A Review of the Range of Effects of

Niacinamide in Human Skin

Paul J. Matts1), John E. Oblong2) and Donald L. Bissett2)

Keywords: Niacinamide, nicotinamide, skin, ceramide, ageing, differentiation, barrier

Abstract History of Niacinamide

Niacinamide (also known as nicotinamide, Niacinamide is the amide of vitamin B3, also
3-pyridinecarboxamide) is the physiologi- known by the pseudonym »Vitamin PP«, that
cally active form of niacin or vitamin B3, the is, »Pellagra-Preventive«. The name is not
deficiency of which results in the nutritional without meaning. The first case of pellagra
disease pellagra with distinct cutaneous was reported in the U.S. in 1902; four
manifestations. Since its discovery and iso- decades of a pellagra epidemic followed
lation, a host of dermatological therapeutic during which, in states south of the Potomac
benefits and mechanisms have also been and Ohio rivers, some 3 million cases and
ascribed to this essential water-soluble vit- 100,000 deaths were reported [1]. Pellagra
amin when used as a topical agent. These in- patients presented with a variety of debili-
clude its apparent role as an anti-acne ac- tating symptoms including, significantly, a
tive, an up-regulator of epidermal sphingo- spectrum of cutaneous lesions. Tragically,
lipid synthesis, an up-regulator of markers of this led to the public exclusion of thousands
epidermal differentiation and dermal prolif- of victims, who came almost exclusively
eration (with concurrent stratum corneum from poor, rural, working-class families who
barrier benefits), and as a moderator of pho- fed themselves on a bland staple diet of
toimmunesuppression and accompanying cornmeal, molasses and fatback. Joseph
tumor genesis. More recently, fresh evi- Goldberger, a Hungarian emigrant who es- Fig. 1: Pellagra suffer, US South, early 20th
century
dence points to a role in modifying the cos- tablished himself as a renowned clinical epi-
The authors acknowledge the Waring Historical
metic appearance of skin through suppres- demiologist, reversed steadfast medical Library of the Medical University of South Caroli-
sion of epidermal melanosome transfer with opinion that pellagra was an infectious, na, Charleston, SC
subsequent effect on skin pigmentation and communicable disease. He proved that sim-
a role in modifying epidermal surface topo- ple dietary supplementation could both pre-
graphy. The mechanisms for these cutane- vent and cure pellagra. In 1927, after 13 years
ous effects are still unclear. However, since of work, Goldberg persuaded the American Physiological Role of Niacinamide
niacinamide is an important precursor of Red Cross to distribute dried yeast to Mis-
NADH and NADPH, it has been postulated sissippi flood victims and, thus, prevented a The substituted pyridine derivative niacin-
that topical application of niacinamide can further devastating epidemic. It was not un- amide is an essential constituent of the oxi-
promote this reported broad spectrum of til 1937 that nicotinic acid and its derivatives doreduction coenzymes nicotinamide ade-
activity through local correction of homeo- (including niacinamide) were shown to be nine dinucleotide (NAD) and nicotinamide
static balance of these two nucleotide coen- the elusive »PP« factor. By 1945, Goldber- adenine dinucleotide phosphate (NADP)
zymes. As there has been a dramatic in- ger’s legacy was permanent; public educa- (Fig. 2). During glycolysis and the TCA cycle,
crease in research into and use of niacin- tion had changed forever the poor diet of the 10 molecules of NAD+ (per molecule of glu-
amide in recent years, this review will cover South and pellagra was eliminated in the cose) are reduced to 10 NADH by the trans-
the current scope of knowledge of this im- United States. fer of a hydride ion to the 4-position of the
portant vitamin, including mechanistic un- niacinamide ring. The hydride ion of NADH
derstanding and cutaneous physiological serves effectively as an energy storage unit,
activity. giving up a pair of high-energy electrons to
the mitochondrial electron transport chain
when needed. In this process of oxidative
1) The Procter & Gamble Company, Rusham Park Technical Centre, Egham, Surrey, UK phosphorylation, electron pairs are trans-
Email: matts.pj@pg.com ferred from NADH to a final acceptor (oxy-
2) Miami Valley Laboratories, Cincinnati, Ohio, USA gen) via a series of electron carriers. This
transfer of electrons is thermodynamically

IFSCC Magazine – vol. 5, no 4 / 2002 285

 (as a marker of newly-synthesized secreted
collagen) and 14C-proline (as a marker of to-
tal protein) were extracted, separated and
quantified using HPLC equipped with a ra-
diometric detector. Results indicated firstly
that dermal fibroblasts from an aged donor
secreted significantly (p<0.05) less collagen
than those from a young donor and, further-
more, that NADPH / NADP redox ratios were
also lower (p<0.05) in fibroblasts from the
aged donor (results were normalized to the
cell number from the respective culture
well). Secondly, it was found that supple-
mentation of the aged cell culture with
niacinamide produced significant increases
in total collagen secreted (by 54%), total pro-
tein secreted (by 41%) and also in the num-
ber of cells (by 20%), relative to a vehicle
control. Importantly, there was also a signif-
Fig. 2: Structure of niacinamide and inclusion within NAD molecule icant 35% increase in the collagen / total pro-
tein ratio (relative to a vehicle control), indi-
cating some specificity for collagen biosyn-
favorable, i.e., ∆G is negative, and is coupled fibroblasts from the aged donor contained thesis and secretion. These data suggest,
to the pumping of protons out of the mito- decreased NADP redox ratios and total therefore, that treatment with niacinamide
chondrial matrix. The flow of protons back NADPH + NADP+ levels relative to those would have a positive impact on the dermal
into the matrix, in turn, catalyses the pro- from the young donor (51% and 28% respec- compartment, both in terms of its connective
duction of ATP by F0F1 ATP-synthase. Total tively). It does appear, therefore, that there tissue and gel matrix components. These
energy yield (∆G’) for this process is high is a reduction in nicotinamide coenzymes effects would be of particular significance in
(–52.7kcal). associated with senescence. aged and photodamaged skin.
Whereas NADH is involved in catabolism, Importantly, Oblong et al. [5] also found that
NADPH tends to serve as an electron (hy- supplementation of human dermal fibroblast
dride ion) donor in anabolic processes, that cultures derived from elderly donors with Niacinamide Up-regulates Epider-
is, biosyntheses. For example, NADPH is the 14C-niacinamide and 14C-nicotinic acid mal Ceramide Synthesis with Con-
reducing co-factor used by fatty acid syn- (niacinamide precursor) increased intracel- current Epidermal Barrier Benefits
thetase in lipid biosynthesis and by desmo- lular concentrations of NADPH. It appears
lases and hydroxylases in steroid biosynthe- that a localized supply of niacinamide, there- Ceramides are now known to play a central
sis. fore, can be utilized by aged cutaneous cells role in the structural and functional integrity
to restore intracellular nicotinamide coen- of the stratum corneum barrier function. A
zyme homeostasis. decrease in ceramide fraction has been re-
Nicotinamide Coenzymes in Skin It is worth noting, however, that despite the ported in aged and atopic skin [6]. Tanno et
are Depleted with age; Niacin- efficacy noted above, nicotinic acid (niacin) al. showed that in cultured human epidermal
amide can Help Normalize this Im- produces a well-documented cutaneous va- keratinocytes, niacinamide could induce up
balance sodilatation (»flushing«) when applied to- to a 5-fold up-regulation in ceramide syn-
pically. Niacin, therefore, presents a chal- thesis (p<0.05) in a dose-dependent fashion
NADH and NADPH can, thus, be viewed as lenge to cosmetic applications; there are no [7]. Further work by the same group [8]
fundamental energy »currency« units within such issues with the use of niacinamide. showed up-regulation of other sphingolipid
cells, driving the metabolism of cells involv- fractions (glucosylceramide and sphingo-
ed in both catabolic and anabolic process- myelin) as well as free fatty acid and cho-
es. There is an increasing pool of evidence Aged Fibroblasts Secrete Less lesterol synthesis (by 2.3 and 1.5-fold, re-
for a decline in systemic and intracellular Collagen than Young Cells; spectively). The workers proposed a mech-
concentrations of these two coenzymes Niacinamide can Stimulate New anism for these observations based on in-
with age in human and animal models [2,3,4] Collagen Synthesis creased levels of intra-cellular acetyl-CoA
and recent new data appear to confirm this. (the precursor common to epidermal lipid
Oblong et al. [5] established human dermal Oblong et al. [5] used 14C-proline to monitor synthesis) and increased expression of ser-
fibroblast cell lines from a 7-year old and a incorporation of label into collagen protein ine-palmitoyltransferase. Tanno et al. [8] al-
72-year old and used these to measure en- secreted from cultured human dermal fibro- so showed that these in-vitro results had
dogenous NADPH/NADP+ ratios and total blasts taken from a young (7-year old) and clinical significance in-vivo. Topical applica-
NADPH + NADP+ levels. It was found that aged donor (72-year old). 14C-hydroxyproline tion of a vehicle containing 2% niacinamide

286 IFSCC Magazine – vol. 5, no 4 / 2002

to dry lower legs over 4 weeks induced a keratinocytes. In other words, niacinamide Niacinamide Reduces Human
measurable significant increase (p<0.05) in has been shown to both stimulate basal epi- Skin Hyperpigmentation
recovered stratum corneum ceramide and dermal keratinocytes and to up-regulate
free fatty acid lipid fractions, vs. a vehicle biosynthesis of epidermal intermediates Hakozaki et al. [14] performed two studies
control. This was accompanied by a signifi- critical to the formation of a fully functioning demonstrating the effect of niacinamide on
cant reduction (p<0.05) in TEWL vs. vehicle stratum corneum. This may be due to in- skin hyperpigmentation in-vivo. In the first,
control (–27%). Similar significant reduc- creased intracellular levels of reduced 18 female Japanese subjects with hyperpig-
tions in TEWL vs. a vehicle control were not- nicotinamide coenzymes initiated by topical mented facial spots were treated for 8
ed also by Ertel et al. [9] after use of a mois- niacinamide. These effects would be ex- weeks with a vehicle containing 5% niacin-
turizing vehicle containing 2% niacinamide. pected to have a significant positive impact amide vs. a vehicle control in a split-face de-
Furthermore, they also noted that this posi- on ageing epidermal tissue in-vivo. sign. Pigmented spots were qualified and
tive barrier effect was accompanied by an quantified via algorithmic analysis of high-
increase in stratum corneum turnover rate Niacinamide Helps Prevent resolution digital images and subjective
(as measured by dansyl chloride assay). Fi- UV-Induced Deleterious Molecu- grading of images. Results of image analysis
nally, Draelos et al. [10] treated 48 female lar and Immunological Events showed that 5% niacinamide had induced a
subjects with stage I/II rosacea with a mois- significant (p<0.05) reduction in spot area at
turizing vehicle containing 2% niacinamide Shen et al. [11] demonstrated the ability of the 4 and 8 week time-points (vs. vehicle
for 4 weeks and demonstrated a significant niacinamide to protect cultured normal hu- control), accompanied by a significant re-
improvement in global condition (assessed) man keratinocytes against reactive oxygen duction (p<0.05) in graded visible spot pig-
in 96% of the subjects at week 4. They de- species induced by UVC irradiation or expo- mentation at 8 weeks (vs. vehicle control). In
monstrated, once again, that this clinical sure to hydrogen peroxide. They observed the second study, 120 female Japanese sub-
benefit was accompanied by a significant significant (p<0.05) dose-dependent attenu- jects with facial tanning were assigned to 2
improvement in stratum corneum barrier ation of apoptotic morphological changes, a of 3 treatments (SPF 15 sunscreen moistur-
function. decrease in p53 induction and a reduction in izer, 2% niacinamide in SPF 15 sunscreen
It appears that topical niacinamide is able to DNA ladders for niacinamide-treated cells moisturizer and a vehicle control). Subjects
augment the barrier properties of the skin, vs. those treated with a vehicle control. applied treatments split-face for 8 weeks. In
with accompanying clinically relevant ben- These data are consistent with work in ani- this study overall skin lightness was as-
efits, by up-regulating endogenous biosyn- mal models [12] demonstrating clearly the sessed by analysis of digital images and by
thesis of epidermal sphingolipids, in partic- ability of niacinamide to significantly reduce subjective grading. Results of image analy-
ular, ceramides. both induction of photocarcinogenesis and sis showed a significant (p<0.05) increase in
photoimmunesuppression. The mechanism skin lightness vs. the sunscreen moisturizer
by which niacinamide exerts these effects is and vehicle control at the 4 and 6 week time-
Niacinamide Up-regulates not yet clear. points, accompanied by a significant
Biosynthesis of Markers of (p<0.05) increase in graded visible skin light-
Keratinocyte Differentiation ness vs. vehicle control at 4 weeks. These
Niacinamide Inhibits Transfer of in-vivo data appear to confirm, therefore,
Oblong et al. [5] cultured normal human epi- Melanosomes from Melanocytes that the inhibitory role of niacinamide in
dermal keratinocytes to near-confluency to Keratinocytes melanosome transfer noted in-vitro [13],
and then supplemented the medium with does indeed translate to a significant effect
niacinamide. Following a 24h incubation, Boissy et al. [13] used co-cultures of human on hyperpigmentation in-vivo.
cells were counted, harvested and prepared melanocytes and keratinocytes to investi-
for assay for involucrin (by ELISA) and filag- gate the ability of niacinamide to reduce pig-
grin (by an immunoblot procedure). Results mentation in human skin. Use of immuno- Regulation of Sebaceous Lipid and
showed firstly a significant increase (p<0.05) linked dyes specific for each cell type en- Acne by Niacinamide
in the number of niacinamide-treated NHEK abled separate counts of keratinocytes,
relative to a vehicle control. Secondly, ni- melanocytes and keratinocytes containing Topical niacinamide in the form of a com-
acinamide-treated NHEK showed an up- transferred melanosomes to be performed. mercial 4% gel (Papulex®) has been shown
regulation of both involucrin and filaggrin The workers found significant inhibition to provide potent anti-inflammatory activity
biosynthesis vs. that induced by a vehicle (p<0.05) of melanosome transfer to keratino- in the treatment of acne vulgaris. Shalita et
control (by 45% and 100% respectively). cytes from melanocytes incubated in the al. [15] found that after 8 weeks of usage,
These two proteins are both critical to the presence of niacinamide (by 25-45%). It was 82% of subjects with inflammatory acne
differentiation process and the formation of also confirmed that niacinamide had no in- showed an improvement in global evalua-
fully integral keratinized corneocytes; filag- hibitory effect on melanocyte tyrosinase tion, with a significant reduction in papules /
grin plays a vital role in aggregation and activity. These data suggest that treatment pustules (–60%) and acne severity (–52%).
alignment of keratin tonofilaments in granu- of human skin in-vivo with topical niacin- Indeed, many practitioners use the treat-
lar cells and involucrin is an essential pre- amide would lead to a reduction in pigmen- ment citing a combination of efficacy and
cursor in the formation of the insoluble tation with time via this novel, elegant mech- lack of bacterial-resistance. Shalita et al.
cornified envelope surrounding terminal anism. [15] and others postulate that niacinamide

IFSCC Magazine – vol. 5, no 4 / 2002 287

may act via its apparent antihistaminic ef- pathogenesis. It is accepted that acne is a control and vehicle containing 5% niacin-
fect, activity as an electron scavenger, or its disease involving the pilosebaceous duct amide; n=88) split-face for 8 weeks. Skin tex-
inhibition of 3’-5’ cyclic-AMP phosphodi- and Propionibacterium acnes. Despite the ture appearance was assessed as above.
esterase activity. on-going debate as to the exact interplay of The niacinamide-containing treatment pro-
Recent data, however, appear to demon- these factors, it is without doubt that a sig- vided a significant improvement in skin tex-
strate an altogether more fundamental role nificant reduction both in total sebaceous ture appearance relative to the vehicle con-
for topical niacinamide in acne treatment. lipid bulk and in the triglyceride fraction trol at the 8 week time-point, confirming the
Biedermann et al. [16] used viable human fa- would be expected to impact positively results of the first study.
cial biopsies (from face-lift surgery) to mea- acne-form skin. This effect on skin surface texture is consis-
sure the effect of niacinamide on sebaceous tent with that noted in a 10-week clinical
lipogenesis. Cultured biopsies were treated study where Matts & Solechnick [18] used
with niacinamide or trans-retinoic acid (tRA) Niacinamide Exerts Multiple multiple-angle reflectance spectrophoto-
for 4 days, after which they were incubated Benefits on the Appearance of metry to measure the diffuse component of
with 14C-acetate. Lipid components were Ageing / Photodamaged Skin, skin reflection. They noted a significant in-
subsequently isolated, fractionated and In-vivo crease in the diffuse component of 5%
identified using analytical TLC and radiome- niacinamide-treated dorsal hand skin vs.
try. Niacinamide produced significant dose- Bissett et al. [17] studied the effects of topi- vehicle control after 10 weeks of treatment
dependent reductions in total sebaceous cal niacinamide in ageing human facial skin (p<0.05), consistent with significant blind
lipogenesis (–42% at 25 mM [p<0.01]). Fur- in two double-blinded clinical studies. In the self-rated preferences for texture appear-
thermore, the reduction induced by 25 mM first, 40 female subjects aged 35 - 60 applied ance over vehicle control (p<0.05). This
niacinamide was equivalent to that pro- a vehicle and vehicle containing 5% niacin- change was consistent with a shift in texture
duced by 1 µM tRA (–32% [p=0.01]). When amide (randomized split-face) for 12 weeks. distribution towards the finer, anisotropic
discrete lipid classes were identified and High-resolution digital images were taken at features characteristic of younger skin.
quantified, it was found that niacinamide baseline, 4, 8 and 12 weeks and texture and
had produced marked reductions in both hyperpigmentation were evaluated by
triglyceride and fatty acid synthesis vs. the judges (comparing blind-coded image pairs, Niacinamide is Delivered Effec-
control (–52% and –46% respectively for 25 baseline vs. another treatment time-point). tively from a Range of Vehicles
mM niacinamide [p<0.05]). It is now known Judges were able to perceive a significant and Demonstrates Excellent Skin
that triglycerides represent by far the largest improvement in skin texture appearance at Compatibility
proportion of sebaceous gland lipid (50- 4 weeks (p<0.1) and 12 weeks (p<0.05) and a
60%); the observed effect of niacinamide on significant improvement in hyperpigmented Franz [19] determined niacinamide absorp-
total lipogenesis is, therefore, probably at- spot appearance by 8 weeks (p<0.05) (Fig. 3). tion in-vitro through full-thickness abdomi-
tributable to triglyceride reduction. In a second study, female subjects aged 35- nal skin mounted in flow-through diffusion
This has important implications for acne 60 applied blind-coded products (vehicle cells. Franz used acetone as a carrier and
found 28.8% of the starting dose in the re-
ceptor medium at 24 h. Delivery of niacin-
amide (2-20%) from a range of cosmetic for-
Baseline 12 Weeks
mulae (including moisturizers, foundations
and lipsticks) was studied using a modified
in-vitro Franz flow-through cell technique
[20]. For formulae containing 2% niacin-
amide, approximately 10% of the starting
dose was detected in the receptor medium
at 48 h. Importantly, these studies highlight-
ed the apparent independence of niacin-
amide penetration rate from diverse vehicle
matrices.
The Cosmetic Ingredient Review Expert Pan-
el report for niacinamide [21] details a very
wide range of cutaneous tolerance studies
confirming the excellent profile of niacin-
amide as a cosmetic skin care ingredient.

Conclusion
Niacinamide, therefore, has been shown to
Fig. 3: Same subject at baseline and after 12 weeks of topical treatment with 5% niacinamide be a cosmetic ingredient with an extraordi-

288 IFSCC Magazine – vol. 5, no 4 / 2002

nary breadth and history of cutaneous ben- foliation without compromising barrier [21] »Safety assessment of niacinamide and
efits. It is thought that its fundamental role as function, 58th Annual Meeting of the niacin; tentative report of the Cosmetic
a precursor of reduced nicotinamide coen- American Academy of Dermatology, San Ingredient Review Expert Panel«, Sep-
Francisco, 2000. tember 17, 2001
zymes such as NADH and NADPH is pivotal
[10] Draelos, Z.D., Ertel, E., Berge, C., and Am-
to its observed effects. It displays distinct
burgey, M.S., A facial moisturizing prod-


advantages over other ingredients with sim- uct as an adjunct in the treatment of
ilar benefits, such as retinol, in that it is well rosacea, 59th Annual Meeting American
tolerated, and is not subject to oxidation or Academy of Dermatology, Washington,
photolysis. In short, the multiplicity of effects 2001.
and formulation benefits seen with niacin- [11] Shen, S.C., Yoshii, T., Chen, Y.C., Tsai, T.H.,
amide make it an ideal choice for a variety of Hu, C.H., and Lee, W.R., Niacinamide re-
duces DNA damage caused by reactive
cosmetic products targeting young and old oxygen species, 60th Annual Meeting
skin alike. American Academy of Dermatology, New
Orleans, 2002.
[12] Gensler, H.L., Prevention of photoim-
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