DOI: 10.1111/j.1468-3083.2011.04130.

x JEADV

REVIEW ARTICLE

Natural options for the management of hyperpigmentation

J.J. Leyden,† B. Shergill,‡ G. Micali,§ J. Downie,– W. Wallo**,*
†
University of Pennsylvania, Philadelphia, PA, USA
‡
Brighton General Hospital, Brighton, UK
§
Department of Dermatology, School of Medicine, University of Catania, Catania, Italy
–
Mountainside and Overlook Hospitals, Montclair, NJ, USA
**Johnson & Johnson Consumer Companies, Inc., Skillman, NJ, USA
*Correspondence: W. Wallo. E-mail: wwallo@its.jnj.com

Abstract
Facial hyperpigmented disorders are a common complaint in the adult population of all races. First-line topical
treatments are usually hydroquinone or topical retinoids, which can cause irritant reactions. The need for better
tolerated, yet effective, skin lightening agents that could be utilized by a wider population has led to the investigation
of several potential botanical ⁄ natural compounds. There are currently many topical cosmetic formulations claiming
skin depigmenting effects. A few of the ingredients (e.g. soy) are supported not only by in vitro results but also by a
body of controlled clinical efficacy studies; other ingredients, instead, are backed mostly by in vitro data and a few
small uncontrolled clinical studies. In this review, we describe the most common natural ingredients used for skin
depigmentation and their major published studies: soy, licorice extracts, kojic acid, arbutin, niacinamide,
N-acetylglucosamine, COFFEEBERRYTM and green tea.
Received: 11 April 2011; Accepted: 5 May 2011

Conflict of interest
Warren Wallo is an employee of Johnson & Johnson Consumer Companies, Inc, the manufacturer of AVEENO
products. The preparation of this manuscript was sponsored in full by Johnson & Johnson Consumer Products
EAME. James J Leyden MD, Bav Shergill MBBS MRCP, Giuseppe Micali MD and Jeanine Downie MD, are
consultants for Johnson & Johnson Consumer Companies, Inc.

Introduction and melanocyte damage with discharge of melanosomes into the

Hyperpigmented conditions such as melasma, post-inflammatory dermis.5 In melasma, hyperpigmentation seems to derive from a
hyperpigmentation (PIH) and solar lentigines affect a very large combination of factors such as UV exposure, genetic background,
segment of the adult population. These disorders represent a local- hormones and maybe inflammation; paracrine mechanisms
ized increase in pigmentation, which may be due to an increased involving the dermal stem cell factor and its c-kit receptor have
number of melanocytes (e.g. solar lentigo) or to an increase in also been recently suggested.6
melanin pigment (e.g. melasma and PIH). PIH has not only The understanding of pigment formation and of the pathoge-
increased epidermal melanin but also melanin deposits in dermal netic mechanisms underlying these disorders is important for
macrophages. targeting the correct pigmentation pathway; some of the mecha-
Skin pigmentation is the result of various biochemical and nisms used for decreasing pigmentation are: tyrosinase inhibition
cellular processes, including melanocyte homeostasis, regulation of (e.g. hydroquinone, arbutin, kojic acid and licorice extract),7–10
melanogenesis via microphthalmia-associated transcription factor inhibition of melanin ⁄ melanosome transport into keratinocytes
(MITF-M),1 melanin formation via tyrosinase and other melano- (e.g. soy and niacinamide),11,12 increased epidermal turnover
genic enzymes and melanosome transfer.2 Endogenous and exoge- (e.g. a-hydroxyacids and retinoids),13–15 anti-inflammatory ther-
nous factors can up-regulate or down-regulate these processes and apy,16 as well as a combination of multiple mechanisms (e.g. ret-
create pigment alterations. For example, UV is well-known to inoids).17
stimulate pigmentation;3,4 therefore, sunscreens are a first-line of Common topical agents currently used to treat hyperpigmenta-
protection against hyperpigmented conditions. Skin inflammation tion include hydroquinone, retinoids, glycolic acid and azelaic
too can induce hyperpigmentation by causing melanocyte hyper- acid.18,19 However, these compounds can cause adverse effects,
activity, release of inflammatory factors that stimulate melanocytes mostly in the form of skin irritation. In addition, hydroquinone,

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Natural options for hyperpigmentation 1141

a very effective depigmenting agent, can rarely produce an unto- COFFEEBERRYTM (VDF FutureCeuticals, Momence, IL, USA)
ward skin pigmentation called exogenous ochronosis.20 Many and green tea.
patients, therefore, do not tolerate such depigmenting ingredients
and request milder yet efficacious compounds. Both patients and Soy
physicians are increasingly welcoming the use of natural depig- Historically, soy is among the first crops farmed by man. The first
menting agents in view of their high tolerance and efficacy as well written reports on soybean cultivation were found in Northern
as their cosmetically appealing and easily accessible formulations. China dating back to about the 11th century BC;29 the first soy-
Botanical and other naturally occurring ingredients have been bean plant appeared in North America in the 18th century.30
used empirically as topical therapeutic agents since ancient times. In recent years, many biologically active compounds have been
Among the most widely used naturals in dermatology are colloidal identified in soybean. Some of these include well-known dermato-
oatmeal, soy and green tea.21,22 Only recently, though, the clinical logically active ingredients, such as isoflavones (antioxidants),31,32
efficacy of some of these natural ingredients has been substantiated vitamin E and small serine protease inhibitors.12,33 The latter are
through clinical studies and modern technologies.23 In this regard, particularly important in the regulation of pigmentation and
many clinical studies on pigmentation are now supplementing the include soybean trypsin inhibitor (STI) and Bowman-Birk prote-
clinical efficacy evaluation with objective methods for the quantifi- ase inhibitor (BBI).12,33 It is important to note that serine protease
cation of pigmentation; these include standardized digital inhibitors can be damaged by heat;34 thus, to maintain their effi-
photography for storage and image analysis and videodermatosco- cacy, soybean extracts must be preserved. Recently, a manufactur-
py ⁄ dermatoscopy, while reflectance spectroscopy and confocal ing process has been developed to retain in topical formulations a
microscopy are still not widely available. Standardized digital pho- broad spectrum of non-denatured proteins (including STI and
tography and videomicroscopy (especially in cross-polarization), in BBI), essential fatty acids, carbohydrates and vitamins.35
combination with image analysis of hyperpigmentation, are partic- Many in vitro studies have shown that soybean extracts stimu-
ularly helpful in monitoring treatments, thanks to objective quanti- late collagen synthesis,36,37 initiate the elastin repair process,38
fication of lesion count and size and of pigment darkness.24,25 inhibit melanosome transfer,11,12 and have antioxidant ⁄ anti-
In this review, our aim was to examine the mechanism of inflammatory actions.31 These properties are reflected in the
action and the supporting clinical studies of various ‘natural’ clinical benefits of topical soy formulations: anti-inflammatory,
ingredients used as depigmenting agents in cosmeceuticals. moisturizing, photorejuvenation ⁄ photoprotection, amelioration of
fine lines and skin lightening ⁄ brightening.39
A note on hyperpigmentation disorders in skin of With regard to skin lightening in particular, there are many
colour in vitro studies confirming the depigmenting action of serine pro-
Skin colour differences between races are due to variations in the tease inhibitors through the inhibition of a keratinocyte external
number, size and aggregations of melanosomes and not in the membrane receptor called protease-activated receptor 2 (PAR-
number of melanocytes. In black skin, melanosomes are large and 2).11 The PAR-2 pathway regulates phagocytosis of melanosomes
singly dispersed in keratinocytes, while, in Caucasian and Asian by keratinocytes.40,41 Therefore, PAR-2 inhibition determines
skin, melanosomes are aggregated within a surrounding mem- decreased melanosome transfer to keratinocytes.41,42 This is
brane. Also, the epidermal melanin unit of black skin contains reflected, clinically, in the achievement of reversible depigmenta-
more melanin overall and this may undergo slower degradation.26 tion and skin tone amelioration.11,12,43
Over half of the patients with skin of colour (SOC) complain Another important dermatological feature of non-denatured
about uneven skin tone, hyperpigmentation or dark spots.27 The soy extracts is protection against UVB-induced damage.44 Preclini-
reason is an increased susceptibility of SOC patients to pigmentary cal studies show that non-denatured soymilk inhibits the develop-
abnormalities compared to Caucasians. The higher rate of PIH ment of UVB-induced skin tumours.45 In a study by Chen et al.,
and other pigmentary disorders in SOC patients results from mel- soy extracts reduced UVB-induced damage through several mech-
anocytes with larger melanosomes, increased melanin content and anisms: enhanced UVB-induced checkpoint kinase-1 activation
greater melanin-manufacturing capacity, which lead to an exagger- (which prolongs cell cycle thus allowing more time for DNA
ated response of melanocytes to cutaneous damage.28 Additionally, repair), reduced UVB-induced T-T dimer formation, reduced
many SOC patients do not wear sunblock, which can increase the UVB-induced cyclo-oxygenase-2 expression and prostaglandin E2
degree of PIH. secretion, and inhibited p38 MAP kinase activation.44
With regard to patient concerns, in the United States, women Soy has also been shown to stimulate collagen and elastin syn-
with deeply pigmented skin often seek to even their natural skin thesis in short-term pre-clinical studies.36,38 In cultured normal
tone but not to lighten their overall colour; in Africa and Asia (e.g. human dermal fibroblasts, a 3-day treatment with a stabilized
Japan, China), instead, some women desire lighter skin tones. soy formulation increased the rate of collagen synthesis by 58%.36
Some of the favourite natural ingredients used to manage Another pre-clinical study showed that 8–12 weeks of
hyperpigmentation in SOC are: soy, licorice extracts, arbutin, non-denatured soy application enhanced staining of elastic fibres

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1142 Leyden et al.

in the upper dermis, similar to the ‘repair zone’ seen in UV- In commercial formulations, this ingredient is present in concen-
damaged skin treated with retinoids, increased highly branched trations between 10% and 40%.
fine elastic fibres perpendicular to the dermal-epidermal junction Pre-clinical studies have shown that glabridin works as a tyrosi-
(DEJ), and increased tropoelastin mRNA and desmosine con- nase inhibitor.10 Yokota et al. reported a reduction in UVB-in-
tent.38 Desmosine crosslinks are unique to elastin fibres and are duced pigmentation and erythema in brownish guinea pigs when
used to measure the amount of elastin in skin. This implies that glabridin was applied for 3 weeks after UVB irradiation.10 Other
topical soy increases both elastin synthesis and the quantity of studies have demonstrated the antioxidative action of glabridin48
mature elastin fibres. It has been shown that soy-induced improve- as well as its anti-inflammatory effect through a dual-inhibition
ment in elastic tissue occurs, in vitro, thanks to enhanced elastin on cyclooxygenase and lipoxygenase products (PGE-2, TXB-2 and
promoter activity, inhibited elastase activity, and protection of LTB-4).10,49
elastic fibres from degradation by exogenous elastases (partial pro- Despite the preclinical evidence, only few clinical studies on the
tection with 0.02% soy extracts, complete protection with efficacy of glabridin in melasma have been presented at meetings,
0.05%).38 Investigations are in progress to understand whether soy where they showed some in vivo depigmenting effects. However, a
can also up-regulate hyaluronic acid, which, by binding massive PubMed search for the key words ‘glabridin’ or ‘licorice extracts’
amounts of water, produces an effacement and smoothing of fine and ‘melasma’ or ‘pigmentation’ or ‘skin lightening’ did not
lines and wrinkles. return any clinical studies.
Several double-blind, placebo-controlled clinical trials have been
conducted in recent years showing the efficacy of a stabilized soy Kojic acid
formulation in the improvement of hyperpigmentation and other Kojic acid is a fungal metabolic product of the species Acetobacter,
photodamage features. These formulations have also been shown Aspergillus and Penicillium. In vitro studies have shown that it
to be very well tolerated. In a study by Pierard et al.,46 16 Hispanic inactivates tyrosinase through copper chelation;9,50 however, there
women with melasma, applied a stabilized total soy extract once have been no peer-reviewed clinical studies demonstrating a depig-
daily for 3 months to one melasma lesion, while a second melasma menting effect of kojic acid in monotherapy. Its efficacy as a
lesion served as untreated control. At the end of the study, 14 out depigmenting agent is, therefore, uncertain.
of 16 subjects showed some degree of melasma improvement; However, several clinical studies have reported some efficacy
hyperpigmentation was reduced on average by 12%.46 In a larger in the treatment of melasma when kojic acid was combined with
double-blind, parallel-group, vehicle-controlled study, 63 women glycolic acid and ⁄ or hydroquinone.51,52 In a split-face, 12-week
with photodamage applied a soy moisturizer (containing non- randomized study in 40 Chinese women, the addition of kojic
denatured serine protease inhibitors) or its vehicle (both with acid to a formulation containing 10% glycolic acid and 2%
SPF) twice daily to the face for 12 weeks.39 Dermatologist evalua- hydroquinone, improved melasma slightly more compared to the
tions showed a significant improvement in mottled hyperpigmen- same formulation without kojic acid.52 Another split-face study
tation, blotchiness, fine lines, dullness, overall skin tone and by Garcia and Fulton showed that two formulations containing
overall appearance within the first few weeks of use, compared to either 2% kojic acid ⁄ 5% glycolic acid or 2% hydroquinone ⁄ 5%
vehicle. Improvement of these parameters continued throughout glycolic acid where equally effective for skin depigmentation
the study.39 With regard to mottled hyperpigmentation, almost all when tested on 39 patients with melasma and other hyper-
subjects showed some degree of depigmentation (28 of 31) in the pigmented conditions.51 It is noteworthy that the kojic acid for-
soy group by the 12th week of study; the vehicle group had a mulation was more irritating.51 Lastly, a recent 12-week, paired,
more limited (17 of 32 subjects) and weaker depigmentation, double-blind study by Draelos et al. compared a preparation
which was attributed to seasonal change. containing kojic acid, emblica extract and glycolic acid to hydro-
These studies support the efficacy and safety of stabilized soy quinone 4% in 80 multiethnic subjects with facial dyschromia.53
formulations in the improvement of hyperpigmentation, texture, The results showed efficacy parity in skin bleaching between the
brightness and photodamage. two groups.53

Other natural ingredients Arbutin

Many other botanical agents, such as licorice, arbutin and Arbutin is a naturally occurring b-D-glucopyranoside derivative of
niacinamide, have been reported in the literature to improve hydroquinone found in bearberry (Arctostaphylos uva ursi) and
hyperpigmentation by inhibiting melanogenesis without melano- other trees.54 It is another botanical bleaching agent that works via
cytotoxicity.47 reversible inhibition of tyrosinase,8 in this case as a glycosylated
hydroquinone. However, like kojic acid, clear proof of its depig-
Licorice extract menting clinical efficacy is lacking.
Glabridin is the main licorice compound extracted from the root In fact, despite several cosmeceutical formulations containing
of Glycyrrhiza glabra linneva with effects on skin depigmentation. arbutin, as well as several reports on arbutin as a skin depigmenting

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Natural options for hyperpigmentation 1143

agent, only a few small clinical studies on its efficacy have been pub- dimer formation and inflammation, as well as a faster restoration
lished in peer-reviewed journals.55 For example, in an open-label of skin structures after UVB exposure.64 A pilot study on 30 sub-
study, a gel formulation containing arbutin was given to 10 subjects jects (20 full-face and 10 split-face) with moderate photodamage
with melasma, and pigmentation was assessed by Mexameter; all 10 showed an improvement in the appearance of fine lines and wrin-
subjects showed a significant response compared to baseline.55 kles, hyperpigmentation and overall skin appearance following
6 weeks of CBE application compared to baseline.65 Additionally,
Niacinamide the split-face group of the panel (n = 10) showed a 15% (CBE) vs.
Niacinamide (nicotinamide and vitamin B3) is a natural com- 5% (vehicle) improvement in pigmentation from baseline. How-
pound found in many food groups, including vegetables and ever, peer-reviewed clinical studies demonstrating the various skin
seeds. It is part of a very important group of coenzymes (NAD, benefits are lacking.
NADP, NADH and NADPH) involved in cellular reactions.
There are several in vitro studies showing that niacinamide may Green tea
reduce skin hyperpigmentation by reversibly inhibiting melano- Green tea is widely known for its antioxidant properties; its
some transfer to keratinocytes.56,57 Various clinical studies have extracts are polyphenolic compounds that modulate biochemical
also observed a significant decrease in hyperpigmentation and pathways.62,63 These compounds have anti-inflammatory and anti-
increased skin lightness with niacinamide applications compared oxidant properties and are important in anticarcinogenic
to vehicle alone.56,57 In a randomized split-face double-blind study responses.66 The main active ingredient in green tea is epigallo-
on 18 women with hyperpigmentation (senile lentigines, melasma, catechin-3-gallate (ECGC).
or freckles), a 5% niacinamide moisturizer was significantly better It has been speculated that green tea polyphenols, when com-
than vehicle in reducing hyperpigmentation and increasing skin bined in formulations with traditional sunscreens, may have a syn-
lightness after 4 weeks of use.56 A recent 10-week, controlled study ergistic effect.67 A study by Elmets et al.,68 found that the in vivo
on over 200 Indian women with epidermal hyperpigmentation on topical application of ECGC and epicatechin-3-gallate to normal
the face reported that a lotion containing niacinamide, panthenol skin followed by irradiation with 2-MEDs resulted in a dose-
and tocopheryl acetate improved the appearance of hyperpigmen- dependent inhibition of UV-induced erythema; these extracts also
tation and evenness of skin tone compared to the control lotion.58 reduced the number of sunburn cells and partially protected DNA
and Langerhans cells from UV. It is noteworthy that these extracts
N-acetylglucosamine in combination with niacinamide do not absorb in the UVB and thus do not act merely as sun-
N-acetylglucosamine (NAG) is a carbohydrate and represents the screens.68
monomeric unit of chitin, which forms the outer shell of insects With regard to skin depigmentation, No et al. showed in vitro
and crustaceans. It seems to work as a skin depigmenting agent by inhibition of mushroom tyrosinase by green tea polyphenolic
inhibiting the conversion of pro-tyrosinase to tyrosinase; addition- components.69 However, peer-reviewed clinical studies demon-
ally, in skin equivalent cultures, NAG was not only shown to strating the depigmenting effect of these compounds are needed to
decrease melanin synthesis compared to vehicle but also to up- or substantiate this action in vivo. In fact, a PubMed search for the
down-regulate the expression of various pigmentation-related key words ‘green tea’ and ‘melasma’ or ‘pigmentation’ or ‘skin
genes.59 lightening’ did not return any clinical studies on depigmentation.
A few clinical studies have been published using either NAG
alone or in combination with niacinamide. Bissett et al. reported Other compounds
that 2% NAG reduced the appearance of facial hyperpigmenta- There are many other natural compounds that seem to have some
tion in an 8-week, double-blind, placebo-controlled, split-face depigmenting efficacy when studied in vitro and which may repre-
clinical study. The same authors also performed a second clinical sent some future clinical options. Some of these are: paper
study using a combination of 2% NAG and 4% niacinamide mulberry, grape seed, vitamin C, Chinese herbs, Aloe vera, Cuc-
and found that the depigmenting effect was even greater.60 In umis sativus, longan seed and raspberry.
another more recent 10-week, double-blind, vehicle-controlled,
parallel-group study, the combination 2% NAG and 4% niacin- Conclusions
amide was significantly better than vehicle in reducing the Although hydroquinone and retinoids are still the most efficacious
detectable area of facial spots and the appearance of hyperpig- treatments for hyperpigmentation, these can be irritating and
mentation.61 hydroquinone has also been withdrawn from several European
countries. It is, thus, clear that there is a significant need to further
COFFEEBERRYTM clinical investigation of natural ingredients.
COFFEEBERRYTM extract (CBE) is a powerful antioxidant.62,63 Among natural agents for skin depigmentation, soy and niacin-
Pre-clinical and small clinical studies reported a protective effect amide are the ones with the largest in vivo scientific evidence
of CBE against oxidative damage and UVB-induced pyrimidine substantiating this clinical effect. Because soy formulations are

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JEADV 2011, 25, 1140–1145 Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology
1144 Leyden et al.

much better tolerated than retinoid formulations, they can be used 9 Cabanes J, Chazarra S, Garcia-Carmona F. Kojic acid, a cosmetic skin
more frequently and in a larger number of people, including those whitening agent, is a slow-binding inhibitor of catecholase activity of
tyrosinase. J Pharm Pharmacol 1994; 46: 982–985.
who are more sensitive to retinoid irritation. Studies longer than 10 Yokota T, Nishio H, Kubota Y, Mizoguchi M. The inhibitory effect of
12 weeks should be conducted to confirm the empirical experience glabridin from licorice extracts on melanogenesis and inflammation.
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11 Seiberg M, Paine C, Sharlow E et al. Inhibition of melanosome transfer
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13 Yamamoto Y, Uede K, Yonei N et al. Effects of alpha-hydroxy acids on
compounds, possibly producing even greater efficacy compared to
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15 Yoshimura K, Tsukamoto K, Okazaki M et al. Effects of all-trans reti-
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JEADV 2011, 25, 1140–1145 Journal of the European Academy of Dermatology and Venereology ª 2011 European Academy of Dermatology and Venereology