James Odell, OMD, ND, LAc
Niacinamide, also known as nicotinamide, is a form of vitamin B3 that plays an important role in energy metabolism and cellular health. It has been shown to offer benefits related to skincare, and certain cancers (particularly skin cancers), chronic kidney disease, inflammatory conditions, and dementia. This article will explain the history behind niacinamide, its association with pellagra, and current research on its many health benefits.
Niacin, B3, is a water-soluble vitamin that occurs in two chemical forms: nicotinic acid and nicotinamide (also known as niacinamide). Although niacin and nicotinamide are considered similar in their role as vitamins, their pharmacologic indications, effects, and side effects are different. Niacin has a high affinity to a G-protein-coupled receptor HM74A in human cells resulting in the release of prostaglandins that cause vasodilation or flushing of the skin. It also lowers cholesterol levels, while nicotinamide is taken to treat arthritis and pellagra.
B3 can be obtained directly from diet or synthesized from dietary tryptophan in the liver. However, the conversion of tryptophan to vitamin B3 is generally low, as it takes 60 mg of tryptophan to make just 1 mg of vitamin B3.1
Pellagra
A deficiency of vitamin B3 can lead to a disease called pellagra, which is characterized by the four D’s — diarrhea, dermatitis, dementia, and if left untreated, death. Though pellagra is rare in North America, it still exists in many developing countries.2, 3 Historically, vitamin B3 was called vitamin PP, an acronym for pellagra-preventive. It was in the USA around the middle of the 20th century that most studies on the etiology, prevention, and cure of pellagra were undertaken.
The first case of pellagra was reported in the U.S. in 1902; four decades of a pellagra epidemic followed during which, in states south of the Potomac and Ohio rivers, some 3 million cases and 100,000 deaths were reported. Pellagra patients present with a variety of debilitating symptoms including, significantly, a spectrum of cutaneous lesions. Tragically, this led to the public exclusion of thousands of victims, who came almost exclusively from poor, rural, working-class families who fed themselves on a bland staple diet of cornmeal and molasses.
Joseph Goldberger, a Hungarian emigrant who established himself as a renowned clinical epidemiologist, reversed steadfast medical opinion that pellagra was an infectious, communicable disease. He proved that simple dietary supplementation could both prevent and cure pellagra. In 1927, after 13 years of work, Goldberg persuaded the American Red Cross to distribute dried yeast to Mississippi flood victims and, thus, prevented a further devastating epidemic. It was not until 1937 that nicotinic acid and its derivatives (including niacinamide) were shown to be the elusive »PP« factor. By 1945, Goldberger’s legacy was permanent; public education had changed forever the poor diet of the South, and pellagra was eliminated in the United States.
Elsewhere, the introduction of maize as a primary dietary staple resulted in incidences of pellagra. For example, corn, used here in the sense of "Indian corn" or maize, was brought to Europe from America, and over the period 1750-1850 became the typical staple in many of the areas bordering the Mediterranean. By the end of that period, it had also come to be recognized that pellagra had become a serious, chronic disease in these same countries, flaring up each spring amongst the poorest people living on diets containing much corn and very little animal food (i.e., meat, eggs, or dairy products). Pellagra in South Africa coincided with an outbreak of rinderpest (also known as cattle plague) in 1897 leading to the death of cattle, thus necessitating a change in the lifestyle of the Bantu population from meat- to maize-eating, with little meat or milk intake.4
Pellagra in India has been associated with the intake of maize and another staple, jowar (a variety of sorghum). In the Southern USA, pellagra became a serious medical problem following the American civil war, due to subsistence on a largely maize-based staple.5
The maize-induced pellagra associated with reduced B3 malnutrition is compounded by the presence of relatively large amounts of the essential amino acid leucine. Whereas the average tryptophan content of maize is only 37.5 and 62.5 mg/g nitrogen, respectively, the corresponding leucine content is 794 and 700 mg/g nitrogen.6
With marginal niacin or tryptophan intake, an excess of leucine can induce pellagra by actions on enzymes of the hepatic kynurenine pathway of tryptophan degradation, during which niacin is synthesized.
Thus, pellagra is a disease of malnutrition involving deficiency not only of B3, but also its tryptophan precursor, and is also compounded by deficiencies of other nutrients, notably other B vitamins and possibly also zinc. Niacin deficiency alone would not induce pellagra if adequate amounts of tryptophan are consumed in meat, dairy products, eggs, or certain plant sources, and if the metabolism of tryptophan to niacin along the hepatic kynurenine pathway is not impaired. Thus, tryptophan metabolism along this pathway is also a major determinant of pellagra. Alcoholism also contributes to pellagra incidence through the associated malnutrition and B vitamin deficiencies, impaired conversion of tryptophan to niacin, and induction of zinc deficiency.7
Both nicotinic acid and niacinamide can treat pellagra, but niacinamide is preferred since it is associated with fewer side effects.8, Unlike nicotinic acid, niacinamide does not reduce cholesterol or cause flushing of the skin.9
Food Sources
Good food sources of B3 include yeast, meat, poultry, redfish (e.g., tuna, salmon), cereal (especially fortified cereal), legumes, and seeds. Milk, green leafy vegetables, coffee, and tea also provide some niacin.10
In plants, especially mature cereal grains like corn and wheat, niacin may be bound to sugar molecules in the form of glycosides, which significantly decreases its bioavailability.11
Thus, many refined grain products, including cereals, are fortified with niacinamide. Since niacinamide is water-soluble, the body does not store this vitamin, which is why it is necessary to consume foods that contain nicotinic acid or niacinamide daily.
Biochemistry and Benefits
Niacinamide is the precursor to the all-important molecule nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP). NAD+ can be phosphorylated (NADP) and reduced (NADH and NADPH). The reduced forms, NADH and NADPH, are potent intracellular antioxidants. Thus, NAD+ and NADP are the primary mediators in cell redox reactions and prevent the protein glycation mechanism that occurs when sugars crosslink with proteins.
Excess protein glycation is associated with skin age spots. In short, NAD+ is an essential coenzyme that is required by every cell of the body and directly and indirectly, influences many key cellular functions, including metabolic pathways, DNA repair, cellular senescence, and immune cell function. These cellular processes and functions are critical for maintaining tissue and metabolic homeostasis and for healthy aging. Recent studies have explained some of the mechanisms underlying the therapeutic effectiveness of niacinamide. These appear to be predominantly mediated by its conversion to NAD+.
Pharmacological strategies that boost intracellular NAD+ are highly coveted for their therapeutic potential. One approach is the activation of nicotinamide phosphoribosyl transferase (NAMPT) to increase the production of nicotinamide mononucleotide (NMN), the predominant NAD+ precursor in humans. NAMPT has both intra- and extracellular forms in mammals. Intracellular NAMPT is an essential enzyme in the NAD+ biosynthetic pathway starting from niacinamide. Although niacinamide and niacin are both called vitamin B3, niacin will not activate NAMPT like niacinamide, so it is best to use niacinamide to increase NAD+. Additionally, niacinamide, unlike niacin, will not cause flushing which is due to a large release of histamine.
Reducing Oxidative Free Radical Pathology
NAD+ has been shown to increase mitochondria function and ATP production, the "power plant" and energy currency of cells that drive energy and metabolism.12 By increasing the amount of NAD+, niacinamide administration alters mitochondrial physiology and reduces oxidative free radical pathology. It also benefits the activity of many proteins. Because niacinamide raises NAD+ levels, it can help prevent and treat many neurological conditions, including Alzheimer’s and ischemic stroke.
Reducing Neural Degeneration
NAD+ pathways have been shown as critical to prevent neuronal degradation and counteract processes that lead to cognitive decline as seen in Alzheimer’s and Parkinson’s. Since declining NAD+ levels appear to be what’s behind the neurodegenerative processes, increasing NAD+ using precursors such as nicotinamide can be very therapeutic.
Improving DNA and Cellular Repair
NAD+ is the sole substrate for Poly (ADP-ribose) polymerase enzymes. PARP is a family of proteins involved in several cellular processes such as DNA repair, genomic stability, and programmed cell death. Thus, NAD is important for cellular stability and to improve tissue healing.
Reducing Age-related Diseases
NADH and NADPH can, thus, be viewed as fundamental energy currency units within cells, driving the metabolism of cells involved in both catabolic and anabolic processes. There is an increasing pool of evidence for a decline in systemic and intracellular concentrations of these two coenzymes with age in human and animal models.13, 14, 15 and recent new data appear to confirm their decline with age. This decline is linked to age-related diseases like cognitive decline, cancer, kidney disease, endothelial health “blood vessels,” metabolic disease, neuropathy, and frailty.
Many of these processes have been shown to slow or even reverse by restoring NAD+ levels. It has been shown in mice that increasing NAD+ increases endurance and regeneration of skeletal muscle tissue and reduces symptoms of inflammatory activity and associated heart failure.16
Improving Skin Health
Niacinamide plays an important role in keeping skin healthy. For this reason, it is a popular additive in the cosmetic and skincare industry. When applied topically or taken orally as a supplement, niacinamide has been shown to have anti-inflammatory effects on the skin. It has been used to treat skin conditions like acne and rosacea, a facial skin disorder characterized by redness. This makes niacinamide a popular alternative to oral or topical antibiotics for treating acne or rosacea.
Shen et al. demonstrated the ability of niacinamide to protect cultured normal human keratinocytes against reactive oxygen species induced by UVC irradiation or exposure to hydrogen peroxide.17
Other Benefits
Niacinamide also has potent anti-obesity effects, can help prevent neurodegeneration and heart failure, and reverse leaky gut or altered bowel permeability.
Safety
Niacinamide is generally considered safe with few side effects at appropriate doses. The optimum intake of niacin for health promotion and chronic disease prevention is not yet known. The RDA is 16 mg daily for men and 14 mg for women.
Dosage
Dosage should always be tailored to the individual and condition being treated. Many doctors prescribe niacinamide at a low dosage of 50 mg three times a day. Most people respond favorably to this simple intervention for increasing NAD+. Niacinamide comes in powders, capsules, and tablets and is very inexpensive. However, most capsules and tablets are 500 mg. So, to achieve the lower dosage it will probably be necessary to use a powder and measure out 50 mg. It is also advisable to supplement all the other B vitamins, as they too are crucial for mitochondrial function, especially regular niacin, riboflavin, and folate. Riboflavin, vitamin B6, and iron are required in some of the reactions involved in the conversion of tryptophan to NAD via the liver. Frequently, decreased mitochondrial function is in part due to a deficiency of B vitamins. Thus, this can be simply remedied with a low-dose high-quality non-synthetic form of B complex.
References:
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16. Zhou, Bo, Dennis Ding-Hwa Wang, Yanhua Qiu, Sophia Airhart, Yaxin Liu, April Stempien-Otero, Kevin D. O’Brien, and Rong Tian. "Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure." The Journal of clinical investigation 130, no. 11 (2020): 6054-6063.
17. Shen, S.C., Yoshii, T., Chen, Y.C., Tsai, T.H., Hu, C.H., and Lee, W.R., Niacinamide reduces DNA damage caused by reactive oxygen species, 60thAnnual Meeting American Academy of Dermatology, New Orleans, 2002