Niacinamide

Niacinamide is a form of Vitamin B and undoubtedly one of the best-studied cosmeceutical ingredients. It is remarkably potent at reversing the visible hallmarks of aged skin, including sallowness, pigmentation and wrinkles.

Effects


Grade Level of Evidence
A Multiple double-blind, controlled clinical trials.
B 1 double-blind, controlled clinical trial.
C At least 1 controlled or comparative clinical trial.
D Uncontrolled, observational, animal or in-vitro studies only.
Grade Effect Size of Effect Comments

A

Wrinkle treatment

Strong

Improves wrinkles and lines by upregulating the production of collagen, keratin, fillagrin and involucrin in aging cells.

A

Skin lightening

Strong

Inhibits the transfer of melanized melanosomes to keratinocytes, thereby brightening the skin and reducing hyperpigmentation.

A

Photoprotection

Mlid

Prevents UV-induced immunosuppression, possibly via alterations in complement, apoptosis pathways and energy metabolism.

B

Increased skin elasticity

Mild

Makes the skin more elastic after twice daily treatment with 5% niacinamide for 12 weeks.

B

Smoother skin

Mild

Improved the texture of the skin according to expert grading after 10 week of treatment.

B

Psoriasis treatment

Mild

Enhances the efficacy of calcipotriol when used in combination for topical treatment.

B

Less oiliness

Mild

Decreases sebum production and hence sebum levels of the face.

C

Enhanced barrier function

Strong

Reduces water loss from the skin and increases the skin's resistance to damaging agents.

C

Increased skin hydration

Moderate

Raises the hydration retention capacity of the skin via a thicker stratum corneum and an improved barrier function.

C

Acne treatment

Moderate

Effective in treating mild to moderate acne vulgaris. Affects the production of sebum and inhibits P. acnes-induced IL-8 promoter activation.

C

Melasma treatment

Moderate

Decreases the amount of pigmentation, inflammatory infiltrate and solar elastosis in melasma patients.

D

Increased skin thickness

Moderate

Results in a thicker stratum corneum by stimulating keratinocyte differentation.

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Scientific Research


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Table of contents:

1. Sources

Niacinamide, also known as nicotinamide, is a form of Vitamin B3 (niacin, nicotinic acid). Vitamin B3 is found in many foods including dairy products, eggs, enriched breads and cereals, fish, lean meats, legumes, nuts and poultry. Ingested vitamin B3 is converted to niacinamide in vivo.[1]

2. Bioavailability

One study performed on excised human skin found in vitro absorption of nicotinamide to be close to 30%.[2] An early in vivo study also determined that approximately 10% of nicotiamide was absorbed percutaneously after topical administration to the forearm.[3] In addition, several other studies have used increased levels of NAD in skin cells after the topical application of niacinamide, as evidence of percutaneous penetration.[4] Its maximum absorption rate appears to be at 48-72 hours.[5]

Interestingly, ultrasound radiation seems to enhance the absorption and transepidermal transport of niacinamide, as evidenced in a study investigating the effects of high-frequency ultrasound together with a coupling gel containing niacinamide and ascorbyl glucoside.[6]

3. Effects on the skin

3.1 Increased epidermal barrier function

Niacinamide improves epidermal barrier function by increasing barrier components, reducing transepidermal water loss (TEWL) and increasing the skin’s resistance and response to damaging agents such as sodium lauryl sulfate (SLS) and dimethyl sulfoxide (DMSO).[7]

In a study on human keratinocytes, niacinamide upregulated the rate of biosynthesis of barrier components in the stratum corneum, including glucosylceramide, sphingomyelin, free fatty acids and cholesterol. It also increased serine palmitoyl transferase activity, the rate-limiting enzyme in sphingolipid synthesis.[8]

Repeated daily application of a topical niacinamide-containing formulation over 28 days also led to larger and more mature corneocytes, augmented the thickness of the stratum corneum, and decreased transepidermal water loss compared to pre-treatment baseline and untreated or vehicle-control treated sites, according to a randomized controlled trial.[9] Another double-blind study on 41 female subjects discovered that 2% niacinamide, when applied daily for 24 days to the forearms, not only significantly reduced TEWL levels but also rendered the skin more resistant to damage caused by agents such as SLS and DMSO.[7] Furthermore, niacinamide/glycerin body moisturizers have been demonstrated to improve stratum corneum integrity and reduce cosmetic xerosis over time, as evidenced by improved visual dryness grading, skin hydration as measured by a corneometer, and barrier integrity as measured by TEWL.[10]

Topical tretinoin causes irritation consistent with stratum corneum barrier compromise.[11] The use of niacinamide to improve the stratum corneum barrier prior to beginning topical tretinoin therapy has been determined to facilitate facial retinization and augment the treatment response, as evidenced by a paired, double-blinded study in which women applied a cosmetic moisturizer containing niacinamide, panthenol and tocopheryl acetate for 10 weeks before commencing tretinoin treatment 2 weeks later.[12]

It has also been theoreticized that niacinamide improves the skin barrier function by stimulating keratinocyte differentiation.[8][13] Given that the functional limitations of aging skin include reduced turnover of the epidermis due to a deficiency of NADP in aging cells, it seems that topical application of niacinamide increases intracellular NADP levels, which in turn stimulates keratinocyte differentiation. This results in a thicker stratum corneum, which is associated with improved barrier function and a greater hydration retention capacity.[14]

3.2 Anti-wrinkle effect

Multiple clinical studies have demonstrated the positive effects of niacinamide on wrinkles and fine lines. In one, a 12-week, randomized, double-blind, placebo-controlled, split-face trial on 50 Caucasian female subjects, significant improvements were seen in the appearance of fine lines and wrinkles, among other parameters, after application of 5% niacinamide.[15][16] A study on 30 Japanese females showed that 4% niacinamide also resulted in marked or moderate improvement on wrinkles in the eye areas in 64% of subjects after 8 weeks.[17] A treatment period of just 4 weeks also appears to be effective in smoothening periorbital skin and reducing the depth of larger wrinkles when a niacinamide-containing product is applied twice daily.[18]

Niacinamide in combination with other purported anti-aging agents have also been demonstrated to reduce wrinkles. One double-blind, placebo-controlled, split-face study on 52 Taiwanese subjects discovered that both 4% niacinamide and 4% niacinamide + 0.03% kinetin significantly reduced wrinkle counts, among other effects, within 12 weeks.[19] Topical N-acetyl glucosamine or palmitoyl pentapeptide (Pal-KTTKS) + niacinamide in a facial moisturizer also improved the appearance of facial fine lines and wrinkles when applied twice daily over 4-8 weeks.[20][21]

In another study, an 8-week, randomized, controlled comparative study, 196 women with moderate to moderately severe periorbital wrinkles were subjected to a cosmetic moisturizer regimen to compare its efficacy versus a prescription regimen with 0.02% tretinoin. Subjects assigned to the cosmetic regimen used a moisturizing lotion (Olay Professional Pro-X Age Repair Lotion SPF 30) in the morning and a night cream (Olay Professional Pro-X Wrinkle Smoothening Cream) in the evening, as well as a wrinkle treatment (Olay Professional Pro-X Deep Wrinkle Treatment) twice daily. All the test products in the cosmetic regimen contained niacinamide, the peptides Pal-KT and Pal-KTTKS, and carnosine in a moisturizing base; the daytime lotion also contained a broad spectrum sunscreen and vitamins C and E, while the wrinkle treatment also included 0.3% retinyl propionate. Subjects assigned to the prescription regimen applied 0.02% tretinoin in an emollient base (Neutrogena Healthy Defense Daily Moisturizer SPF 30) every morning for the first 2 weeks, and 0.02% tretinoin every evening thereafter. Expert visual grading and image analysis assessed that the niacinamide-containing regimen provided comparable benefits with the tretinoin treatment, while being significantly better tolerated.[22]

A few mechanisms may be involved in niacinamide's ability to improve fine lines and wrinkles. First, niacinamide has been proven to stimulate the production of collagen and the epidermal proteins keratin, fillagrin and involucrin in aging cells.[15] This is important as keratin deficiency affects epidermal cell structure and its water-binding capacity, fillagrin is an antecedent of natural moisturizing factor and affects skin hydration, and involucrin is seen as significant for the cell envelope and structure of the stratum corneum.[13] The second mechanism which may be relevant is the ability of niacinamide to reduce excess dermal glycosaminoglycans (GAGs), but this is controversial as both the elevation and depletion of dermal GAGs are associated with photodamaged or wrinkled skin.[13]

3.3 Lightening effect

Niacinamide has well-documented effects as a skin lightening agent. Apart from its potential for melasma treatment,[23] niacinamide also appears to be suitable for treating hyperpigmentation. In a 9 week, randomized double-blind, placebo-controlled trial, patients assigned to apply a cream containing 4% niacinamide experienced significantly higher reduction in axillary hyperpigmentation compared to the placebo group. At least mild improvement was observed in 68% of patients treated with niaciamide, with 24% achieving a good to excellent response. Histological assessment also showed a reduction in epidermal melanin in the niacinamide-treated axillae.[24]

Niacinamide also improves the appearance of facial hyperpigmentation alone or when combined with other compounds, such as N-undecylenoyl phenylalanine (Sepiwhite),[25] N-acetyl glucosamine (NAG)[26] and tranexamic acid (TXA).[27] 2 clinical trials involving 18 subjects who used 5% niacinamide or vehicle moisturizer and 120 subjects who used 2% niacinamide + sunscreen, sunscreen alone or vehicle respectively, was found to result in significantly decreased hyperpigmentation and increased skin lightness after only 4 weeks.[28]

2 other clinical studies found that 5% niacinamide + 1% Sepiwhite, a reported alpha-melanocyte-stimulating hormone receptor antagonist, was significantly more effective than vehicle and 5% niacinamide alone in reducing facial hyperpigmentation.[25] Another clinical trial found that 4% niacinamide + 2% NAG induced a reduction in the appearance of irregular facial pigmentation, including hypermelanization, beyond that achieved with a regular SPF 15 sunscreen.[26]

A study on 42 Korean females likewise concluded that 2% niacinamide + 2% TXA decreased facial hyperpigmentation significantly better than sunscreen, according to measures using a mexameter and chromameter, in addition to physicians' assessment using clinical photographs.[27]

Niacinamide is also effective in Indian women. In a trial on 207 Indian women, subjects were randomly assigned a test lotion containing niacinamide, panthenol and tocopherol acetate, or a control lotion. Women who used the test lotion experienced lightened skin and reduced hyperpigmentation among other effects, after 10 weeks of daily application to the face.[29]

It has been shown that, surprisingly, the decrease in cutaneous pigmentation is not due to the direct influence of niacinamide on melanin synthesis by melanocytes. Rather, niacinamide reversibly inhibits the transfer of melanized melanosomes from melanocytes to neighboring keratinocytes.[30] In a keratinocyte/melanocyte co-culture model, niacinamide was found to give 35-68% inihibition of melanosome transfer.[28]

Apart from its anti-wrinkle and lightening effects, niacinamide also achieves an array of other benefits including improvements in redness/blotchiness, skin sallowness (yellowing) and elasticity. 5% topical niacinamide applied daily over 12 weeks has been found to improve skin texture, red blotchiness, skin sallowness and skin elasticity (as measured via cutometry) in 2 separate trials on Caucasian women.[15][16] A moisturizing lotion containing 4% niacinamide has also been demonstrated to improve skin texture and skin tone evenness in a trial on Indian women.[29]

The mechanism by which niacniamide improves skin redness/blotchiness is thought to be related to the improved skin barrier function. Increased barrier function may mean less irritation when the skin encounters environmental insults, such as the use of detergents and soaps, and hence less redness of the skin. This theory has yet to be substantiated, however.[13]

The yellowing of skin that accompanies aging may be a result of glycation of proteins in the skin due to the Maillard reaction, a spontaneous oxidative reaction between protein and sugar that results in crossed-linked proteins called Amadori products that are yellowish-brown in color.[31][32] These glycation end products can accumulate in the extracellular matrix components like collagen and elastin[33] in the aging process in response to oxidative stress and UV exposure.[34] In fact, published data show a five-fold increase in collagen oxidation products in human skin from age 20 to 80.[31] Since NADH and NADPH are antioxidants and their levels can be increased with niacinamide administration, it is possible that topical niacinamide inhibits oxidative processes such as protein oxidation, glycation and the Maillaird reaction, thereby inhibiting skin yellowing.[13]

3.5 Photoprotection

Ultraviolet radiation can profoundly suppress the immune system, thus enhancing carcinogenesis. Longwave UVA, in particular, is highly immune suppressive even at low doses equivalent to 20 minutes of sun exposure. Agents that prevent UV-induced immunosuppression may thus reduce skin cancer.[35] Sunscreens however, tend to provide greater protection against shortwave UVB than UVA radiation, and can hence provide only partial protection from the mutagenic and immune suppressive effects of sunlight.[36]

Niacinamide has been shown to prevent immunosuppression and skin tumor induction by UVB radiation when applied topically to mice[37]. 5% niacinamide also protects against solar-simulated UVA- and UVB-induced immunosuppression in humans, as demonstrated in 5 different clinical studies.[35][38]

Based on analysis of data from gene chip microarrays, it has been hypothesized that the mechanims of protection may include alterations in complement, energy metabolism and apoptosis pathways.[38] Other studies have supported the view that nicotinamide may exert its UV protective effects on the skin via its role in cellular energy pathways.[36][39][40] As UV irradiation depletes keratinocytes of cellular energy, it has been suggested that niacinamide, as a precursor of NAD, may act at least in part by providing energy replenishment to irradiated cells.[36]

3.6 Acne treatment

Niacinamide has been assessed in multiple clinical studies for the treatment of inflammatory skin diseases, including acne vulgaris, as the mainstays of acne treatment, antibiotic and retinoid use, are known to contribute to the development of bacterial resistance and to cause side effects such as photosensitivity, respectively.[41] The first study utilizing niacinamide for treating acne vulgaris was published in 1995. In that study, topically applied 4% niacinamide gel was considered to be of comparable efficacy to 1% clindamycin gel, on the basis of statistically similar reductions in acne lesions and acne severity.[42] A more recent study in 2013 evaluated 5% niacinamide gel, and found it to be as effective as 2% clindamycin gel for treatment of mild to moderate acne vulgaris.[43]

The combination of niacinamide and clindamycin may not have benefits in treating resistant acne, however. In a study on 75 patients with acne vulgaris, there was no difference in the efficacy of the combination of 4% niacinamide + 1% clindamycin and 1% clindamycin, leading the authors to conclude that the addition of niacinamide provided no added advantage in the treatment of resistant acne.[44]

Niacinamide may exert its effects in acne vulgaris treatment in several ways. A 2% niacinamide moisturizer has been shown to affect facial sebum production, decreasing sebum excretion rates in Japanese individuals and casual sebum levels in Caucasians.[45] Niacinamide also inhibited the production of IL-8 in immortalized and primary human keratinocyte cell lines through downregulation of Propionibacterium acnes-induced IL-8 promoter activation via the NF-kappaB and MAPK pathways.[46] This may explain niacinamide's effectiveness, as P. acnes has been implicated in the inflammatory phase of acne vulgaris.[47]

3.6 Rosacea treatment

Rosacea is a chronic inflammatory condition of facial skin characterized by facial redness and sometimes pimples.[48] A large study evaluating niacinamide for the treatment of acne or rosacea has confirmed the potential benefits of oral tablets containing niacinamide (750mg niacinamide, 25mg zinc, 1.5mg copper, 500µg folic acid) as an alternative approach to oral antibiotics for the treatment of acne vulgaris and rosacea.[49][50]

The susceptibility to irritability, exogenous insults and subjective symptoms associated with rosacea are reminiscent of the symptoms reported for sensitive skin.[51][52] A deficient stratum corneum barrier contributes to sensitive skin, and skin sensitivity and reactivity have been found to decrease with treatments that improve stratum corneum barrier function.[53][54] Rosacea has also been linked to barrier impediment on the facial skin.[55] This suggests that individuals with rosacea may benefit from an improved stratum corneum barrier. Indeed, 2% niacinamide-containing facial moisturizer (Olay Total Effects 7X Visible Anti-Aging Vitamin Complex Fragrance Free) applied twice daily for 4 weeks to the face and forearms led to reduced transepidermal water loss, increased stratum corneum hydration and decreased wheal-and-erythema responses when challenged with DMSO, consistent with an improved skin barrier function. There was also a parallel improvement and mitigation of rosacea signs and symptoms, suggesting that niacinamide-containing moisturizers have a possible role as an adjuvant in the management of rosacea.[56]

3.7 Psoriasis treatment

Psoriasis is a chronic skin disorder characterized by symmetrical erythematous papules and plaques with a silver scale.[57] It is associated with hyperproliferation of the skin’s epidermal layer, which is attributed to premature maturation of keratinocytes and dermal inflammatory infiltrates comprising dendritic cells, macrophages and T cells.[58][59][60] Psoriatic skin also has a defective outer layer, which under normal circumstances protects from infection and dehydration.[61]

Niacinamide improves skin barrier function[7][8][9] and increases the biosynthesis of ceramides, which is associated with the induction of keratinocyte apoptosis.[62] In addition, niacinamide also has myriad anti-inflammatory effects including inhibition of poly (ADP-ribose) polymerase-1 (PARP-1), which plays a central role in the expression of inflammatory cytokines, chemokines, adhesion molecules, and inflammatory mediators,[63] suppression of neutrophil chemotaxis[64] and inhibition of nitric oxide synthase mRNA induction in activated macrophages.[65] Hence, niacinamide may be useful in the treatment of psoriasis.[62]

An early clinical trial concluded that the combination of topical 6-aminonicotinamide, a nicotinamide analog, with oral niacinamide therapy was a promising treatment for psoriasis.[66] In another pilot study, patients with psoriasis were randomized to two of 7 treatments -- placebo, calcipotriene 0.005% alone, nicotinamide 1.4% alone, calcipotriene plus nicotinamide 0.05%, calcipotriene plus nicotinamide 0.1%, calcipotriene plus nicotinamide 0.7%, or calcipotriene plus nicotinamide 1.4% -- each administered to lesions on one side of the body or to one of two lesions at least 5 cm apart, for 12 weeks. 50% of patients in the calcipotriene and nicotinamide 1.4% combination group achieved a clear to almost clear outcome, compared with only 18.8% of patients treated with placebo, 25% of patients treated with nicotinamide 1.4% alone and 31.5% of patients treated with calcipotriene alone, suggesting that 0.005% calcipotriene+1.4% nicotinamide was the best concentration of this combination.[67] A third clinical trial also found that the combination of 0.05% calcipotriol and 4% nicotinamide is more effective than calcipotriol alone in treatment of psoriasis. It appears, therefore, that niacinamide can enhance the efficacy of this vitamin D derivative when used in together for topical psoriasis treatment, and may be a good adjuvant to current treatment regimens.[57]

3.8 Melasma treatment

Niacinamide has been proposed as a therapeutic alternative for melasma treatment, since it reduces pigmentation and inflammation with minimal adverse events. One double-blind, left-right randomized clinical trial on 27 patients suffering from melasma found that 4% niacinamide led to good to excellent improvements in 44% of patients, based on skin pigment evaluation by a chromameter, melasma area and severity index (MASI), physician global assessment (PGA) by an independent observer, conventional photography, and infrared thermography. Digital analysis of post-treatment biopsies found that the amount of epidermal stained melanin had diminished significantly, and that the average inflammatory filtrate of mast cells was also reduced.[23]

4. Side Effects

Niacinamide is relatively non-toxic. In a report on the safety assessment of niacinamide and niacin by the Cosmetic Ingredient Review Expert Panel, clinical testing of niacinamide produced no stinging sensations at concentrations up to 10%, use tests produced no irritation at concentrations up to 5%, and a 21-day cumulative irritation test at concentrations up to 5% resulted in no irritancy. Niacinamide was also neither a sensitizer nor a photosensitizer. Overall, niacinamide was considered non-toxic at levels considerably higher than would be experienced in cosmetic products, and was hence considered safe as used in cosmetic formulations.[5]

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