Paper Mulberry—Paper mulberry extract comes from the roots of the Broussonetia papyrifera tree and functions by inhibiting tyrosinase activity. It is widely used in South Africa and Europe.22
Resveratrol—Resveratrol is an ingredient extracted from Morus alba L and functions as an antimelanogentic agent by directly inhibiting tyrosinase as well as transcriptional and posttranscriptional processing of tyrosinase.23 It also holds antiproliferative, anti-inflammatory, and antioxidant properties and has widely been used for antiaging and skin lightening purposes.24
Newer Non-HQ Lightening Agents
Silymarin—Silymarin (also known as milk thistle [Silybum marianum]), is a polyphenolic flavonoid that possesses anticarcinogenic, antioxidant, and anti-inflammatory properties. It prevents melanin production in a dose-dependent manner by inhibiting levodopa (L-dopa) oxidation activity of tyrosinase and also reduces the expression of tyrosinase protein.25 In combination with vitamins C and E and hexylresorcinol, silymarin has been found to reduce the effects of photodamage, brighten skin, improve evenness and lines, as well as improve global facial appearance.26
Malassezin—Malassezin is an indole produced by Malessezia furfur yeast and has recently been investigated for melanogenesis suppression. Grimes et al27 assessed the efficacy of topical malassezin in 7 patients with facial hyperpigmentation applied twice daily for 14 weeks. Punch biopsies were taken at weeks 0, 8, 14, and 22. Biopsies from weeks 8 and 14 demonstrated reduced epidermal melanin compared to baseline in all participants; however, at 22 weeks, biopsies showed no difference in melanin content compared to baseline, indicating a temporary process induced by the malassezin.27 More clinical studies are needed to investigate this further.
N-acetyl-glucosamine—N-acetyl-glucosamine is an aminosaccharide that inhibits the glycosylation of tyrosinase as well as its function in melanogenesis.28 It is synthesized and included in topical products for wound healing, rhytides, moisturization, and pigmentation disorders.
Topical Tranexamic Acid—Tranexamic acid traditionally has been used orally for the treatment of menorrhagia but also has been found to be beneficial as a therapy for hyperpigmentation and erythema. Tranexamic acid interferes with plasmin activity, thus indirectly inhibiting melanogenesis while also inhibiting angiogenesis by targeting vascular endothelial growth factor (VEGF) receptors.29 It also leads to an increase in the levels of β-endorphin and μ-opioid receptors as well as the expression of estrogen receptor β on the surface of mast cells.30 Its oral benefit led to the development of topical formulations, typically in 2% to 5% concentrations. It has proven particularly beneficial in the treatment of melasma due to its effects on improving pigmentation, erythema, and skin barrier function.31 Topical tranexamic acid has a relatively high safety profile, with minor side effects such as transient skin irritation and erythema being reported.32
Cysteamine—Cysteamine inhibits tyrosinase, peroxidase, and chelating copper ions necessary for melanogenesis. It has proven to be effective in treating melasma and chronic severe postinflammatory hyperpigmentation when used in a 5% cream formulation.33,34 Lima et al35 were the first to compare the effects of topical cysteamine to HQ in the treatment of facial melasma. They found that the mean reduction in modified Melasma Area and Severity Index score was 24% for cysteamine and 41% for HQ after 60 days. There were no severe adverse effects with either treatment group.35
Final Thoughts
Hydroquinone remains the gold standard for treatment of hyperpigmentation; however, its side-effect profile and risk of ochronosis with long-term use has ushered in various other safe and effective skin lightening agents that can be used as monotherapies or in combination with other lightening agents. Many of these products also can be used effectively with procedural treatments such as chemical peels, lasers, and microneedling for enhanced absorption and efficacy. As newer agents are developed, additional well-designed studies will be needed to determine their safety and efficacy in different skin types as well as their role in the treatment of pigmentary disorders.