Review

Treatment of melasma: a review of less commonly used

antioxidants
Kayla M. Babbush1, BS, Remy A. Babbush2, and Amor Khachemoune3,4, MD, FAAD, FACMS

1
Division of Dermatology, Department of Abstract
Medicine, Albert Einstein College of Melasma, a common cause for seeking dermatologic care, is a chronic condition of skin
Medicine/Montefiore Medical Center, Bronx,
hyperpigmentation. With a poorly understood pathogenesis, and no universal cure,
NY, USA, 2Department of Food Science,
Cornell University, Ithaca, NY, USA,
melasma is a challenge for many dermatologists. For decades, there has been
3
Department of Dermatology, State investigation into the role of oxidative stress in melasma. In this literature review, we
University of New York Downstate, introduce the role of oxidative stress in melasma and discuss the function of various topical
Brooklyn, NY, USA, and 4Department of and oral antioxidant therapies for patients suffering from melasma. Numerous studies have
Dermatology, Veterans Health
shown efficacy of various antioxidant therapies for treatment of hyperpigmentation, and in
Administration, Brooklyn, NY, USA
this review, we focus primarily on those with less widespread use. Vitamin E, niacinamide,
Correspondence polypodium leucotomos, pycnogenol, grape seed extract, amino fruit acids, phytic acid,
Amor Khachemoune, MD, FAAD, FACMS zinc, silymarin, Korean red ginseng powder, plant extracts, and parsley all have well-
Veterans Affairs Medical Center demonstrated evidence of antioxidant properties, and these substances have been studied
State University of New York Downstate
in the context of skin hyperpigmentation. Although there is conflicting evidence of their
800 Poly Place
therapeutic efficacy, the use of these naturally occurring substances is promising for
Brooklyn, NY 11209
USA patients and medical providers seeking alternative therapeutic options.
E-mail: amorkh@gmail.com

Conflict of interest: None.

Funding source: None.

doi: 10.1111/ijd.15133

familial occurrence of melasma has been reported to be as

INTRODUCTION
Pigmentary disorders can be divided into acquired, congenital,
hypopigmentary, hyperpigmentary, or mixed disorders. Pig-
mentary disorders have a well-demonstrated impact on patient
quality of life, and as a result, they are a common cause for
seeking dermatologic care.1-3 Melasma is a chronic, acquired
pigmentary disorder that presents with hypermelanosis of sun-
exposed areas of skin. Female predominance has been
demonstrated in various studies, and this disorder, also known
as the “mask of pregnancy,” often plagues gravid women. Mel-
asma, along with other disorders of hyperpigmentation, occurs
more commonly in skin of color.4 There is evidence of mel-
asma in all population groups; however, epidemiological stud-
ies have found a higher prevalence among populations of East
Asians (Japanese, Korean, and Chinese), Indians, Pakistanis,
Middle Easterners, Mediterranean-Africans, and Hispanics with
increased exposure to ultraviolet radiation.5 Genetic predispo-
166
sition plays a role in the development of the disease, and
high as 61%.6
The diagnosis of melasma is clinical, and biopsy is rarely
necessary. The severity of melasma can be estimated using the
Melasma Area and Severity Index (MASI) score, the modified
MASI (mMASI) score, colorimetry, and mexametry. The Mel-
asma Quality of Life scale (MelasQoL) can also be used to
guide treatment and track improvement. This 10-item scale can
assess the level of impairment individuals suffer from due to
their melasma.5,7
The pathogenesis of melasma is multifactorial and incom-
pletely understood, and this poses a challenge for disease man-
agement. Ultraviolet light exposure, which induces reactive
oxygen species (ROS), altered cutaneous vasculature, family
history, and hormonal influences are all known to play a role in
development of melasma.8,9 Biopsies of melasma skin show an
increased number of melanocytes, melanosomes in ker-
atinocytes, and dendrites.10,11 There is also evidence of
increased activity of melanogenic enzymes in affected skin and

International Journal of Dermatology 2021, 60, 166–173 ª 2020 the International Society of Dermatology
Babbush, Babbush, and Khachemoune
increased melanin deposition in both the epidermis and der-
mis.10,11
Combination therapy is often recommended for patients, as
there is no universally efficacious treatment. Topical therapies
include, but are not limited to, hydroquinone, retinoids, and
numerous bleaching combination formulas. Superficial peels,
microdermabrasion, and various laser and light therapies are
often used in conjunction with topical therapies. Oral tranexamic
acid has also been used. It is critical for patients to avoid exac-
erbating factors, which include ultraviolet light exposure, hor-
monal therapy, and various oral medications.8 Antioxidants are
commonly part of this treatment method, as they are functional
in controlling oxidative stress linked with skin aging and pigmen-
tation disorders. Furthermore, recent investigation has explored
the use of topical cytidine, which is believed to play a role in
melanogenic pathways.12-14
Oxidative stress in dermatology
The skin is the site of numerous biochemical reactions, many of
which result in the generation of free radicals including ROS.15-17
Oxidative stress occurs with a disturbance in the balance
between free radicals and antioxidant defenses.18 This imbalance
exists in photodamage, non-melanoma skin cancers, psoriasis,
vitiligo, scleroderma, lichen planus, acne vulgaris, alopecia
areata, seborrheic dermatitis, and pemphigus foliaceus.17,19,20
Sunlight, a primary trigger of oxidative damage, results in features
of premature skin aging, namely rhytids, dyspigmentation, telang-
iectasias, and xerosis.21
Oxidative stress in melasma
There is clear evidence of oxidative stress in melasma. Seckin
et al.22 reported significantly elevated levels of malondialdehyde
(MDA), nitric oxide (NO) and enzyme activity of superoxide dis-
mutase (SOD) and glutathione peroxidase (GSH-Px) in serum
of melasma patients compared with controls. Elevated MDA, a
product of lipid peroxidation, NO, a free radical secreted by
endothelial cells, and SOD and GSH-Px, intracellular antioxi-
dants, are markers of oxidative damage. Paradoxically, the
authors found significantly lower protein carbonyl levels in the
patient group.22 Protein carbonyl is an indicator of oxidative
stress in amino acids and is used to evaluate oxidative protein
damage.
In addition to reporting elevated oxidative markers in mel-
asma patients, Choubey et al.23 identified a significant positive
correlation between MASI score and serum MDA.
ANTIOXIDANT THERAPY IN MELASMA
There is evidence of oxidative stress in melasma pathogenesis.
We have previously reported on a number of well-known antiox-
idants that play a role in control of skin pigmentation.24 These
antioxidants include vitamin C,25-47 azelaic acid,48-52 cys-
teamine,53,54 glutathione,55-57 carotenoids,58,59 curcuma
ª 2020 the International Society of Dermatology
Antioxidant treatment for melasma Review 167
longa,60,61 ellagic acid,62,63 kojic acid,64,65 and reservatrol.66-69
However, in addition to the previously mentioned antioxidants,
there are a number of other compounds with antioxidant proper-
ties that may have therapeutic value for melasma and hyperpig-
mentation (Table 1). These antioxidant compounds show
efficacy in both topical and oral routes of administration.
Vitamin E
Vitamin E has a number of health benefits, and its numerous
isoforms have the ability to neutralize free radicals.70 Because
of its antioxidant abilities, oral and topical applications of vitamin
E have been investigated for treating hyperpigmentation.
Hayakawa et al.25 conducted a double-blind trial in which
patients received an oral combination of vitamins C and E or
single preparation of one vitamin. Combined treatment had sta-
tistically better improvement for patients with chloasma and pig-
mented contact dermatitis. Handog et al.26 studied a test drug
containing procyanidin and vitamins A, C, and E. Patients
showed significant improvement in MASI score and a significant
decrease in pigmentation. Guevara et al.71 investigated a cream
containing hydroquinone, buffered glycolic acid (GA), vitamins C
and E, and sunscreen and found a significant decrease in pig-
mentation compared with sunscreen alone.
Although not a clinical trial, one study found significant inhibi-
tion of melanization in human melanocytes with a compound of
alpha-tocopherol (a form of vitamin E) and ferulic acid.72
Niacinamide/nicotinamide
Niacinamide, or nicotinamide, is an amide of vitamin B3. Nicoti-
namide suppresses ROS in human cells and effectively reduces
oxidative damage.73 Topical niacinamide has been investigated
in various dermatologic conditions including acne, rosacea,
aging, atopic dermatitis, blistering disorders, and skin cancer
prevention.74
Navarrete-Solis et al.75 conducted a split-face study of mel-
asma patients who applied sunscreen and either niacinamide
or hydroquinone cream. All patients showed pigment improve-
ment; however, a greater percentage observed good to excel-
lent results with hydroquinone. Of note, a greater number of
patients reported side effects with hydroquinone. Hakozaki
et al.76 conducted both in vitro and in vivo studies with niaci-
namide and found a significant decrease in cutaneous hyper-
pigmentation and an increase in skin lightness compared with
vehicle alone. Campuzano-Garcia et al.77 considered DNA
hypermethylation in melasma lesions and determined treat-
ment with sunscreen and niacinamide, retinoic acid, or placebo
resulted in a significant reduction in DNA methyltransferase 1
expression.
Others have investigated niacinamide, in conjunction with
other therapies, for skin pigmentation. Hakozaki et al.32 studied
a gel containing vitamin C and niacinamide, in conjunction with
ultrasound radiation. Desai et al.78 studied a topical facial serum
containing tranexamic acid, kojic acid, and niacinamide.
International Journal of Dermatology 2021, 60, 166–173
168 Review Antioxidant treatment for melasma Babbush, Babbush, and Khachemoune

Table 1 Summary of clinical investigations discussed in this manuscript

Route of
Antioxidant administration Type of study Conclusion References

Amino fruit acids Topical Randomized single-blind Amino fruit acid peel is less irritating and better tolerated 86
right–left comparison trial than glycolic acid peel for melasma, but there is significant
melasma regression with both peeling methods
Korean red Oral Uncontrolled observational Korean red ginseng powder shows good tolerability and 100
ginseng powder study beneficial effects for melasma
Niacinamide/ Topical Randomized double-blind Niacinamide (compared with hydroquinone) is a safe and 75
nicotinamide clinical trial effective therapeutic agent for melasma
Topical Randomized double-blind Niacinamide significantly decreased hyperpigmentation 76
split-face trial and increased skin lightness compared with vehicle alone
Topical Randomized double-blind After treatment with niacinamide, retinoic acid, or placebo, 77
controlled trial expression of DNA methyltransferase (DNMT) 1 is decreased,
which correlates with clinical improvement of melasma
Topical Clinical trial A tranexamic acid, kojic acid, and niacinamide containing 78
serum is an effective and well-tolerated treatment option
for addressing hyperpigmentary conditions
Topical Randomized split-face High-frequency ultrasound radiation together with 32
clinical trial skin-lightening gel (ascorbyl glucoside and niacinamide)
is effective to reduce hyperpigmentation
Petroselinum Topical Randomized double-blind The effect of petroselinum crispum on melasma severity 103
crispum clinical trial is the same as that of hydroquinone
Phytic acid Topical Clinical trial Easy phytic peel (commercial product composed of 88
phytic acid, glycolic acid, lactic acid, and phenyl glycolic
[mandelic] acid) is effective, safe, and well-tolerated
for melasma
Topical Split-face study Triple combination (20% azelaic acid + 10% 89
resorcinol + 6% phytic acid) is as effective as 50%
glycolic acid peel for melasma
Topical Randomized clinical trial Glycolic acid and salicylic–mandelic acid peels are more 90
effective than phytic acid peels for melasma
Plant extracts Topical Split-face study Orchid-rich plant extracts possess similar efficacy to 101
vitamin C derivative for skin whitening
Polypodium Oral Randomized double-blind Oral PLE is not significantly better than placebo as an 80
leucotomos placebo-controlled clinical trial adjunct to topical sunscreen for melasma
Oral Randomized double-blind Oral polypodium leucotomos extract appears to be a safe 81
placebo-controlled clinical trial and effective adjunctive treatment in combination with
topical hydroquinone and sunscreen for melasma
Pycnogenol/grape Oral Clinical trial Pycnogenol 75 mg is therapeutically effective and safe in 84
seed extract patients suffering from melasma
Oral Clinical trial Grape seed extract is safe and useful for improving chloasma 85
Silymarin Topical Randomized double-blind Silymarin shows improvement melasma in a 98
placebo-controlled clinical trial dose-dependent manner
Topical Comparative study There are no significant differences in the therapeutic 99
response between topical silymarin (0.7% and 1.4%)
versus hydroquinone 4% for melasma
Vitamin E Oral Multiclinical double-blind trial Vitamin C + E combination treatment has significantly 25
better results than vitamin C alone for chloasma
Oral Randomized double-blind Oral procyanidin + vitamins A, C, and E is safe and 26
placebo-controlled trial effective for epidermal melasma
Topical Randomized double-blind Cream containing 4% hydroquinone, 10% buffered 71
placebo-controlled trial glycolic acid, vitamins C + E, and sunscreen is
safe and effective for melasma

International Journal of Dermatology 2021, 60, 166–173 ª 2020 the International Society of Dermatology
Babbush, Babbush, and Khachemoune
Table 1 Continued
Route of
Antioxidant administration Type of study
Zinc Topical Clinical trial
Topical Randomized double-blind
comparative trial
Topical Randomized double-blind
controlled trial
Topical Pilot study
Other antioxidants used for treatment of melasma include: azelaic acid, carotenoids, curcuma longa (turmeric), cysteamine, ellagic acid, glu-
tathione, kojic acid, resveratrol, and vitamin C.
Polypodium leucotomos
Polypodium leucotomos (PL) is used for the management of
various skin conditions, and this species of fern acts as a direct
scavenger of various ROS.79 Two randomized, double-blind,
placebo-controlled trials investigated oral PL extract (PLE) for
treatment of melasma. In a study of Hispanic women, the PLE
treatment group and placebo group both had improvment in
melanin index and MASI score, but there was no significant
intergroup difference.80 Additionally, a study of Asian patients
resulted in a significant decrease in mMASI scores for both
treatment and placebo groups with a significantly lower mMASI
score and an improvement in the MelasQoL score in the PLE
group compared with placebo.81
Pycnogenol/grape seed extract
Pycnogenol is an extract from French maritime pine. It contains
various flavonoids, namely phenolic acids and procyandins, and
it has been used as a therapeutic remedy for various conditions
including circulatory dysfunction and wound healing. It has
strong antioxidant capacity and interacts with other cellular
antioxidants.82 Grape seed extract also contains many flavo-
noids, including proanthocyanidin, with similar antioxidant
effects against oxygen free radicals and oxidative stress.83
Ni et al.84 conducted a study in which women with melasma
took oral tablets of pycnogenol tri-daily. After 30 days, overall effi-
cacy rate was 80%, and there was a significant decrease in pig-
mentary intensity and average melasma area. Yamakoshi et al.85
studied the efficacy of oral grape seed extract for melasma treat-
ment and found a significant decrease in melanin index.
Amino fruit acids
Amino fruit acids are carboxylated acidic amino acids with
strong antioxidant properties and evidence of anti-aging and
anti-photopigmenting agents.86 Ilknur et al.86 conducted a sin-
gle-blind randomized study of melasma patients to compare GA
peels with amino fruit acid peels. There was significant
ª 2020 the International Society of Dermatology
Antioxidant treatment for melasma Review 169
Conclusion References
Topical 10% zinc sulfate solution is safe and 93
effective for melasma
Topical zinc is not highly effective in reducing 94
the severity of melasma
10% zinc sulfate is not as effective as 4% hydroquinone 95
cream in the treatment of melasma
A combination of tazarotene 0.075%, azelaic acid 20%, 96
tacrolimus 0.1%, and (microfine) zinc oxide 10% could
potentially be an effective, safe, and tolerable treatment
for moderate-to-severe melasma
melasma regression for both peeling methods but no significant
difference between groups; however, the amino fruit acid peel
was less irritating and better tolerated.
Phytic acid
Phytic acid, unlike other antioxidants, is a stable plant antioxidant
that is not consumed by reacting with activated oxygen species.
Phytic acid has a high iron affinity, enabling it to effectively inhibit
various oxidative reactions, block hydroxyl radical formation and
diminish lipid peroxidation.87 Combination peels containing phytic
acid have been investigated in various studies.
Al-Mokadem et al.88 investigated a chemical peel containing
phytic acid, GA, lactic acid, and mandelic acid in melasma
patients. The reduction in MASI score was significant; however,
pigmentation recurred because of unprotected sun exposure
and lack of patient compliance. Faghihi et al.89 determined a tri-
ple-combination peeling agent consisting of azelaic acid, resor-
cinol, and phytic acid was safe and as effective as GA peel for
melasma treatment. However, Sarkar et al.90 found GA and sal-
icylic–mandelic acid peels equally more efficacious than phytic
acid combination peels.
Zinc
Zinc is an essential trace element critical for the structure and
function of many macromolecules and enzymes in humans.91
There are numerous mechanisms by which zinc functions as an
antioxidant; however, zinc deficiency and excess can cause an
increase in oxidative stress.92 Many studies have investigated
the efficacy of zinc in treating melasma, but there is conflicting
evidence about whether or not this trace metal provides thera-
peutic value.
In a study by Sharquie et al.,93 melasma patients were trea-
ted with topical zinc sulfate solution and displayed significant
improvement in MASI score, with most patients maintaining
improvement 3 months after therapy cessation. Iraji et al.94 and
Yousefi et al.95 also conducted studies to assess the efficacy of
International Journal of Dermatology 2021, 60, 166–173
170 Review Antioxidant treatment for melasma
topical zinc, and both concluded zinc was not as effective in
reducing melasma severity compared with hydroquinone. Kirsch
et al.96 studied a combination cream containing tazarotene, aze-
laic acid, tacrolimus, and zinc oxide and found this compound
to be effective and safe for melasma.
Silymarin
Silymarin is a polyphenolic antioxidant from the milk thistle
plant, and it functions as both a free radical scavenger and lipid
peroxidation inhibitor.97
In a study by Altaei,98 melasma patients used silymarin
cream and were 100% satisfied with significant pigment
improvement and lesion size reduction. Likewise, in a study by
Nofal et al.,99 melasma patients received 0.7 or 1.4% silymarin
cream versus 4% hydroquinone cream. MASI scores were sig-
nificantly reduced in all groups with no significant difference
between groups. Unlike with hydroquinone, there were no signif-
icant adverse events with silymarin treatment.
Korean red ginseng powder
Korean red ginseng powder has therapeutic value for antioxi-
dant, anti-aging, anti-inflammatory, and immunomodulatory pro-
cesses.100 It contains phenolic compounds, which inhibit
tyrosinase and ginsenoside, and prevent elevated intracellular
ROS Song et al.100 found that oral Korean red ginseng powder
leads to a reduction in MASI score, improvement in MelasQoL,
reduced pigmentation, and improved global improvement scales
in melasma patients.
Plant extracts including orchid extract
The Orchidaceae plant kingdom family consists of thousands of
species. The antioxidant and scavenging abilities of orchids
contribute to their pharmacological use. Tadokoro et al.101 con-
ducted a study of Japanese females to investigate the whitening
efficacy of topical orchid extracts in patients with melasma and
lentigo senilis. Their study, which had no adverse events, con-
cluded that topical application of the orchid-containing plant
extract has similar efficacy to vitamin C in skin whitening.101
Petroselinum crispum
Petroselinum crispum, or English parsley, is a common food sub-
stance with hypoglycemic, hypolipidemic, hepatoprotective, diure-
tic, antimicrobial, anticoagulant, and antioxidant properties.102
Khosravan et al.103 conducted a double-blind, randomized trial to
assess the efficacy of topical petroselinum crispum compared
with hydroquinone cream for melasma. Patients receiving either
therapy achieved significant reductions in MASI score; however,
there was no significant difference between groups.
CONCLUSION
Oxidative stress has been shown to play a role in the patho-
physiology of melasma. This has resulted in exploration of the
International Journal of Dermatology 2021, 60, 166–173
Babbush, Babbush, and Khachemoune
therapeutic value of various antioxidants for those suffering from
this chronic disease. Vitamin E, niacinamide, polypodium leuco-
tomos, pycnogenol, grape seed extract, amino fruit acids, phytic
acid, zinc, silymarin, Korean red ginseng powder, plant extracts,
and parsley all have clear evidence of antioxidant properties
and have been studied for treatment of hyperpigmentation and
melasma.
Although these compounds do not all have substantial evi-
dence of benefit for patients with melasma, the investigation of
numerous naturally occurring antioxidant compounds is encour-
aging for dermatologists and patients suffering from this skin
condition with a well-demonstrated impact on quality of life.
REFERENCES
1 Jiang J, Akinseye O, Tovar-Garza A, et al. The effect of
melasma on self-esteem: a pilot study. Int J Womens Dermatol
2017; 4: 38–42.
2 Yadav A, Garg T, Mandal AK, et al. Quality of life in patients
with acquired pigmentation: an observational study. J Cosmet
Dermatol 2018; 17: 1293–1294.
3 Taylor A, Pawaskar M, Taylor SL, et al. Prevalence of
pigmentary disorders and their impact on quality of life: a
prospective cohort study. J Cosmet Dermatol 2008; 7: 164–
168.
4 Taylor SC. Epidemiology of skin diseases in ethnic
populations. Dermatol Clin 2003; 21: 601–607.
5 Handel AC, Miot LDB, Miot HA. Melasma: a clinical and
epidemiological review. An Bras Dermatol 2014; 89: 771–782.
6 Handel AC, Lima PB, Tonolli VM, et al. Risk factors for facial
melasma in women: a case-control study. Br J Dermatol 2014;
171: 588–594.
7 Balkrishnan R, McMichael AJ, Camacho FT, et al.
Development and validation of a health-related quality of life
instrument for women with melasma. Br J Dermatol 2003; 149:
572–577.
8 Ogbechie-Godec OA, Elbuluk N. Melasma: an up-to-Date
comprehensive review. Dermatol Ther (Heidelb) 2017; 7: 305–318.
9 Kim EH, Kim YC, Lee E-S, et al. The vascular characteristics
of melasma. J Dermatol Sci 2007; 46: 111–116.
10 Grimes PE, Yamada N, Bhawan J. Light microscopic,
immunohistochemical, and ultrastructural alterations in patients
with melasma. Am J Dermatopathol 2005; 27: 96–101.
11 Kang WH, Yoon KH, Lee ES, et al. Melasma: histopathological
characteristics in 56 Korean patients. Br J Dermatol 2002; 146:
228–237.
12 Baswan SM, Leverett J, Pawelek J. Clinical evaluation of the
lightening effect of cytidine on hyperpigmented skin. J Cosmet
Dermatol 2019; 18: 278–285.
13 Baswan SM, Yim S, Leverett J, et al. LB1591 <em>In-vitro</
em> and <em>in-vivo</em> evaluation of skin lightening
efficacy of cytidine. J Invest Dermatol 2018; 138: B21.
14 Baswan SM, Yim S, Leverett J, et al. Cytidine decreases
melanin content in a reconstituted three-dimensional human
epidermal model. Arch Dermatol Res 2019; 311: 249–250.
15 Baek J, Lee MG. Oxidative stress and antioxidant strategies in
dermatology. Redox Rep 2016; 21: 164–169.
16 Wagener FA, Carels CE, Lundvig DM. Targeting the redox
balance in inflammatory skin conditions. Int J Mol Sci 2013; 14:
9126–9167.
ª 2020 the International Society of Dermatology
Babbush, Babbush, and Khachemoune
17 Addor FAS. Antioxidants in dermatology. An Bras Dermatol.
2017; 92: 356–362.
18 Betteridge DJ. What is oxidative stress? Metabolism 2000; 49
(2 Suppl 1): 3–8.
19 Sener S, Akbas A, Kilinc F, et al. Thiol/disulfide homeostasis
as a marker of oxidative stress in rosacea: a controlled
spectrophotometric study. Cutan Ocul Toxicol 2019; 38: 55–58.
20 Kilinc F, Sener S, Akbas A, et al. Oxidative stress parameters
in localized scleroderma patients. Arch Dermatol Res 2016;
308: 625–629.
21 Armstrong D, Stratton RD. Oxidative Stress and Antioxidant
Protection: The Science of Free Radical Biology and Disease.
Wiley; 2016.
22 Seckin HY, Kalkan G, Bas Y, et al. Oxidative stress status in
patients with melasma. Cutan Ocul Toxicol 2014; 33: 212–217.
23 Choubey V, Sarkar R, Garg V, et al. Role of oxidative stress in
melasma: a prospective study on serum and blood markers of
oxidative stress in melasma patients. Int J Dermatol 2017; 56:
939–943.
24 Babbush KM, Babbush RA, Khachemoune A. The therapeutic
use of antioxidants for melasma. J Drugs Dermatol 2020; 19:
788–792.
25 Hayakawa R, Ueda H, Nozaki T, et al. Effects of combination
treatment with vitamins E and C on chloasma and pigmented
contact dermatitis. A double blind controlled clinical trial. Acta
Vitaminol Enzymol 1981; 3: 31–38.
26 Handog EB, Galang DA, de Leon-Godinez MA, et al. A
randomized, double-blind, placebo-controlled trial of oral
procyanidin with vitamins A, C, E for melasma among Filipino
women. Int J Dermatol 2009; 48: 896–901.
27 Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A
double-blind randomized trial of 5% ascorbic acid vs. 4%
hydroquinone in melasma. Int J Dermatol 2004; 43: 604–607.
28 Shaikh ZI, Mashood AA. Treatment of refractory melasma with
combination of topical 5% magnesium ascorbyl phosphate and
fluorescent pulsed light in Asian patients. Int J Dermatol 2014;
53: 93–99.
29 Aboul-Einien MH, Kandil SM, Abdou EM, et al. Ascorbic acid
derivative-loaded modified aspasomes: formulation, in vitro,
ex vivo and clinical evaluation for melasma treatment. J
Liposome Res 2020; 30: 54–67.
30 Hwang SW, Oh DJ, Lee D, et al. Clinical efficacy of 25% L-
ascorbic acid (C’ensil) in the treatment of melasma. J Cutan
Med Surg 2009; 13: 74–81.
31 Kim WS. Efficacy and safety of a new superficial chemical peel
using alpha-hydroxy acid, vitamin C and oxygen for melasma.
J Cosmet Laser Ther 2013; 15: 21–24.
32 Hakozaki T, Takiwaki H, Miyamoto K, et al. Ultrasound
enhanced skin-lightening effect of vitamin C and niacinamide.
Skin Res Technol 2006; 12: 105–113.
33 Zhou HL, Hu B, Zhang C. Efficacy of 694-nm fractional Q-
switched ruby laser (QSRL) combined with sonophoresis on
levorotatory vitamin C for treatment of melasma in Chinese
patients. Lasers Med Sci 2016; 31: 991–995.
34 Chen YT, Chang CC, Hsu CR, et al. Combined vitamin C
sonophoresis and neodymium-doped yttrium aluminum garnet
(NdYAG) laser for facial hyperpigmentation: an outcome
observation study in Asian patients. Indian J Dermatol
Venereol Leprol. 2016; 82: 587.
35 Lee MC, Chang CS, Huang YL, et al. Treatment of melasma
with mixed parameters of 1,064-nm Q-switched Nd:YAG laser
toning and an enhanced effect of ultrasonic application of vitamin
C: a split-face study. Lasers Med Sci 2015; 30: 159–163.
ª 2020 the International Society of Dermatology
Antioxidant treatment for melasma Review 171
36 Dayal S, Sahu P, Yadav M, et al. Clinical efficacy and safety
on combining 20% trichloroacetic acid peel with topical 5%
ascorbic acid for melasma. J Clin Diagn Res 2017; 11: WC08–
WC1.
37 Soliman MM, Ramadan SA, Bassiouny DA, et al. Combined
trichloroacetic acid peel and topical ascorbic acid versus
trichloroacetic acid peel alone in the treatment of melasma: a
comparative study. J Cosmet Dermatol 2007; 6: 89–94.
38 Murtaza F, Bangash AR, Khushdil A, et al. Efficacy of trichloro-
acetic acid peel alone versus combined topical magnesium
ascorbyl phosphate for epidermal melasma. J Coll Physicians
Surg Pak 2016; 26: 557–561.
39 Yoo JM, Park HJ, Choi SW, et al. Vitamin C-iontophoresis in
melasma. Korean J Dermatol 2001; 39: 285–291.
40 Huh CH, Seo KI, Park JY, et al. A randomized, double-blind,
placebo-controlled trial of vitamin C iontophoresis in melasma.
Dermatology 2003; 206: 316–320.
41 Taylor MB, Yanaki JS, Draper DO, et al. Successful short-term
and long-term treatment of melasma and postinflammatory
hyperpigmentation using vitamin C with a full-face
iontophoresis mask and a mandelic/malic acid skin care
regimen. J Drugs Dermatol 2013; 12: 45–50.
42 Sobhi RM, Sobhi AM. A single-blinded comparative study
between the use of glycolic acid 70% peel and the use of
topical nanosome vitamin C iontophoresis in the treatment of
melasma. J Cosmet Dermatol 2012; 11: 65–71.
43 Kim S, Seaung YO, Seung HL. Comparative study of glycolic
acid peeling vs. vitamin C-iontophoresis in Melasma. Korean J
Dermatol 2001; 39: 1356–1363.
44 Choi YK, Rho YK, Yoo KH, et al. Effects of vitamin C vs.
multivitamin on melanogenesis: comparative study in vitro and
in vivo. Int J Dermatol 2010; 49: 218–226.
45 Balevi A, Ustuner P, Ozdemir M. Salicylic acid peeling
combined with vitamin C mesotherapy versus salicylic acid
peeling alone in the treatment of mixed type melasma: a
comparative study. J Cosmet Laser Ther 2017; 19: 294–299.
46 Ustuner P, Balevi A, Ozdemir M. A split-face, investigator-
blinded comparative study on the efficacy and safety of Q-
switched Nd:YAG laser plus microneedling with vitamin C
versus Q-switched Nd:YAG laser for the treatment of
recalcitrant melasma. J Cosmet Laser Ther 2017; 19: 383–
390.
47 Iraji F, Nasimi M, Asilian A, et al. Efficacy of mesotherapy with
tranexamic acid and ascorbic acid with and without glutathione
in treatment of melasma: a split face comparative trial. J
Cosmet Dermatol 2019; 18: 1416–1421.
48 Lowe NJ, Rizk D, Grimes P, et al. Azelaic acid 20% cream in
the treatment of facial hyperpigmentation in darker-skinned
patients. Clin Ther 1998; 20: 945–959.
49 Verallo-Rowell VM, Verallo V, Graupe K, et al. Double-blind
comparison of azelaic acid and hydroquinone in the treatment
of melasma. Acta Derm Venereol Suppl (Stockh) 1989; 143:
58–61.
50 Farshi S. Comparative study of therapeutic effects of 20%
azelaic acid and hydroquinone 4% cream in the treatment of
melasma. J Cosmet Dermatol 2011; 10: 282–287.
51 Balina LM, Graupe K. The treatment of melasma. 20% azelaic
acid versus 4% hydroquinone cream. Int J Dermatol 1991; 30:
893–895.
52 Sarkar R, Bhalla M, Kanwar AJ. A comparative study of 20%
azelaic acid cream monotherapy versus a sequential therapy in
the treatment of melasma in dark-skinned patients.
Dermatology 2002; 205: 249–254.
International Journal of Dermatology 2021, 60, 166–173
172 Review Antioxidant treatment for melasma
53 Mansouri P, Farshi S, Hashemi Z, et al. Evaluation of the
efficacy of cysteamine 5% cream in the treatment of epidermal
melasma: a randomized double-blind placebo-controlled trial.
Br J Dermatol 2015; 173: 209–217.
54 Farshi S, Mansouri P, Kasraee B. Efficacy of cysteamine
cream in the treatment of epidermal melasma, evaluating by
Dermacatch as a new measurement method: a randomized
double blind placebo controlled study. J Dermatolog Treat
2018; 29: 182–189.
55 Arjinpathana N, Asawanonda P. Glutathione as an oral
whitening agent: a randomized, double-blind, placebo-
controlled study. J Dermatolog Treat 2012; 23: 97–102.
56 Watanabe F, Hashizume E, Chan GP, et al. Skin-whitening
and skin-condition-improving effects of topical oxidized
glutathione: a double-blind and placebo-controlled clinical trial
in healthy women. Clin Cosmet Investig Dermatol 2014; 7:
267–274.
57 Handog EB, Datuin MS, Singzon IA. An open-label, single-arm
trial of the safety and efficacy of a novel preparation of
glutathione as a skin-lightening agent in Filipino women. Int J
Dermatol 2016; 55: 153–157.
58 Wanick F, Zink BS, Lopes RF. Efficacy evaluation of lycopene,
beta-carotene and Lactobacillus johnsonii in the maintenance
treatment of melasma during the summer: a comparative
study. Surg Cosmet Dermatol 2011; 3: 297–301.
59 Teo WL, Gan E, Jinghan A, et al. Double blind placebo
controlled trial to evaluate of the effectiveness of a dietary
supplement rich in carotenoids as adjunct to topical lightening
cream for the treatment of melasma: a pilot study. J Pigment
Disord 2015; 2: 1–6.
60 Swanson C, Deng D, Robinson L, et al. Topical turmeric
extract in a moisturizing cream formula reduces the
appearance of facial spots and fine lines and wrinkles on
human facial skin. J Am Acad Dermatol 2010; 62: AB19.
61 Park SY, Jin ML, Kim YH, et al. Aromatic-turmerone inhibits
alpha-MSH and IBMX-induced melanogenesis by inactivating
CREB and MITF signaling pathways. Arch Dermatol Res 2011;
303: 737–744.
62 Ertam I, Mutlu B, Unal I, et al. Efficiency of ellagic acid and
arbutin in melasma: a randomized, prospective, open-label
study. J Dermatol 2008; 35: 570–574.
63 Shimogaki H, Tanaka Y, Tamai H, et al. In vitro and in vivo
evaluation of ellagic acid on melanogenesis inhibition. Int J
Cosmet Sci 2000; 22: 291–303.
64 Lim JT. Treatment of melasma using kojic acid in a gel
containing hydroquinone and glycolic acid. Dermatol Surg
1999; 25: 282–284.
65 Deo KS, Dash KN, Sharma YK, et al. Kojic acid vis-a-vis its
combinations with hydroquinone and betamethasone valerate
in melasma: a randomized, single blind, comparative study of
efficacy and safety. Indian J Dermatol 2013; 58: 281–285.
66 Jo DJ, Seok JK, Kim SY, et al. Human skin-depigmenting effects
of resveratryl triglycolate, a hybrid compound of resveratrol and
glycolic acid. Int J Cosmet Sci 2018; 40: 256–262.
67 Kim SY, Park KC, Kwon SB, et al. Hypopigmentary effects of
4-n-butylresorcinol and resveratrol in combination. Pharmazie
2012; 67: 542–546.
68 Kwon SH, Yang JH, Shin JW, et al. Efficacy of liposome-
encapsulated 4-n-butylresorcinol and resveratrol cream in the
treatment of melasma. J Cosmet Dermatol 2020; 19: 891–895.
69 Ryu JH, Seok JK, An SM, et al. A study of the human skin-
whitening effects of resveratryl triacetate. Arch Dermatol Res
2015; 307: 239–247.
International Journal of Dermatology 2021, 60, 166–173
Babbush, Babbush, and Khachemoune
70 Peh HY, Tan WS, Liao W, et al. Vitamin E therapy beyond
cancer: tocopherol versus tocotrienol. Pharmacol Ther 2016;
162: 152–169.
71 Guevara IL, Pandya AG. Safety and efficacy of 4%
hydroquinone combined with 10% glycolic acid, antioxidants,
and sunscreen in the treatment of melasma. Int J Dermatol
2003; 42: 966–972.
72 Funasaka Y, Komoto M, Ichihashi M. Depigmenting effect of
alpha-tocopheryl ferulate on normal human melanocytes.
Pigment Cell Res 2000; 13(Suppl 8): 170–174.
73 Kwak JY, Ham HJ, Kim CM, et al. Nicotinamide exerts
antioxidative effects on senescent cells. Mol Cells 2015; 38:
229–235.
74 Chen AC, Damian DL. Nicotinamide and the skin. Australas J
Dermatol 2014; 55: 169–175.
75 Navarrete-Solis J, Castanedo-Cazares JP, Torres-Alvarez B,
et al. A double-blind, randomized clinical trial of niacinamide
4% versus hydroquinone 4% in the treatment of melasma.
Dermatol Res Pract 2011; 2011: 1–5.
76 Hakozaki T, Minwalla L, Zhuang J, et al. The effect of
niacinamide on reducing cutaneous pigmentation and suppression
of melanosome transfer. Br J Dermatol 2002; 147: 20–31.
77 Campuzano-Garcia AE, Torres-Alvarez B, Hernandez-Blanco
D, et al. DNA methyltransferases in malar melasma and their
modification by sunscreen in combination with 4% niacinamide,
0.05% retinoic acid, or placebo. Biomed Res Int 2019; 2019:
9068314.
78 Desai S, Ayres E, Bak H, et al. Effect of a tranexamic acid,
kojic acid, and niacinamide containing serum on facial
dyschromia: a clinical evaluation. J Drugs Dermatol 2019; 18:
454–459.
79 Gomes AJ, Lunardi CN, Gonzalez S, et al. The antioxidant
action of Polypodium leucotomos extract and kojic acid:
reactions with reactive oxygen species. Braz J Med Biol Res
2001; 34: 1487–1494.
80 Ahmed AM, Lopez I, Perese F, et al. A randomized, double-
blinded, placebo-controlled trial of oral Polypodium leucotomos
extract as an adjunct to sunscreen in the treatment of
melasma. JAMA Dermatol 2013; 149: 981–983.
81 Goh CL, Chuah SY, Tien S, et al. Double-blind, placebo-
controlled trial to evaluate the effectiveness of polypodium
leucotomos extract in the treatment of melasma in asian skin:
a pilot study. J Clin Aesthet Dermatol 2018; 11: 14–19.
82 Packer L, Rimbach G, Virgili F. Antioxidant activity and biologic
properties of a procyanidin-rich extract from pine (Pinus
maritima) bark, pycnogenol. Free Radic Biol Med 1999; 27:
704–724.
83 Bagchi D, Bagchi M, Stohs SJ, et al. Free radicals and grape
seed proanthocyanidin extract: importance in human health
and disease prevention. Toxicology 2000; 148: 187–197.
84 Ni Z, Mu Y, Gulati O. Treatment of melasma with pycnogenol.
Phytother Res 2002; 16: 567–571.
85 Yamakoshi J, Sano A, Tokutake S, et al. Oral intake of
proanthocyanidin-rich extract from grape seeds improves
chloasma. Phytother Res 2004; 18: 895–899.
86 Ilknur T, Bicak MU, Demirtasoglu M, et al. Glycolic acid peels
versus amino fruit acid peels in the treatment of melasma.
Dermatol Surg 2010; 36: 490–495.
87 Graf E, Eaton JW. Antioxidant functions of phytic acid. Free
Radic Biol Med 1990; 8: 61–69.
88 Al-Mokadem S, Al-Aasser O, Nassar A, et al. Easy phytic peel
as a therapeutic agent in acne vulgaris and melasma. Egypt J
Dermatol Venerol 2013; 33: 6.
ª 2020 the International Society of Dermatology
Babbush, Babbush, and Khachemoune
89 Faghihi G, Taheri A, Shahmoradi Z, et al. Solution of azelaic
acid (20%), resorcinol (10%) and phytic acid (6%) versus
glycolic acid (50%) peeling agent in the treatment of female
patients with facial melasma. Adv Biomed Res 2017; 6: 9.
90 Sarkar R, Garg V, Bansal S, et al. Comparative evaluation of
efficacy and tolerability of glycolic acid, salicylic mandelic acid,
and phytic acid combination peels in melasma. Dermatol Surg
2016; 42: 384–391.
91 Jarosz M, Olbert M, Wyszogrodzka G, et al. Antioxidant and
anti-inflammatory effects of zinc. Zinc-dependent NF-kappaB
signaling. Inflammopharmacology 2017; 25: 11–24.
92 Lee SR. Critical role of zinc as either an antioxidant or a
prooxidant in cellular systems. Oxid Med Cell Longev 2018;
2018: 1–11.
93 Sharquie KE, Al-Mashhadani SA, Salman HA. Topical 10%
zinc sulfate solution for treatment of melasma. Dermatol Surg
2008; 34: 1346–1349.
94 Yousefi A, Khani Khoozani Z, Zakerzadeh Forooshani S, et al.
Is topical zinc effective in the treatment of melasma? A double-
blind randomized comparative study. Dermatol Surg 2014; 40:
33–37.
95 Iraji F, Tagmirriahi N, Gavidnia K. Comparison between the
efficacy of 10% zinc sulfate solution with 4% hydroquinone
cream on improvement of melasma. Advanced Biomed Res
2012; 1: 39.
96 Kirsch B, Hoesly PM, Jambusaria A, et al. Evaluating the
efficacy, safety, and tolerability of the combination of
ª 2020 the International Society of Dermatology
Antioxidant treatment for melasma Review 173
tazarotene, azelaic acid, tacrolimus, and zinc oxide for the
treatment of melasma: a pilot study. J Clin Aesthet Dermatol
2019; 12: 40–45.
97 Federico A, Dallio M, Loguercio C. Silymarin/silybin and
chronic liver disease: a marriage of many years. Molecules
(Basel, Switzerland) 2017; 22: 191.
98 Altaei T. The treatment of melasma by silymarin cream. BMC
Dermatol 2012; 12: 18.
99 Nofal A, Ibrahim AM, Nofal E, et al. Topical silymarin versus
hydroquinone in the treatment of melasma: a comparative
study. J Cosmet Dermatol 2019; 18: 263–270.
100 Song M, Mun JH, Ko HC, et al. Korean red ginseng powder in
the treatment of melasma: an uncontrolled observational study.
J Ginseng Res 2011; 35: 170–175.
101 Tadokoro T, Bonte F, Archambault JC, et al. Whitening
efficacy of plant extracts including orchid extracts on Japanese
female skin with melasma and lentigo senilis. J Dermatol
2010; 37: 522–530.
102 Tang EL, Rajarajeswaran J, Fung S, et al. Petroselinum
crispum has antioxidant properties, protects against DNA
damage and inhibits proliferation and migration of cancer cells.
J Sci Food Agric 2015; 95: 2763–2771.
103 Khosravan S, Alami A, Mohammadzadeh-Moghadam H, et al.
The effect of topical use of petroselinum crispum (parsley)
versus that of hydroquinone cream on reduction of epidermal
melasma: a randomized clinical trial. Holist Nurs Pract 2017;
31: 16–20.
International Journal of Dermatology 2021, 60, 166–173