimelanogenic activity through the downregulation of the cAMP-response element binding protein (CREB)-microphthalmia-associated transcription factor (MITF)-tyrosinase pathway.[76] It also prevents UVB-induced photodamage and scavenges ROS. A monocentric study of 38 showed significant inhibition of melanogenesis with a 0.4% formulation of natural pterostilbene.[77] Moreover, it induced even skin tone, reduced fine lines, and improved elasticity.

Ginkgo biloba extract

Ginkgo biloba leaf contains flavonoids such as quercetin, kaempferol, and isorhamnetine. It is known to have antioxidant and photoprotective properties. In a study, twice-daily application of a new formula containing ferulic acid, Ginkgo biloba, lipohydroxyacid, niacinamide, and thermal spring water in 44 Chinese subjects with chloasma showed a significant improvement in MASI compared with placebo (P = 0.003).[78] It has been widely studied in Vitiligo Vulgaris, although its role in melasma is not well researched.

Oral formulations

Proanthocyanidin/Pycnogenol

PAs are a form of flavonoids available, particularly in grape seeds. They are primarily known for their antioxidative properties. In an 8-week RCT, oral PA with vitamins A, C, and E proved effective among 50 Filipino women with epidermal melasma. Mexameter and MASI scores validated a significant decrease in the degree of pigmentation.[79] Oral PA-rich GSE showed improvement in 10 women with chloasma in the first 6 months (P < 0.01).[80] Red wine oligomeric procyanidins significantly reduced the pigmentation scores and melanin index (P < 0.05) at 12 weeks.[81]

Pycnogenol, a French maritime pine bark extract, consists of PAs and various polyphenolic compounds. A double-blind RCT compared the efficacy of 75 mg oral pycnogenol twice-daily dose with a control group. A significant reduction in mMASI scores and colorimetric contrast was noted in the pycnogenol group (P < 0.05) with no adverse effects.[82] In another trial, 25 mg pycnogenol thrice daily was prescribed to 30 women with melasma. At the end of 30 days, the melasma area and pigmentation decreased significantly (P < 0.001).[83]

Polypodium leucotomos extract (Fernblock)

Polypodium leucotomos extract (PLE) is a fern extract known mainly for its photoprotective properties. It inhibits ROS production and prevents DNA damage.[84] Four refractory cases of melasma were treated with three clinic peels (4 weeks apart) and daily home treatment containing depigmenting creams, sunscreen, oral PLE, green tea extract, Vitis vinifera, vitamins C, E, and D, and carotenoids. At the end of the study, three showed excellent (>75%) improvement, and one showed good (50%–75%) improvement.[85] In another study, at the end of 4, 8, and 12 weeks, there were statistically significant differences between the mMASI scores of patients who received oral PLE supplementation (P ≤ 0.01).[86] A double-blinded RCT in 40 Hispanic patients showed improvement in MASI and melasma-related quality of life with oral PLE (240 mg thrice a day) for 12 weeks[87] [Table 1].
Table 1: Botanicals in melasma

Click here to view



  Conclusion Top


Newer discoveries in the pathogenesis of melasma have made it crucial to target all possible influencing factors for its treatment. The development of novel therapeutic targets is essential to tackle the chronicity and relapsing nature of the condition. This review focuses on newer botanicals having multiple actions and variable efficacy on pigmentation. However, the level of research is comparatively insufficient for its use as monotherapy or adjunct. But with known adverse effects of modified Kligman’s formula depigmenting agents, botanicals are likely to be used more frequently in the future for their safety potential.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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