Natural options for management of melasma, a review

Figures & data

Table 1. Causes of acquired hypermelanosis (41).

Exogenous sources

Cosmetics

Photosensitizing agents (bergamot oil)

Drugs (Isotretinoin, tetracycline, Methotrexate, griseofulvin, sulphonamides)

UV exposure (melasma, solar lentigo, freckles)

Skin disorders and conditions

Melasma

Linea fusca

Poikeloderma of civatte

Erythromelanosis follicularis

Riehl’s malanosis

Post inflammatory hyperpigmentation

Other causes

Pregnancy

Hemochromatosis

Liver disease

Addison’s disease

Pituitary tumor

Figure 1. Fitzpatrick skin phototype V with total face involvement melasma. (a) Female full face melasma involvement. (b) Male pattern melasma involving upper mentonian lesions, mandibular, zygomatic, temporal, and frontal (researchers’ collection).

Table 2. Frequency of facial features affected by melasma (adapted from Ref. (29)).

Topographies	Percentage
Mandibular	18
Temporal	24
Glabella	25
Mentonian	29
Parotid	30
Nasal	40
Supralabial	51
Zygomatic	84

Originally published in Handel AC, Lima PB, Tonolli VM, Miot LDB, Miot HA. Risk factors for facial melasma in women: a case-control study. Br J Dermatol. 2014 © British Association of Dermatologists. Reproduced by permission of British Association of Dermatologists. Permission to reuse must be obtained from the rightsholder.

Table 3. Studies evaluating the use of topical natural therapies as monotherapy versus other therapies used for treatment of Melasma.

			Treatment measurements
Ref.	Natural intervention	Study design	Objective	Subjective	No. of subjects	Results	Mechanism of action	Side effects	Comments
(43)	Topical VIT C iontophoresis	Randomized, double-blind, placebo-controlled trial, 12 weeks treatment	Colorimeter	Self-assessment	29 Female participants	Gradual reduction of colorimeter L values compared to the placebo. Self-assessment indicated >75% improvement	Inhibit melanin formation and reduce oxidized melanin	Mild electric shock, itching, erythema, burning sensation, and facial dryness	VIT C needs to be stabilized its inability to permeate the skin may result in skin irritations
(51)	Topical VIT L-ascorbic acid versus HQ	A double-blind, randomized trial of 5% ascorbic acid versus 4% HQ in melisma, 16 weeks	Colorimetry, digital photography, and regular color slides	Patient assessment	16 Female participants	Lightening effect of HQ was evident in the first month of treatment; effect of l-ascorbic acid was noted in the third month. Colorimetric measures showed no statistical differences	Suppresses melanin synthesis through its antioxidant effect or by the inhibition of tyrosinase	Fewer, tolerable side effects on the l-ascorbic side compared to the HQ side	l-Ascorbic acid has less side effects, therefore could be used for longer periods
(54)	Topical KA acid	Comparative study of 4% HQ and 0.75% kojic acid cream (containing 0.75% KA and 2.5% VIT C) applied once daily application at night, 12 weeks	MASI, Wood’s light examination	Color photographs	60 Participants of either sex	HQ proved to be highly efficacious, with faster onset of action compared to KA	Anti-tyrosinase	No reported side effects	Broad SPF was used. Poor KA effects could be that KA is a lighter agent compared to HQ. The efficacy of KA in this study may have been potentiated by VIT C
(52)	KA 1% alone, vis-a-vis its separate combinations	A randomized, single blind, comparative study group A—kojic acid 1% cream, group B—kojic acid 1% and hydroquinone 2% cream, group C—kojic acid 1% and betamethasone valerate 0.1% cream, and group D—kojic acid 1%, hydroquinone 2%, and betamethasone valerate 0.1% cream, 3 months	MASI	Photographs, global assessment scale	80 Participants of either sex	Improvement in MASI from all four groups	Tyrosinase inhibition and suppression of melanogenesis	No reported side effects	Combination of KA with HQ is a superior depigmenting agent, use of daily SP was enforced. Wood’s lamp unreliable to examine depth of pigmentation in Indian skin types IV and V
(56)	Topical soybean and soya milk paste applied daily for 8–9 weeks	Both in vivo and in vitro	F&M staining of histologic sections	–	–	STI treated Co-cultures demonstrate reduced tyrosinase activity Decreased pigment deposition was observed	Inhibit melanosome transfer to tokeratinocytes, antioxidant properties	No visual irritation, histologic analyses revealed no markers of irritation or other pathological signs	Soybean could be a promising agent for treatment of melasma. Soybean extracts did not require the addition of any delivery vehicle to exert their depigmenting activity
(58)	Topical liquiritin 2% with a vehicle cream	Split face clinical trial, 4 weeks	–	5 point scale, millimeter grid scale, color photographs and clinical evaluation	20 Female participants	60% with reduction in lesion size, 75%, 70% with reduction in pigment intensity by 3 levels	Melanin dispersibility via the amelanodermic and epidermal stain removing property	Mild skin irritation in the form of erythema and burning sensation	Good response with sun protection and no reported chronic toxicity
(59)	Topical licorice	Efficacy study, 12 weeks	MASI	PGA	34 Female participants	Significant improvement	Inhibits tyrosinase enzyme and anti-inflammatory effects	No side effects recorded	Safe lightening agent due to its anti-inflammatory properties
(60)	Topical licorice, 4%	Randomized, double-blind, placebo-controlled clinical trial, 12 weeks	MMASI	Classification of efficacy of the interventions in four levels	40 Female participants	Notable decrease in MMASI	Solid lipid nanoparticles technology	Minimal side effects	Nanoparticles technology allows large use of large amounts of licorice and increases efficacy
(62)	Topical solution of mequinol	Pilot small case series study. 2% mequinol and 0.01% tretinoin applied twice daily, 12 weeks	–	Digital photographs	5 Male participants	Complete clearance of melasma at 12 weeks	Competitive inhibitor of tyrosinase	Minimal tolerable side effects such as stinging	Sample size very small
(63)	Topical niacinamide	A double-blind, randomized clinical trial of niacinamide 4% versus HQ 4% for 8 weeks	MASI, Colorimeter assessment, Histopathology, Spectrophotometry	Two independent blinded observers	27 Female participants	Niacinamide induces a decrease in pigmentation, inflammatory infiltrate	Serine protease inhibitors	Mild tolerable side effects on niacinamide reported as erythema, pruritus, and burning	Niacinamide is a safe and effective therapeutic agent
(66)	Glucosamine cream A (4% N-acetyl glucoseamine and 2% nicotinamide) cream B (4% HQ)	A randomized, double-blinded, split-face clinical trial. Treatment creams applied twice daily, 12 weeks	MMASI	Digital photography; patient’s rating	30 Female participants	Efficacy of N-acetyl glucosamine + nicotinamide was slightly more	Prevents thyrosinase glycosylation	Erythema, pruritus, and burning were reported less in cream A compared to cream B	Cream A treatment could be a good alternative to hydroquinone
(71)	Arbutin 1% topical gel and plant extract containing Ea	A randomized, prospective, open-label study for 4 weeks with a 6-month follow-up period	Mexameter	Clinical photographs	20 Female participants	A significant response was obtained from all of 10 patients who used arbutin	Whitening agent	No side effects were reported	Possible treatment intervention, use of sun protection remains key
(80)	Topical mulberry extract	Randomized, single-blind, placebo-controlled trial comparative study 75% mulberry (Morus alba) extract oil versus placebo, 8 weeks	MASI, Mexameter, MELASQoL	–	50 Participants	MASI score, significantly improved Mexameter readings showed a significant drop MELASQoL score also improved tremendously for the mulberry group	Whitening agent with antioxidant properties	Mild itching in four patients from the 75% mulberry extract oil group and 12 cases of either itching or erythema reported from the placebo group	Safe and effective skin-lightening ingredient
(66)	Glucosamine cream A (4% N-acetyl glucoseamine and 2% nicotinamide) and cream B (4% HQ)	A randomized, double-blinded, split-face clinical trial. Treatment creams applied twice daily, 12 weeks	MMASI	Digital photography; patient’s rating	30 Female participants	Efficacy of N-acetyl glucosamine + nicotinamide was slightly more	Prevents thyrosinase glycosylation	Erythema, pruritus, and burning were reported less in cream A compared to cream B	Cream A treatment could be a good alternative to hydroquinone
(71)	Arbutin 1% topical gel and plant extract containing Ea	A randomized, prospective, open-label study, 4 weeks with a 6-month follow-up period	Mexameter	Clinical photographs	20 Female participants	A significant response was obtained from all of 10 patients who used arbutin	Whitening agent	No side effects were reported	Possible treatment intervention, use of sun protection remains key
(80)	Topical mulberry extract	Randomized, single-blind, placebo-controlled trial comparative study 75% mulberry (Morus alba) extract oil versus placebo, 8 weeks	MASI, Mexameter, MELASQoL	–	50 Participants	MASI score significantly improved. Mexameter readings showed a significant drop; MELASQoL score also improved tremendously for the mulberry group	Whitening agent with antioxidant properties	Mild itching was reported in 4 patients from the 75% mulberry extract oil group while there were 12 cases of either itching or erythema reported from the placebo group	Safe and effective skin-lightening ingredient
(84)	Hesperidin	Efficacy study to determine the anti-melanogenic effect of hesperidin, in vitro	PASW statistics ver.18.0	–	–	Hesperidin decreased tyrosinase activity leading to melanin decrease expression of MITF and MITF’s downstream melanogenesis-related proteins	Inhibits melanogenesis through scavenging (ROS) and interacting with melanogenic intermediates	–	Hesperidin could be a promising, safe, and healthy skin depigmenting agent with added antioxidant and skin barrier strengthening effects
(88)	Oral ginseng—3 g	Open-label, prospective clinical study	MASI, Mexameter, MELASQoL	Global improvement scale	25 Female participants	MASI decreased and MELASQoL showed improvement 74% of the patients showed some improvement on the patient- and investigator-rated global improvement scales	Inhibition of key enzymes of melanogenesis and enhancing production of antimelanogenic factor	Mild gastrointestinal discomfort and nausea	Novel skin whitening ingredient
(89)	Topical AA	Randomized, double-blind comparison of azelaic acid (20%) and hydroquinone (2%) applied twice daily, 24 weeks	–	5 point grading scale, millimeter grid and color photographs	155 Female participants	AA results categorized as being good to excellent improvement	Tyrosinase inhibitor	Mild side effects reported as burning, itching, and stinging. These were associated with improper cleansing of the face	Therapeutic response compared to HQ group
(94)	Oral grape seed extract rich with proanthocyanidin	Efficacy study, 6 months	Colorimetry Focal macule size	–	12 Female participants	Improvement maximally achieved after 6 months and there was no further improvement after this period	Antioxidant, reduces melanin, biosynthesis as well as UV-induced hyperpigmentation	No adverse effects reported	No clear distinction from melasma

VIT: Vitamin; AA: azelaic acid, MASI, PGA, MMASI: Modified Melasma Area and Severity Index; Ea: ellagic acid; ROS: reactive oxygen species; MITF: microphthalmia-associated transcription factor; p-Erk1/2: phospho-extracellular signal-regulated kinase 1/2; MELASQoL: Melasma Quality of Life Scale.

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