While hyperpigmentation isn’t easy to treat, there seems to be almost a horde of topical options to choose. The most documented and used ones include: hydroquinone, its glycosylated cousin arbutin, mequinol, retinoids, hydroxy acids, azelaic acid, kojic acid, vitamins B3 (amide) and C, licorice, soy, and N-acetyl glucosamine. And because hyperpigmentation is such a common problem, more and more “options” are discovered every few years.
Therefore, as we prepare for New Year’s Eve and look towards the future with personal resolutions and whatnot, it seems germane to discuss some topical emerging therapies that have the potential to become a more standard component of one’s skin care arsenal or armamentarium when it comes to dealing with hyperpigmentary conditions in the future.
So without further ado, here are three ingredients that show varying degrees of promise.
This ingredient has the distinct advantage of already being approved by the FDA for use on humans. Therefore, most of the mechanisms of action, drug interactions, side effects, and toxicity, etc., have already been discovered and enumerated. However, this drug has only been approved to be used as an oral antithyroid medication. Very little of the data has any relevance to skin lightening.
However, in a case study on a 27-year-old male with postinflammatory hyperpigmentation (due to an acid burn), it was shown that 5% methimazole provoked a “moderate to marked improvement of the hyperpigmentation lesions within 6 weeks of once-daily application.” Furthermore, as someone with an impaired epidermis (due to the acid burn), the patient was able to tolerate this novel therapy very well (Dermatology, 2005).
Now, when taken orally, among the major side effects is agranulocytosis, which is when a person’s white blood count drastically drops to life-threatening levels. This acute (meaning temporary as opposed to chronic) condition is dangerous because it suppresses an individual’s ability to fight off infections. Therefore, it is vital to assess the pharmacokinetics of topical methimazole (Drugs.com).
While the above-cited case study indicated that after 6 weeks of once-daily topical application, no methimazole or any of the thyroid hormones (free thyroxin, free triiodothyronine, and the thyroid-stimulating hormone) were detected in the serum of the patient, a larger test (population) sample is needed to substantiate these initial findings.
This was done at the Department of Dermatology at the Geneva University Hospital, which performed an enhanced version of the case study with 26 patients. 6 volunteers took a 5-mg tablet of methimazole, while the other 20 applied 5% methimazole for 6 weeks (once per day) to the skin. “From 15 min up to 24 h after application, methimazole was undetectable in the serum of the individuals receiving single topical methimazole dosing. Methimazole, however, was detected in serum after 15 min of oral administration and remained detectable in serum up to 24 h after administration.” Furthermore, after 6 weeks, none of the serum levels of the thyroid hormones (free thyroxin, free triiodothyronine, and TSH) exhibited statistically significant changes. Adverse cutaneous side effects were also not apparent. The study concluded that “present data together with the previously shown non-cytotoxic and non-mutagenic characteristics of methimazole indicate that this agent could be considered as a safe skin-depigmenting compound for topical treatment of skin hyperpigmentary disorders in humans” (Skin Pharmacology and Physiology, 2008).
Overall, I agree with these two studies that methimazole represents an exciting new tributary to the main course of skin lightening ingredients. Unfortunately, as this is a prescription-only product, I can’t see this ever being introduced into the skin care industry en masse. And of course larger, longer, and more relevant studies need to be done before any physician would ever consider prescribing this for off-label use.
Probably the best advantage of dioic acid is that it inhibits the tyrosinase enzyme via a different mechanism than hydroquinone and its derivatives. Dioic acid appears to modulate tyrosinase activity by binding to three types of peroxisome proliferator-activated receptors (PPARs), which mediate melanogenesis. By binding to PPARgamma, PPARalpha, and PPARdelta, the levels of tyrosinase and its corresponding mRNA were reduced, leading to decreased melanogenesis (the production of melanin) (International Journal of Cosmetic Science, 2005).
Its in vivo efficacy was demonstrated in a study done on 96 female patients, which compared the effectiveness of 1% dioic acid against that of 2% hydroquinone. After 12 weeks of twice-daily application, hydroquinone was shown to be only marginally more effective than dioic acid, though the difference was not statistically significant. Furthermore, irritation was present less evidently with those that applied dioic acid (International Journal of Dermatology, 2009).
If I were a dermatologist, would I recommend dioic acid over hydroquinone? No. But, I wouldn’t deny that dioic acid shows quite a bit of potential. Unfortunately, there are very few products that contain this ingredient in “efficacious” amounts, so there’s nothing for me to recommend. One reader did mention the Skinceuticals Blemish and Age Defense ($61.99, amazon.com). However, I can’t wholeheartedly recommend this product because of the inclusion of so much alcohol. Usually, I’m okay with alcohol so long as it isn’t present in high amounts. However, seeing as there’s more ethanol than water… Anyways, as with most things, all we can do is wait.
[Related: Is Ethanol in Skin Care Products Safe?]
The biggest advantage of undecylenoyl phenylalanine (UP) is that there are already products on the market containing this ingredient. But before we get into recommendations, let’s discuss the evidence.
Like with dioic acid, UP (allegedly) represents a novel mechanism by which to inhibit melanogenesis. It has been postulated and suggested that it does this by acting as an antagonist to alpha-melanocyte-stimulating hormone (MSH), which is an important component of the melanogenesis process. In the same double-blind, vehicle-controlled study, 2% UP was shown to have a moderate to marked improvement in the treatment of solar lentigines (Clinical and Experimental Dermatology, 2010).
In another (open-label) study done by Procter & Gamble, 1% UP with 5% niacinamide was shown to be more effective than both the vehicle and the 5% niacinamide formulation alone (Journal of Cosmetic Dermatology, 2009). And that makes sense, since niacinamide inhibits melanogenesis via a different mechanism (by inhibiting melanosome transfer) than UP.
Conclusion (and Product Recommendations!):
While it’s likely that no existing product contains anywhere near 1-2% undecylenoyl phenylalanine, it may be worthwhile to introduce this ingredient into you routine if you’ve had unsatisfactory results with established protocols; or are simply curious to see how it performs.
For drier skin types, the Philosophy Miracle Worker Dark Spot Corrector ($57.99, amazon.com) is an excellent option. Besides the good amounts of niacinamide and UP, this product contains good to decent amounts of three vitamin C esters (tetrahexyldecyl ascorbate, ascorbyl linoleate, and ascorbyl palmitate), as well as moderate amounts of resveratrol and a vitamin E ester, and dashes of green tea; all of which have evidence supporting the ability to lighten the skin. Everything is embedded in a silky lotion-like texture comprised of glycerin, several fatty alcohols, and two coconut oil fatty acids.
Note that phenylethyl resorcinol is NOT the same compound as resorcinol. It is unreasonable and inaccurate to claim that the former ingredient carries all of the positive and negative characteristics surrounding the latter, considering that only a single study establishes SOME potential for efficacy (Journal of Cosmetic Dermatology, 2011). Originally, I didn’t think that this ingredient was particularly worth mentioning. However, after reading another product review on this site, I wanted to clarify that the two compounds should not be treated equally. The same concept applies to hexylresorcinol.
Water, Glycerin, Cetyl Alcohol, Behenyl Alcohol, Niacinamide, Caprylic/Capric Triglyceride, Cetearyl Olivate, Hexyldecanol, Sorbitan Olivate, Butylene Glycol, Tetrahexyldecyl Ascorbate, Ascorbyl Linoleate, Undecylenoyl Phenylalanine, Hexylresorcinol, Phenylethyl Resorcinol, Resveratrol, Tocopheryl Ferulate, Ethyl Linoleate, Cyclopentasiloxane, Cychohexasiloxane, Ethylhexylglycerin, Glycine Soja (Soybean) Sterols, Safflower Glyceride, Potassium Cetyl Phosphate, Sodium Hyaluronate, Hydrogenated Palm Glycerides, Camellia Sinensis Leaf Extract, Rumex Occidentalis Extract, Brassica Campestris (Rapeseed) Sterols, Tocopheryl Acetate, Ascorbyl Palmitate, Linoleic Acid, Phospholipids, Bisabolol, Cetylhydroxyproline Palmitamide, Arginine, Heptapeptide-12, Beta-Glucan, Retinyl Palmitate, Lysolecithin, Methyl Dihydroxybenzoate, Disodium EDTA, Stearic Acid, Xanthan Gum, Chlorphenesin, Phenoxyethanol
For oilier skin types, the Mary Kay TimeWise Even Complexion Essence ($16.99, amazon.com) is also a very good option. Besides good amounts of niacinamide and UP, this product contains two vitamin C derivatives (ascorbyl glucoside and magnesium ascorbyl phosphate), two peptides, a vitamin E ester, as well as moderate amounts of the licorice, green tea, ginseng, and mulberry extracts; all of which have evidence supporting the ability to lighten the skin. Everything is embedded in a watery serum comprised of propylene glycol, dimethicone, and glycerin. Note that this does contain very faint shimmer particles.
Water, Propylene Glycol, Dimethicone, Isododecane, Glycerin, Niacinamide, Ascorbyl Glucoside, Triethanolamine, Betaine, Magnesium Ascorbyl Phosphate, 1-Methylhydantoin-2-Imide, Undecylenoyl Phenylalanine, Palmitoyl Oligopeptide, Palmitoyl Tetrapeptide, Tocopheryl Acetate, Dipotassium Glycyrrhizate, Citrus Medica Limonum Fruit Extract, Cucumis Sativus Fruit Extract, Camellia Oleifera Leaf Extract, Panax Ginseng Root Extract, Thymus Extract, Sanguisorba Root Extract, Morus Alba Bark Extract, Oenothera Biennis Seed Extract, Serine, Threonine, Proline, Arginine, Glycine, Alanine, Lysine, Glutamic Acid, Sodium PCA, Sorbitol, Polysorbate 20, Butylene Glycol, Laurenth-7, C13-14 Isoparaffin, PEG-12 Dimethicone, Polyacrylamide, Boron Nitride, Carbomer, Sodium Citrate, Disodium EDTA, Phenoxyethanol, Methylparaben, Ethylparaben, Propylparaben, Butylparaben, Isobutylparaben, Mica, Titanium Dioxide
In the paradoxically adamant yet ever-changing world of skin care, my approach has always been to support the documented, the chronicled, and the corroborated. However, it would be rather parochial of me to reject emerging remedies. I may never be ruled by the newest vicissitude, but, with caution, I do gradually consider and implement them into my knowledge base and perception.