Mequinol is a derivative of hydroquinone. Its mechanism of action is unclear. It acts as a substrate for tyrosinase, thereby inhibiting the formation of melanin precursors. In a randomized parallel group study involving 216 subjects, mequinol 2%/tretinoin 0.01% solution was found to be highly effective and well tolerated treatment for solar lentigines and related hyperpigmented lesions on the forearms and of similar efficacy for lesions on the face. It is marketed in USA at a concentration of 2% in combination with 0.01% tretinoin. The combination can cause erythema, burning, pruritus, desquamation, skin irritation, halo hypopigmentation. Combination with sunscreens reduces the incidence of adverse effects. 
- It is very important that you use mequinol and tretinoin only as directed.
- Do not use more of it, do not use it more often, and do not use it for a longer time than your doctor ordered. To do so may cause irritation of the skin. 
Check with your doctor as soon as possible if any of the following side effects occur while taking mequinol / tretinoin topical: More common : Burning feeling or stinging skin (severe), itching (severe), peeling of skin (severe), redness of skin (severe). Less common : Allergic reaction, large blisters on the skin. 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663177/ –  https://www.drugs.com/cons/mequinol-and-tretinoin-topical.html –  https://www.drugs.com/sfx/mequinol-tretinoin-topical-side-effects.html
Arbutin is one of the most widely prescribed skin-lightening and de-pigmenting agent worldwide. Arbutin, the b-D-glucopyranoside derivative of hydroquinone, is a naturally occurring plant derived compound found in the dried leaves of a number of different plant species including, bearberry (Arctostaphylos uva-ursi), blueberry, cranberry, and pear trees.
Arbutin, inhibits tyrosinase activity competitively but at non-cytotoxic concentrations in a dose dependent manner in cultured melanocytes. It also inhibits melanosome maturation and is less cytotoxic to melanocytes than hydroquinone. Although, higher concentrations may be more efficacious, greater risk for paradoxical hyperpigmentation exists.
Controlled trials on treating hyperpigmentation are lacking. However, several studies have shown that arbutin is less effective than kojic acid for hyperpigmentation. Deoxyarbutin is a synthesized topical derivative. Studies have shown that it has an enhanced sustained improvement, general skin lightening and a safety profile comparable to hydroquinone. 
- Most strong and well reputable skin lightening products combine this primary ingredient with others such as kojic acid, glutathione and hydroxides.
According the studies and research by the German Institute of Food and research, it was found that this element can easily be converted to hydroquinone by the intestinal bacteria. This can however lead to intestinal cancer related conditions.
Alpha Arbutin when used in large amount can also associate other side effects such as skin irritation that can transform to skin acne. Lower concentrations such as 3-4 % are tested to be safe for human consumption. Therefore, while shopping for your alpha arbutin best skin lightening cream, soap or lotion, ensure that it contains lower concentration of this element. 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663177/ –  http://www.beautyclue.com/skin-whitening/side-effects-of-alpha-arbutin-soap-cream-serum-lotion/
Furthermore, known as nicotinamide (3-pyridine-carboxamide) is the physiologically active amide of niacin (vitamin B3).
Study done on pigmented reconstructed epidermis showed that niacinamide interferes with the interaction between keratinocytes and melanocytes, thereby inhibiting melanogenesis. It also modulates the protease-activated receptor that is involved in the transfer of melanosomes from melanocytes to surrounding keratinocytes.
Clinical trials using 2% niacinamide have shown that it significantly reduces the total area of hyperpigmentation and increases skin lightness after 4 weeks of treatment. There is a plateau in treatment effect which could be due to balance between the up-regulation of melanogenesis in the hyperpigmented area and the down-regulation by niacinamide. Alternatively, the plateau could reflect the fraction of the hyperpigmented area that is sensitive to niacinamide treatment. The study also showed that the daily use of niacinamide with sunscreen was effective in reducing hyperpigmentation and in increasing lightness of basal skin colour compared with sunscreen alone. 
- Niacinamide is the main ingredient of the most popular cosmeceutical used for hyperpigmentation in the market, that is Fair and Lovely fairness cream where it is combined with sunscreen for additional benefits. In another variety of the same product, niacinamide is used along with Vitamin C.
If you use a niacinamide cream, dermatologists suggest that you start with a small amount of the cream on your skin so you can take note of any negative skin reactions. If you notice redness or peeling of the skin, you should discontinue use of the niacinamide cream and contact your dermatologist.
grape seed extract
Grape seed extract contains proanthocyanidin, which is a powerful antioxidant. Although, there are no studies on the topical use of grape seed extract, but oral intake for 6 months has been found beneficial in patients with melasma in a study conducted by Yamakoshi, et al 
- There are many benefits to using products containing Grape Seed Extract in your skincare regime as it contains many powerful nutrients. All of these nutrients help towards giving you a healthier, more radiant and hydrated complexion.
While the benefits of using this extract are clear, there are some possible side effects of which you should be aware, including bleeding disorders, drug interactions, complications with pregnancy, allergic reactions, stomach upset and dizziness. 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663177/ –  https://www.organicfacts.net/grape-seed-extract.html
A study was conducted in 48 female patients to evaluate the efficacy of a cosmetic formulation containing orchid extract and compared it to 3% vitamin C derivative. The authors found that orchid extract has efficacy similar to vitamin C in melasma and lentigines.
After 8 weeks of treatment, both the clinical evaluations by a dermatologist and the questionnaire surveys by volunteers indicated that the cosmetic formulation containing plant extracts was significantly effective in improving the size, brightness, color intensity, clarity, visibility and global appearance of the pigmented spots, and also the luminosity complexion and skin clarity of the face. 
- other orchid extract benefits: Reparative and protective properties, Moisturizing, Fighting free radicals, Reducing fine lines and wrinkles. 
Contact dermatitis is the medical term for an allergic reaction that appears on your body after touching an irritant, in this case an orchid. The condition is characterized by red bumps, itching, dry or cracked skin, blisters and pain. The severity of the symptoms depends on the amount of contact you experienced and your sensitivity to orchids. 
 https://www.researchgate.net/publication/44662208_Whitening_efficacy_of_plant_extracts_including_orchid_extracts_on_Japanese_female_skin_with_melasma_and_lentigo_senilis –  https://porcelainfacespa.com/blog/orchid-extract-benefits/ –  https://www.livestrong.com/article/548445-allergic-reactions-to-orchids/
Pycnogenol obtained from the bark of French maritime pine Pinus pinaster is evolving for its use in hyperpigmentation. Its main constituents are procyanidins, polyphenolic monomers, phenolic or cinnamic acids. It has antioxidant and anti-inflammatory properties and hence scavenges free radicals. Pine extract has been used in various market preparations. Oral pynogenol has been found to reduce melasma severity although, studies on topical use are lacking. 
Thirty women with melasma completed a 30-day clinical trial in which they took one 25 mg tablet of Pycnogenol with meals three times daily, i.e. 75 mg Pycnogenol per day. After a 30-day treatment, the average melasma area of the patients decreased by 25.86 +/- 20.39 mm and the average pigmentary intensity decreased by 0.47 +/- 0.51 unit. The general effective rate was 80%. 
- Pycnogenol is available in both topical products and supplements. When taken as a supplement, Dr. Oz recommended 50 mg, twice a day for optimal results. You can find this supplement in capsule or liquid form.
Pycnogenol is POSSIBLY SAFE when taken by mouth in doses of 50 mg to 450 mg daily for up to one year, and when applied to the skin as a cream for up to 7 days or as a powder for up to 6 weeks. Pycnogenol can cause dizziness, gut problems, headache, and mouth ulcers. 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663177/ –  https://www.ncbi.nlm.nih.gov/pubmed/12237816 –  https://www.webmd.com/vitamins-supplements/ingredientmono-1019-pycnogenol.aspx?activeingredientid=1019
marine algae extract
In a study, Cha, et al. evaluated the effect of 43 marine algae extracts on melanin synthesis and found that few extracts evidenced potent tyrosinase inhibitory activity similar to that of positive control, kojic acid without causing any side effects. Hence, these extracts can be used as an ingredient in skin lightening cosmeceuticals. 
- Marine algae, in particular, are widely used in skincare products. There are at least 28,000 species varying from single cell organisms to plant-like structures called seaweed. Each variety has its own properties and benefits but in general, algae from the ocean is very high in minerals like copper, iodine, iron, magnesium, manganese, phosphorus, potassium, and zinc. It’s also rich in vitamins especially A, B-vitamins, C, D, E, and K 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663177/ –  https://www.babble.com/beauty/beauty-ingredients-demystified-marine-extracts/
It is a phenyl propanoid derivative occurring in plants that inhibits tyrosinase activity as demonstrated in studies conducted on human and guinea pig melanocytes. Study conducted by Tan et al. found that cinnamic acid (2 mmol/L; 0.5 mmol/L) showed greater inhibition of tyrosinase activity compared to hydroquinone (0.5 mmol/L). 
- The American Shea Butter Institute notes that shea butter contains the ingredient cinnamic acid, an anti-inflammatory agent, which is a substance closely related to the same cinnamon you find in your kitchen cabinet. The less pure the shea butter, the less cinnamic acid present; therefore, the shea butter benefits greatly decrease. 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663177/ –  https://draxe.com/raw-shea-butter/
green tea extracts
Green tea extracts contain polyphenolic compounds that act on various biochemical pathways hence causing anti-inflammatory, anti-oxidant and anti-carcinogenic effects. Epigallocatechin-3-gallate is the main active ingredient contained in green tea.
Study conducted by No, et al. has shown that green tea extracts cause in vitro inhibition of mushroom tyrosinase, which may be responsible for the de-pigmenting effect. However, more in vivo studies are needed to substantiate this action. 
Antioxidants in the tea help prevent free radical damage, and encourage healing of cells – all of which fight signs of premature aging like age spots, wrinkles, and sun damage.
- If you do decide to add green tea masks or creams to your skin care kit, be sure to follow all packaging instructions to reduce your risk of side effects.
Most of the side effects associated with green tea apply only if taken orally. Using green tea for skin problems has a very low instance of side effects and very few people experience irritation as a result. However, allergic reactions to green tea are possible and you should use any product that contains it sparingly until you know how it will affect you.
 https://www.ncbi.nlm.nih.gov/pubmed/10576599/ –  https://www.livestrong.com/article/193644-what-are-the-dangers-of-patchouli-oil/
Coffeeberry extract is known to have anti-oxidant properties. However, its de-pigmenting action is yet to be proven. Study conducted by McDaniel et al. in 30 patients with photo-damage showed improvement in hyperpigmentation following 6 weeks of coffeeberry extract application.
- Choose a cream that contains coffeeberry extract. With daily use, you will reverse the signs of aging such as uneven skin tone, fine lines and wrinkles. You may get an overall skin–lightening–improving effects.
A clinical trial was conducted on CoffeeBerry-based skin care products, which recruited 30 participants, reported a total of 22 adverse events in 13 participants, including acne flare-up (6 participants), redness (4 participants) and peeling (1 participant). All of the adverse events were of mild serverity. 
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3663177/ –  http://wisderm.com/ingredients/CoffeeBerry
Mulberry extract is derived from the plant Morus alba L from the Moraceae family. The leaves of this plant have anti-hyperglycaemic activity. The derivatives of its root bark have been found to have skin lightening effect.
IC50 (concentration causing 50% inhibition of activity of tyrosinase) is very low (0.396%) as compared to 5.5% for hydroquinone and 10.0% for kojic acid. However, clinical trials regarding skin lightening effects are lacking. 
- Cosmetices containing white mulberry extract can also improve the appearance of fine lines and wrinkles by helping to restore fibrillin. White mulberry and paper mulberry are both considered suitable for dermatological use. 
Mulberry extract use on the skin is being associated with occurrence of skin cancer and must be therefore used with caution. 
 https://www.cosyoil.com/14-essential-oils-melasma-bonus-5-recipes/ –  http://skinwhiteningnews.org/7-natural-ingredients-that-really-whiten-skin/ –  http://www.tophealthremedies.com/10-unexpected-side-effects-of-mulberry/#5_Risk_Of_Skin_Cancer
soy (glycine soja)
Several skin care products containing soy are available to improve hyperpigmentation. Soy has proven to be both efficacious and safe. 
The major components of soy are phospholipids (45-60%), and essential fatty oils (30-35%). It also contains active ingredients like isoflavones, vitamin E and serine protease inhibitors-soybean trypsin inhibitor (STI) and Bowman-Birk protease inhibitor (BBI). 
- Skin lightening benefit can be seen after 12 weeks of twice daily application. The de-pigmenting effect of soymilk is reversible and daily topical treatments for 7 months result in no adverse effects.