Systematic Review of the Efficacy and Safety of Topical Glutathione in Dermatology

J Clin Aesthet Dermatol. 2025;18(9):51–54.

by Rayva Khanna, MD; Pooja Rambhia, MD; and Anne Chapas, MD

Dr. Khanna is with Medstar Georgetown University Hospital Department of Dermatology in Washington, District of Columbia. Dr. Rambhia and Dr. Chapas are with UnionDerm in New York, New York.

FUNDING: No funding was provided for this article.

DISCLOSURES: The authors declare no conflicts of interest relevant to the content of this article.

Abstract: Background: Glutathione, a potent antioxidant, has gained attention for its skin-lightening effects, leading to ethical debates. Social media influence has popularized its use in various skincare products such as under-eye creams, face masks, sunscreens, and moisturizers. Despite its popularity, scientific research on topical glutathione is limited. Objective: To perform a review of existing literature on the safety and efficacy of topical glutathione. Methods: A PRISMA-guided systematic review was conducted using PubMed and MEDLINE databases with search terms “glutathione” AND “topical” AND “skin” OR “dermatology.” From 446 articles, only clinical trials on topical glutathione were included, excluding reviews, animal studies, and research on oral or intravenous glutathione. Five clinical trials met the inclusion criteria. Results: Studies suggest glutathione may improve hyperpigmentation and provide antioxidant advantages. A glutathione amino acid precursor (GAP) blend increased the glutathione reduced monomers (GSH) oxidized dimers glutathione disulfide (GSSG) ratio, a surrogate measure for oxidative damage repair capacity. S-acyl glutathione 2% cream significantly reduced ultraviolet-induced erythema (p=0.0003). A 2% oxidized glutathione lotion decreased the melanin index (p<0.05), total epidermal water loss (TEWL) (p<0.05), and wrinkles (p<0.01). Combination creams with glutathione also showed benefits, though tolerability was varied. Safety data is limited and warrants further exploration. Conclusion: Topical glutathione shows promise for dermatological applications. Further randomized controlled trials are necessary to fully evaluate its efficacy in hyperpigmentation, TEWL, skin elasticity, and ultraviolet (UV) damage. Additionally, ethical considerations regarding its use as a skin-bleaching agent must be addressed to avoid reinforcing structural racism and healthcare disparities. Keywords: Glutathione, topical, antioxidant, pigmentary disorders, skin bleaching

Introduction

Glutathione, a low molecular weight thiol-tripeptide, is renowned for its potent antioxidant properties and has recently garnered attention for its potential skin-lightening effects, raising significant ethical debates regarding its use. The pervasive impacts of global colonization have contributed to colorism, where numerous racial and ethnic groups, both overtly and subconsciously, equate lighter skin tones with higher socioeconomic status, greater access to education, enhanced personal development opportunities, and aesthetic appeal.¹ Conversely, glutathione may offer substantial cosmetic benefits for individuals suffering from disorders of hyperpigmentation, in addition to antioxidant benefits for skin. It is postulated that glutathione inhibits tyrosinase through three primary mechanisms: direct antioxidant activity, chelation of the copper site within tyrosinase via its thiol group, and disruption of tyrosinase’s cellular transport to pre-melanosomes.^2,3

Though both oral and intravenous (IV) formulations of glutathione have been explored in the literature, the evidence regarding their bioavailability, safety, and efficacy remains inconclusive.⁴ Randomized control trials on oral glutathione supplementation have yielded mixed results. One study, administering 500mg twice daily for four weeks to 40 healthy adults, showed no significant change in serum glutathione levels.⁵ Conversely, another study with 54 adults over six months demonstrated increased glutathione levels at the same dose.⁶ As evidenced by these findings, data regarding the effectiveness of oral glutathione in raising plasma levels is limited and controversial. Despite its common use in many Asian countries as a skin lightening agent, efficacy in skin lightening of IV glutathione remains unclear due to the lack of human clinical trials evaluating the efficacy.² There is no evidence regarding dosing, duration, or need for maintenance treatment. Furthermore, safety data is inadequate; IV glutathione use has been linked to serious adverse effects such as liver failure, kidney failure, and Stevens-Johnson syndrome, calling into question its safety.¹ However, despite its inconclusive safety and efficacy, glutathione is widely used as an antioxidant and skin lightening agent, particularly in countries like Singapore, Thailand, Malaysia, and Indonesia. Wahab et al⁷ conducted double-blind randomized controlled clinical trial evaluated the efficacy of topical and oral glutathione as skin-whitening agents. The study involved 46 participants who were divided into groups receiving oral placebo, oral glutathione, topical placebo, and topical glutathione. Results showed that the combination of topical and oral glutathione significantly reduced melanin index and increased skin brightness compared to placebo and monotherapy groups. The study concluded that both topical and oral glutathione are effective skin-lightening agents, with the combination therapy potentially offering superior results.⁷ However, to date, there are very few clinical trials discussing the efficacy of topical glutathione alone.

Recently, partially influenced by social media, topical glutathione has been incorporated into a wide range of skin brightening and lightening product including under eye creams, face masks, eye masks, sunscreens, and moisturizers. However, the use of topical glutathione remains underexplored in scientific research. This systematic review aims to evaluate the safety and efficacy of topical glutathione, thereby elucidating its potential applications in dermatological practice.

Methods

A PRISMA-guided systematic review (Figure 1) was performed using PubMed and MEDLINE databases, employing search terms “glutathione” AND “topical” AND “skin” OR “dermatology,” yielding 446 articles with no time restriction. Only clinical trials investigating the effects of topical glutathione were included, excluding review articles, animal studies, and research on oral or intravenous glutathione. Five clinical trials met the inclusion criteria.

Results

Protection from oxidative damage and environmental stress.

As the primary barrier to environmental and metabolic stress, the skin is susceptible to oxidative damage.² To combat oxidative damage, the thiol containing tri-peptide glutathione (GSH) plays a central role. GSH exists in two main forms: reduced monomers (GSH) and oxidized dimers, glutathione disulfide (GSSG). The GSH/GSSG ratio serves as a primary determinant of the cellular redox state, as reduced GSH is thought to repair oxidative damage to protein thiols and to support redox signaling, the regulation of cell proliferation, control of the cell cycle, initiation of apoptosis, modulation ofthe immune response, and maintenance of skin pigmentation. Therefore, it is hypothesized that an increased GSH/GSSG ratio is a measure of the antioxidant effect of topical glutathione.^2,8  While glutathione’s antioxidant properties are well-documented, its topical formulations suffer from poor bioavailability.⁸ To enhance bioavailability, Unilever R&D developed a glutathione amino acid precursor (GAP) blend to stimulate de novo glutathione synthesis. A randomized, double-blind, placebo-controlled study involving 21 Chinese women (ages 30–45 years) demonstrated that GAP increased the GSH/GSSG ratio significantly at 48 hours post ultraviolet (UV) exposure (p=0.02).⁸ Ex vivo studies further confirmed GAP’s efficacy in reducing oxidative deoxyribonucleic acid (DNA) lesions and cyclobutene pyrimidine dimers under UVA and UVB irradiation, respectively, though these findings were limited by the small number of biomarkers evaluated.⁴ In another study evaluating topical glutathione’s role on UV-induced erythema, Grandi et al⁹ found that subjects pre-treated with S-acyl glutathione 2% cream, a linoleic acid pre-conjugate, had a significantly lower minimal erythema dose compared to placebo, indicating UV protective properties (p=0.0003).

Hyperpigmentation. One study evaluated the efficacy of topical glutathione on improvement in pigmentation. Watanabe et al¹⁰ conducted a randomized controlled, split-face trial involving 30 healthy women in the Philippines to assess the efficacy of 2% w/w oxidized glutathione (GSSG) lotion on skin lightening. Patients were instructed to wash their faces with soap and water and pat it dry. They were furthermore advised to avoid sun exposure, make-up, moisturizers, skincare products. They were also advised to discontinue oral vitamin A, C, and E supplementation. Participants applied the lotion to one half of their faces for 10 weeks. The melanin index, measured with a Mexameter (Courage + Khazaka electronic GmbH), showed a statistically significant reduction from Week 1 to Week 10 (p<0.05).¹⁰

Trans-epidermal water loss. One study evaluated the efficacy of topical glutathione on improvement in trans-epidermal water loss (TEWL). Watanabe et al¹⁰ investigated the impact of 2% w/w GSSG lotion on TEWL using a Corneometer (Courage + Khazaka electronic GmbH). Results indicated a significant reduction in TEWL after 10 weeks of treatment (p<0.05).

Skin elasticity and wrinkles. One randomized control trial evaluated the effects of 2% w/w GSSG lotion on skin elasticity and wrinkle reduction involving lateral canthal lines. Using SkinSys software for scientific evaluation, the study found a significant reduction in skin wrinkles after 10 weeks of treatment (p<0.01) compared to placebo, though no significant improvement in skin smoothness was observed.¹⁰

Combination creams. Two clinical trials assessed the efficacy and tolerability of creams containing topical glutathione. One trial involving 24 Asian women used a cream with niacinamide 5%, tranexamic acid 2%, oxyresveratrol 2%, glutathione disulfide 2%, and linoleic acid 1% applied twice daily. The study reported a significant reduction in melanin index at eight weeks (p<0.05) and improvement in erythema index by 12 weeks.¹¹  Another trial evaluated a cream containing modified glutathione (0.1% GSH-C4), 0.5% beta-glycyrrhetic acid, and 10% azelaic acid in patients with mild-to-moderate rosacea, showing a reduction in inflammatory papules at Week 8.¹²  However, the lack of a control groups in both of these studies and combination topical cream containing other active ingredients makes it impossible to attribute these benefits solely to glutathione’s antioxidant effect alone.

Safety and tolerability. Watanabe et al¹⁰ evaluated the safety and tolerability of a 2% oxidized glutathione (GSSG) lotion. All 30 subjects completed the study without significant adverse reactions. One subject experienced mild erythema on Days 2 and 3, which resolved by Day 4 without discontinuing the lotion. Overall, the GSSG lotion was well-tolerated with no reported negative symptoms.¹⁰ In the study by Jung et al,¹¹ no adverse effects were reported after 12 weeks of use among the 24 participants. The study monitored for erythema, itching, scarring, atrophy, telangiectasias, and post-inflammatory hyperpigmentation, none of which were observed.¹¹ Conversely, in a study assessing a cream containing 0.1% GSH-C4, 0.5% beta-glycyrrhetic acid, and 10% azelaic acid, 10 percent of the participants discontinued due to lower skin irritation. However, attributing the intolerance to a specific agent within the combination cream remains challenging.¹²

Discussion

To date, there are few studies demonstrating utility of topical glutathione in treating hyperpigmentation, oxidative damage, TEWL, and improving skin elasticity. The existing randomized control trials using topical glutathione provided promising evidence in increasing the GSH/GSSG ratio (p=0.02) and subsequently reducing oxidative damage, lowering the minimal erythema dose (p=0.003), reduction in melanin index (p<0.05) reducing TEWL (p<0.05), and skin wrinkles (p<0.01).

However, the conclusions that can be drawn from the included studies are significantly limited given small sample size, limited follow-up time, and a lack of control groups. Furthermore, there is a lack of randomized control trials assessing the benefits of topical glutathione alone. Larger, randomized controlled trials (RCTs) with longer follow-up periods are necessary to evaluate the efficacy and safety of topical glutathione more robustly. Safety data is similarly limited, with the tolerability of creams and long-term effects sparsely analyzed in the literature. Additionally, many studies with tolerability data involve combination creams, making it difficult to assess glutathione’s specific tolerability.

Furthermore, the ethical considerations surrounding its use as a skin bleaching agent are significant, particularly in the context of addressing racial injustices and colorism. Recent societal awareness has highlighted the critical need to reevaluate the implications of skin lightening practices. Liu et al¹³ emphasized the disproportionate impact of these agents on patients of color and the importance of regulating their use. Historically, structural racism and colorism have linked lighter skin tones with higher socioeconomic status and beauty, perpetuating inequalities.¹⁴

Physicians must navigate the ethical landscape by considering both the potential benefits and the broader societal implications. While skin bleaching might improve individual socioeconomic opportunities, it risks reinforcing structural racism and healthcare disparities.¹³ Nonetheless, localized use of skin bleaching agents may be of benefit to pigmentary disorders, thus it’s important to fully evaluate the safety and efficacy of topical glutathione in this context.

Conclusion

Although topical glutathione shows promise for dermatological applications, further larger randomized controlled trials with long-term follow-up are necessary to evaluate its utility more comprehensively in improving hyperpigmentation, erythema, and reducing free-radical damage.

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