Clinical studies on senile pigmentation have investigated a formulation containing magnesium ascorbate phosphate salt, arbutin, and ellagic acid, which are active ingredients in quasi-drugs that prevent melanin production and freckles; a formulation containing kojic acid, which is no longer used in quasi-drugs because of concerns over its carcinogenic properties; a formulation containing vitamin A acid [82,83,84], which is involved in regulating epidermal turnover and is used in the United States to treat diseases such as acne vulgaris and psoriasis, and is effective in treating wrinkles and pigmentation caused by sun damage; and a formulation containing 2% 4-hydroxyanisole and 0.01% vitamin A acid, which is marketed in the United States as a treatment for senile pigmentation [85,86]. The effectiveness of these compounds is summarized in Table 2.

In an open study of 34 patients, including 17 with senile pigmentation, patients were given a formulation containing 10% magnesium L-ascorbyl-2-phosphate—a content exceeding the 3% in most quasi-drugs. A total of 88.3% of patients with senile pigmentation showed slight or even higher effectiveness, as assessed by skin color measurement [4]. A 7% arbutin formulation demonstrated an effectiveness rate of 81.3% on senile pigmentation after 3 months in an open test, and effectiveness was observed for all patients when the treatment period was extended to 6 months and 1 year [87]. An open study in 13 women treated with a 0.5% formulation of ellagic acid for 1–3 months found improved effectiveness on senile pigmentation in 69.2% of participants [36]. In a study in 18 patients (5 men and 13 women) with senile pigmentation who received topical application of 1% kojic acid and 0.1% oil-soluble licorice extract over a 16-week period, 77.8% of participants showed an improved effectiveness rate [26]. Additionally, 2% 4-hydroxyanisole and 0.01% vitamin A acid have been found to be more effective than 3% hydroquinone in treating senile pigmentation [85]. In a double-blind study investigating the topical effectiveness of 2% 4-hydroxyanisole for 6 months in 421 patients, the improved effectiveness was 84.1%. Complete disappearance of pigmented lesions was observed in some cases, thus indicating high effectiveness, but some adverse effects including erythema and irritation were also observed [86].

Reported effectiveness rates differ depending on whether the effectiveness criteria were “effective”, “somewhat effective”, higher. In each study, different criteria are used to determine the level of improvement as “effective” or “somewhat effective”. In some studies, the criteria for determining effectiveness are unclear, and placebos may or may not be used to control effectiveness. Therefore, caution should be exercised in comparing effectiveness rates across studies in which the criteria for determining effectiveness are unclear or in open studies lacking placebo controls.

Most Japanese tests of the effectiveness of pharmaceutical skin-lightening cosmetics have assessed the degree of prevention of skin darkening caused by artificial UVB irradiation. Skin-lightening effects are exclusively evaluated on skin that darkens when exposed to ultraviolet light in humans. There are two types of evaluation methods: the anti-pigmentation test and the accelerated pigmentation disappearance test. The former is a double-blind controlled study in which a test sample is applied before, during, or after the UV irradiation period and the degree of pigmentation formation is compared with a placebo. The latter is a double-blind controlled trial in which the test sample is applied to the pigmented area and the degree of fading of the pigmentation is compared with a placebo. Both are assessed by visual evaluation and instrumental measurement based on superiority or inferiority comparisons or score judgments.

Consumers expect that skin lightening products will “lighten spots and freckles”. Moreover, many consumers expect these products to “eliminate spots and freckles” [88] and want skin-lightening cosmetics to have an effect on spots that have already formed, rather than preventing formation, or promoting the fading, of pigmentation caused by ultraviolet rays. However, problems exist regarding the lightening effects of such cosmetics when actually used on spots and freckles: test results published in scientific journals are lacking, and a possibility exists that these cosmetics might cause skin problems.

Skin-lightening active ingredients can be divided into four categories according to their clinical effectiveness and adverse effects. This review discusses academic research and development regarding skin-lightening ingredients in Japan. We have compiled a table of effectiveness indices for Japanese skin-lightening ingredients, on the basis of the published scientific literature (Table 3).

Category A: Effectiveness of the same concentration of cosmetic formulations on human pigment spots has been described in scientific journals and is highly recommended. Examples include tranexamic acid, arbutin, 3-O-ethyl ascorbic acid, magnesium ascorbyl phosphate (APM), ellagic acid, kojic acid, linoleic acid, 4-n-butylresorcinol, chamomile extract, and adenosine monophosphate.

Category B: Effectiveness of higher concentrations than those used in cosmetics on human pigment spots has been described in scientific journals and is recommended. Examples include oil-soluble licorice extract containing 50% glabridin, niacinamide, placenta extract, retinol, ascorbyl glucoside (AA-2G), and azelaic acid.

Category C: No effectiveness for human pigment spots has been described in scientific journals but may be considered; however, evidence is insufficient. Examples include potassium 4-methoxysalicylic acid and dexpanthenol.

Category D: Not recommended, because of toxicity data described in scientific journals. Examples include Rhododenol, Magnolignan, and ascorbyl tetra-2-hexyldecanoate.

The use of a hydrophilic ointment containing 3% APM for hyperpigmentation (melasma and Riehl melanosis) was reported in 1969 [2]. It was reported in 1996 that APM 10% cream was found to be significantly beneficial in 19 of 34 patients with melasma and senile freckles and in 3 of 25 patients with normal skin [4]. The use of 3% human placenta extract for treating facial hyperpigmentation in women (47 cases of melasma and 2 cases of freckles) was reported in 1982 [17]. Other topically applied products with good results for melasma include 1% or 2.5% kojic acid [23], 3% arbutin [31], 1% tranexamic acid [66], 0.1% linoleic acid S [52], 0.3% Rucinol [37], and 0.5% ellagic acid [36]. Examples of topically applied products with good results for senile pigmentation include 3% APM [2], 10% APM [3,4], 1% or 2.5% kojic acid [23,24,25], 0.5% ellagic acid [36], 7% arbutin [87], and 0.5% chamomile extract [51]. Topical application of 1% or 2.5% kojic acid [23], 0.5% ellagic acid [36], 1% tranexamic acid [66], and 7% arbutin [87] has been used with good results in the treatment of freckles. In some cases, 1% vitamin C ethyl has shown effectiveness in pigmentation after natural light exposure and burns [8]. The effectiveness of these pharmaceutical skin-lightening cosmetics was not evaluated in a comparative study with a placebo, but instead was assessed in a study that examined the effectiveness of the formulations before and after continuous use, without double-blinding. In examining effectiveness, attention must be paid to changes in skin tone with seasonal variations and the effects of the base agent.

Examples of topical effectiveness in double-blind comparative studies include 0.1% retinoic acid (Tretinoin) [83], 0.2% oil-soluble licorice extract [89], and 20% azelaic acid [92] for melasma. Topical 0.1% retinol has been reported to be effective in photodamaged skin in a double-blind, controlled study [90]. Iontophoresis of 20% AA-2G has been reported to be effective in melasma and postinflammatory hyperpigmentation [91]. For senile pigmentation, both 0.1% retinoic acid (tretinoin) [84] and 2% 4-methoxyphenol/0.01% retinoic acid [85,86] have shown topical effectiveness in double-blind comparative studies, but these are not active ingredients in pharmaceutical cosmetics. Thus, a pharmaceutical skin-lightening cosmetic product is defined as a pharmaceutical product if its effectiveness against melasma and senile pigmentation is statistically demonstrated in actual use in a double-blind comparison test.