REVIEW

The use of botanically derived agents forhyperpigmentation: A systematic review

Whitney A. Fisk, MS,a Oma Agbai, MD,b Hadar A. Lev-Tov, MD,b,c and Raja K. Sivamani, MD, MS, AHEb

Sacramento and Mather, California

See related articles on pages 281 and 369

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Background: Hyperpigmentation disorders are common among those seeking care from dermatologistsand primary care physicians. The cosmeceutical and natural product industries are rapidly growing andmany botanical agents are purported to improve hyperpigmentation disorders.

Objective: We sought to review clinical evidence for the use of botanical agents in the treatment ofhyperpigmentation.

Methods: We searched MEDLINE and Embase databases and a total of 26 articles met inclusion criteria.Study methodology was analyzed and the reproducibility of the studies was graded.

Results: Several botanical agents appear promising as treatment options but few studies were method-ologically rigorous. Several plant extract and phytochemicals effectively lighten signs of epidermalmelasma and hyperpigmentation induced by ultraviolet radiation exposure. Results were mixed fortreatment of solar lentigines or dermal hyperpigmentation.

Limitations: There were few rigorously designed studies; future research will be critical to furtherascertain the discussed results.

Conclusions: The subtype of hyperpigmentation is important for treatment prognosis, with dermalhyperpigmentation less responsive to treatment. Botanical extracts may play an integrative role in thetreatment of hyperpigmentation and further studies that integrate them with standard therapies are needed.Side effects, including worsened hyperpigmentation, need to be discussed when considering thesetherapies. ( J Am Acad Dermatol 2014;70:352-65.)

Key words: botanical; hyperpigmentation; lentigo; melasma; natural; phytochemical; plant.

Hyperpigmentation is a common symptomencountered by dermatologists and primarycare physicians. Pigmentation disorders

were the third most common diagnosis in a cohortof 2000 dark-complexioned dermatology patients,1

secondary only to acne and eczema. Common hyper-pigmentation disorders include melasma, solar len-tigines, postinflammatory hyperpigmentation (PIH),and chloasma, which refers to melasma precipitatedin the setting of hormonal stimulation such as preg-nancy or oral contraceptive use. Ultraviolet (UV)exposure can exacerbate all of these conditions.2

the School of Medicinea and Department of Dermatology,b

niversity of CaliforniaeDavis, Sacramento; and Veterans Af-

irs Northern California Health Care System, Mather.c

ing sources: None.

licts of interest: None declared.

pted for publication September 20, 2013.

Darker-complexioned individuals are more likely todevelop disorders of hyperpigmentation.3

Clinically, hyperpigmentation manifests as brownor blue skin discoloration depending on whethermelanin deposition occurs in the epidermis or thedermis, respectively.4 The location of pigmentdeposition can be evaluated with Wood’s lamp andmay impact treatment decisions.4 For example,epidermal melasma responds better to topical ther-apies,2 than does dermal or mixed-type melasma,both of which include a component of dermalpigment deposition. Dermal hypermelanosis is less

Reprint requests: Raja K. Sivamani, MD, MS, AHE, Department of

Dermatology, University of CaliforniaeDavis, 3301 C St, Suite

1400, Sacramento, CA 95816. E-mail: rksivamani@ucdavis.edu.

Published online November 25, 2013.

0190-9622/$36.00

� 2013 by the American Academy of Dermatology, Inc.

http://dx.doi.org/10.1016/j.jaad.2013.09.048

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VOLUME 70, NUMBER 2Fisk et al 353

responsive to treatment partially because residentdermal macrophages phagocytose pigment andmany therapies do not target these cells5 (Fig 1).

‘‘Cosmeceuticals,’’ products containing biologi-cally active ingredients that purportedly improvethe appearance of skin, are increasingly popularalternatives to standard depigmenting agents (Table

CAPSULE SUMMARY

d Topical botanical therapies areincreasingly popular alternativetherapies.

d Clinical studies suggest botanicals mosteffectively treat superficial forms ofhyperpigmentation, including epidermalmelasma.

d Botanicals should be considered forintegration with standard therapies forhyperpigmentation and furtherintegrated clinical studies are needed.

I).6 Such products are attrac-tive to consumers becausethey are presumed safe, of-ten inexpensive, and avail-able over the counter.Evidence-based knowledgeof the beneficial effects, theside effects, and the indica-tions of these cosmeceuticalswill be increasingly helpfulfor dermatologists, who willundoubtedly encountermany patients using theseproducts. This review sys-tematically reviews clinicalstudies examining the effectsof plant extracts, herbal

preparations, and isolated plant-derived compoundsin the treatment of hyperpigmentation disorders.

METHODSBetween April and August 2013 we searched

Embase and MEDLINE databases for published clin-ical studies examining the use of plant-derivedproducts for the treatment of hyperpigmentation.Embase database was searched using Emtree searchterms ‘‘phytotherapy,’’ ‘‘plant medicinal product,’’‘‘herbal medicine,’’ and ‘‘hyperpigmentation,’’ whichincluded subcategories ‘‘flavonoid,’’ ‘‘herbaceousagent,’’ ‘‘melanosis,’’ ‘‘post-inflammatory hyperpig-mentation,’’ ‘‘chloasma,’’ ‘‘lentigo,’’ and ‘‘melanocy-tosis.’’ MEDLINE database was searched using theMeSH terms ‘‘phytotherapy,’’ ‘‘plants, medicinal,’’‘‘plant extracts,’’ ‘‘complementary therapies,’’ and‘‘hyperpigmentation,’’ which included the subcate-gories ‘‘flavonoids,’’ ‘‘melanosis,’’ ‘‘post-inflamma-tory hyperpigmentation,’’ and ‘‘lentigo.’’ The term‘‘melasma’’ is not specifically included in eitherPubMed MeSH or Embase Emtree databases; it isincluded under the umbrella terms ‘‘melanosis’’ and‘‘chloasma,’’ respectively. Given this, we includedthe key word ‘‘melasma’’ in searching both data-bases, in addition to the MeSH and Emtree termslisted above. Studies involving plant-derived com-pounds and pigmentation as an outcome measurewere included. The searches were filtered to onlyinclude clinical studies and those written in English.

Bibliographies were searched for additional studiesthat met inclusion and exclusion criteria. Of 149articles found, 26 met inclusion criteria (Table II).

RESULTS/DISCUSSIONThe studies are summarized in Table II. Botanical

therapies were studied as topical, oral, adjunctive,

and preventative treatments.Oral therapies includedprocyanidin,7 Pycnogenol(standardized extract ofFrench maritime pine bark),8

Polypodium leucotomos ex-tract,9 and Chinese herbs,10-12

all of which have strong anti-oxidant activities. Several stud-ies examined botanicals incombination with standardtreatments,7,13,14butonly1 iso-lated the complimentary effectof the botanical compound14

by studying a cosmetic formu-lation with and without theextract.

Therapeutic mechanisms of actionHyperpigmentation results from excessive mela-

nin deposition, which leads to areas of increasedpigment density or areas of unusual pigmentdispersion.4 Inhibition at any stage of melaninproduction or dispersion may affect clinicalpigmentation and botanicals inhibit pigmentationthrough a variety of mechanisms.

As shown in Tables III and IV, several botanicalsinhibit tyrosinase, the enzyme that catalyzes severaloxidative reactions required for melanin synthesisfrom its precursor amino acid, tyrosine.15 Tyrosinaseis a glycoprotein located within the membrane ofvesicles that transport melanin polymers, termed‘‘melanosomes.’’15

Once formed in epidermal melanocytes, melano-somes are transferred to surrounding keratinocytes(Fig 1). Soy extract contains serine protease inhibi-tors, heat labile enzymes that suppress melanosometransfer through inhibition of the keratinocyteprotease-activated-receptor 2.16,17

Several botanicals inhibit hyperpigmentationthrough anti-inflammatory and antioxidant effects. Invitro studies have shown that inflammatory mediatorsenhance melanogenesis; leukotrienes C4 and D4 andprostaglandin E2 stimulate melanocyte cell growthand dendrite proliferation and several inflammatorymediators stimulate melanocyte pigment production,including interleukin-1, interleukin-6, and reactiveoxygen species.18-20 Also, inflammation-induced

Fig 1. Hyperpigmentation: pathogenic mechanisms. Epidermal hyperpigmentation may resultfrommelanocyte proliferation, melanocyte hyperactivity, or increased transfer of melanosomesto keratinocytes. Melanin extravasation into the dermis leads to the blue discoloration ofdermal hyperpigmentation. Dermal melanin can be phagocytosed by macrophages to formmelanophages. (1) Increased synthesis of melanin from its tyrosine precursor is a tyrosinase-dependent process and requires several oxidative reactions. (2) Increased transfer of melano-somes to keratinocytes is dependent on activation of the keratinocyte protease-activatedreceptor-2. (3) Melanophages are dermal macrophages that have phagocytosed melaningranules. The presence of these cells results in a blue hyperpigmentation, which is oftenresistant to topical therapies.

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melanocyte cell damage facilitates aberrant transfer ofmelanosomes into the dermis.2 UV radiation mayexacerbate dyspigmentation partially by up-regulating inflammatory mediators. For example,UV-induced lipid-membrane peroxidation increasesthe production of reactive oxygen species.21 UV radi-ation contributes to hypermelanosis through othermechanisms as well, including up-regulated keratino-cyte expression of melanogenic mediators22-24 andprotease-activated-receptor 2.17

Several extracts contain flavonoids, a class ofphytochemicals with potent antioxidant activities.Flavonoids in silymarin, Pycnogenol, and soyextract suppress melanogenesis by inhibiting reac-tive oxygen species formation. However, flavo-noids are not universally antimelanogenic. Forexample, the citrus flavonoid naringenin25 in-creased melanogenesis in vitro in melanoma cells,although this effect has not been investigatedclinically.

Role of subtype of hyperpigmentation inrelation to treatment response

Botanical therapies consistently improved epider-mal melasma,7,8,26-31 subclinical photoaging,32,33 andacute pigmentation induced by UV exposure.9,14,34

Results were mixed for solar lentigines33,35,36 anddermal melasma.37,38 This suggests botanical treat-ments are most effective for acute forms of hyper-pigmentation and hyperpigmentation confined tothe epidermis. These factors may be more predictiveof treatment success than the underlying cause ofhyperpigmentation.

This conclusion is reinforced by several studies.Licorice extract significantly lightened melasma, butwas less effective when melasma included a com-ponent of dermal pigmentation.38 Soy lightenedsubclinical hyperpigmentation but did not clinicallyimprove solar lentigines despite reducing pigmentload in the epidermis of these macules.33 Thissuggests soy reduces epidermal pigment but may

Table I. Standard treatments of hyperpigmentation

Treatment Mechanism of action Side effects Notes

Retinoids 1) Tyrosinase inhibition2) Increased keratinocyteturnover

3) Increased keratinocytepigment granule dispersal

Erythema, irritation, desquamation Slow onset if used asmonotherapy

Azelaic acid 1) Tyrosinase inhibition2) Melanocyte proliferationinhibition

3) ROS suppression

Irritation, pruritus, erythema

Chemical peels Removal of melanin throughthinning of stratumcorneum and epidermolysis

Erythema, atrophy, scarring,hypopigmentation, hyperpigmentation

Unpredictable results

Laser treatments Thermal damage to melanin Atrophy, scarring, hypopigmentation,hyperpigmentation

Unpredictable results,hyperpigmentation muchmore likely in phototypesIV-VI

Kojic acid 1) Tyrosinase inhibition2) ROS scavenger

Irritation, sensitization

Hydroquinone 1) Tyrosinase inhibition2) Melanocyte DNA and RNAsynthesis inhibition

Irritation, transient or permanentdepigmentation, allergic contactdermatitis, ochronosis

Carcinogenic in animalstudies, yet not proven inclinical studies

ROS, Reactive oxygen species.

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not improve dermal hypermelanosis. Tadokoroet al35 found an inconsistent lightening effect of atopical botanical formulation on solar lentigines.35

Poor responders may have had a component ofdermal pigmentation, but this was not specificallyassessed.

PIH and drug-induced hyperpigmentation werenot specifically evaluated in any of the reviewedstudies. Because PIH may occur through a distinctmechanism involving aberrant dermal transfer ofmelanin,5 it is not clear if treatments for other formsof hyperpigmentation will be useful for PIH. Drug-induced hyperpigmentation is a special subset ofpigmentary disorders because the causes are pro-tean, including increased melanin, iron, lipofuscin,and drug-melanin complexes.39,40 In addition thepigmentation may be found in the epidermis, der-mis, or both.39,40 More clinical studies are needed toassess botanical therapies of dermal hyperpigmen-tation, PIH, and drug-induced hyperpigmentation.

Use as preventative agentsSeveral studies10,28,32,41 suggest that botanicals

may effectively prevent the development of hyper-pigmentation. One study reported that soy extractmay prevent the pigmentary changes that precedeclinically apparent hyperpigmentation,32 and an-other found that oral proanthrocyanidin preventedworsening of melasma during summer months.28

Glechomahederacea extract suppressedUV-induced

pigmentation but did not lighten pre-existingmelasma lesions.41 Ha et al41 suggest Glechomahederacea extract has an antipigmenting effect,rather than depigmenting effects, because of antiox-idant and anti-inflammatory effect. Thus, somebotanicals may be more appropriately used as pre-ventative, rather than therapeutic, agents. Individualswith risk factors such as chronic sun exposure or afamily history of dyspigmentation may benefit fromthese preventative measures.

LimitationsInterpretation of these results is limited by incon-

sistencies in study methodology and botanicalextractionmethod. Also, controlling for confoundingvariables, such as sun exposure and sunscreen use, isdifficult in clinical studies.

The reproducibility of botanical studies is depen-dent on equivalent methods of preparing botanicalingredients. The potency and composition of activephytochemicals varies significantly with differentextractionmethods.42 Only one third of the reviewedstudies provided a reasonably reproducible methodfor obtaining their active ingredient (Table V). Ofnote, extraction methodologies of ingredients ob-tained from companies may be proprietary andtherefore incompletely described.

Hyperpigmentation severity can be assessed sub-jectively, semiquantitatively, or objectively. UV lightphotography and MASI scores are examples

Table II. Summary of clinical studies

Intervention

Pigmentation

disorder

Study

design Subjects Comparison

Major outcome

measures Major results Study limitations

Level of

evidence*

Melasma7% Alpha-arbutin

combined withlaser treatment

Polnikorn,37 2010

Melasma(dermaland mixed)

Singlegroup efficacytrial

N = 35 None Visual inspection forfading of lesion on5-point scale

67% Of participants with[50%reduction of melasma after6-mo treatment

1) Arbutin not studied independentof laser treatment

2) Criteria for 5-point scaleevaluation of not described

IIB

Chinese herbs (oral)combined withHe-Ne lasertreatment

Wu et al,10 2009

Chloasma RCT N = 90 Oral vitaminsC and E withtopical 20%azelaic acidcream

1) Serum LPO and SOD2) Visual inspection for

change in size andcolor

1) Treatment significantlymore effective thancontrol based on totaleffectiveness rate

2) Significant decrease inserum LPO and increasein serum SOD levels aftertreatment

1) Color evaluated subjectively2) Area calculation not described3) Macule size and color data

not reported4) Herbs not studied independently

IB

Chinese herbs (oral)combined withacupuncture

Feng et al,12 2010

Chloasma RCT N = 60 Oral vitaminsC and E

Visual inspection forchange in size andcolor

Chinese herbs significantlymore effective thancontrol based on totaleffectiveness rate

1) 3 Different herb combinationsused in treatment group

2) Macule size and color datanot reported

3) Chinese herbs not studiedindependently

IB

Chinese herbs (oral)combined withacupuncture

Shi and Xu,11 2007

Melasma RCT N = 61 Both groupsreceived oralvitamins C andE with topicalChinese herbalpreparation

1) Scored size and color ofskin lesions

2) Re-evaluated lesions1-2 y after study

1) Significantly greater totaleffectiveness rate andimproved area and colorscores in treatment group

2) Continued improvementsat long-term follow-up

1) Semiquantitative analysis2) Chinese herbs not studied

independently

IB

Ellagic acid, plantderived

Ertam et al,26 2008

Melasma(epidermaland mixed)

RCT,open-labeldesign

N = 30PhototypeII-IV

1) Arbutin2) Synthetic

ellagic acid

Mexameter (Chourage-Khazaka Electronic,Cologne, Germany)measurementfor pigment density

Significant improvement inpigment density in allgroups, with no statisticaldifference between them

Plant-derived ellagic acid not studiedindependently (treatment groupreceived combination of syntheticand plant-derived ellagic acid)

IB

Emblica, licorice, andbelides extracts

Costa et al,46 2010

Melasma(epidermaland mixed)

RCT N = 56PhototypeI-IV

HQ 2% 1) UV image analysis (Visia,Canfield Scientific Inc,Fairfield, NJ)for number, size, andtone of macules

2) Subjective medicaland self-evaluations

Statistically significantimprovement in subjectiveevaluations and number,size, and tone of lesions inboth groups, comparedwith baseline; no statisticallysignificant differencebetween groups

1) Participants not blinded to treatment2) Burning and erythema more common

in HQ group (no statistical analysisfor significance of this difference)

IB

Grape seedextract rich inproanthrocyanidin (oral)

Yamakoshi et al,28

2004

Chloasma Single groupefficacy study

N = 12 None 1) Colorimetry(spectrophotometerfor L*, a*, and b* values)

2) Melanin index (from L*,a*, and b* values)

3) Focal macule size

1) Significant lightening(decrease in melanin index)effect with maximum benefitat 6 mo

2) Decreased size of lesions3) Unclear distinction from

melasma

1) Authors did not comment onstatistical analysis of change in focalmacule size

2) No comparative control group

IIB

LiquiritinZubair and Mujtaba,29

2009

Melasma(epidermal)

RCT N = 90 HQ 4% 1) Color compared withnormal-appearing skin

2) Focal macule size3) Change in photographic

appearance

4% Liquiritin significantlymore effective than HQand 2% liquitirin basedon change in maculecolor, macule size, andimprovement inphotographic appearance

1) Subjective assessments2) Macule size data not reported3) Authors suggest that liquiritin

depigments skin more evenly thanHQ, but do not provide evidence

4) No report on potential confoundingbecause of sunscreen noncompliancerate between groups

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LiquiritinAmer and Metwalli,30

2000

Melasma(epidermal)

Split-facecontrolledclinical trial

N = 20 Vehicle cream(ingredientsnot described)

1) Color compared withnormal-appearing skin

2) Focal macule size

1) 60% With reduction inlesion size[75%

2) 70% With reduction inpigmentintensity by 3 levels

3) Control with only verymild improvement in2 patients

1) No statistical analysis performed2) Size measurements not described

IIA

Mulberry extractAlvin et al,31 2011

Melasma(epidermaland mixed)

RCT N = 50PhototypeIII-V

Vehicle(coconutoil base)

1) MASI score2) Mexameter

measurement formelanin andhemoglobin content

3) Melasma QOL score

1) Significant improvementin MASI score, averageMexametermeasurements, andQOL scores intreatment group

2) No significantimprovements inthe placebo group

1) Methods to ensure consistency ofareas chosen for Mexameterreadings were not discussed

2) Investigators not blinded

IB

ProcyanidinHandog et al,7 2009

Melasma(epidermal)

RCT N = 60PhototypeIII-V

Placebo tabletscontainingstarch

1) Mexametermeasurement formelanin andhemoglobin indices

2) MASI score

Treatment group withsignificantly improvedMexameter measurementsand MASI scorescompared with placebo

Procyanidin combinedwith vitamins A, C, and E and notstudied independently of these

IB

Pycnogenol:standardized barkextract of Frenchmaritime pine (oral)

Ni et al,8 2002

Melasma Single groupefficacytrial

N = 30 None 1) Focal macule size2) Pigment intensity

based on nationalstandard color chart

1) Significant decrease indiameter, averagedecrease of 25.8 mm2

2) Significant decrease inpigment intensity,average of 0.47 U

3) Overall effective rateof 80%

1) Effectiveness defined as any reductionin the size of macule or reduction inpigment intensity by $ 1 point

2) Semiquantitative analysis of color3) No comparative control group

IIB

Rumex occidentalisextract

Sabancilar et al,13

2011

Melasma(epidermal,dermal, andmixed)

Single groupefficacytrial

N = 30PhototypeII-IV

None 1) Colorimetry for L, H, andC values

2) Clinical evaluation byphysician for overallimprovement

1) Significant skinlightening after twicedaily application

2) Milder significant skinlightening after twiceweekly application

3) Good or moderateimprovement in 55% ofparticipants by clinicalassessment

1) Contribution of Rumex occidentalisunclear as there was no vehiclecontrol

2) Vehicle contained glycolic acid,salicylic acid, and sunscreen, whichmay contributed to lightening

IIB

SilymarinAltaei,53 2012

Melasma RCT N = 96 Vehicle cream 1) Focal macule size2) MASI3) Physician Global

Assessment4) Subject survey for

satisfaction

1) Treatment group withsignificant improvementsin macule size, MASI scores,and physician assessments;no significant improvementsin control group

2) 100% Satisfaction reportedby subjects in treatmentgroup

Melasma type not specified IB

Plant extracts includingorchid extract

Tadokoro et al,35 2010

Melasma(type notspecified)and lentigosenilis

Split-facecontrolledclinicaltrial

N = 48 Formulationcontainingvitamin-Cderivative

1) Mexametermeasurement formelanin index

2) Skin tone color scale3) Focal macule diameter4) Clinical assessment for

lesion color intensity,number, skin clarity,global appearance,and complexionhomogeneity

5) Subject survey

1) Significant improvementsin macule size, macule color,and subjective surveys in bothgroups

2) Lentigo color improvedsignificantly only in olderparticipants

3) Melanin indices unchangedin both groups

4) Global assessment improvedonly with orchid extract

1) Melanin indices unchanged despiteclinical lightening effect

2) The vehicle cream containedcomponents such as licorice root,which is a known to modulatemelanin production and confoundsanalysis of orchid extract

3) Melasma type not specified

IIA

Chronic UV-induced hyperpigmentation

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Table II. Cont’d

Intervention

Pigmentation

disorder

Study

design Subjects Comparison

Major outcome

measures Major results Study limitations

Level of

evidence*

Coffea arabica, fruit andvegetable extracts

Palmer and Kitchin,54

2010

Photoaging(Glogauscale IIor III)

RCT N = 40CaucasianphototypeI-IV

Control facewash andmoisturizer(ingredientsnot described)

1) Clinical evaluationby dermatologist forhyperpigmentationrated on 0-9 scale

2) Subject self-assessment3) UV imaging

Statistically significantimprovement inhyperpigmentation,compared with control,assessed by clinical gradingand confirmed by self-assessment questionnairesand UV imaging

1) Did not describe criteria for clinicalgrading scales

2) Did not report between-groupsstatistical analysis

3) Did not describe other vegetableand fruit extracts in formulation

IB

Plant HQ glucosidesClarys and Barel,36

1998

Solar lentigo Single groupefficacytrial

N = 14Caucasian

None Colorimetry (chromometermeasurements for L, a,and b values)

1) Significant lightening effectbased on increase in L value

2) Trend toward shift away fromred and yellow pigmentation,based on a and b values

Authors claim treated lesions werevisibly lighter than untreated lesionsat conclusion of study but did notconfirm this with colorimetricevaluation

IIB

Soybean extractWallo et al,55 2007

Photoaging RCT N = 68PhototypeI-III

Moisturizervehicle

1) Clinical evaluationby dermatologist forhyperpigmentation,lentigines, blotchiness,dullness on 0-9 scale

2) Chroma Meter, KonicaMinolta, Ramsey, NJ(Colorimetry for L, a,and b values)

3) Subject self-assessment

1) Soy moisturizer significantlymore effective than vehiclefor improving mottledpigmentation, blotchiness,dullness, and overall skin tone

2) Self-assessment withsignificant improvementsafter 1 wk with soy and after12 wk with vehicle

Results of colorimetry not consistentwith clinical assessment; authorssuggest this may be becausecolorimetry evaluates a small areawhereas clinician assessedaverage appearance

IB

Soybean extractHermanns et al,32

2000

Subclinicalfacialhyperpig-mentation

Controlledclinicaltrial

N = 15PhototypeII

1) 15% Azelaicacid

2) 12% Glycolicacid

UV light image analysisusing highmagnification tomeasure total area ofhyperpigmentation

Significant decrease in totalarea of hyperpigmentationin azelaic acid and soygroups but not in glycolicacid group

1) Selection of participants for treatmentgroups not described

2) No between-groups comparisonsdone

3) Outcome measure only evaluatedarea, not density, of macules

IIA

Soybean extractHermanns et al,33 2002

Solar lentigoandsubclinicalhyperpigmen-tation onarms

Controlledclinicaltrial

N = 30 Asian Untreatedskin

1) Spectrophotometermeasurement formelanin index

2) Corneomelametry3) UV light image

recording ofperilesional skin toassess subclinicalhyperpigmentation

1) No decrease in melaninindex of solar lentigines

2) Soy significantly reducedmelanin load in stratumcorneum of solar lentigo

3) Soy showed significantdepigmenting effect onsubclinical hyperpigmentation

No vehicle control was used IIA

Acute UV-induced hyperpigmentation

Alpha-bisabololLee et al,34 2010

UVA and UVBtanned skin(with solarsimulator)

Controlledclinicaltrial

N = 28PhototypeIII-IV

Vehiclecream

1) Spectrophotometermeasurement for L, a,and b values

2) Clinical evaluation

1) Significantly more effectivelightening as measured byspectrophotometer thanvehicle control

2) No difference between groupsdetected by clinical evaluation

1) Lightening effect measured withspectrophotometer not detected inclinical evaluation

2) Did not describe criteriaused for clinical evaluation

IB

DPMammone et al,14

2010

UVB tannedskin (withsolarsimulator)

Controlledclinicaltrial

N = 10Per panelphototypeIII

1) 4% HQ2) Kojic acid3) Vehicle for

DP (cosmeticblend)

4) Cream offluocinoloneacetonide 0.01%,HQ 4%, tretinoin0.05% cream

5) Untreated skin

Colorimetrymeasurements forchange in L valuesplotted against timeto evaluate rate offade of induced tan

1) Addition of DP to cosmeticformulation increased rate offade of tan

2) Authors concluded effect ofDP was similar to that of HQand kojic acid

1) No between-groups analysis of data tocompare effects of DP with standardtreatments

2) No discussion of randomization orblinding

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Glechoma hederaceaextract

Ha et al,41 2011

UVA and UVBtanned skinon forearm(with solarsimulator)and facialhyperpig-mentation

Split-faceRCT

N = 23 AsianphototypeII-IV

1) Vehicle lotion2) Untreated skin

1) Spectrophotometermeasurement for L, a,and b values

2) Clinical assessmentof skin color on a9-point scale

3) Clinical assessmentof facialhyperpigmentationtreated with Glechomahederacea

1) Significantly weakerinflammatory reaction(lower a value), weakerpigmentation, and fasterfading of pigmentation afterUV radiation, compared withplacebo and untreated skin

2) Significantly faster fadingof pigmentation by clinicalexamination

3) No difference betweenGlechoma hederaceaetreatedand placebo-treated facialhyperpigmentation

Characteristics of facialhyperpigmentation not described;unclear whether macules werea result of melasma, lentigines, orsome other cause

IB

Polypodiumleucotomosextract (oral)

Middelkamp-Hupet al,9 2004

Psoralen-UVA-inducedpigmentationand skindamage

Singlegroupefficacytrial

N = 10PhototypeII-III

All outcomemeasurescomparedbetweenlesions inducedbefore and afterPolypodiumleucotomosingestion

1) Clinical evaluationusing erythema andedema scoring system

2) Histology for sunburncells

3) Immunohistochemistryfor Langerhans cells,proliferatingkeratinocytes, dermalmast cells, andendothelial cells

1) Significantly lower erythemaand edema scores in maculesinduced after Polypodiumleucotomos treatment

2) Pigmentation reduced 4mo later in lesions inducedafter Polypodium leucotomostreatment

3) Significantly fewer sunburncells and dermal mast cells,less depletion of Langerhanscells and less vasodilation inlesions induced afterPolypodium leucotomostreatment

1) Follow-up evaluation donequalitatively and only in 6 patients

2) No objective measurement ofdifference in color

IIB

AbstractsGreen tea extract

(EGCG analogue)Syed et al,56 2009

Melasma RCT N = 60 Placebo Investigator GlobalAssessment,clearing of lesions

Significant results in bothgroups, treatment creamsignificantly more effective

Awaiting final manuscript for completemethods and results

IB

Oral hesperidinGueniche et al,57 2012

Solar lentigo RCT N = 66 Maltodextrinsupplement

Brightness and agespots measured

Significant improvement inbrightness compared withplacebo

Awaiting final manuscript for completemethods and results

IB

Glycyrrhiza glabraextract

Tsilika et al,38 2011

Melasma Singlegroupefficacytrial

N = 10PhototypeII-IV

None 1) Clinicalexamination

2) MASI score3) Standard and

UV-lightphotographs

4) RCM examination

1) Significant reduction inMASI score confirmedby UV photography

2) Significant decrease inhyperpigmentedkeratinocytes detectedby RCM

3) Patients with dermalmelanophages onmicroscopy had limitedresponse and melanophagespersisted after treatment

Awaiting final manuscript for completemethods and results

IIB

DP, 1-(2,4-Dihydrophenyl)-3-(2,4-dimethoxy-3-methylphenyl) propane; EGCG, epigallocatechin-3-gallate; HQ, hydroquinone; LPO, lipoperoxide; MASI, Melasma Area and Severity Index; QOL, quality

of life; RCM, reflectance confocal microscopy; RCT, randomized controlled trial; SOD, superoxide dismutase; UV, ultraviolet Color spaces: L, C, H; L,a,b; and L*,a*,b* color spaces are similar in that

L represents lightness (black/white), C/a/a* represent the red/green color space, and H/b/b* represent the blue/yellow color space.

*Levels of evidence: IA: evidence from meta-analysis of randomized controlled trials. IB: evidence from at least 1 randomized controlled trial. IIA: evidence from at least 1 controlled study without

randomization. IIB: evidence from at least 1 other type of experimental study.

JAM

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Fisk

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Table III. Mechanism of action of botanicals and extracts

Scientific name Common name Mechanism of action Active constituents

Bellis perennis flowers46 Belides 1) Anti-inflammatory46

2) ROS suppression46

3) Suppresses melanosometransfer46

Polyphenols

Brassocattleya marcella35 Orchid ROS suppression58

Camellia sinensis56 Green tea 1) ROS suppression59

2) Anti-inflammatory59

3) Tyrosinase inhibitor60

Polyphenols including EGCG

Coffea arabica fruit54 Coffee fruit(coffeeberry)

ROS suppression61 Polyphenols includingproanthrocyanidins

Glechoma hederacea41 Ground ivy 1) Anti-inflammatory62

2) ROS suppression63

Glycine max32,33,55 Soy bean 1) Suppresses melanosometransfer (serine proteaseinhibitors)17

2) ROS suppression64

(isoflavones)

Serine protease inhibitorsFlavonoidsIsoflavones including genistein

Glycyrrhiza glabra46 Licorice 1) ROS suppression65

2) Tyrosinase inhibition66Flavonoids including liquiritin andglabridin

Morus alba31 Mulberry plant 1) Tyrosinase inhibition67

2) ROS suppression67Flavonoids including mulberroside F(moracin M-6, 3’-di-O-beta-D-glucopyranoside)

Phyllanthus emblica fruit46 Emblica 1) ROS suppression68

2) Tyrosinase inhibitionPolyphenols

Pinus pinaster8 French maritimepine (Pycnogenol)

1) ROS suppression69

2) Regenerates active formsof vitamins C and E70

3) Tyrosinase inhibition

Flavonoids including procyanidin

Polypodium leucotomosextract9

Cabbage palm fern ROS suppression71 Caffeic acid and ferulic acid(non-flavonoid catacholicantioxidants)72

Rumex occidentalis13 Western dock Tyrosinase inhibition73

Silybum marianum53 Milk thistle extract(silymarin)

1) ROS scavenger2) Tyrosinase inhibition74

Flavonoids

Vitis vinifera28 Grape seed extract ROS suppression75 Polyphenols including procyanidin

EGCG, Epigallocatechin-3-gallate; ROS, reactive oxygen species.

Table IV. Mechanism of action of isolated compounds

Compound Structure Example sources Mechanism of action

Alpha-arbutin37 Beta-D-glucopyranoside(derivative of hydroquinone)

Pear, blueberry, cranberry, wheat Tyrosinase inhibition74,75

Alpha-bisabolol34 Sesquiterpene alcohol German chamomile Inhibits a-MSH-inducedmelanogenesis76

DP14 DP Dianella ensifolia 1) ROS suppression2) Tyrosinase inhibition77

Ellagic acid26 Polyphenol Strawberry, geranium, grapes,cherries, walnuts, green tea

Tyrosinase inhibition throughcopper chelation78

Hesperidin57 Flavonoid Citrus fruits 1) Tyrosinase inhibition79

2) Suppression of UVA-inducedoxidative damage80

Liquiritin29,30 Flavonoid Licorice Melanin dispersion81,82

a-MSH, Alpha-melanocyte stimulating hormone; DP, 1-(2,4-dihydrophenyl)-3-(2,4-dimethoxy-3-methylphenyl) propane; ROS, reactive oxygen

species; UV, ultraviolet.

J AM ACAD DERMATOL

FEBRUARY 2014360 Fisk et al

Table V. Reproducibility of studies

Active ingredient Study Extraction method Method of obtaining materials

Reproducibility

of active

ingredientz

Isolated compoundsAlpha-bisabolol Lee et al,34 2010 N/A Purchased from Sigma

Chemical Co, St Louis, MO1

Alpha-arbutin Polnikorn,37 2010 N/A Obtained from Skin AdvanceLaboratory, Tokyo, Japan

1

Dianella ensifolia Mammone et al,14 2010 Not described Not described 3Liquiritin Amer and Metwalli,30

2000Not described Not described 3

Liquiritin Zubair and Mujtaba,29

2009N/A Obtained from a licensed

pharmacy in Multan, Pakistan2

Procyanidin Handog et al,7 2009 N/A Obtained procyanidin tabletscontaining defined amountof active ingredients;supplier not identified

2

Silymarin Altaei,53 2012 Not described Obtained from App-Chem-Bio,China

2

Herbal preparationsChinese herbs Wu et al,10 2009 Not described Not described 3Chinese herbs Feng et al,12 2010 Not described Not described 3Chinese herbs Shi and Xu,11 2007 Not described Not described 3

Plant extractsEllagic acid Ertam et al,26 2008 Methanol

extractionCastanea sativa stem barks andJuglans regia leaves collectedfrom Sultanhisar, Turkey(Malgecemir village) in Aydin

Eucalyptus camaldulensis leavescollected from EgeUniversity, Izmir, Turkey, inSeptember 2002

2

Glechoma hederacea Ha et al,41 2011 Ethanol extraction Not described 2Grape seed Yamakoshi et al,28 2004 Aqueous ethanol

extract*Product provided: grape seedextract; (Gravinol, KikkomanCo, Chiba, Japan)

2

Mulberry extract Alvin et al,31 2011 Not described Not described 3Polypodiumleucotomos

Middelkamp-Hup et al,9

2004N/A Capsules containing 180 mg

Polypodium leucotomossupplied by IF Cantabria SA,Madrid, Spain

1

Soy bean Hermanns et al,32 2000 N/A Formulation provided by theJohnson & Johnson SkinResearch Center

2

Soy bean Hermanns et al,33 2002 Not described Not described 3Commercial formulationsCoffea arabica Palmer and Kitchin,54

2010Not described Not describedy 3

Emblica, licorice, andbelides

Costa et al,46 2010 N/A Product obtained, identified as:Clariderm Clear, StiefelLaboratories Inc, Guarulhos,Brazil

1

Hydroquinoneglucosides(plant derived)

Clarys and Barel,36 1998 N/A Product obtained: QuniodermEemedis, Brussels, Belgium

1

Continued

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VOLUME 70, NUMBER 2Fisk et al 361

Table V. Cont’d

Active ingredient Study Extraction method Method of obtaining materials

Reproducibility

of active

ingredientz

Orchid extracts(combination withother plant extracts)

Tadokoro et al,35 2010 N/A Formulation developed byLVMH Recherche, Saint Jeande Braye, France

2

Pycnogenol Ni et al,8 2002 N/A Patented commercial product,provider not identified

2

Rumex occidentalis Sabancilar et al,13 2011 N/A Babe Depigmentation Cream,Spain

1

Soy bean Wallo et al,55 2007 N/A Aveeno Positively Radiant soymoisturizer, Johnson andJohnson CCI, Skillman, NJ

1

Poster abstractsOral hesperidin Gueniche et al,57 2012 Not described in

abstractNot described 3

Green tea extract Syed et al,56 2009 Not described inabstract

Not described 3

Glycyrrhiza glabraextract

Tsilika et al,38 2011 N/A (commercialproduct)

Product identified asDermamelan (Mesoestetic,Barcelona, Spain)

1

N/A, Not available.

*Paper does not described method, instead references process described by Yamaguchi et al, 1999.75

yFootnotes mention www.replere.com, a World Wide Web site advertising cosmetic skin care products but article does not specify which

product used.z1 = Reasonably reproducible; 2 = some information missing to be reasonably reproducible; 3 = no information is provided to be reasonably

reproducible.

J AM ACAD DERMATOL

FEBRUARY 2014362 Fisk et al

of subjective and semiquantitative assessmentmethods, respectively.4 Colorimetry is the mostcommonly used objective measurement andanalyzes pigment based on wavelength of reflectedlight.43 Skin color is analyzed with the L*a*b* systemin which L* represents the black/white scale, a*represents the red/green scale, and b* represents theyellow/blue scale.44 Corneomelametry, anotherobjective method, assesses melanin content ofthe stratum corneum by histochemical analysis ofskin-surface scrapings.45

Fourteen of the reviewed studies incorporatedobjective assessments of hyperpigmentation. Ofnote, 2 studies35,45 reported conflicting resultswhen comparing objective and subjective measure-ments. For example, orchid extract clinically light-ened melasma without altering colorimetricanalysis.35 The authors suggest colorimetry detectschanges in pigment density but may not accuratelymeasure changes in melanin distribution. Given this,future clinical studies should include both objectiveand subjective measurements. Objective measure-ment techniques need to be refined to allow forassessment of melanin density, depth, and distribu-tion so that they can integrate better with subjectiveassessments.

Adverse effectsBotanical agents are commonly assumed to be

safer than pharmaceuticals. Among the reviewedstudies, botanicals were shown to be lessirritating than conventional therapies.29,46 However,plant-based therapies are known to cause allergicreactions47 and phototoxic reactions.48 Infrequently,serious adverse events are possible,49 especially withoral and high-concentration formulations. Of note,the Food and Drug Administration does not requirerigorous efficacy and safety testing of botanicalsbefore marketing.50 Also, botanical creams adulter-ated with potent corticosteroids have been reported,which would put consumers at risk for steroid sideeffects including atrophy, acneiform eruptions, anddyspigmentation.51,52

CONCLUSIONSDermatologists should be aware of the evidence

to support or avoid the use of botanically derivedproducts in the treatment of hyperpigmentation. Theuse of botanical therapies for the treatment ofhyperpigmentation is promising, although morerigorous clinical studies are needed. Assessment ofthe subtype and the depth of hyperpigmentation arecritical in determining the success of treatment,

J AM ACAD DERMATOL

VOLUME 70, NUMBER 2Fisk et al 363

regardless of whether this includes standard orbotanical therapies. As research continues to expandin this exciting field, we continue to refine ourunderstanding of how botanical therapies may beintegrated into the therapy of hyperpigmentation.Finally, all patients should be counseled on theimportance of sun hygiene and sun-protectivehabits, as this is the cornerstone to any effectivetreatment regimen against hyperpigmentation.

We are grateful to McKenzie Fisk for her artistic exper-tise in creation of the figure used in this article. We alsothank Bruce Abbot for his valuable guidance in searchingthe scientific literature.

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