Review

Melasma: systematic review of the systemic treatments

Linghong Linda Zhou1, BHSc, and Akerke Baibergenova2, MD, PhD, MPH

1
Faculty of Medicine, University of Ottawa,
Ottawa, Ontario, Canada, and 2Division of
Dermatology, University of Toronto,
Toronto, Ontario, Canada
Correspondence
Akerke Baibergenova MD, PhD, MPH
144 Tamworth Road
Toronto, ON, M2N 2P5
Canada
E-mails: akerke_b@yahoo.com;
dr.akerke2012@gmail.com
Funding sources: This article has no
funding source.
Conflict of interest: The authors have no
conflict of interest to declare.
doi: 10.1111/ijd.13578
Abstract
Currently available treatment options for melasma include prevention of UV radiation,
topical lightening agents, chemical peels, and light-based and laser therapies. However,
none have shown effective and sustained results, with incomplete clearance and frequent
recurrences. There has been increasing interest recently in oral medications and dietary
supplements in improving melasma. We sought to evaluate the efficacy and safety/
tolerability of oral medications and dietary supplements for the treatment of melasma.
Multiple databases were systematically searched for randomized clinical trials (RCTs)
evaluating the use of oral medication for treatment of melasma alone or in combination
with other treatments. A total of eight RCTs met inclusion criteria. Oral medications and
dietary supplements evaluated include tranexamic acid, Polypodium leucotomos extract,
beta-carotenoid, melatonin, and procyanidin. These agents appear to have a beneficial
effect on melasma improvement. In conclusion, oral medications have a role in melasma
treatment and have been shown to be efficacious and tolerable with a minimal number and
severity of adverse events. Therefore, dermatologists should keep oral medications and
dietary supplements in their armamentarium for the treatment of melasma.

filter strategies included RCT, therapy, human studies, and

Introduction
Melasma is a common disorder of pigmentation affecting people
with darker skin types, most commonly Fitzpatrick skin types
III–IV. Reported prevalence varies depending on ethnic make-
up of the population and ranges from 8.8 to 40%.1,2
The etiology and pathogenesis of melasma remains poorly
understood but is thought to be a combination of several factors
including exposure to ultraviolet and even visible lights,3 genetics,
and hormonal influences.4 Existing treatment modalities include
prevention of UV radiation, topical lightening agents, chemical
peel, and light-based and laser therapies. However, incomplete
clearance and frequent recurrences make melasma a frustrating
condition. There has been some interest recently in oral medica-
tions and dietary supplements in improving melasma.4
The objective of this systematic review was to evaluate the
current state of evidence for oral treatment or prevention of
recurrences of melasma.
Methods
A literature search was conducted using the MEDLINE,
EMBASE, and Cochrane databases from January 1974 to May
2016 to identify relevant publications. Key search terms included:
melasma, chloasma, facial pigmentation, oral medication, dietary
supplement, controlled study, clinical trial, and treatment. Search
English-language articles, where possible. In addition, references
of relevant articles and reviews were manually searched for
additional sources. Both authors reviewed the abstracts to find
those that met eligibility (inclusion and exclusion) criteria.
We included randomized controlled trials (RCTs) exploring
the efficacy of oral medications or dietary supplements for the
treatment of melasma, either alone or in combination with other
treatments. Studies had to report one of the melasma outcome
measures such as the Melasma Area and Severity Index
(MASI), the modified Melasma Area and Severity Index
(mMASI), the melanin index, or photographic and clinical
assessment.5 A study was excluded if it was not an RCT, did
not study melasma patients, did not report melasma specific
outcome measures, or consisted of fewer than 10 subjects.
Results
Initial search yielded 629 papers evaluating a variety of mel-
asma treatments. However, very few articles focused primarily
on the role of systemic treatments. After screening the titles
and abstracts of initial articles for relevance, only 35 articles
were selected for further review. After the application of inclu-
sion and exclusion criteria, only eight studies met eligibility crite-
ria (see Fig. 1). The eight selected RCTs focused on one of
three groups of oral treatments: tranexamic acid (TA), 1

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2 Review Melasma: review of systemic treatments
Polypodium leucotomos extract (PLE), and miscellaneous diet-
ary supplements including carotenoids, melatonin, and procyani-
din (see Table 1). Below, we review each of these subgroups of
medications.
Tranexamic acid
Tranexamic acid (TA), a synthetic derivative of the amino acid
lysine, is used as a hemostatic agent to treat and prevent
excessive bleeding. Its usage in the treatment of melasma was
first reported in 1979.6 The lightening effect of TA is possibly
related to its antiplasmin activity.7 Increased levels of plasmin in
keratinocytes induce synthesis or arachidonic acid and increase
alpha-melanocyte-stimulating hormone (alpha-MSH) levels, both
of which stimulate melanogenesis.7 By competitively inhibiting
the activation of plasminogen activator through reversible
interactions with its lysine-binding sites, melanin synthesis is
inhibited.8
As a skin-lightening agent, TA has been used as a topical,
an intralesional microinjection, and as a systemic agent.9 Here,
Figure 1 Systematic review of oral medications and dietary supplements in the treatment of melasma. Flow chart of study selection process
International Journal of Dermatology 2017
Zhou and Baibergenova
we review three RCTs reporting the use of oral TA in melasma
treatment.
Shin et al.10 randomized 48 Korean women with melasma,
into an 8-week study of 750 mg daily TA with laser treatment,
or laser treatment alone. Though the mMASI score decreased
significantly in both groups, the mean reduction 4 weeks after
the second treatment session was significantly higher in TA and
laser treatment group than in the laser-only treatment group
(37.8 vs. 21.9, P = 0.02). Furthermore, seven (31%) were
graded as having marked or near total clinical improvement in
the TA and laser treatment group versus only two (11%) in the
laser-only treatment group.
Padhi et al.9 randomized 40 Indian melasma patients, ran-
ging in age from aged 24–55, into an 8-week study involving
500 mg daily TA or placebo, with a daily triple-combination
cream. At the end of the study, the average MASI score
showed a significant reduction (P = 0.014) in the treatment
group (88% reduction from 18.243 to 2.19) versus the placebo
group (54.65% reduction from 15.425 to 6.995). Furthermore,
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Zhou and Baibergenova Melasma: review of systemic treatments Review 3

Table 1 Characteristics of included studies on oral medications/supplements for treatment of melasma

Study design, number of

Study Intervention and dose subjects Outcome measure Results

Tranexamic acid (TA)

Shin et al., 2013 TA, 750 mg daily, for RCT, 48 patients with mMASI The mMASI scores showed
8 weeks, with laser melasma significantly greater improvement in
treatment the combination treatment group
(P = 0.02)
Padhi et al., 2015 TA, 500 mg daily, for RCT, 40 melasma patients MASI MASI scores showed greater
8 weeks, with topical improvement in the combination
cream treatment group (P = 0.014)
Karn et al., 2012 TA, 500 mg daily, for RCT, 260 melasma MASI MASI scores showed a significant
12 weeks, with topical patients decrease in the treatment group
cream (P < 0.05), not seen in the placebo
group
Polypodium leucotomos extract (PLE)
Martin et al., 2012 PLE, twice daily, for RCT, 21 female melasma MASI and MELASQoL MASI (P < 0.05) and MELASQoL
12 weeks patients scores (P < 0.05) scores decreased
significantly in the treatment group
Ahmed et al., 2013 PLE, 720 mg daily, for RCT, 33 female melasma Melanin index and MASI Melanin indices (P = 0.14) and MASI
12 weeks patients scores scores (P = 0.62) showed greater
improvement in the treatment group
Miscellaneous dietary supplements
Teo et al., 2015 Oral carotenoid, 800 mg RCT, 44 melasma patients Erythema index and Erythema index and mMASI score
daily, for 84 days mMASI score showed a greater reduction in the
treatment group (P < 0.05 and
P < 0.379, respectively)
Hamadi et al., 2010 Oral melatonin, 3 mg RCT, 36 melasma patients MASI MASI scores showed significant
daily, for 90 days, with and 10 healthy subjects improvement in the treatment group
topical melatonin (P < 0.05), not seen in the placebo
group (P > 0.05)
Handog et al., 2009 Oral procyanidin, 48 mg RCT, 56 female melasma MASI in the malar regions MASI scores showed a significant
daily, for 8 weeks patients reduction (P = 0.001) in both malar
regions

MASI, melasma assessment severity index; mMASI, modified melasma assessment severity index; MelasQoL, melasma-related quality-of-life;
RCT, randomized clinical trial.

patients were followed up for 6 months, and efficacy was found
to be maintained throughout this period.
Karn et al.8 randomized 260 melasma patients to a 12-week
study involving oral TA, 500 mg daily or placebo, with routine
topical hydroquinone. At 12 weeks follow-up, there was a statisti-
cally significant decrease in the mean MASI score in the treat-
ment group (7.84, P < 0.05), not seen in the placebo group
(9.26, P > 0.05). Patient satisfaction was found to be significantly
better in the treatment group with 82.4% rating their satisfaction
as good or excellent versus only 40.8% in the placebo group.
In reviewed studies, no patients had any serious adverse
events that led to discontinuation of the medication.8–15
Polypodium leucotomos extract
Polypodium leucotomos extract (PLE), derived from the tropical
South American Polypodium leucotomos fern, has been used
as a dietary supplement in a variety of skin conditions such as
psoriasis, atopic dermatitis, and polymorphous light eruptions.16
Though the mechanism of action is not entirely understood, it
has been proposed that PLE increases matrix metalloproteinase
expression and inhibits collagen synthesis, working to maintain
the structural integrity of the extracellular matrix typically
affected by ultraviolet damage.17
Two RCTs reported the effectiveness of oral PLE in mel-
asma patients. Martin et al.16 studied the clinical efficacy of
PLE in an RCT randomizing 21 female patients with epider-
mal melasma, aged 18–50, to receive either oral PLE or pla-
cebo twice daily for 12 weeks. Each subject applied SPF45
sunscreen daily. At the end of the study, patients treated with
PLE had significantly decreased mean MASI scores (5.7 to
3.3, P < 0.05), whereas the placebo group did not (4.7–5.7,
P > .05). Patient self-assessments revealed 50 and 13% of
patients achieved mild and marked improvement, respectively,
versus 17 and 0% for placebo-treated patients.
Ahmed et al.18 randomized 40 Hispanic female patients with
moderate to severe melasma (33 of whom completed the study)
to either 720 mg daily PLE, or placebo, for 12 weeks. Each
subject applied SPF55 topical sunscreen daily. At the end of

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4 Review Melasma: review of systemic treatments
the study, both groups showed significant improvement in mela-
nin index with 28.8% improvement in the PLE group and 18.3%
improvement in the placebo group, though the intergroup differ-
ence was not statistically significant (P = 0.14). The MASI
scores similarly showed improvement in both groups, though
the intergroup difference was not statistically significant
(P = 0.62). The MelasQoL scores showed minimal change in
either group. It is important to keep in mind that while PLE may
be beneficial, it has not been proven to be statistically effective
and is thus not considered as effective as compared to the
other agents.
The safety and tolerability of PLE has been studied in
dosages from 480 mg19 to 1200 mg20 daily, and no significant
adverse effects have been reported.16,18–20
Miscellaneous dietary supplements
Carotenoid
Carotenoids, naturally occurring pigments synthesized by
plants, algae, and photosynthetic bacteria, have recently been
studied for their anti-inflammatory, antioxidant, and protection
against photodamaging effects.21 Fruits and vegetables, such
as tomatoes and tomato paste, provide the majority of carote-
noids in the human diet. When ingested in a high concentration,
carotenoids concentrate in the skin and are able to absorb ultra-
violet radiation and work by scavenging reactive oxygen species
induced by ultraviolet radiation damage.22 Carotenoids also
possess absorption spectra in both UVB and UVA range and
are able to block the formation of melanin, causing reduction of
the existing melanin in melanocytes.23
One RCT evaluating the efficacy of oral carotenoids on melasma
was included. Teo et al.24 conducted a double-blind placebo-con-
trolled trial of 44 melasma patients, randomized to receive either
800 mg carotenoids, or placebo, daily for 84 days, in addition to a
commercially available cream. At the end, the median mMASI
score fell significantly in both groups, but there was a greater
decrease in the treatment group ( 2.1 vs. 1.8, P < 0.379). Fur-
thermore, the erythema score showed greater improvement in the
treatment group compared to placebo (median difference = 30,
P = 0.018, vs. median difference = 20, P = 0.020).
There is generally minimal concern of adverse effects with
oral carotenoid intake, as carotenoids are naturally occurring
pigments found in the human diet. The most common side
effect is skin color change, particularly at high dosages for pro-
longed periods of time, though reversible on discontinuation.
Melatonin
Melatonin, a hormone synthesized and secreted by the pineal
gland, is a powerful antioxidant and free radical scavenger. In25
melatonin creams, a clear dose-response relationship has been
observed between topical use and the degree of UV-induced
26
damage. It has been proposed that melatonin enhances mel-
asma treatment because of its ability to reduce UV-induced free
International Journal of Dermatology 2017
Zhou and Baibergenova
radicals. In addition, it is able to effectively inhibit alpha melano-
cyte-stimulating hormone (MSH) and reverse alpha-MSH-
induced darkening.27 Furthermore, melatonin has been said to
affect other hormones involved in the pathogenesis of melasma,
such as estrogen and progesterone.28
Hamadi et al.29 studied the clinical efficacy of both topical
and oral melatonin in the management of melasma. In a dou-
ble-blind manner, 36 melasma patients and 10 healthy controls,
aged 17–38, were randomized to receive oral melatonin, 3 mg
daily, in combination with topical melatonin, topical melatonin
alone, or with sunscreen, for 90 days, compared to 4% hydro-
quinone cream as the standard therapy. The severity of mel-
asma was evaluated using the MASI score, and the oxidative
stress status was evaluated by plasma malondialdehyde (MDA)
and glutathione (GSH) levels. At the end of the treatment per-
iod, all melasma patients demonstrated significant reduction in
MASI score. Specifically, oral melatonin was found to augment
topical melatonin as a hypopigmentation agent. In addition,
plasma MDA levels were found to be decreased, and plasma
GSH levels were increased.
In general, oral melatonin is considered safe and well toler-
ated in adults in dosages up to 10 mg daily, as studied in sleep
disorder patients, and thus found its main side effect to be only
a mild, transient drowsiness.30
Pinus pinaster (procyanidin)
The French maritime pine (Pinus pinaster) bark extract contains
many active compounds such as monomeric phenolic com-
pounds (catechin, epicatechin, and taxifolin), phenolic acids,
and condensed flavonoids such as procyanidin.31 Though the
exact mechanism by which procyanidin may inhibit the expres-
sion of genes involved in skin hyperpigmentation is yet to be
elucidated, it has been proposed that its strong antioxidant and
anti-inflammatory properties may play a role.32 The antioxidant
effects of procyanidin are several times as powerful when com-
pared to vitamins C and E; furthermore, it is able to recycle vita-
min C, regenerate vitamin E, and increase the endogenous
antioxidant enzyme system.33
Though there were several studies found evaluating the
effectiveness of procyanidin, only one study met our inclusion
criteria. Handog et al.,34 conducted a randomized, double-blind,
placebo-controlled trial to evaluate oral procyanidin with vita-
mins A, C, and E in the treatment of melasma. Sixty female Fili-
pino women with bilateral epidermal melasma (56 of whom
completed the trial) were randomized to receive oral procyani-
din, 24 mg twice daily, or placebo for 8 weeks. At the end,
MASI scores showed a significant improvement (P = 0.001) and
similarly, Mexameter results demonstrated a significant
decrease in pigmentation (P < 0.0001).
Overall, procyanidin proves to be safe and well tolerated, with
minimal adverse effects.33 The most common side effect is
the metallic taste,34 which is reversible on discontinuation of
therapy.
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Zhou and Baibergenova Melasma: review of systemic treatments Review 5

both RCTs were on overall lightening effects of this dietary sup-

Discussion
plement and did not focus on patients with melasma.
Melasma remains to be a challenging disorder of pigmentation, Advantages of oral supplements include protection of the skin
despite the large variety of treatment options available. To date, at a deeper cellular level because of their antioxidant effects,
none of the existing treatment modalities have provided quick, which make them useful in other pigmentary disorders such as
effective, and sustained results. Although the mainstay of treat- solar lentigines, postinflammatory hyperpigmentation, and the
ment for melasma are strict sun protection and topical agents, prevention of photodamage. Furthermore, oral therapies are
systemic treatments such as oral medications and dietary sup- convenient, easy to administer, and generally preferred by
plements may be considered as good alternatives, with both patients. The disadvantages of oral medications are they may
photoprotective and lightening effects. be unsuitable for those who do not want or cannot take oral
In this review, we have discussed the mechanism of action, medications. They may also be absorbed unpredictably
efficacy, safety, and tolerability of tranexamic acid, Polypodium because of stomach acid and enzyme degradation, though this
leucotomos extract, carotenoid, melatonin, and procyanidin. has generally not been an issue.
Of the systemic agents reviewed, oral TA has the greatest
evidence for the management of melasma. Although only three
Conclusion
RCTs involving TA were included, our search yielded five
other original studies, including one case control and three In conclusion, a few of the systemic agents studied thus far
cohort studies on the effect of oral TA on melasma, and one may be useful in enhancing the clinical efficacy of melasma
RCT evaluating the effect of TA on the incidence of postin- treatment. As the current state of evidence suggests that some
flammatory hyperpigmentation after laser treatment for solar agents are effective, safe, and well tolerated, we propose that
lentigenes. TA is also considered an efficient treatment option melasma patients may be beneficially treated by the addition of
for postinflammatory hyperpigmentation (PIH), frequently con- oral agents with anti-inflammatory and antioxidant effects, and
fused with melasma with an inflammatory component.11 TA is we recommend that dermatologists may add these systemic
the only oral agent reviewed in this study available by pre- agents in their armamentarium for the treatment of melasma.
scription only. With approval for use since the 1970s, TA has
obtained a well-established safety profile of up to 4.5 grams
Questions (answers provided after
daily long-term use with no serious side effects.15 However,
references)
rare adverse effects reported include myocardial infarction,
anaphylaxis, visual disturbances, deep vein thrombosis, and
(1) Who does melasma most commonly affect?
pulmonary embolism;8 with this knowledge, a careful screening
a. Females with lighter skin types, most commonly Fitzpatrick
for personal and familial risk factors of thromboembolism
35
skin types I–II
should be completed prior to initiation. Furthermore, oral TA
b. Females with darker skin types, most commonly Fitz-
dosing in melasma is far less than that prescribed for its
patrick skin types III–IV
hemostatic action;8 most studies evaluating TA use in mel-
c. Males with lighter skin types, most commonly Fitzpatrick
asma patients use a maximum dosage of 750 mg per day,
skin types I–II
whereas the conventional dose of TA as a hemostatic agent is
d. Males with darker skin types, most commonly Fitzpatrick
1500 mg per day.9
skin types III–IV
Polypodium leucotomos extract oral supplements have been
(2) What is the reported prevalence of melasma?
used for the last several decades, in Europe and New Zealand,
a. 1–2% of the population, depending largely on ethnic
marketed under the trademark name, “Heliocare”,36 where it
make-up
has demonstrated beneficial antioxidant, anti-inflammatory, and
19
b. 5–6% of the population, depending largely on gender and
photoprotective properties. It possesses a good safety profile,
age
though there is some concern regarding its possible interaction
c. 8–40% of the population, depending largely on ethnic
with medications that affect cardiac and respiratory function,
make-up
as PLE has not been thoroughly tested for medication
d. 40–80% of the population, depending largely on gender
interactions.37
and age
Oral carotenoids, procyanidin, and melatonin supplements
(3) What are current treatment options for melasma?
were each reviewed by one RCT that evaluated efficacy and
a. Prevention of UV radiation
safety in the management of melasma. Each of these is avail-
b. Topical lightening agents
able over the counter and considered to be an antioxidant with
c. Chemical peels
a good safety profile. One dietary supplement that also has
d. Light-based and laser therapies
been studied for its lightening effects is oral glutathione. In our
e. All of the above
search, we found two RCTs on oral glutathione.38,39 However,

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6 Review Melasma: review of systemic treatments Zhou and Baibergenova

(4) Of the systemic agents reviewed in the study, which oral

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Answers to questions:
(1) b
(2) c
(3) e
(4) a
(5) b
(6) c
(7) a
(8) e
(9) c
(10) a
International Journal of Dermatology 2017