. 2018 Feb 1;11(2):28–37.

TABLE 1.

Summary of clinical studies evaluating the efficacy of natural ingredients as hypopigmenting agents

NATURAL INGREDIENTS	STUDY	HYPOPIGMENTING MECHANISM	COMPARISON	PIGMENTATION DISORDER	CONCLUSION	LEVEL OF EVIDENCE^*
AZELAIC ACID (AZA)	Randomized controlled, open-label trial (Farshi et al)2	Mitochondrial oxidoreductase inhibition, DNA synthesis inhibition, Tyrosinase inhibition	20% AzA vs. 4% hydroquinone cream	Melasma	Melasma responded better to AzA during second treatment month	IB
	Nonrandomized open-label trial (Kircik et al)3		None	PIH	15% AzA gel applied twice daily reduced PIH over 16 week period	IIA
	Controlled trial (Dayal et al)^**		Glycolic acid peel with twice daily 20% AzA cream vs. 20% AzA cream	Melasma	At 12 weeks, AzA/glycolic acid combination has a statistically significant decrease in MASI score compared with AzA alone	IIA
	Controlled trial (Mazurek)^***		None	PIH	Dermocosmetics containing AzA showed improvement in pigmentation	IIA
ALOESIN	Controlled Trial (Choi et al, 2002)7	Tyrosinase inhibition, tyrosine hydroxylase, DOPA oxidase	Aloesin vs. Arbutin vs. Aloesin/Arbutin	UVR-induced hyperpigmentation	Dose-dependent suppression in pigmentation with application of aloesin; synergism between arbutin and aloesin	IIA
MULBERRY	RCT (Alvin et al)11	Tyrosinase inhibition, melanogenesis inhibition, ROS Scavenger	75% mulberry extract	Melasma	Compared to placebo, 75% mulberry extract showed significant improvement in MASI score, average Mexamater measurements, and MelasQoL scores	IB
LICORICE EXTRACTS	Split-face controlled clinical trial (Amer et al)17	Tyrosinase inhibition (glabridin)	None	Melasma	Sixteen out of 20 patients had an “excellent response” to 20% liquitin cream applied BID for four weeks Glabridin was more efficacious compared to HQ	IIA
	Controlled Trial (Makino et al)15	ROS cavenger (glabridin)	None	UVR-induced hyperpigmentation	Skin brightener containing glabridin was shown to be clinically efficacious	IIA
	RCT (Costa et al)16	Disperses melanin (liquiritin)	Cream with belides, emblica, and licorice vs. 2% HQ	Melasma	Although depigmentation was seen in both groups, no statistical difference in efficacy	IB
	RCT (Zubair et al)10	Disperses melanin (liquiritin)	4% liquiritin vs. 2% liquiritin and HQ	Melasma	4% liquiritin significantly more effective than combination group	IB
LIGNIN PEROXIDASE	RCT (Mauricio et al)18	Oxidizes and breaks down melanin	Lignin peroxidase cream vs. placebo or 2% HQ	Mottled hyperpigmentation	According to Mexameter evaluation, lignin peroxidase had more rapid and observable skin-lightening effect compared to placebo or HQ	IB
LIGNIN PEROXIDASE	RCT/Split-face (Draelos et al, 2015)19	Oxidizes and breaks down melanin	Lignin peroxidase cream vs. none, lignin peroxidase cream vs. 4% HQ	Facial dyspigmentation	Lignin peroxidase was more effective than applying nothing at all based on dermatospectrophotometer. Lignin peroxidase was superior to 4% HQ in aesthetics when including skin texture, lack of clarity and radiance, roughness, and overall appearance. Parity was demonstrated between both agents when evaluating skin lightening efficacy.	IB
KOJIC ACID (KA)	Prospective controlled study (Monteiro et al)21	ROS scavenger, tyrosinase inhibition	0.75% KA with 2.5% Vitamin C vs. 4% HQ	Melasma	Patients responded faster and better to HQ	IIA
	RCT (Draelos et al, 2010)63		Compound (KA, emblica extract, glycolic acid) vs. 4% HQ	Facial dyschromia	Both treatment equally efficacious	IB
	RCT (Deo et al)22		1% KA vs. KA with 2% HQ vs, KA with 0.1% betamethasone vs. combination of products	Melasma	KA with HQ was most effective combination	IB
NIACINAMIDE	RCT (Lee et al)23	Inhibits melanosome transfer to keratinocytes	Cream containing 2% niacinamide with 2% tranexamic acid vs. vehicle control	Irregular facial hyperpigmentation	Niacinamide with TXA combination product showed efficacy	IB
	RCT (Castanedo-Cazares et al)24		Niacinamide 4% vs. desonide 0.05% vs. control	Axillary hyperpigmentation	4% Niacinamide with 0.05% desonide emulsion showed significant colorimetric improvement, though desonide alone was more effective	IB
	Open-label controlled trial (Farris et al)^**		None	PIH	Skin brightening compound containing retinol 0.5%, niacinamide 4.4%, resveratrol 1%, and hexylresorcinol 1.1% improved hyperpigmentation	IIA
ELLAGIC ACID	RCT (Ertam et al)29	Tyrosinase inhibition	1% arbutin vs. synthetic 1% ellagic acid vs. synthetic 1% ellagic acid with plant extracts containing natural ellagic acid	Melasma	All three treatments show efficacy	IB
ELLAGIC ACID	RCT (Dahl et al)30	Tyrosinase inhibition	0.5% ellagic acid combined with 0.1% salicylic acid vs. 4% HQ	Hyperpigmentation and dark spots	Based on clinical grading, physical measurement of spot size by Chroma Meter, and patient questionnaire analysis, the compound had comparable efficacy to HQ but better aesthetics	IB
ARBUTIN	RCT (Ertam et al)32	Tyrosinase inhibition	1% arbutin vs. synthetic 1% ellagic acid vs. synthetic 1% ellagic acid with plant extracts	Melasma	All three treatments show efficacy	IB
ARBUTIN	Single-group efficacy trial (Polnikorn et al)33	Tyrosinase inhibition	None	Melasma	7% alpha arbutin in conjunction with the MedLite C6 Q-switched Nd:YAG laser showed favorable results	IIB
GREEN TEA	RCT (Syed et al)36	Antioxidant	2% analogue of green tea extract vs. placebo control	Melasma	2% analogue of green tea extract in hydrophilic cream shows clinical efficacy	IB
TURMERIC	RCT/split-face (Swanson et al)38	Antioxidant	Turmeric extract cream formulation vs. unknown control	Facial hyperpigmentation	Formulation improved areas of hyperpigmentation by 14.16% (P<.0001) at four weeks	IB
SOY	Controlled trial (Hermanns, 2000)52	Anticarcinogenic (Isoflavones), inhibits melanosome transfer to keratinocytes (serine protease inhibitors)	Azelaic acid vs. glycolic acid vs. soy extract	Facial hypermelanosis	Soybean extract showed clinical efficacy based on video camera analysis	IIA
	Controlled trial (Pierard et al)53		None; authors compared affected vs. unaffected areas	Melasma	Application of soy extract to melasma lesions once daily for 3 months led to an average reduction of hyperpigmentation of 12%	IIA
	RCT (Wallo et al)45		Soy moisturizer vs. vehicle control	Facial photodamage	Application of soy-containing moisturizer improved mottled pigmentation, blotchiness, dullness, fine lines, overall texture, overall skin tone, and overall appearance	IB
ASCORBIC ACID	Single group Efficacy Trial (Kim et al)56	UVA-mediated catalase inactivation	Topical AA with trichloroacetic acid peel vs. trichloroacetic acid peel	Severe melasma	Melasma peel (alpha-hydroxy acid, AA, and oxygen) showed improvement in 95 percent of patients at eight weeks	IIB
	Controlled trial (Soliman et al)57	Glutathione depletion, oxidant formation	Combined trichloroacetic acid peel and topical ascorbic acid vs. trichloroacetic acid peel	Bilateral epidermal melasma	According to digital photography and MASI score, combination product showed greater improvement	IIA
	RCT/Split-face (Huh et al)59	Nitrous oxide production	Vitamin C vs. distilled water	Melasma	After 12 weeks of vitamin C iontophoresis treatment, the colorimeter recorded a clinically significant reduction in luminance value on the treated side	IB
	Single group efficacy Trial (Taylor et al)60	ROS scavenger, tyrosinase inhibition	None	Melasma and post-inflammatory hyperpigmentation	Novel full-face iontophoresis mask and ascorbyl glucoside preparation over a 1 to 2 month period showed clinical efficacy. *In conjunction to the treatment, patients adhered to a regimen of mandelic/malic acid skin care regimen, broad-spectrum UVA/UVB sunblock, and basic sun protection.	IIB

Level of evidence—IA: evidence from meta-analysis of randomized controlled trials; IB: evidence from at least one randomized controlled trial; IIA: evidence from at least one controlled study without randomization; IIB: evidence from at least one other type of clinical study;

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Dayal SS. Combination of glycolic acid peel and topical 20% azelaic acid cream in melasma patients: efficacy and improvement in quality of life. J Cosmetic Dermatol. 2016 Aug 8;

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Mazurek K. Comparison of efficacy of products containing azelaic acid in melasma treatment. J Cosmetic Dermatol. 2016;15(3):269–282; PIH: post-inflammatory hyperpigmentation; MASI: Melasma Area Severity Index; UVR: Ultraviolet radiation; MelasQoL: The Melasma Quality of Life Scale; RCT: Randomized controlled trial; ROS: reactive oxygen species; HQ: hydroquinone

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Farris PP. Efficacy and tolerability of a skin brightening/anti-aging cosmeceutical containing retinol 0.5%, niacinamide, hexylresorcinol, and resveratrol. J Drugs Dermatol. 2016;15(7):863–868;PIH: post-inflammatory hyperpigmentation; RCT: Randomized controlled trial; ROS: reactive oxygen species; HQ: hydroquinone; TXA: tranexamic acid