Try out PMC Labs and tell us what you think. Learn More. This phenomenon has seen a recent surge owing to aggressive marketing and capitalization of pharma-cosmeceutical companies. Even though parenteral glutathione is approved only for severe liver disorders and for prevention of chemotherapy associated neurotoxicity, the lack of statutory laws governing the use of systemic glutathione in most countries has contributed to its unchecked use for skin lightening.
In this article, we shall review and discuss the current status of glutathione as a skin lightening agent and address the sundry unanswered queries regarding the dosage, duration of use and longevity of accrued effects based on clinical evidence and recent insights into its antimelanogenic mechanism. The preoccupation with exploration of treatment options that may help attain a lighter skin tone or fairer complexion has been an ongoing phenomenon in people with skin of color SOC. The direct implication of this craze is the exploitation of topical agents originally developed for treatment of hyperpigmentation, such as skin lightening therapies.
Topicals containing hydroquinone, alpha and beta hydroxy acids, tretinoin, mequinol, arbutin, vitamin C, soy extracts and concoctions of multiple ingredients, including newer cosmeceuticals, are now in vogue for treatment of facial melanoses especially melasma [ 1 ] and for general skin lightening, at least of the face, neck and other exposed parts.
The local adverse effects of these agents [ 1 ] and the quantity required for large surface area application constitute major limitations of this approach. Understandably, the effect of such locally applied topicals remains limited to the application site alone without any notable systemic skin lightening effect. The quest for a systemic skin-whitening agent ensues.
Oral antioxidants, such as vitamin C, vitamin E, tranexamic acid, flavonoids, and various botanical extracts have been tried in melasma and disorders of hyperpigmentation, but none has proven to provide an overall skin lightening effect [ 12 ]. Glutathione GSHa low molecular weight thiol-tripeptide is central to the maintenance of intracellular redox balance [ 3 ].
Currently, to the best of our knowledge, IV GSH has been approved by different statutory drug regulatory authorities for specific systemic disorders. The indications approved by the Central Drugs Standard Control Organization CDSCO in India are: 1 alcoholic fatty liver, 2 alcoholic liver fibrosis, 3 alcoholic liver cirrhosis, and 4 alcoholic hepatitis [ 4 ].
The Philippines Food and Drug Administration FDA has approved its use glutathione an adjunctive treatment to reduce neurotoxicity associated with cisplatin chemotherapy [ 5 ]. In addition to it being one of the richest antioxidants, it is being promoted as a skin-lightening agent, following the discovery of its antimelanogenic properties [ 7 ]. Amongst the many mechanisms postulated to contribute to its antimelanogenic properties Figure 1inhibition of tyrosinase enzyme, skewing of melanogenesis from the darker eumelanin to the lighter phaeomelanin, and scavenging of free radicals seem to be the most important [ 8 ].
Unfortunately, there is a clear contradiction between the exact evidence supporting its efficacy and safety, and the hype around its depigmentary properties, with pharma-cosmeceuticals inundating dermatology therapeutics pill glutathione tablets, capsules, topical preparations and parenteral preparations across the globe [ 9 ]. Mechanisms postulated to be responsible for the skin lightening effect of glutathione. For more detailed background information regarding the basic and applied physiology of glutathione, readers may refer to a ly published exhaustive article on this aspect [ 6 ].
The side whitening, GSH, seems to be instrumental in the depigmenting properties of this unique molecule. Apart from these two major forms, GSH may be esterified to form glutathione esters [ 7 ]. At the time of authoring this article, there were only four published effects that evaluated the efficacy of oral, topical, and parenteral glutathione as a skin-whitening agent Table 1 [ 10 — 13 ]. The primary efficacy outcome in both the trials was to evaluate the pre- and post-treatment melanin indices.
The randomized, double-blind, two-arm, placebo-controlled study conducted by Arjinpathana and Asawanonda in 60 healthy medical students showed a consistent reduction in the melanin indices at all the six sites evaluated in the GSH group subjects, with a statistically ificant reduction over placebo at two sites [ 10 ].
The open-label, single-arm pilot study conducted by Handog et al. The tolerance to GSH was excellent in both the studies. The singular randomized, double-blind, placebo-controlled clinical trial by Watanabe et al. The of this split-face, protocol-based study revealed statistically ificant reduction of skin melanin index with glutathione compared to placebo, with no adverse drug effects. However, the of these studies need to be interpreted with caution owing to certain limitations in their study de.
Good advice, in small doses.
Other parameters such as skin moisture, curvature index, keratin index also improved in the GSSG group. The major limitations of these studies included: small sample size, cohort consisting of healthy volunteers, extremely short study period with an even shorter follow-up, and lack of measurement of blood levels of glutathione [ 10 — 12 ]. Details of the inclusion criteria, methodology, and specific limitations of these studies have been comprehensively catalogued in Table 1. Despite the rampant use of intravenous IV glutathione injections for skin lightening in certain countries, evidence favoring such a practice remains elusive.
For years, the strong lobby of proponents of IV glutathione for skin lightening, including manufacturers, distributors, many skin clinics, and med spas, have been recommending arbitrary dosage schedules, despite complete lack of evidence [ 1314 ]. It is only recently, that Zubair et al.
Although the from this singular trial did not favor IV glutathione as an effective or lasting treatment for skin tone lightening, the inherent flaws of the study de mandate cautious analysis.
The methodology was flawed due to the employment of a highly subjective visual Taylor scale for pre- and post-treatment evaluation of change in skin hue and tone and lack of mention of statistical tests applied. The Taylor scale is an unreliable tool for observing subtle changes in skin pigmentation with a very high inter-investigator variability in its interpretation [ 16 ]. based on Taylor scale, rather than a reliable objective parameter like the melanin index using a Mexameter MX, at best, are speculative. Further, the major adverse effect reported in the IV GSH treated group was liver dysfunction, which was neither qualified nor quantified.
Development of liver dysfunction in healthy individuals receiving IV GSH is surprising, since the medication is approved by the CDSCO for the treatment of various liver disorders mentioned earlier [ 4 ]. The researchers also did not evaluate baseline or post-treatment renal nor thyroid function of the subjects, both of which were reported to be adversely affected by IV glutathione in the position paper by the FDA, Department of Health, Republic of the Philippines [ 5 ].
Side effects of skin whitening pills
There is no restriction on its availability in this form in the US, Philippines and Japan. Furthermore, the duration of therapy and long-term efficacy is yet to be established. Although the overall safety of IV GSH, extrapolated from studies evaluating its use for male infertility and liver disorders seems to be convincing [ 1819 ], several adverse effects of IV GSH have been documented in the Philippines Figure 2detailed in the position paper by the FDA, Department of Health, Republic of the Philippines [ 5 ] with a warning for the public on the subject of the safety of the off-label use of glutathione solution for injection Figure 3.
Apart from the lack of evidence favoring IV GSH for skin lightening, the extremely high cost of injection vials constitutes another compelling deterrent to its use.
Adverse effects reported with intravenous glutathione injections by the Food and Drug Administration, Department of Health, Republic of the Philippines [ 5 ] and the intravenous GSH trial by Zubair et al. Limitations of intravenous glutathione as a skin lightening agent.
A reasonable intracellular concentration of GSH and its unimpeded transportation into the melanosomes are essential for GSH to inhibit tyrosinase and switch melanogenesis from eumelanin to pheomelanin. Trans-melanosomal transportation can be achieved through a membrane channel or diffusion, both of which seem to be lacking for GSH, a fact well established in research [ 2021 ].
Chung et al. The authors attributed this effect to the lipophilicity of the esterified derivatives of GSH. However, these need further validation in both in vitro and clinical trials before drawing definitive conclusions.
There is little convincing evidence in favor of glutathione as a therapy for hyperpigmentation at the present time, and there are many unresolved controversies that surround its use Figure 5.
The trials available to date that have evaluated the role of glutathione in skin lightening administered through different modes have numerous limitations. Although the safety of topical and oral GSH seems to be good, their efficacy especially long-term remains questionable. The extant evidence to support or discourage use of IV GSH as a therapeutic modality for improving skin tone or pigmentation is minimal and contradictory; notwithstanding the austere concern regarding the potential adverse effects associated with this mode of administration.
More evidence in the form of high quality trials with better study de, larger sample size, and long-term follow-up is vital, before our patients are subjected to glutathione-based treatments. Controversial aspects of glutathione as a potential skin lightening therapy.
Funding: None. Competing interests: The authors have no conflicts of interest to disclose. National Center for Biotechnology InformationU. Journal List Dermatol Pract Concept v. Dermatol Pract Concept. Published online Jan Sidharth Sonthalia1 Abhijeet K. Abhijeet K. Author information Article notes Copyright and information Disclaimer.
Corresponding author. Corresponding author: Dr. : moc. Received Jun 6; Accepted Nov This is an open-access article distributed under the terms of the Creative Commons Attributionwhich permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article has been cited by other articles in PMC. Introduction The preoccupation with exploration of treatment options that may help attain a lighter skin tone or fairer complexion has been an ongoing phenomenon in people with skin of color SOC.
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Figure 1. An evidence-update on glutathione as a skin-lightening agent At the time of authoring this article, there were only four published studies that evaluated the efficacy of oral, topical, and parenteral glutathione as a skin-whitening agent Table 1 [ 10 — 13 ]. Injection glutathione mg or normal saline placebo injected over 30 minutes Frequency of evaluation Baseline; weekly for 10 weeks Baseline; and at 4 weeks Baseline, twice weekly for 8 weeks Baseline, twice weekly for 8 weeks Primary outcome Melanin index—by Mexameter MX18 Melanin index—by Mexameter Melanin index—by Mexameter Visual Taylor hyperpigmentation scale Subjective parameters Global evaluation on a 7-point rating scale Global evaluation s on a 4-point rating scale Global evaluation on a 5-point rating scale None Melanin index Melanin index reduction ificant in GSSG group vs.
Small sample size Poor study de No mention of statistical analysis Only two sites evaluated Unreliable method of efficacy evaluation No information on baseline bio-chemical parameters No details on hepatic adverse effects, nature, severity and recovery Serum GSH levels not measured.
Glutathione as a skin whitening agent: facts, myths, evidence and controversies. Indian J Dermatol Venereol Leprol.
Figure 2. Figure 3. Figure 4. The pharmacological game changer: recent insights from research on the effect of GSH versus esterified GSH in tyrosinase inhibition A reasonable intracellular concentration of GSH and its unimpeded transportation into the melanosomes are essential for GSH to inhibit tyrosinase and switch melanogenesis from eumelanin to pheomelanin. Conclusion There is little convincing evidence in favor of glutathione as a therapy for hyperpigmentation at the present time, and there are many unresolved controversies that surround its use Figure 5.