A small spot on the cheek leaves behind this pesky dark spot that takes forever to go. Well, what you have is post-inflammatory hyperpigmentation (PIH).
Dark spots or hyperpigmentation are a type of skin blemishes and can occur due to several reasons. The two common reasons are post-inflammatory hyperpigmentation and melasma.
- Post-inflammatory hyperpigmentation (PIH) is skin darkening that occurs after an inflammatory process which can occur due to acne, rosacea, eczema, psoriasis, or any injury like a scratch or bite. People with darker skin tones are more prone to post-inflammatory hyperpigmentation since they have more melanin content.
- Melasma is a chronic disorder of hyperpigmentation that results in symmetrical dark patches.
Now let’s talk about the various ingredients and products you can include in your routine to get rid of hyperpigmentation and brighten your complexion.
This is a rather long post, so if you are interested in any particular ingredient, just click on the links below and you will get to that particular ingredient directly.
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1. Sunscreen
An article about hyperpigmentation is incomplete without talking about sunscreens. UV rays and visible light are one of the main triggers of hyperpigmentation. Sunscreen can prevent the worsening of existing dark spots. In addition, research suggests that using broad-spectrum sunscreen daily can help in fading dark spots.
Sunscreen filters can protect our skin from UV rays but not from high-energy visible light or blue light. To protect our skin from blue light, we need iron oxides in our routine.
So, look for a good tinted sunscreen if hyperpigmentation is your main issue. If you are a daily makeup wearer, iron oxides in foundation or other cosmetics can provide some protection from visible light. But do not forget your sunscreen.
Also make sure to supplement it with sun-protective clothing, hats, umbrellas, and sunglasses (one without a metal frame).
Next, we will talk about the other skincare ingredients useful for dark spots and hyperpigmentation. These topicals usually interrupt one or the other step involved in melanin synthesis (that is around the enzyme tyrosinase which synthesizes melanin pigment).
2. Hydroquinone
Hydroquinone is the most commonly used topical agent in the treatment of hyperpigmentation and melasma. It works by inhibiting the tyrosinase enzyme (which makes melanin pigment) and destroying the melanosomes (structures that have melanin pigment in them).
Hydroquinone (4%) can lead to significant improvement in post-inflammatory hyperpigmentation and melasma. The effects can be seen in around 5-7 weeks.
Precautions and side effects
It is recommended to take a break from it and use it on and off to reduce any possible side effects such as irritation, erythema, allergic contact dermatitis, areas of hyperpigmentation, and ochronosis (blue-black pigmentation).
Hydroquinone is an oxidizing agent, so if you see a color change in the product from white to brown, it’s time to get a new product. It used to be available over the counter (up to 2% concentration) in the US but recently guidelines have changed, so you can get this only by prescription.
It should not be used by pregnant women due to its Category C characterization [Animal reproduction studies have shown an adverse effect on the fetus, but there are no adequate and well-controlled studies of humans].
Combination with other ingredients
For more severe cases, it is combined with a retinoid and a steroid – triple combination therapy (available by prescription). The first combination to be used was the Kligman-Willis formula (5% hydroquinone, 0.1% tretinoin, 0.1% dexamethasone).
The combination of 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide, has also proven to be efficacious. Topical retinoids can help hydroquinone to penetrate better. Steroids can help by reducing inflammatory mediators thus inhibiting pigment production.
In one study, daily use of a triple combination of 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide (used at night) was more effective than twice daily 4% hydroquinone use.
3. Retinoids
Retinoids are vitamin A derivatives, which are loved due to the multiple benefits they offer our skin. They have been proven to reverse photodamage, thicken the skin, improve the skin barrier function, and provide antioxidant effects.
Topical retinoids can help in decreasing dark spots by increasing cell turnover. In addition, it downregulates tyrosinase transcription resulting in a decrease in tyrosinase enzyme, thus decreasing melanin pigment formation.
Research data
Below are the studies which show the benefit of retinoids for dark spots
- In one study, 0.1% tretinoin was found to be more effective than the vehicle for treating patients with melasma. However, it took longer, 24 weeks, to see significant improvement.
- In another study, 0.1% tazarotene cream was found effective against post-inflammatory hyperpigmentation compared with the vehicle. The results were seen in 18 weeks.
- In a 40-week study done on 54 patients with hyperpigmentation, topical tretinoin (0.1 percent retinoic acid cream) was more effective in lightening post-inflammatory hyperpigmentation (PIH) than the vehicle.
- In a study done on 65 patients with dark skin tone, daily use of 0.1 % adapalene for 12 weeks improved acne. It also improved areas of hyperpigmentation in 2/3 of the patients.
- In one 8-week study, a stabilized 0.1% retinol-containing moisturizer was compared with a vehicle (used once daily). The retinol moisturizer was significantly more efficacious than the vehicle in improving lines and wrinkles, pigmentation, elasticity, firmness, and overall photodamage.
Tretinoin and Tazarotene (Tazorac) are prescription drugs and should be used under the supervision of a professional. Adapalene, a synthetic retinoid, is however available over the counter. It is available by the name of Differin (0.1% adapalene).
Retinol is the precursor of retinoic acid and is available over the counter. Skin cells need to do a two-step conversion of retinol to retinoic acid, for it to be effective.
Retinaldehyde or retinal on the other hand is one step closer to retinoic acid and needs just one step of conversion. These can give results similar to tretinoin, but it will take longer to work, and the results might be moderate.
Precautions and side effects
Retinoids come with their challenge of side effects like retinol peeling. So, it is important to start using them slowly in the routine. It is better to start using it a couple of times a week and increase the frequency.
Also, in the start use it after applying your moisturizer and letting the skin completely dry. The retinoids can penetrate through the moisturizer. Doing this will minimize any irritation.
Caution: Retinoids should not be used by pregnant women due to their Category C characterization.
4. Bakuchiol
Bakuchiol is a purified extract found mainly in the seeds of the Indian plant Psoralea corylifolia (babchi). Though it is structurally different from retinol, they both induce similar gene expression in the skin leading to anti-aging effects. It also has antioxidant properties.
It can be of help in hyperpigmentation by its antioxidant properties and by disrupting melanin synthesis. It acts by blocking α-melanocyte-stimulating hormone activation and tyrosinase (the enzyme in melanin synthesis).
Research data
In two studies (first and second), bakuchiol 0.5% cream has been shown to be equally effective as retinol 0.5% cream in reducing wrinkles and hyperpigmentation.
Precautions and side effects
Bakuchiol is often referred to as a natural alternative to retinol. However, every natural thing is not completely safe. Bakuchiol is known to cause contact dermatitis. When choosing a product, make sure it has bakuchiol and not babchi extract.
Is it safe during pregnancy? Well, we don’t have any safety data. You may find mixed opinions on this matter from different people. Personally, I avoided using it during my pregnancies. There are so many other safer choices so why take a risk?
5. Azelaic acid
Azelaic acid is a naturally occurring dicarboxylic acid that competitively inhibits tyrosinase, an enzyme involved in the formation of melanin. It is an effective anti-acne ingredient. However, due to its effect on tyrosinase, it can be used to treat hyperpigmentation disorders like PIH and melasma.
It has a direct cytotoxic effect on the abnormal melanocytes, so it has no depigmentation effect on normal skin. Oxidative stress is believed to contribute to hyperpigmentation, and since azelaic acid is an antioxidant, it can further help hyperpigmentation disorders.
Research data
Below are the studies which show the benefit of azelaic acid for dark spots
- In patients with melasma, 20% azelaic acid was found to be as effective as 4% and superior to 2% hydroquinone, but without side effects.
- In another 16-week study of 20 patients with Fitzpatrick Skin Types IV to VI, 15% azelaic gel used twice daily showed a reduction in acne and post-inflammatory hyperpigmentation (PIH). At the end of the study, all patients showed improvement in hyperpigmentation.
Azelaic acid is considered safe to use during pregnancy. It is available over the counter in lower percentages. It might take longer to show results, but the side effects will be less as well.
Potassium Azeloyl Diglycinate (PAD)
Potassium Azeloyl Diglycinate is a derivative of azelaic acid, which is easier to formulate and gentler on the skin. However, it has less data as compared to the parent ingredient azelaic acid. If you are someone with dry skin and cannot tolerate azelaic acid, this is something that might be of help.
6. Vitamin C
Ascorbic acid
Ascorbic acid, aka vitamin C, has antioxidant properties and reduces the formation of melanin pigment by interacting with copper at the active site of tyrosinase. It also plays a significant role in collagen synthesis.
It is a highly unstable molecule in an aqueous solution. It gets oxidized to dehydroascorbic acid (a reversible reaction), and subsequently to 2,3-diketo-L-gulonic acid (an irreversible reaction).
This results in the loss of ascorbic acid properties. This is the reason our colorless Vitamin C serums start turning yellow after opening them for a while.
Ascorbic acid is a water-loving charged molecule and the outer horny layer of our skin is water-repelling so effective delivery of ascorbic acid through topical preparations is a major issue. The pH of the formulation should be on the acidic side (pH 3.5) for it to penetrate the skin.
Most of the ascorbic acid serums will have a pH in this range. However, if you are not getting good results with your Vitamin C serum, try to check its pH to make sure it’s in the 3-4 range.
The clinical efficacy/results are proportional to the concentration but only up to 20%. So, higher than this concentration is not going to give any better results but rather can cause irritation. Vitamin C is found to be effective in the range of 8-20%.
Research data
Below are the studies which show the benefit of ascorbic acid for hyperpigmentation
- In one study, 5% ascorbic acid cream was compared to 4% hydroquinone when used every night for 16 weeks (on 16 women). Both were found to be equally effective, however, hydroquinone had more side effects.
- Another study used a 25% l-ascorbic acid on 40 patients with melasma for 16 weeks and found a significant decrease in pigmentation.
Magnesium ascorbyl phosphate
Magnesium ascorbyl phosphate (a water-soluble derivative of ascorbic acid) can also be beneficial for hyperpigmentation. It is the most stable ascorbyl ester. In vitro, studies show evidence that magnesium ascorbyl phosphate can penetrate the skin and form ascorbic acid in the skin.
In one study, a 10% concentration reduced pigmentation significantly in 19 of 34 patients with melasma and senile freckles.
If you have sensitive skin, this form can be beneficial since it doesn’t require an acidic pH to be effective.
7. Tranexamic acid
Tranexamic acid is a synthetic version of lysine and a hemostatic agent. It blocks the conversion of plasminogen to plasmin and the binding of plasminogen to keratinocytes. This results in a decrease in melanin synthesis. It also decreases mast cells and the formation of new blood vessels in the dermis.
It is currently used in the treatment of hyperpigmentation and melasma via several routes: oral, topical, intradermal, and micro-needling.
The oral form (which should be used under the supervision of a doctor) is the one with the best results and most data. The topical formulation is less efficacious than the oral formulation. In most studies, results are seen in 8 to 12 weeks.
Topical tranexamic acid doesn’t require a prescription and can be found in a few over-the-counter products. Most people tolerate it well, however patch test any new product.
Research data
Below are the studies that show the benefit of tranexamic acid for hyperpigmentation
- In one study, 5% liposomal tranexamic acid had similar efficacy compared with 4% hydroquinone after twice-daily treatment for 12 weeks in melasma.
- In another study, 5% tranexamic acid or 2% hydroquinone when used twice daily, had similar efficacy in melasma.
Cetyl tranexamate mesylate
A new topical tranexamic acid lipophilic derivative, that is, cetyl tranexamate mesylate has also been developed.
In one study, a facial serum containing 2% of this derivative when used twice daily for two weeks resulted in an improvement in skin tone, facial redness, and a decrease in dark spots.
8. Cysteamine
Cysteamine is a metabolite of L-cysteine (an amino acid) and a natural cellular component. It inhibits melanin synthesis by inhibiting enzymes tyrosinase and peroxidase and by chelating iron and copper ions required in pigment formation. It also has antioxidant benefits.
Research data
Below are the studies that show the benefit of cysteamine for hyperpigmentation
- In two double-blinded studies of 50 and 40 patients with epidermal melasma, 5% cysteamine showed promising results when used once daily for 4 months.
- In another comparative study, 5% cysteamine and 4% hydroquinone were used on 40 women with melasma (once daily). Hydroquinone performed better than cysteamine in this study.
Side effects
It can cause side effects like erythema, dryness, itching, burning sensation, and irritation so it should be used as per the directions of the manufacturer.
Cyspera
The only product (that I know of) with this ingredient is Cyspera (different countries might have different regulations in regard to the sale of this).
As per directions of the manufacturer, it needs to be used in an intense (daily for 16 weeks) and maintenance phase (biweekly) for best results. This product does contain fragrance.
9. Niacinamide
Niacinamide is a versatile skincare ingredient with several benefits for the skin. It is an anti-inflammatory (good for acne, rosacea, and psoriasis), increases skin ceramides levels, enhances skin barrier function, and has anti-aging benefits.
It can have beneficial effects on melasma and hyperpigmentation in different ways:
- Reduction of melanosome transfer (35-68% inhibition of melanosome transfer – in vitro study)
- Photoprotective
- Anti-inflammatory properties
- Antioxidant properties
Research data
In one study, niacinamide moisturizer decreased hyperpigmentation and increased skin lightness compared with vehicle alone, after 4 weeks of use.
Precautions
Multiple studies have shown the beneficial effects of niacinamide at a concentration of 2-5%, so a higher concentration does not mean better results. Higher concentrations can increase the risk of redness and irritation.
10. 4-N-butylresorcinol (Rucinol)
4-N-butylresorcinol was first shown to have an inhibitory effect on the enzyme tyrosinase in (in vitro) studies in 1995. Since then few in vitro studies have shown that it can decrease melanin pigment formation by inhibiting both tyrosinase and tyrosinase-related protein-1 (TRP-1).
Research data
- Some studies have shown that 4-n-butylresorcinol is superior to hydroquinone, arbutin, and kojic acid in inhibiting the tyrosinase enzyme.
- Also, it is more effective than the other analogs, 4-hexylresorcinol, and 4-phenylethylresorcinol.
- In a double-blind study of 8 weeks, 4-n-butylresorcinol 0.1% cream (used twice daily) showed significant improvement in melasma.
11. Alpha-hydroxy acids
Alpha-hydroxy acids (AHAs) such as glycolic acid (GA) and lactic acid (LA) have been shown to be effective in treating pigmentary lesions such as melasma, solar lentigines (patches of dark skin due to sun exposure), and post-inflammatory hyperpigmentation.
They directly inhibit tyrosinase and also decrease hyperpigmentation by exfoliation or increasing cell turnover. At higher concentrations, they are also used in professional peels for hyperpigmentation.
Research data
In a 12-week clinical study, a facial emulsion containing 10% glycolic acid, 2% phytic acid, and a soothing complex showed significant improvement in the appearance of post-inflammatory hyperpigmentation, texture, and tone. The results were evident beginning at week 4 and continued through week 12.
Side effects
Using high concentrations of these exfoliating acids too frequently can damage the skin barrier. This can lead to post-inflammatory hyperpigmentation.
12. Kojic acid
Kojic acid is produced by various fungi species; Aspergillus, Acetobacter, and Penicillium spp. Kojic acid and its derivatives inhibit the production of free tyrosinase and inhibit tyrosinase enzyme through the chelation of copper at the enzyme’s active site.
It is available over the counter at 1-2% concentration. It also has antioxidant and anti-inflammatory properties.
Side effects
It can cause contact dermatitis as a side effect in a few people.
13. Licorice extract
Licorice extract is obtained from the root of Glycyrrhiza Glabra. It contains several compounds including glabridin, liquiritin, flavonoids, and licochalcone A. These are behind its numerous benefits for the skin (anti-inflammatory, antioxidant, skin soothing, wound healing, and dark spot reduction).
- Glabridin is one of the most potent licorice compounds. It has antioxidant properties and has been shown to decrease oxidative stress, decrease inflammation, inhibit tyrosinase enzyme, and inhibit UVB-induced pigmentation.
- Liquiritin, a flavonoid component of licorice, does not inhibit the enzyme tyrosinase. It decreases hyperpigmentation by multiple pathways – dispersion of melanin, reducing inflammation, and reducing UVB-induced redness.
14. Arbutin
Arbutin is the naturally occurring β-d-glucopyranoside derivative of hydroquinone that is derived from some plants like the bearberry. It has antioxidant properties.
Arbutin naturally breaks down to hydroquinone, leading to its slow release. It produces skin lightening by direct, dose-dependent inhibition of tyrosinase.
It also inhibits melanosome maturation and is less cytotoxic to melanocytes than hydroquinone and hence has fewer side effects.
Deoxyarbutin is a dehydroxylated derivative of arbutin. Synthetic forms of arbutin, alpha-arbutin, and deoxyarbutin, are more potent in inhibiting tyrosinase enzymes than natural beta arbutin.
Research data
In a study done on 59 patients, both 2% deoxyarbutin and 4% hydroquinone showed similar significant depigmenting effects at 12 weeks.
Side effects
Although higher concentrations may be more effective, it can cause paradoxical hyperpigmentation.
15. N-Acetyl Glucosamine (NAG)
N-acetyl glucosamine (NAG) is an amino sugar with multiple benefits for our skin. It combines with glucuronic acid to form hyaluronic acid, which increases the moisture content of our skin making it soft and hydrated.
It is also a great antioxidant, soothes skin, reduces hyperpigmentation, and has anti-aging properties. It can enhance our skin’s natural exfoliation process, thus making it a great alternative to hydroxy acids like glycolic acid/lactic acid for people with sensitive skin.
It reduces hyperpigmentation by inhibition of tyrosinase glycosylation, thus preventing its activation. It is often used at a concentration of 2% alone or in combination with niacinamide since it acts on different steps of melanin synthesis.
Research data
- In one study, 2% NAG reduced the appearance of facial hyperpigmentation. The combination of topical 2% NAG with 4% niacinamide, was more effective on hyperpigmentation.
- In another study, the combination of 2% NAG and 4% niacinamide was significantly better than the vehicle in reducing the dark spots and areas of hyperpigmentation.
16. Soy extract
Soy extract is known for its soothing, antioxidant, and anti-aging benefits. The major components of soy include phospholipids (45-60%), essential fatty oils (30-35%), isoflavones, vitamin E and serine protease inhibitors-soybean trypsin inhibitor (STI), and Bowman-Birk protease inhibitor (BBI).
The activation of protease-activated receptor 2 (PAR-2) cell receptors on the skin cells leads to the transfer of melanosomes from melanocytes to surrounding skin cells (keratinocytes).
Soy proteins such as soybean trypsin inhibitor (STI) and Bowman-Birk inhibitor (BBI), inhibit the activation of these cell receptors, resulting in reduced melanosome transfer and reversible depigmentation.
Research data
In a 12-week study, done on 65 women with moderate facial photodamage, a moisturizer with stabilized soy extract showed significant improvement in the mottled pigmentation (patchy skin color), blotchiness, dullness, fine lines, overall appearance, texture, and tone.
17. Resveratrol
Resveratrol is a natural polyphenol present in various fruits and vegetables. The benefits of resveratrol for the skin include anti-inflammatory, anti-oxidant, UV protection, antiaging, and inhibition of melanogenesis.
Resveratrol not only directly inhibits the enzyme tyrosinase but is also involved in the transcription and post-transcriptional processing of tyrosinase.
Inflammation and oxidative stress of skin cells lead to the formation of melanin. Resveratrol can play an important part in regulating the inflammatory pathway in the skin cells and protecting them from oxidative stress.
This eventually prevents the skin cells from inducing pigment formation by the melanocytes.
Research data
- Resveratryl triglycolate is a derivative formed by the esterification of resveratrol with glycolic acid. In one clinical study, resveratryl triglycolate at a concentration of 0.4% improved artificially induced skin pigmentation by UV rays, when used twice daily for 8 weeks.
- Topical resveratryl triacetate (at a concentration of 0.4%), a prodrug of resveratrol, also showed a significant reduction of both hyperpigmentation and artificial UV-induced pigmentation in a study.
18. Vitamin F
Vitamin F constitutes two essential fatty acids, linoleic and linolenic acid. These fatty acids have anti-inflammatory properties and can also help in decreasing acne.
In vitro experiments on animal models showed a reduction in melanin formation, most efficiently by alpha-linolenic acid, followed by linoleic acid, and then by oleic acid.
Linoleic acid and alpha-linolenic acid also increased the cell turnover of the stratum corneum, leading to the removal of melanin pigment from the epidermis. Thus, they can play an important role in hyperpigmentation disorders.
These fatty acids have many other benefits such as decreasing inflammation and enhancing barrier function (if you have read my post on melasma, you probably know that barrier function disruption can be behind hyperpigmentation).
They can be combined with any other active. There are very few products that have free linoleic acid, so you can look for products with linoleic-rich oils. These include grape seed oil, evening primrose oil, safflower oil, sunflower oil, hemp oil, etc.
19. Undecylenoyl phenylalanine
Undecylenoyl phenylalanine is a derivative of the amino acid, phenylalanine. It acts by inhibiting the binding of alpha-melanocyte stimulating hormone (a-MSH) to its receptor. This stops the signaling pathway which tells melanocytes to make more melanin.
Research data
- In one study, a combination of 5% niacinamide and 1% N-undecylenoyl phenylalanine, was more effective than 5% niacinamide alone or a vehicle in reducing the appearance of hyperpigmentation after 8 weeks of treatment.
- In another study done on 40 patients, 2% undecylenoyl phenylalanine when used twice daily for 12 weeks resulted in an improvement of melasma.
Summary
A gentle skincare routine can minimize the chances of getting hyperpigmentation. Avoid aggressive physical exfoliation, don’t damage your skin barrier by using multiple actives together and if you get that spot, try not to pick at it.
Sun protection is another important step toward the effective management of dark spots and hyperpigmentation. Since the role of visible light has become important in hyperpigmentation and photo-aging, it is important to include iron oxides in our routine.
To get rid of existing hyperpigmentation, ingredients that target different steps in the formation of melanin pigment are most beneficial. Hydroquinone, retinoids, azelaic acid, vitamin C, and niacinamide are some of the ingredients with a lot of data and research behind them.
It is best to use a combination of different product actives in one product. It cuts the cost and makes the skincare routine quite simple. Some of the ingredients can cause irritation so make sure to patch-test any new product.
A higher concentration of an ingredient doesn’t mean that it will be more effective, or results will be faster. It comes with the risk of irritation. So, listen to your skin and use what it can tolerate.
If you are not getting desired results from using over-the-counter topicals, it is best to consult a professional and look into prescription topicals or other in-office treatments like laser, chemical peels, and microdermabrasion.
Disclaimer: This blog post is for information purposes only and does not replace medical advice.