What a wonderful world! On the one hand, the Caucasian race advocates bronze skin tone “tanning”; while on the other hand, the dark-skinned race is always looking for “whitening” miracle drugs. Topical, oral, and even intravascular injections of various “whitening” ingredients are now widely available in the market. Many topical ingredients act on the pre-, mid- and post-biosynthesis of melanin, and sunscreen ingredients are also widely used for facial whitening. In response to the demand for full-body whitening, oral ingredients are also popular, and tranexamic acid is one of them (popular in many Asian regions, especially Japan). There is insufficient evidence to support the safety of oral tranexamic acid (a protease inhibitor) for long-term use for whitening. Another oral whitening ingredient is glutathione (a cysteine-glycine-glutamate tripeptide), which inhibits melanogenesis by affecting tyrosinase activity; more importantly, when glutathione or cysteine is used on melanosclerotic or melanoma cells, the melanogenic pathway shifts from the formation of true melanin to the formation of pseudomelanin. Glutathione, after oral administration, is poorly absorbed through the gastrointestinal tract; therefore, in many countries (especially in Southeast Asian countries), glutathione is used for intravascular injection. Recently, intravascular glutathione injection for skin whitening has become popular in Thailand, and the Thai government is considering banning it to prevent serious allergic reactions In this context, the authors conducted a randomized, double-blind, placebo-controlled study on the whitening efficacy of oral glutathione. OBJECTIVE: To determine whether oral glutathione/glutathione (500 mg daily for 4 weeks) affects skin melanin index (compared to placebo group). METHODS: – Randomized, double-blind, two-arm, placebo-controlled. – Chulalongkorn Memorial Hospital, Bangkok, Thailand. – Sixty healthy medical students were randomly selected and divided into a dosing group (500 mg twice daily in total) and a control group for a 4-week trial period. – Primary outcome: The mean amount of melanin index reduction was measured by melanometry (CK Inc.) at 6 sites on the whole body (including face, arm den sun-exposed and unexposed sites); secondary outcome: recorded using VISIA imaging system (Canfield Inc.) (including UV spot counting). – Statistical comparison between the oral dosing group and the placebo group using ANCOVA Results: – At 4 weeks of dosing, all subjects in the dosing group had a reduction in melanin index at all 6 body sites. – The reduction in melanin index was statistically significant for the right face and left forearm (sun-exposed areas) compared to the placebo group (p-values: 0.021, 0.036, respectively) – Similar results were obtained using VISIA for UV spot counting. – Tolerability: both the drug-taking and placebo groups were good. CONCLUSIONS: According to a small pilot study, oral glutathione has a skin tone reducing effect. However, the associated long-term safety remains to be confirmed in more extensive clinical trial studies. Discussion: (omitted) It is worth noting that glutathione only has an effect on melanin neoplasia, but not on established pigmentation.