Niacinamide was recognized in early 20^thcentury asthe vitamin that prevents pellagra [2], anepidemic diseasewith severecutaneous lesions. Originally, niacinamide was named Vitamin PP as pellagra-preventive active.Nicotinamide and niacin both are identical in their vitamin functions but nicotinamide does not possess the same pharmacological and toxicological effects as niacin. In cells, niacin is converted to nicotinamide invivo as nicotinamide adenine di-nucleotide (NAD) and nicotinamide adenine dinucleotide phosphate(NADP). 

Identifiers:

CAS No.: 98-92-0

EINECS No.: 202-713-4

Pub Chem: 7847104

Chem Spider: 911

Drug Bank: DB02701

ATC Code: A11HA01

Empirical Formula

Emp. Formula: C₆H₆N₂O

Mol. Weight: 122.12 g/mol

Recommended use level: 0.5 – 5%

Physical Properties

Appearance: White crystalline powder or colourless crystals

Melting Point: 128-131 °C

pH: 6.5-7.5 (5% aqueous solution)

Stability: Stable, not compatible with strong oxidizing agents

Boiling Point: 157°C at 5.00E-04 mm Hg

Specific Gravity: 1.40 at 25°C

Solubility: Freely soluble in water and ethanol

Chemical Identification

A. Melting point: 128°C-131°C.

B. By IR absorption spectrometry.

C. Boil 0.1 gm of niacinamide with 1 mL of dilute sodium hydroxide solution. Ammonia is evolved which is recognizable by its odour or with white fumes when glass rod dipped in HCl is being taken to its mouth.

D. Dilute 2 mL solution to 100mL with water. To 2mL of this solution, add 2 mL of cyanogen bromide solution and 3mL of 25gm/litre solution of aniline and shake. Ayellow colourwill develop in the solution.

Applications/Benefits

The protective cutaneous effect of niacinamide has been a subject of scientific interest for nearly hundred years ever since the B3 deficiency was identified as the reason for pellagra [2]. Thereafter, niacinamidehas been studied in order to identify its potential benefit to the skin and/or on hair. A lot of ingredients have disappointed dermatologists due to their low efficacy in treating various skin problems or various side effects. However, multiple beneficial effects based on clinical testing on the skin and no toxicological effects within cosmetically allowed limits/uses have made the niacinamide an ideal ingredient for topical cosmetic applications. At the same time, continuing research in in vivo and cell culture models is helping in elucidating the cellular and molecular mechanisms underlying the well documented cutaneous physiological activity of niacinamide.

Niacinamide is being used in cosmetics and personal care products like bath products, shampoos, hair tonics, skin moisturizers and other skin care preparations and cleansing products. In Hair care products, it enhances the appearance and feel of hair by increasingsuppleness or sheen and by improving the texture of hair. In skin care formulations, niacinamide enhances the appearance of dry or damaged skin by reducing flaking, improving skin'selasticity, enhancing its barrier function and also helps to erase discolorations/hyperpigmentation and revives skin's healthy tone and texture. Furthermore, niacinamide is stable, safe and well tolerated in topical formulations even at relatively high concentrations. In view of the above and considering its well-researched biochemistry, stability, solubility, good safety profile and low cost availability, niacinamide shows substantial promise as a versatile skin care and rejuvenating agent. A detailed description of various skin care applications where niacinamide is used is as follows:

1. Acne Treatment

Acne is the skin condition characterized by excess sebum production and irregular shedding of dead skin cells [3]. The dead skin cells and sebum clog hair follicles causes inflammation. Niacinamide shows antioxidant and anti-inflammatory properties which makes it effective for treating acne. Niacinamide also helps in treating other inflammatory skin conditions such as psoriasis and rosacea. Typical antimicrobial agents used in the treatment of acne may provoke skin irritation and/or can attain bacterial resistance on prolong use. Niacinamide has the advantage over the antibiotics in treating acne that it does not give rise to microbial resistance.

A randomized controlled studyperformed by Shalita and colleagues [4] showed that4% niacinamide (Papulex^©) is of comparable efficacy as 1% clindamycin(a topical antibiotic) in the treatment of acne (Fig. 1). Around 82% of subjects with inflammatory acne showed an improvement after 8 week of 4% niacinamide usage, accompanied by significant reduction (60%) in papules/pustules and acne severity (52%), whereas it is only 38%with clindamycin.There were no side effects in either group. The researchers postulated that these effects may be due to niacinamide’s apparent anti-histaminic effect, its activity as electron scavenger or due to inhibition of 3’-,5’- cyclic AMP phosphodiesterase activity. However, later studies suggested that anti-inflammatory activity of niacinamide may have contributed to its effect on acne [5]. 

Fig.1: The study with 4% niacinamide gel or with 1% antibiotic clindamycin gel twice daily for8 weeks showed reduction in acne lesions (papulesandpustules).

The efficacy of niacinamide in combination with zinc (Nicomide^©) has been assessed in clinical studies for the treatment of inflammatory skin diseases such as acne vulgaris and bullous pemphigoid [6-8]. Studies by Fivensonhas shown 79% improvement in appearance and reduction in lesions as moderately better or much better compared to control after 4 weeks of treatment. The percentage of patients who responded to therapy has increased further after 8 weeks of treatment. 

2. Anti-Aging/Skin Rejuvenation

Skin aging is characterized by major skin changes like reduced skin elasticity, poorer structure and appearance of wrinkles [9].An important factor is the gradual loss of collagen (a protein that supports skin and gives it its youthful firmness) and elastin fibers synthesized in fibroblasts. Oblong and coworkers [10] in their study on human dermal fibroblast cell lines have found an age associated reduction in nicotinamide coenzymes. More interestingly, they have observed an increase in intracellular concentration of NADPH, when the aged fibroblast cultures are supplemented with ¹⁴C-nicotinamide. This suggests that a localized supply of niacinamide can be utilized by aged cutaneous cells to restore intracellular nicotinamide coenzyme homeostasis.

A recommended strategy in preventing skin aging is to reduce collagen breakdown, while increasing fibroblasts[11]. Studies [10, 12-13] with human fibroblasts showed that niacinamide stimulates cells in the dermis to produce new fibroblasts by 20%, total protein secretion by 41% and collagen secretion by 54% relative to control vehicle. Another study conducted by Procter & Gamble, whose Olay skincare line sells several products with niacinamide have demonstrated mitigating effects of niacinamide on some of the deleterious effects of UV light. Of particular interest, is a well designed (double-blind, placebo-controlled, split-face, left-right randomized) 12-week study [14] on the effects of 5% topical niacinamide in 50 women of various signs of skin aging. The researchers reported significant improvement in the appearance of fine lines/wrinkles, hyper pigmentation spots, texture, sallowness, red blotchiness and improved elasticity.

3. Up-regulation and Augmentation of Skin Barrier Properties

Evidences from the clinical studies suggest that niacinamide help in treating various skin problems associated with mature skin i.e., excessive dryness, cracked skin, wrinkles etc. by up-regulating endogenous bio-synthesis of epidermal sphingolipids including ceramides [15]. Skin softness, suppleness and skin hydration are related to the barrier properties of epidermis. It is known that several lipids such as fatty acids and ceramides are critical for the structural and functional integrity of the stratum corneum. Ceramides, along with other lipids like cholesterol and fatty acids are natural emollients and form a protective barrier against water loss and shield it from bacteria and the environment [16]. These lipids decrease as the skin ages [17]. Topically applied niacinamide has been shown to increase ceramide and free fatty acid levels in skin and thus prevent it from losing water content, stimulate microcirculation in the dermis and helps to keep skin moist and supple [18].

The skin barrier function can be assessed by transepidermal water loss (TEWL) measurements. A study conducted by Tanno et. al. [18] showed that 2% niacinamide reduced the TEWL by 24% in 4 weeks. At the same time free fatty acids and ceramides in stratum corneum were boosted by 67% and 34%, respectively. In another research, Ertel and colleagues [19] demonstrated that a moisturizing vehicle containing 2% niacinamide can produce significant reduction in TEWL compared to vehicle control along with an increase in the rate of stratum corneum turnover (as measured by densyl chloride assay).

Niacinamide has also been shown to stimulate the keratin synthesis and biosynthesis of two epidermal proteins, filaggrin and involucrin which play critical role for the differentiation and formation of a fully functional stratum corneum (Fig. 2). Filaggrins play a central role in the aggregation of keratinocytes, whereas, involucrin is a component of the cornified envelope of the corneocytes. Oblong and co-workers [20] by using cultured Normal Human Epidermal Keratinocytes (NHEK) have demonstrated that supplementation of NHEK with niacinamide had increased NHEK numbers significantly and showed up-regulation in both filaggrin and involucrin biosynthesis by 100% and 45%, respectively relative to control. Thus niacinamide helps to normalize and soothe sensitive skin by stimulating biosynthesis of epidermal keratinocytes and proteins.

Fig.2: The in vitro study with human keratinocytes showedsignificant increase of barrier layer proteins by niacinamide.

4 Skin pigmentation/Skin-lightening

Another skin problem that goes along with ageing is increased skin pigmentation.It is common for people with more mature skin having age spots and patchy areas of increased pigmentation from years of sun exposure. Extended exposure to sun light is the main reason for hyper pigmentation. The melanocytes are the skin’s pigment producers (Fig.3). Melanocytes in deeper skin layers produce melanosomes that contain the pigment melanin. These are then released to keratinocytes that move upwards to the upper epidermis and give colour to skin.The contact between melanocyte and keratinocytes is made via dendritic branches. Under normal circumstances, one melanocyte supplies around 36 keratinocytes.

Fig. 3: Ultra Structure of Skin and Melanin Transfer Process.

Chronic UV exposure can damage melanocytesin a variety of different ways. This damage can lead to a loss of cellular control and the production of chemicals that allow the cells to keep producing more and more melaninwhich eventually leads to age spots and uneven discoloration [21]. Additionally, as skin ages, cell turnover slows down and “melanin dust" (microscopic particles of melanin) can become trapped in the upper layers of skin, resulting in a duller appearance.

A clinical trial by Hakozakiet. al., where melanin production was measured using purified mushroom tyrosinase assay had shown that niacinamide had no effect on the catalytic activity of mushroom tyrosinase or on melanogenesis in cultured melanocytes [22]. However, further studies by Hakozakiet. al.and Lei et. al. [22-23] revealed that although niacinamide does not inhibit the production of melanin but inhibits the transferof the melanosomes to the surrounding keratinocytes upto 68%in the co-culture model(Fig. 4).In the clinical studies with 5% niacinamide, significant decrease in hyperpigmentation and increase in skin texture (lightness) after 4 weeks of usecompared to vehicle alone was also observed. Some follow-up human clinical studies by Greatens et. al.and others [21, 24-25] to assess the effect of niacinamide on facial hyperpigmented spots have demonstrated a dose dependent and reversible reduction in hyperpigmented lesions with niacinamide treatment. In-vitro and in-vivo data show that when niacinamide treatment stops, the melanosomes transfer and hyperpigmentation will resume. An 8-week, double-blind, placebo-controlled, left-right randomized, split-face clinical study by Procter & Gamble [26] had demonstrated significant reduction in the amount and appearance of hyper-pigmentation, age spots and uneven melanin distribution with the formulation comprising a combination of 4% niacinamide and 2% glucosamine (N-Acetyl Glucosamine). 

Fig. 4:N-acetyl glucosamine and niacinamide block melanin production by interfering in the process at two different points - reducing formation and appearance of age spots.

A clinical trial by Hakozakiet.al.with 5% niacinamidefor 8 weeks on volunteers has also confirmed the skin lighteningactivity [22]. Ageing spots around the eye and cheekwere also reducedsignificantly (Fig. 5).

Fig. 5: Image analysis of facial age spots after 8 weeks of dailyapplication with either a 5% niacinamide cream or the placebo.

5 Protection from UV Induced Damage

The protective role of niacinamide against UV induced damage is supported by clinical studies on animal models and human cell lines. For example, work by Shen et. al.[27] in cultured human keratinocytes has demonstrated that niacinamide can protect against damage from reactive oxygen species induced by UVC irradiation or exposure to hydrogen peroxide. Niacinamide treatment significantly attenuated apoptotic morphological changes in a dose dependent manner. Niacinamide treated cells also had decreased p53 induction and reduction in DNA ladders vs those treated with a control vehicle. These data are consistent with other research demonstrating the ability of niacinamide to significantly reduce both induction of photo-carcinogenesis and photo-immune suppression [28-29].

6 Treatment/Improvement In Skin Appearance (Skin Tone & Yellowing)

Niacinamide also has a growing reputation for being able to treat an uneven skin tone and red marks (known as post-inflammatory hyperpigmentation - PIH) [30]. This is likely due to an increased production or deposition of melanin into the epidermis or dermis by labile melanocytes. A variety of endogenous or exogenous inflammatory conditions can culminate in PIH and typically most epidermal lesions will appear tan, brown or dark brown while dermal hypermelanosis has a blue-gray discoloration. Studies [21-26] showed that niacinamide helps to lighten areas of pigmentation and age spots. It also reduces blotchiness and evens out skin tone while improving skin texture.  Niacinamide with retinyl palmitate has been shown to improve hyper pigmentation and increase skin lightening after 4 weeks of treatment compared with vehicle alone. In a separate clinical study, topical niacinamide was also shown to decrease collagen oxidation products and improve aging-induced yellowing or sallowness. Tissue studies showed a reduction in melanin and an increase in collagen. Three double-blinded placebo controlled clinical studies involving more than 200 subjects, showed improvement in hyper pigmentation and skin tone and a decrease in the size of age spots.

A clinical study by Matts and Solechnick [31], where they used multiple angle reflectance spectrophotometry to measure the diffuse component of skin reflection have shown significant increase in diffused component in dorsal hand skin treated with 5% niacinamide vs a control vehicle after 10 weeks of treatment. This suggests a shift in texture towards finer, anisotropic features characteristic of younger skin.

A randomized, double-blind trial by Mizoguchi et. al. [32] on adult Indian women between 30-60 years of age with epidermal hyperpigmentation in which they were treated for 10 weeks with lotioncontaining niacinamide, panthenol and tocopherol acetate had shown significant reduction in the appearance of hyperpigmentation, improvement in skin tone evenness and appearance of lightening of skin and positive effects on skin texture. Improvements versus control were seen as early as within 6 weeks. The test lotion was well tolerated there were no side effects apart from very common mild burning sensation.

Another appearance problem is skin sallowness (yellowing of skin) which is caused by glycation (a spontaneous oxidative cross-linking reaction of sugar with protein). The glycation product is yellow in colour and such collagen products accumulate in skin. Since NAD and NADPH are endogenous anti-oxidants and niacinamide is a precursor to them in skin, topical niacinamide treatment has potential to be effective against skin sallowness. Research with 50 Caucasian women (ages 40-60) has demonstrated that an oil in water emulsion with 5% niacinamide concentration visibly diminished skin yellowing at 12 weeks vs a placebo that did not contain niacinamide [13].

7 Rosacea (Skin Redness)

Rosacea is a condition associated with excessive skin redness, irritability, sensitivity and inflammation. In one study, niacinamide was shown to improve skin barrier function in rosacea patients, leading to diminished reaction to irritants, such as detergents. In another study, treatment with 1-methylnicotinamide (metabolite of niacinamide with known anti-inflammatory effects) resulted in improvement in 26 out of 34 treated subjects [33].

8 Medicinal Applications

Apart from above skin care applications, niacinamide also has following medicinal applications:

1. Studies have proved that niacinamide prevents or delay the onset of Type 1 diabetes among high-risk individuals [34-41].Niacinamide has three major benefits for diabetics. First, it reduces nitric oxide synthase which helps retard beta cell death. Second, it enhances ox/redox function through restoration of NAD levels which help prevent cellular damage and improve regeneration. Third, it reduces glycosylated hemoglobin levels which reduce the peripheral organ and blood vessel oxidation load and damage from sugar metabolites.

2. Niacinamide works synergistically with other supplements such as vitamin E, calcium-AEP, chromium picolinate, vanadyl sulfate and lipoic acid etc. to reduce blood sugar and glycosylated hemoglobin and the same time also regulate blood insulin.

3. Niacinamide acts as an antioxidant by preventing NAD depletion during DNA repair by inhibiting poly (ADP-ribose) polymerase (PARP), which also modulates Major Histo-compatibility Complex (MHC) class II expression. Niacinamide also inhibits free radical formation and facilitates beta-cell regeneration in vivo and in vitro [42-43].

4. Treatment with niacinamide (1.5-6 g/day) is claimed to be most effective for patients suffering from schizophrenia (a psychiatric conditions) [2, 44-47].

5. Niacinamide also produce an anti-anxiety effect equivalent to a highly potent benzodiazepine [48-50].

6. Clinical data suggest that niacinamide is very effective in the treatment of osteoarthritis [51-53],since, it inhibit nitric oxide (NO) production [54]. Niacinamide shows enhanced inhibition of arthritis when co-supplemented with N-acetyl cysteine [55].

7. Niacinamide empowers the body to convert carbohydrates, fats and proteins into energy and amino acids. The metabolism of tryptophan accounts for about 66% of niacinamide in the body.

8. In vitro studies on human fibroblasts have demonstrated that niacinamide may have a mitigating effect on skin tumors [28-29, 56].

9. Niacinamide has been used to treat several types of dermatological pathologies and had shown promising results when used in combination with tetracycline [57-60].

10. Clinical studies have shown that simultaneous supplementation of niacinamide with radioactive iodine for the treatment of hyperthyroid goiter has increased the effectiveness of radiation at lower doses due to niacinamide’s radio sensitization [61]. Studies by Denekamp et. al.have confirmed niacinamide’s ability to increase tissue sensitivity to radiation [62].

11. Concomitant use of niacinamide and antiepileptic drugs, specifically carbamazepine, diazepam and sodium valproate, apparently potentiates the anticonvulsant action of these drugs [63]. In addition, niacinamide may decrease clearance of carbamazepine when used simultaneously [64].

12. Niacinamide has application to cure heart disease, including hardening of the arteries (atherosclerosis). It also reduces the risk of second heart attack in men with heart or circulatory disorders.

13. For the treatment of Diarrhea from an infection called cholera.

14. For the prevention of Cataract.

15. Niacinamide health benefits also include increased energy, more strength, less fatigue, better sleep, reduced inflammation and greater capacity for work and exercise [65].

16. Apart from these above mentioned applications, there are insufficient evidences to rate effectiveness of niacinamide for migraine, headache, dizziness, depression, motion sickness, alcohol dependence, improving orgasm and attention deficit-hyperactivity disorder (ADHD).

Mode of Action

Niacinamide serves as a precursor of NADH and NADPH, which are co-enzymes for various metabolic pathways. In particular, these co-enzymes play a key role in metabolism of glucose, cellular energy production and synthesis of lipids etc.With a sufficient supply of both enzymes, skin creates an effective barrier to external factors that influence the aging process. However, the levels of both NADH and NADPH decline with age [17, 66-67]. The topical niacinamide supplementationsappear to reverse this decline. Since topical application of niacinamide can help preserve levels of NADH/NADPH, it contributes to the support of the skin’s barrier against pollutants and other irritants. As a result, many skin conditions, such as acne, the redness associated with rosacea and other inflammatory signs can be actively managed. Also, vitamin B3 has shown to be useful for encouraging the production of natural emollients that can help the skin remain hydrated.

Genes and gene therapy are proving to be a powerful tool in the latest frontier in the fight against aging. Cellulardifferentiation depends on gene expression as well as on gene silencing. In other words, which genes are ‘expressed’ determines the cell purpose and activity. Imai et. al. have identified genes that influence ageing of cells. In particular, a gene labeled Sir2 (silent information regulator 2) has been shown to produce a protein, Sir2p that extends cell life. Studies have shown that Sir2p is a NAD-dependent histone deacetylase that connects metabolism, gene silencing and cellular life extension [68]. Niacinamide by increasing NAD (which is essential for cellular metabolism) level, enhances Sir2p activity. MIT researchers have proposedthat by slowing metabolism, NADs are spared, thereby enhance Sir2p activity. Increasing intracellular NAD not only mimics the metabolic benefits of calorie restricted diets, but also helps maintain a balance of silent and active genes. Nutritional supplementation with niacinamide is an effective way to increase intracellular NAD levels. Additionally, Sir2 activity is also thought to influence ADP-ribosyl transferase activity [69-70]. Studies suggest that the increased intracellular NAD levels may positively influences ADP-ribosyl transferase activity in favor of Sir2p activity over nitric oxide synthase, which results in the inhibition of nitric oxide [51-55] and accounts for niacinamide’s benefit in the treatment of arthritis and diabetes, as well as protection of the brain (Alzheimer’s disease).

Regulatory Aspects and Toxicity Profile

The safety of niacinamide and niacin has been assessed by the Cosmetic Ingredient Review (CIR) Expert Panel and based on the available scientific data the panel has concluded that both aresafe (non-toxic) for use in cosmetics and personal care products at the reported practices of use and concentration.TheEnvironmental Working Groupalso classifies it as a low hazard cosmetic ingredient. Theconcentration of use of niacinamide varies from 0.0001% in night preparations to 5-6% in body and hand creams, lotions, powders and sprays. Niacin concentrations of use range from 0.01% in body and hand creams, lotions, powders and sprays to 0.1% in paste masks (mud packs).

Both ingredients are accepted for use in cosmetics in US,Japan and the European Union. Both are GRAS(Generally Recognized As Safe) direct food additives and nutrient and/or dietary supplements and cosmetic ingredient (US FDA).

Older clinical studies report relatively frequentliver enzyme abnormalities [71], however, recentstudies using purified niacinamide have notdetected such abnormalities [72-73]. Nausea is usuallythe first side effect noted with niacinamide. Otherside effects associated with high-dose niacinamideinclude heartburn, vomiting, flatulence and diarrhea.Mild headaches and dizziness have been reportedafter giving niacinamide parenterally [74].

Both ingredients are readily absorbed from skin, blood and intestines and widely distribute throughout the body. Metabolites include N1-methylnicotinamide and N1-methyl-4-pyridone-3-carboxamide. Excretion is primarily through the urinary tract. Short-term oral, parenteral and/or dermal toxicity studies do not identify significant irreversible effects. Niacinamide, evaluated in an in vitro test to predict ocular irritation has not been found an acute ocular hazard. Animal testing of niacinamide in rabbits in actual formulations produced mostly non-irritant reactions, with only some marginally irritating responses. Skin sensitization tests of niacinamide at 5% during induction and 20% during challenge were negative in guinea pigs. Neither cosmetic ingredient was mutagenic in Ames tests, with or without metabolic activation. Niacinamide and niacin at 2 mg/ml were negative in a Chromosome Aberration Test in Chinese Hamster Ovary Cells, but did produce large structural chromosome aberrations at 3 mg/ml. Niacinamide induceSister Chromatid Exchanges in Chinese hamster ovary cells, but niacin did not. Under certain circumstances, niacinamide can cause an increase in unscheduled DNA synthesis in human lymphocytes treated with UV or a nitroso-guanidine compound. Niacinamide itself was not found carcinogenic when administered (1%) in the drinking water of mice. There is no data available on the carcinogenic effect of niacin. Niacinamide can moderate the induction of tumors by established carcinogens. Niacinamide in combination with Streptozotocin (a nitroso- urea compound) or with Heliotrine (a pyrrolizidine alkaloid) produced pancreatic islet tumors. On the other hand, niacinamide reduced the renal adenomas produced by Streptozotocin and intestinal and bladder tumors induced by a preparation of Bracken fern. Niacinamide evaluated in in vitro test systems did affect development but has been shown to reduce their productive/developmental toxicity of 2-amino nicotinamide-amino-1,3,4-thiadiazole hydrochloride and urethane. Clinical testing of niacinamide produced no stinging sensation at concentrations up to 10%.Tests have not shown any irritation at concentrations up to 5% and a 21-day cumulative irritation test at concentrations up to 5% also resulted in no irritancy. Niacinamide isneither a skin sensitizer or a photo-sensitizer nor a skin irritant. Over all, these ingredients are non-toxic at levels considerably higher than would be experienced in cosmetic products. 

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