Vitamin B3

Vitamin B3 also known as Niacin, nicotinamide (pyridine-3-carboxamide), nicotinamide adenine dinucleotide (NAD), nicotinic acid (pyridine-3-carboxylic acid) or nicotinamide riboside is one of the water-soluble B vitamins that occurs in many animal and plant tissues ¹, ², ³, ⁴. Vitamin B3 or Niacin is the generic name for nicotinic acid (pyridine-3-carboxylic acid), nicotinamide (niacinamide or pyridine-3-carboxamide), and related derivatives, such as nicotinamide riboside ⁵, ⁶, ⁷. Niacin is naturally present in many foods, added to some food products, and available as a dietary supplement. Food such as bran, yeast, eggs, peanuts, poultry, red meat, fish, whole-grain cereals, legumes, and seeds are rich sources of niacin or vitamin B3 ⁸. The essential amino acid tryptophan can also be converted into nicotinamide adenine dinucleotide (NAD) via the kynurenine pathway, so tryptophan (an amino acid in protein) is considered a dietary source of niacin ³, ⁴. Note that none of the Niacin vitamers are related to the nicotine found in tobacco, although their names are similar. Likewise, nicotine — but not nicotinic acid — is an agonist of the nicotinic receptors that respond to the neurotransmitter, acetylcholine ³.

Essential to all forms of life, the coenzyme nicotinamide adenine dinucleotide (NAD) is synthesized in all tissues in your body from four precursors that are provided in the diet: nicotinic acid, nicotinamide, nicotinamide riboside, and tryptophan (Figure 1) ⁴. More than 400 enzymes require nicotinamide adenine dinucleotide (NAD) to catalyze reactions in your body, which is more than for any other vitamin-derived coenzyme ⁵. Nicotinamide adenine dinucleotide (NAD) is also converted into another active form, the coenzyme nicotinamide adenine dinucleotide phosphate (NADP), in all tissues except skeletal muscle ⁹.

Most dietary niacin is in the form of nicotinic acid and nicotinamide, but some foods contain small amounts of NAD and NADP.

Humans are able to synthesize nicotinic acid from tryptophan – the liver can synthesize niacin from the essential amino acid tryptophan, but the synthesis is extremely slow and requires vitamin B6 (Pyridoxine); 60 mg of tryptophan are required to make one milligram of niacin ¹⁰. Bacteria in the gut may also perform the conversion but are inefficient. Another source for nicotinic acid is the gut flora. In humans there is no deamidation of nicotinamide to nicotinic acid in the gut. Nicotinamide is rapidly absorbed in stomach and small intestine. In plasma both the acid and the amide form are found. Red blood cells take up the nicotinic acid by a sodium dependent saturable transport system. Both the nicotinic acid and nicotinamide are able to pass the blood-brain barrier, however separate systems for uptake have been identified. Brain cells have a high affinity for nicotinamide, but not for nicotinic acid. Nicotinamide is the main substance that is transported between the different tissues as a precursor of NAD synthesis. The liver, kidneys, brain and red blood cells prefer nicotinic acid as a precursor for NAD synthesis, but testes and ovaries prefer nicotinamide. NAD nucleosidase cleaves NAD with nicotinamide as one of the products. This can be deamidated to form nicotinic acid (and re-converted to NAD) or methylated and released via urine. Excretion of the amide (and its metabolites) tends to be more extensive compared to the acid ¹¹.

Figure 2 illustrates the separate biosynthetic pathways that lead to nicotinamide adenine dinucleotide (NAD) production from the various dietary precursors. Nicotinamide adenine dinucleotide (NAD) is synthesized from nicotinamide and nicotinamide riboside via two enzymatic reactions, while the pathway that yields nicotinamide adenine dinucleotide (NAD) from nicotinic acid – known as the Preiss-Handler pathway — includes three steps ³. The kynurenine pathway is the longest nicotinamide adenine dinucleotide (NAD) biosynthetic pathway: the catabolism of tryptophan through kynurenine produces quinolinic acid, which is then converted to nicotinic acid mononucleotide, an intermediate in nicotinamide adenine dinucleotide (NAD) metabolism. Nicotinamide adenine dinucleotide (NAD) is then synthesized from nicotinic acid mononucleotide in the Preiss-Handler pathway ¹².

All pathways generate intermediary mononucleotides — either nicotinic acid mononucleotide or nicotinamide mononucleotide ³. Specific enzymes, known as phosphoribosyltransferases, catalyze the addition of a phosphoribose moiety onto nicotinic acid or quinolinic acid to produce nicotinic acid mononucleotide or onto nicotinamide to generate nicotinamide mononucleotide ³. Nicotinamide mononucleotide is also generated by the phosphorylation of nicotinamide riboside, catalyzed by nicotinamide riboside kinases (NRKs) ³. Furthermore, adenylyltransferases catalyze the adenylation of these mononucleotides to form either nicotinic acid adenine dinucleotide or nicotinamide adenine dinucleotide (NAD). Nicotinic acid adenine dinucleotide is then converted to nicotinamide adenine dinucleotide (NAD) by glutamine-dependent NAD synthetase (NADSYN), which uses glutamine as an amide group donor (Figure 2) ¹². Of note, nicotinic acid adenine dinucleotide has been reported to form following the administration of high-dose nicotinamide riboside, suggesting that a potential deamidation could occur to convert nicotinamide adenine dinucleotide (NAD) to nicotinic acid adenine dinucleotide when the pool of nicotinamide adenine dinucleotide (NAD) is high ².

When NAD and NADP are consumed in foods, they are converted to nicotinamide in the gut and then absorbed ⁹. Ingested niacin is absorbed primarily in the small intestine, but some is absorbed in the stomach ⁵, ⁶, ⁷.

Niacin or vitamin B3 helps turn the food you eat into the energy you need. Niacin is important for the development and function of the cells in your body ¹³.

As a drug, Niacin or vitamin B3, has two main indications ⁸:

To treat hyperlipidemia (types 2A and 2B or primary hypercholesterolemia) (FDA approved use). Niaspan and generic niacin extended release (ER), available as a prescription medicine, provides 500-1,000 mg extended-release nicotinic acid. It is used to treat high blood cholesterol levels ⁴. The principal antilipemic effect of niacin appears to result mainly from decreased production of very low density lipoprotein cholesterol (VLDL-cholesterol) and is effective in lowering low density lipoprotein (LDL) cholesterol and raising high density lipoprotein (HDL) cholesterol, which makes this agent of unique value in the therapy of dyslipidemia ¹⁴, ¹⁵. Decreased production of VLDL-cholesterol by niacin may be related to the partial inhibition of free fatty acid release from adipose tissue, a decreased delivery of free fatty acids to the liver, and a decrease in triglyceride synthesis and VLDL-triglyceride transport. Enhanced clearance of VLDL-cholesterol and chylomicron triglycerides also may occur, possibly as a result of enhanced activity of lipoprotein lipase. Reductions in LDL-cholesterol concentrations may be related to decreased production and enhanced hepatic clearance of LDL-cholesterol precursors (i.e., VLDL-cholesterol). The mechanism by which niacin increases HDL-cholesterol concentrations has not been fully elucidated but may be related to a decreased hepatic clearance of apo A-I-containing particles and decreased synthesis of apo A-II. Niacin has no effect on cholesterol synthesis or fecal excretion of fats, sterols, or bile acids.
To treat Niacin or vitamin B3 Deficiency, also known as pellagra (Italian for “rough skin”) ¹⁶, ¹⁷, ¹⁸. In the 1700s, pellagra first appeared in Italy, and the name translates into “pella” meaning skin, and “agra” meaning rough ¹⁹. Niacin or vitamin B3 deficiency causes pellagra, a disease characterized by the triad of dermatitis, diarrhea, and dementia that is endemic today in parts of India and China, and may result in death in severe cases ²⁰, ²¹. Other symptoms include irritability, loss of appetite, weakness, and dizziness. Niacin deficiency is rare in the United States but may still be seen in alcoholics, dietary cultists, and patients with malabsorption syndrome ²². Some clinicians prefer niacinamide for the treatment of pellagra because it lacks vasodilating effects ²³.

The coenzymes nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) are required in most metabolic oxidation-reduction (redox) processes in cells where NAD and NADP are oxidized or reduced (Figure 3) ⁴. NAD is primarily involved in catabolic reactions that transfer the potential energy in carbohydrates, fats, and proteins to adenosine triphosphate (ATP), the cell’s primary energy currency ⁹. Nicotinamide adenine dinucleotide (NAD) is also required for enzymes involved in critical cellular functions, such as the maintenance of genome integrity, control of gene expression, and cellular communication ⁹, ⁷. Nicotinamide adenine dinucleotide phosphate (NADP), in contrast, enables anabolic reactions, such as the synthesis of cholesterol and fatty acids, and plays a critical role in maintaining cellular antioxidant function ⁴.

Even when taken in very high doses of 3–4 g, niacin is almost completely absorbed ⁴. Once absorbed, physiologic amounts of niacin are metabolized to nicotinamide adenine dinucleotide (NAD). Some excess niacin is taken up by red blood cells to form a circulating reserve pool. The liver methylates any remaining excess to N1-methyl-nicotinamide, N1-methyl-2-pyridone-5-carboxamide, and other pyridone oxidation products, which are then excreted in the urine ⁴. Unmetabolized nicotinic acid and nicotinamide might be present in the urine as well when niacin intakes are very high ⁴.

Levels of niacin in the blood are not reliable indicators of niacin status ⁴. The most sensitive and reliable measure of niacin status is the urinary excretion of its two major methylated metabolites, N1-methyl-nicotinamide and N1-methyl-2-pyridone-5-carboxamide ⁶. Excretion rates in adults of more than 17.5 micromol/day of these two metabolites reflect adequate niacin status, while excretion rates between 5.8 and 17.5 micromol/day reflect low niacin status ⁴. An adult has niacin deficiency when urinary-excretion rates are less than 5.8 micromol/day ⁴. Indicators of niacin deficiency such as this and other biochemical signs (e.g., a 2-pyridone oxidation product of N1-methyl-nicotinamide below detection limits in plasma or low red blood cell NAD concentrations) occur well before overt clinical signs of niacin deficiency ⁶. Another measure of niacin status takes into account the fact that NAD levels decline as niacin status deteriorates, whereas NADP levels remain relatively constant ⁵, ⁷, ²⁴. A “niacin number” (the ratio of NAD to NADP concentrations in whole blood x 100) below 130 suggests niacin deficiency ²⁵, ²⁶. A “niacin index” (the ratio of red blood cell NAD to NADP concentrations) below 1 suggests that an individual is at risk of developing niacin deficiency ²⁷. No functional biochemical tests that reflect total body stores of niacin are available ²⁴.

The recommended dietary allowance (RDA) of Niacin or vitamin B3 is 14 to 16 mg daily in adults, and slightly more for pregnant women (18 mg) and less for children (2 to 12 mg). No adverse effects have been reported from the consumption of naturally occurring niacin in foods ⁶, ¹⁵. However, high intakes of both nicotinic acid and nicotinamide taken as a dietary supplement or medication can cause adverse effects, although their toxicity profiles are not the same.

30 mg to 50 mg nicotinic acid or more typically causes flushing; the skin on the patient’s face, arms, and chest turns a reddish color because of vasodilation of small subcutaneous blood vessels ⁴. The flushing is accompanied by burning, tingling, and itching sensations ²⁸, ²⁹. These signs and symptoms are typically transient and can occur within 30 minutes of nicotinic acid intake or over days or weeks with repeated dosing; they are considered an unpleasant, rather than a toxic, side effect ⁴. However, the flushing can be accompanied by more serious signs and symptoms, such as headache, rash, dizziness, and/or a decrease in blood pressure. Supplement users can reduce the flushing effects by taking nicotinic acid supplements with food, slowly increasing the dose over time, or simply waiting for the body to develop a natural tolerance ⁴.

When taken in pharmacologic doses of 1,000 to 3,000 mg/day used in the therapy of hyperlipidemia, nicotinic acid can also cause more serious side effects ²⁸, ²⁹, ⁹, ⁶. Many of these effects have occurred in patients taking high-dose nicotinic acid supplements to treat hyperlipidemias. These adverse effects can include hypotension severe enough to increase the risk of falls; fatigue; impaired glucose tolerance and insulin resistance; gastrointestinal effects, such as nausea, heartburn, and abdominal pain; and ocular effects, such as blurred or impaired vision and macular edema (a buildup of fluid at the center of the retina). High doses of nicotinic acid taken over months or years can also cause liver injury; effects can include increased levels of liver enzymes; hepatic dysfunction resulting in fatigue, nausea, and anorexia; hepatitis; and acute liver failure ¹⁵, ⁶, ³⁰, ²⁸, ³¹. Liver injury is more likely to occur with the use of extended-release forms of nicotinic acid ³², ³³, ²⁸.

To minimize the risk of adverse effects from nicotinic acid supplementation or to identify them before they become serious, the American College of Cardiology and the American Heart Association recommend measuring liver transaminase (liver enzyme), fasting blood glucose or hemoglobin A1C, and uric acid levels in all supplement users before they start therapy, while the dose is being increased to a maintenance level, and every 6 months thereafter ³⁰. The American College of Cardiology and the American Heart Association also recommend that patients not use nicotinic acid supplements or stop using them if their liver transaminase (liver enzyme) levels are more than two or three times the upper limits of normal; if they develop persistent high blood sugar level (hyperglycemia), acute gout, unexplained abdominal pain, gastrointestinal symptoms, new-onset atrial fibrillation, or weight loss; or if they have persistent and severe skin reactions, such as flushing or rashes ³⁰.

Nicotinamide does not cause skin flushing and has fewer adverse effects than nicotinic acid, and these effects typically begin with much higher doses ²⁸. Nausea, vomiting, and signs of liver toxicity can occur with nicotinamide intakes of 3,000 mg/day ⁶. In several small studies of participants undergoing hemodialysis, the most common adverse effects from 500-1,500 mg/day nicotinamide supplementation for several months were diarrhea and thrombocytopenia (low platelet count) ²⁹, ³⁴, ³⁵, ³⁶.

The Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine has established Tolerable Upper Intake Level (maximum daily intake unlikely to cause adverse health effects) for niacin that apply only to supplemental niacin for healthy infants, children, and adults ⁶. These Tolerable Upper Intake Levels (ULs) are based on the levels associated with skin flushing. The Food and Nutrition Board acknowledges that although excess nicotinamide does not cause flushing, a Tolerable Upper Intake Level for nicotinic acid based on flushing can prevent the potential adverse effects of nicotinamide ⁶. The Tolerable Upper Intake Level, therefore, applies to both forms of supplemental niacin. However, the Tolerable Upper Intake Level does not apply to individuals who are receiving supplemental niacin under medical supervision ⁶.

Niacin and its metabolites are rapidly excreted in urine. Following oral administration of single and multiple doses of an immediate-release (Niacor) or extended-release (Niaspan) niacin preparation, approximately 88 or 60-76% of the dose, respectively, was excreted in urine as unchanged drug and inactive metabolites ³⁷.

Figure 1. Dietary precursors of nicotinamide adenine dinucleotide (NAD)

Footnote: Dietary precursors of nicotinamide adenine dinucleotide (NAD), including nicotinic acid, nicotinamide, and nicotinamide riboside, are collectively referred to as niacin or vitamin B3. The essential amino acid tryptophan can also be converted into NAD via the kynurenine pathway.

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Figure 2. Nicotinamide adenine dinucleotide (NAD) synthesis

Footnote: Figure 2 illustrates the separate biosynthetic pathways that lead to nicotinamide adenine dinucleotide (NAD) production from the various dietary precursors. Nicotinamide adenine dinucleotide (NAD) is synthesized from nicotinamide and nicotinamide riboside via two enzymatic reactions, while the pathway that yields nicotinamide adenine dinucleotide (NAD) from nicotinic acid – known as the Preiss-Handler pathway — includes three steps ³. The kynurenine pathway is the longest nicotinamide adenine dinucleotide (NAD) biosynthetic pathway: the catabolism of tryptophan through kynurenine produces quinolinic acid, which is then converted to nicotinic acid mononucleotide, an intermediate in nicotinamide adenine dinucleotide (NAD) metabolism. Nicotinamide adenine dinucleotide (NAD) is then synthesized from nicotinic acid mononucleotide in the Preiss-Handler pathway ¹².

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Figure 3. Nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) functions

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What does Vitamin B3 (Niacin) do?

Vitamin B3 or Niacin is essential for maintaining cell function. Vitamin B3 or Niacin is a component of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) required by over 400 enzymes involved in the metabolism of carbohydrates, fats, proteins, and alcohol, as well as DNA repair and cell signalling. Therefore, tissues with a high energy requirement or cell turnover rate such as the skin, bowel, and brain are those affected by pellagra.

Living organisms derive most of their energy from redox reactions, which are processes involving the transfer of electrons. Over 400 enzymes require the niacin coenzymes, nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP), mainly to accept or donate electrons for redox reactions ³⁸. NAD and NADP appear to support distinct functions (Figure 3). NAD functions most often in energy-producing reactions involving the degradation (catabolism) of carbohydrates, fats, proteins, and alcohol. NADP generally serves in biosynthetic (anabolic) reactions, such as in the synthesis of fatty acids, steroids (e.g., cholesterol, bile acids, and steroid hormones), and building blocks of other macromolecules ³⁹. NADP is also essential for the regeneration of components of detoxification and antioxidant systems (4). To support these functions, the cell maintains NAD in a largely oxidized state (NAD+) to serve as oxidizing agent for catabolic reactions, while NADP is kept largely in a reduced state (NADPH) to readily donate electrons for reductive cellular processes ³⁹, ⁴⁰.

The niacin coenzyme, nicotinamide adenine dinucleotide (NAD), is the substrate (reactant) for at least four classes of enzymes. Two classes of enzymes with mono adenosine diphosphate (ADP)-ribosyltransferase and/or poly (ADP-ribose) polymerase activities catalyze ADP-ribosyl transfer reactions. Silent information regulator-2 (Sir2)-like proteins (sirtuins) catalyze the removal of acetyl groups from acetylated proteins, utilizing ADP-ribose from NAD as an acceptor for acetyl groups. Finally, ADP-ribosylcyclases are involved in the regulation of intracellular calcium signaling ³.

Figure 4. Overview of NAD biosynthesis and function

Footnotes: Overview of the NAD biosynthesis and function in humans. NAD can be synthesized from five precursors: tryptophan (Trp), the pyridine bases nicotinamide (Nam) and nicotinic acid (NA) or the nucleosides nicotinamide riboside (NR) and nicotinic acid riboside (NAR), which enter cells by different transport mechanisms. Quinolinic acid (QA), a Trp degradation product, is transformed to nicotinic acid mononucleotide (NAMN) by quinolinic acid phosphoribosyltransferase (QAPRT). Nicotinamide (Nam) and nicotinic acid (NA) are converted to the corresponding mononucleotides (NMN and NAMN) by nicotinamide phosphoribosyltransferase (NamPRT, also known as NAMPT) and nicotinic acid phosphoribosyltransferase (NAPRT), respectively. Nicotinamide mononucleotide (NMN) might also be synthesized by an extracellular NamPRT (eNAMPT). Nicotinamide mononucleotide (NMN) and nicotinic acid mononucleotide (NAMN) are also generated through phosphorylation of nicotinamide riboside (NR) and nicotinic acid riboside (NAR), respectively, by nicotinamide riboside kinases (NRK). Nicotinamide mononucleotide (NMN) and nicotinic acid mononucleotide (NAMN) are converted to the corresponding dinucleotide (NAAD or NAD+) by NMN adenylyltransferases (NMNAT). NAD synthetase (NADS) amidates NAAD to NAD+. Phosphorylation by NAD kinase (NADK) converts NAD+ to NADP+. The oxidized and reduced forms of the dinucleotides, NAD(P)+ and NAD(P)H, serve as reversible hydrogen carriers in redox reactions. Members of the Sirtuin family of protein deacetylases catalyze the transfer of the protein-bound acetyl group onto the ADP-ribose moiety, thereby forming O-acetyl-ADP ribose (OAcADPR). The transfer of a single (mono-ADP-ribosylation) or several (poly-ADP-ribosylation) ADP-ribose units from NAD+ to acceptor protein is catalyzed by diphtheria toxin-like ADP-ribosyltransferases (ARTD). Mono-ADP-ribosylation is also catalyzed by clostridial toxin-like ADP-ribosyltransferases (ARTC) and some Sirtuin proteins. NAD+ and NADP+ are also used for the synthesis of second messengers, nicotinic acid adenine dinucleotide phosphate (NAADP), cyclic ADP-ribose (cADPR) and ADPR, which mediate intracellular calcium mobilization. All the three molecules are synthesized by ecto-NAD glycohydrolases CD38 and CD157. The mechanism of how messengers reach their cytosolic targets is still debated. Signaling-independent interconversions of NAD and its intermediates include NAD hydrolysis to NMN and AMP by Nudix pyrophosphatases (NUDT); NMN dephosphorylation to nicotinamide riboside (NR) by cytosolic 5′-nucleotidases (5′-NT); phosphorolytic cleavage of nicotinamide riboside (NR) to nicotinamide (Nam) by purine nucleoside phosphorylase (PNP); and conversion of Nam to N-methylnicotinamide (1-MNA) by nicotinamide-N-methyltransferase (NNMT). NAD+ can possibly be released from cells through connexin 43 hemichannels (Cx43), and can be degraded to NR by ecto-nucleotidase CD73. Nicotinamide riboside (NR) is hydrolyzed to nicotinamide (Nam) by CD157. Whether cells can take up NAD or NMN is debated.

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Lipid-lowering effects with pharmacologic doses of nicotinic acid

For over half a century, pharmacologic doses of nicotinic acid, but not nicotinamide, have been known to reduce serum cholesterol ⁴¹. However, the exact mechanisms underlying the lipid-lowering effect of nicotinic acid remain speculative. Two G-protein-coupled membrane receptors, GPR109A and GPR109B, bind nicotinic acid with high and low affinity, respectively. These nicotinic acid receptors are primarily expressed in adipose tissue and immune cells (but not lymphocytes). They are also found in retinal pigmented and colonic epithelial cells, keratinocytes, breast cells, microglia, and possibly at low levels in the liver ⁴². Therefore, lipid-modifying effects of nicotinic acid are likely to be mediated by receptor-independent mechanisms in major tissues of lipid metabolism like liver and skeletal muscle. Early in vitro data suggested that nicotinic acid could impair very-low-density lipoprotein (VLDL) secretion by inhibiting triglyceride synthesis and triggering ApoB lipoprotein degradation in hepatocytes ⁴³. In another study, nicotinic acid affected the liver uptake of ApoA1 lipoprotein, thereby reducing high-density lipoprotein (HDL) removal from the circulation ⁴⁴. In fat cells (adipocytes), the binding of nicotinic acid to GPR109A was found to initiate a signal transduction cascade resulting in reductions in free fatty acid production via the inhibition of hormone-sensitive lipase involved in triglyceride lipolysis ⁴⁵. Nonetheless, recent observations have suggested that the lipid-lowering effect of nicotinic acid was not due to its anti-lipolytic activity (22). Trials showed that synthetic agonists of GPR109A acutely lowered free fatty acids yet failed to affect serum lipids ⁴⁶. Aside from its impact on HDL and other plasma lipids, nicotinic acid has exhibited anti-atherosclerotic activities in cultured monocytes, macrophages, or vascular endothelial cells, by modulating inflammation and oxidative stress and regulating cell adhesion, migration, and differentiation ⁴².

Calcium mobilization

In humans, CD38 and CD157 belong to a family of NAD+ glycohydrolases or ADP-ribosylcyclases ³. These enzymes catalyze the formation of key regulators of calcium signaling, namely (linear) ADP-ribose, cyclic ADP-ribose, and nicotinic acid adenine dinucleotide phosphate. Cyclic ADP-ribose and nicotinic acid adenine dinucleotide phosphate works within cells to provoke the release of calcium ions from internal storage sites (i.e., endoplasmic reticulum, lysosomes, mitochondria), whereas ADP-ribose stimulates extracellular calcium entry through cell membrane TRPM2 cation channels ¹². Another TRPM2 agonist, 2’-deoxy-ADP-ribose, was recently identified in vitro. CD38 was found to catalyze the synthesis of 2’-deoxy-ADP-ribose from nicotinamide mononucleotide and 2’-deoxy-ATP ⁴⁷. O-acetyl-ADP-ribose generated by the activity of sirtuins also controls calcium entry through TRPM2 channels ⁴⁰. Intracellular calcium-mediated signal transduction is regulated by transient calcium entry into the cell or release of calcium from intracellular stores. Calcium signaling is critically involved in processes like neurotransmission, insulin release from pancreatic β-cells, muscle cell contraction, and T-lymphocyte activation ⁴⁰.

NAD as a ligand

NAD has been identified as an endogenous agonist of purinergic membrane receptors of the P2Y subclass. In particular, NAD was found to bind to P2Y1 receptor and act as an inhibitory neurotransmitter at neuromuscular junctions in visceral smooth muscles ⁴⁸. Extracellular NAD was also found to behave like a proinflammatory cytokine, triggering the activation of isolated granulocytes. NAD binding to the P2Y11 receptor at the granulocyte surface activated a signaling cascade involving cyclic ADP-ribose and the rise of intracellular calcium, eventually stimulating superoxide generation and chemotaxis ⁴⁹. Similar observations were made with lipopolysaccharide-activated monocytes ⁵⁰. Extracellular NAADP+ and ADP-ribose might also bind to P2Y receptors and trigger intracellular NAADP+- and ADP-ribose-dependent calcium mobilization (see Calcium mobilization) ⁵¹, ⁵².

NAD-dependent deacetylation

Seven sirtuins (SIRT 1-7) have been identified in humans. Sirtuins are a class of NAD-dependent deacetylase enzymes that remove acetyl groups from the acetylated lysine residues of target proteins. During the deacetylation process, the acetyl group is transferred onto the ADP-ribose moiety cleaved off NAD, producing O-acetyl-ADP-ribose. Nicotinamide can exert feedback inhibition to the deacetylation reaction ⁵³. Like ADP-ribosylation, acetylation is a post-translational modification that affects the function of target proteins. The initial interest in sirtuins followed the discovery that their activation could mimic caloric restriction, which has been shown to increase lifespan in lower organisms. Such a role in mammals is controversial, although sirtuins are energy-sensing regulators involved in signaling pathways that could play important roles in delaying the onset of age-related diseases (e.g., cardiovascular disease, cancer, dementia, arthritis). To date, the spectrum of their biological functions includes gene silencing, DNA damage repair, cell cycle regulation, and cell differentiation ⁵⁴.

ADP-ribosylation

Enzymes with ADP-ribosyltransferase activities were formerly divided between mono ADP-ribosyltransferases (ARTs) and poly (ADP-ribose) polymerases (PARPs). ARTs were first discovered in certain pathogenic bacteria — like those causing cholera or diphtheria — where they mediate the actions of toxins. These enzymes transfer an ADP-ribose residue moiety from NAD to a specific amino acid of a target protein, with the creation of an ADP-ribosylated protein and the release of nicotinamide.

Because most PARPs have been found to exhibit only mono ADP-ribosyltransferase activities, a new nomenclature was proposed for enzymes catalyzing ADP-ribosylation: A family of mono ADP-ribosyltransferases with homology to bacterial diphteria toxins was named ARTD, while enzymes with either mono or poly ADP-ribosyltransferase activities and related to C2 and C3 clostridial toxins were included in the ARTC family ⁵⁵, ⁵⁶.

ARTCs are extracellular enzymes that catalyze the mono ADP-ribosylation of membrane or secreted proteins involved in innate immunity and cell communication ¹².
ARTDs are intracellular enzymes with either mono or poly ADP-ribosyltransferase activities. At least 18 ARTDs have been identified. All ARTDs possess a diphtheria toxin-like catalytic domain that binds NAD+. Only ARTDs 1, 2, 5, and 6 catalyze poly (ADP-ribose) transfers; the others have mono ADP-ribosyltransferase activities. ARTDs were shown to be involved in DNA repair and stress responses, cell signaling, transcription regulation, apoptosis, cell differentiation, maintenance of genomic integrity, and antiviral defense ⁵⁶.

How much Vitamin B3 (Niacin) do I need?

The amount of Vitamin B3 or Niacin you need depends on your age and sex. Average daily recommended amounts are listed below in milligrams (mg) of niacin equivalents (NE) (except for infants in their first 6 months) ¹³. The mg niacin equivalents (NE) measure is used because your body can also make niacin from tryptophan, an amino acid in proteins. For example, when you eat turkey, which is high in tryptophan, some of this amino acid is converted to niacin in your liver. Using mg niacin equivalents (NE) accounts for both the niacin you consume and the niacin your body makes from tryptophan. Infants in their first six months do not make much niacin from tryptophan.

Table 1 lists the current Recommended Dietary Allowances (RDAs) for niacin as mg of niacin equivalents (NE) ⁶. The Food and Nutrition Board defines 1 NE as 1 mg niacin or 60 mg of the amino acid tryptophan (which the body can convert to niacin). Niacin RDAs for adults are based on niacin metabolite excretion data. For children and adolescents, niacin RDAs are extrapolated from adult values on the basis of body weight. The Adequate Intake (AI) for infants from birth to 6 months is for niacin alone, as young infants use almost all the protein they consume for growth and development; it is equivalent to the mean intake of niacin in healthy, breastfed infants. For infants aged 7-12 months, the Adequate Intake (AI) for niacin is in mg NE and is based on amounts consumed from breast milk and solid foods.

Most people in the United States get enough niacin from the foods they eat. Niacin deficiency is very rare in the United States ¹³. However, some people are more likely than others to have trouble getting enough niacin:

Undernourished people with AIDS, alcohol use disorder, anorexia, inflammatory bowel disease, or liver cirrhosis
People whose diet has too little iron, riboflavin, or vitamin B6; these nutrients are needed to convert tryptophan to niacin
People with Hartnup disease, a rare genetic disorder
People with carcinoid syndrome, a condition in which slow-growing tumors develop in the gastrointestinal tract

An analysis of data from the 2015–2016 National Health and Nutrition Examination Survey (NHANES) found that the average daily niacin intake from foods and beverages was 21.4 mg for ages 2–19 ⁵⁷. In adults, the average daily niacin intake from foods and beverages was 31.4 mg in men and 21.3 mg in women. An analysis of data from the 2009-2012 NHANES found that only 1% of adults had intakes of niacin from foods and beverages below the Estimated Average Requirements (the average daily level of intake estimated to meet the requirements of 50% of healthy individuals; usually used to assess the nutrient intakes of groups of people and to plan nutritionally adequate diets for them; can also be used to assess the nutrient intakes of individuals) ⁵⁸. Among all racial and ethnic groups, Hispanics had the greatest prevalence, 1.3%, of niacin intakes below the Estimated Average Requirement ⁵⁹.

According to self-reported data from the 2013-2014 NHANES, 21% of all individuals aged 2 and older took a dietary supplement containing niacin ⁵⁷. The proportion of users increased with age from 8% of those aged 12-19 years to 39% of men and 40% of women aged 60 and older. Supplement use doubled or tripled total niacin intakes compared with intakes from diet alone. According to data from the 2003-2006 NHANES, 10% of all individuals aged 2 and older who took dietary supplements had total niacin intakes that reached or exceeded the Tolerable Upper Intake Level (the maximum daily intake unlikely to cause adverse health effects) (see Table 2 below) ⁶⁰.

Table 1. Recommended Dietary Allowances (RDAs) for Vitamin B3 (Niacin)

Life Stage	Recommended Amount
Birth to 6 months*	2 mg
Infants 7–12 months*	4 mg NE
Children 1–3 years	6 mg NE
Children 4–8 years	8 mg NE
Children 9–13 years	12 mg NE
Teen boys 14–18 years	16 mg NE
Teen girls 14–18 years	14 mg NE
Adult men 19+ years	16 mg NE
Adult women 19+ years	14 mg NE
Pregnant teens and women	18 mg NE
Breastfeeding teens and women	17 mg NE

Footnote: Recommended Dietary Allowance (RDA) is the average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.

* Adequate Intake (AI) is intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an RDA.

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Table 2. Tolerable Upper Intake Levels (ULs) for Vitamin B3 (Niacin)

Age	Male	Female	Pregnancy	Lactation
Birth to 6 months	None established*	None established*
7–12 months	None established*	None established*
1–3 years	10 mg	10 mg
4–8 years	15 mg	15 mg
9–13 years	20 mg	20 mg
14–18 years	30 mg	30 mg	30 mg	30 mg
19+ years	35 mg	35 mg	35 mg	35 mg

Footnote: * Breast milk, formula, and food should be the only sources of niacin for infants.

[Source ⁴ ]

What foods provide Vitamin B3 (Niacin)?

Niacin is found naturally in many foods, and is added to some foods. You can get recommended amounts of niacin by eating a variety of foods, including the following:

Animal based foods foods, such as poultry, beef, pork, and fish, provide about 5-10 mg niacin per serving, primarily in the highly bioavailable forms of NAD and NADP ⁷.
Plant-based foods, such as nuts, legumes, and grains, provide about 2-5 mg niacin per serving, mainly as nicotinic acid.
Some types of nuts, legumes, and grains. In some grain products, however, naturally present niacin is largely bound to polysaccharides and glycopeptides that make it only about 30% bioavailable ⁷, ⁹.
Many breads, cereals, and infant formulas in the United States and many other countries contain added niacin. Niacin that is added to enriched and fortified foods is in its free form and therefore highly bioavailable ⁶.

Tryptophan is another food source of niacin because this amino acid—when present in amounts beyond that required for protein synthesis—can be converted to NAD, mainly in the liver ⁷, ²⁴. The most commonly used estimate of efficiency for tryptophan conversion to NAD is 1:60 (i.e., 1 mg niacin [NAD] from 60 mg tryptophan). Turkey is an example of a food high in tryptophan; a 3-oz portion of turkey breast meat provides about 180 mg tryptophan, which could be equivalent to 3 mg niacin ⁴. However, the efficiency of the conversion of tryptophan to NAD varies considerably in different people ⁷.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central (https://fdc.nal.usda.gov) lists the nutrient content of many foods and provides a comprehensive list of foods containing niacin arranged by nutrient content (https://www.nal.usda.gov/sites/www.nal.usda.gov/files/niacin.pdf).

Table 3. Vitamin B3 (Niacin) Content of Selected Foods

Food	Milligrams (mg) per serving	Percent Daily Value (DV)**
Beef liver, pan fried, 3 ounces	14.9	93
Chicken breast, meat only, grilled, 3 ounces	10.3	64
Marinara (spaghetti) sauce, ready to serve, 1 cup	10.3	64
Turkey breast, meat only, roasted, 3 ounces	10	63
Salmon, sockeye, cooked, 3 ounces	8.6	54
Tuna, light, canned in water, drained, 3 ounces	8.6	54
Pork, tenderloin, roasted, 3 ounces	6.3	39
Beef, ground, 90% lean, pan-browned, 3 ounces	5.8	36
Rice, brown, cooked, 1 cup	5.2	33
Peanuts, dry roasted, 1 ounce	4.2	26
Breakfast cereals fortified with 25% DV niacin	4	25
Rice, white, enriched, cooked, 1 cup	2.3	14
Potato (russet), baked, 1 medium	2.3	14
Sunflower seeds, dry roasted, 1 ounce	2	13
Bread, whole wheat, 1 slice	1.4	9
Pumpkin seeds, dry roasted, 1 ounce	1.3	8
Soymilk, unfortified, 1 cup	1.3	8
Bread, white, enriched, 1 slice	1.3	8
Lentils, boiled and drained, ½ cup	1	6
Bulgur, cooked, 1 cup	0.9	6
Banana, 1 medium	0.8	5
Edamame, frozen, prepared, ½ cup	0.7	4
Raisins, ½ cup	0.6	4
Tomatoes, cherry, ½ cup	0.5	3
Broccoli, boiled, drained, chopped, ½ cup	0.4	3
Cashews, dry roasted, 1 ounce	0.4	3
Yogurt, plain, low fat, 1 cup	0.3	2
Apple, 1 medium	0.2	1
Chickpeas, canned, drained, 1 cup	0.2	1
Milk, 1% milkfat, 1 cup	0.2	1
Spinach, frozen, chopped, boiled, ½ cup	0.2	1
Tofu, raw, firm, ½ cup	0.2	1
Onions, chopped, ½ cup	0.1	1
Egg, large	0	0

Footnotes: These values are for the niacin content of foods only. They do not include the contribution of tryptophan, some of which is converted to NAD in the body.

** DV = Daily Value. The U.S. Food and Drug Administration (FDA) developed Daily Values (DVs) to help consumers compare the nutrient contents of foods and dietary supplements within the context of a total diet. The DV for niacin is 16 mg for adults and children aged 4 years and older ⁶¹. The FDA does not require food labels to list niacin content unless niacin has been added to the food. Foods providing 20% of more of the DV are considered to be high sources of a nutrient.

[Source ⁴ ]

What kinds of Vitamin B3 (Niacin) supplements are available?

Vitamin B3 or Niacin is found in multivitamin or multivitamin-mineral supplements. Vitamin B3 or Niacin is also available in B-complex dietary supplements and supplements containing only niacin. The two main forms of niacin in dietary supplements are nicotinic acid and nicotinamide. Some niacin-only supplements contain 500 mg or more per serving, which is much higher than the Recommended Dietary Allowance (RDA) for this nutrient ⁴.Niacin (in the form of nicotinic acid) is also available as a prescription medicine used to treat high blood cholesterol levels.Nicotinic acid in supplemental amounts beyond nutritional needs can cause skin flushing, so some formulations are manufactured and labeled as prolonged, sustained, extended, or timed release to minimize this unpleasant side effect. Nicotinamide does not produce skin flushing because of its slightly different chemical structure ²⁸. Niacin supplements are also available in the form of inositol hexanicotinate, and these supplements are frequently labeled as being “flush free” because they do not cause flushing. The absorption of niacin from inositol hexanicotinate varies widely but on average is 30% lower than from nicotinic acid or nicotinamide, which are almost completely absorbed ²⁸, ⁶², ⁶³. Two niacin-like compounds, nicotinamide riboside and nicotinamide mononucleotide (NMN; also referred to as β-NMN), are also available as dietary supplements, but are not marketed or labelled as sources of niacin ⁴. However, FDA ruled in November 2022 that nicotinamide mononucleotide (NMN) may not be legally marketed as a dietary supplement because it has been authorized for investigation by FDA as a new drug ⁶⁴.

What happens if I don’t get enough Vitamin B3 Niacin?

You can develop niacin deficiency if you don’t get enough niacin or tryptophan from the foods you eat. Severe niacin deficiency leads to a disease called pellagra. Pellagra, which is uncommon in developed countries, can have these effects ¹³:

Rough skin that turns red or brown in the sun
A bright red tongue
Vomiting, constipation, or diarrhea
Depression
Headaches
Extreme tiredness
Aggressive, paranoid, or suicidal behavior
Hallucinations, apathy, loss of memory

In its final stages, pellagra leads to loss of appetite followed by death.

Vitamin B3 Niacin health benefits

Scientists are studying vitamin B3 or Niacin to better understand how it affects health. Here is an example of what this research has shown.

Cardiovascular disease

Scientists have studied the use of large doses of niacin in the form of nicotinic acid to help reduce the risk of heart attack and stroke in people with atherosclerosis. They found that prescription-strength nicotinic acid (more than 100 times the recommended dietary allowance [RDA]) can lower blood levels of LDL (bad) cholesterol, raise levels of HDL (good) cholesterol, and lower levels of triglycerides ⁴. But these favorable effects on blood lipids (fats) don’t affect the risk of having a cardiovascular event, such as heart attack, sudden cardiac death, or stroke. In addition, experts do not recommend high doses of nicotinic acid for people taking a statin medication. Nicotinamide does not have this effect because, unlike nicotinic acid, it does not bind to the receptors that mediate nicotinic acid’s effects on lipid profiles ⁵. Your doctor should approve and supervise any use of very high doses of nicotinic acid (in the thousands of milligrams) to treat atherosclerosis.

Studies conducted since the late 1950s show that these doses can increase high-density lipoprotein (HDL; “good”) cholesterol levels by 10-30% and reduce low-density lipoprotein (LDL; “bad”) cholesterol levels by 10-25%, triglyceride levels by 20-50%, and lipoprotein(a) levels by 10-30% ²⁸. Together, these changes in lipid parameters might be expected to reduce the risk of first-time or subsequent cardiac events, such as heart attacks and strokes, in adults with atherosclerotic cardiovascular disease. However, despite dozens of published clinical trials, experts do not agree on the value of nicotinic acid to treat cardiovascular disease, especially given its side effects, safety concerns, and poor patient compliance ⁶⁵.

In one large clinical trial from the 1970s, 8,341 participants aged 30 to 64 years who had had one or more heart attacks were randomized to take one of five lipid-lowering medications, including 3,000 mg/day nicotinic acid, or a placebo for an average of 6.2 years ⁶⁶. Those taking nicotinic acid lowered their serum cholesterol levels by an average of 9.9% and triglyceride levels by 26.1% over 5 years of treatment ⁶⁶. During 5 to 8.5 years of treatment, these participants had significantly fewer nonfatal myocardial infarctions but more cardiac arrhythmias than those in the placebo group. Their overall rates of mortality and cause-specific mortality, including from coronary heart disease, did not decline ⁶⁶. But 9 years after the study ended, participants who had taken the nicotinic acid experienced significantly fewer (11%) deaths from all causes than those who had taken the placebo ⁶⁷, ⁶⁸.

Statin medications have become the treatment of choice for hyperlipidemia and lowering the risks of atherosclerotic cardiovascular disease. For this reason, clinical trials of nicotinic acid in the past several decades have examined whether it provides any additional cardiovascular protection to people taking statins ³⁰.

In the largest international, multicenter, clinical trial of nicotinic acid to date, 25,673 adults aged 50-80 years (83% men) with cardiovascular disease who were taking a statin were randomized to take 2000 mg/day extended-release nicotinic acid with a medication to reduce nicotinic acid’s flushing effect and therefore improve treatment compliance or a matching placebo for a median of 4 years ⁶⁹, ⁷⁰. The nicotinic acid group had a mean reduction in LDL cholesterol (of 10 mg/dl) and triglycerides (of 33 mg/dl) and an increase in HDL cholesterol (of 6 mg/dl), but this group had no significant reduction in rates of major vascular events compared with the placebo (statin-only) group ⁶⁹, ⁷⁰. Furthermore, the nicotinic acid group had a significantly greater risk of diabetes, gastrointestinal dyspepsia, diarrhea, ulceration, bleeding events in the gut and brain, and skin rashes and ulcerations. An earlier randomized clinical trial of 3,414 patients with established cardiovascular disease was stopped after 3 years when the researchers found that patients taking niacin (1,500-2,000 mg/day extended release) in addition to their cholesterol-reduction medications did not have fewer cardiovascular events than those taking medication alone, even though the niacin reduced triglyceride and LDL-cholesterol levels further and raised HDL cholesterol levels further ⁷¹. The results also showed that patients taking niacin had an increased risk of ischemic stroke.

The authors of two 2017 systematic reviews examining the clinical trial data concluded that nicotinic acid therapy provides little if any protection from atherosclerotic heart disease, even though the therapy raises HDL cholesterol levels and lowers total cholesterol, LDL cholesterol, and triglyceride levels ⁶⁵. One of these reviews examined 23 randomized controlled trials of moderate to high quality in 39,195 participants aged 33-71 years (average 65 years; majority were male). Some had experienced a heart attack, and most were taking a statin. The doses used and treatment duration in these studies varied widely; the median dose of nicotinic acid was 2000 mg/day (range 500 to 4000 mg/day) for a median of 11.5 months (range 6 months to 6 years) ⁶⁵. Overall, use of nicotinic acid did not reduce overall mortality or cardiovascular mortality rates or the number of fatal or nonfatal myocardial infarctions or strokes. Eighteen percent of participants taking nicotinic acid discontinued treatment because of side effects. The second review examined 13 randomized controlled trials with 35,206 participants with, or at risk of, atherosclerotic cardiovascular disease ⁷². Overall, the addition of nicotinic acid supplementation (dose range not specified) to statin therapy taken for a mean of 33 months (with a broad range of 6 to 60 months) did not lead to significant reductions in rates of all-cause or cardiovascular mortality, myocardial infarction, or stroke ⁷². Nicotinic acid treatment was associated with a significantly higher risk of gastrointestinal and musculoskeletal adverse events ⁷². In addition, four of the studies that examined diabetes as an outcome found that the patients taking niacin had a significantly higher risk of developing the disease.

A 2018 review of three randomized controlled trials with 29,195 patients found that all-cause mortality increased by 10% more in those who took 1000 to 3000 mg/day extended release nicotinic acid in addition to a statin medication than patients taking the statin alone ⁷³.

In their guidelines for lowering blood cholesterol levels, the American College of Cardiology and the American Heart Association advise that nonstatin therapies, compared with or in addition to statin therapy, do not provide atherosclerotic cardiovascular disease risk-reduction benefits that outweigh the potential harms of their adverse effects ³⁰. When discussing the use of nicotinic acid supplements to reduce the risk of hyperlipidemia (for example, in patients unable to tolerate statin medications), the two professional societies recommend that patients take 500 mg/day extended-release nicotinic acid supplements and increase the dose to a maximum of 2,000 mg/day over 4 to 8 weeks or take 100 mg immediate-release nicotinic acid three times a day and increase the dose to 3,000 mg/day divided into two or three doses. Their joint statement about monitoring supplement users who take niacin to reduce hyperlipidemia risk for adverse effects is described in the Health Risks from Excessive Niacin section below. In their 2018 report, these two professional societies stated what although niacin may be useful in some cases of severe hypertriglyceridemia, it has only mild LDL-lowering effects. The societies therefore do not recommend using it as an add-on drug to statin therapy ⁷⁴.

Overall, the evidence indicates that nicotinic acid supplementation improves blood lipid profiles but has no significant effects on risk of cardiovascular events ⁴. Although nicotinic acid is a nutrient, if very high doses (thousands of mg) are taken to treat hyperlipidemias, the supplement is being used as a drug. Such doses should only be taken with medical approval and supervision ⁴.

Friedreich’s ataxia

Friedreich’s ataxia, a common form of inherited ataxia, is an early onset recessive disorder with clinical features that includes progressive ataxia, scoliosis, dysarthria, cardiomyopathy, and diabetes mellitus ⁷⁵. Most affected subjects carry homozygous guanine-adenine-adenine (GAA) repeat expansions in the first intron of the gene FXN coding for the protein frataxin. These abnormal and unstable GAA repeats trigger gene silencing through heterochromatin formation, leading to significantly reduced frataxin expression ⁷⁶. Frataxin is a mitochondrial protein needed for the making of iron-sulfur clusters (ISC). ISC-containing subunits are especially important for the mitochondrial respiratory chain and for the synthesis of heme-containing proteins ⁷⁵.

Predominantly localized in the nucleus, SIRT1 is a NAD-dependent deacetylase that promotes gene silencing through heterochromatin formation. Nicotinamide has been shown to antagonize heterochromatization of the FXN locus and upregulate frataxin expression in lymphoblastoid cells derived from Friedreich’s ataxia-affected patients, possibly through inhibiting SIRT1 activity ⁷⁶. In an open-label, dose escalating pilot trial in 10 adult patients with Friedreich’s ataxia, single and repeated doses of nicotinamide (2-8 g) for up to eight weeks were found to be well tolerated ⁷⁷. Repeated daily doses of 3.5 to 6 g of nicotinamide led to significant increases in frataxin concentration in peripheral white blood cells ⁷⁷. Yet, no neurological improvements were reported, suggesting that the duration of the treatment was too short and/or the nervous system of the participants was unresponsive to increases in frataxin ⁷⁸. There is currently no ongoing trial designed to further investigate the effect of nicotinamide in Friedreich’s ataxia-affected patients.

HIV/AIDS

The first step in the kynurenine pathway is catalyzed by the extrahepatic enzyme, indoleamine 2,3-dioxygenase (IDO), which is responsible for the oxidative cleavage of tryptophan. The chronic stimulation of tryptophan oxidation, mediated by an increased activity of indoleamine 2,3-dioxygenase (IDO) and/or inadequate dietary niacin intakes, is observed with the infection of human immunodeficiency virus (HIV), the virus that causes acquired immunodeficiency syndrome (AIDS). Interferon-gamma (IFN-γ) is a cytokine produced by cells of the immune system in response to infection. Through stimulating the enzyme indoleamine 2,3-dioxygenase (IDO), IFN-γ increases the breakdown of tryptophan, thus supporting the finding that the average tryptophan concentration in blood is significantly lower in HIV patients compared to uninfected subjects ⁷⁹. An increased degradation of tryptophan via the kynurenine pathway appears to coexist with intracellular niacin/NAD deficiency in HIV infection ⁸⁰. An explanatory model for these paradoxical observations incriminates the oxidative stress induced by multiple nutrient deficiencies in HIV patients ⁸⁰. In particular, the activation of PARP enzymes (ARTDs) by oxidative damage to DNA could be responsible for inducing niacin/NAD depletion. The breakdown of tryptophan would then be a compensatory response to inadequate niacin/NAD levels.

However, metabolites derived from the oxidation of tryptophan in the kynurenine pathway regulate specific T-lymphocyte subgroups. As mentioned above, circulating IFN-γ, but also viral and bacterial products, can activate indoleamine 2,3-dioxygenase (IDO) during HIV infection. The overstimulation of the tryptophan pathway has been involved in the loss of normal T-lymphocyte function, which characterizes HIV infection ⁸¹, ⁸². The increased IDO activity has been linked to the altered immune response that contributes to the persistence of HIV ⁸¹. Antiretroviral therapy (ART) only partially restores normal IDO activity, without normalizing it, yet induces viral suppression and CD4 T-cell recovery ⁸³. In a monkey model for HIV infection, a partial and transient blockade of IDO with IDO inhibitor 1-methyl tryptophan proved ineffective to reduce the viral load in plasma and intestinal tissues beyond the level achieved by antiretroviral therapy ⁸⁴. At present, a better understanding of the role of kynurenine pathway and other NAD biosynthetic pathways during HIV infection is needed before the relevance and clinical implications of niacin supplementation in HIV treatment could be considered.

Nonetheless, pharmacologic doses of nicotinic acid have been shown to be well tolerated in HIV patients with hyperlipidemia ⁸⁵. Abnormal lipid profiles observed in patients have been attributed to the HIV infection and to the highly active antiretroviral treatment (HAART) ⁸⁶. Moreover, insulin resistance has been detected together with dyslipidemia in antiretroviral therapy-treated patients ⁸⁷. Cardiovascular disease is the second most frequent cause of deaths in the HIV population, and the rate of cardiovascular disease is predicted to increase further as patients are living longer due to successful antiretroviral therapies. As for the general population, statin-based therapy appears to benefit HIV patients in terms of atherogenic protection and cardiovascular disease risk reduction, although contraindications exist due to drug interactions with anti-retroviral therapy. Other first-line treatments include lipid-lowering fibrates, which are preferred to nicotinic acid due to the increased risk of glucose intolerance and insulin resistance ⁸⁸. Nevertheless, an unblinded, controlled pilot study showed that extended-release nicotinic acid (0.5-1.5 g/day for 12 weeks) could effectively improve endothelial function of the brachial artery in antiretroviral therapy-treated HIV subjects with low HDL-cholesterol and no history of cardiovascular disease ⁸⁹. In addition, a combined treatment of fibrates, extended-release nicotinic acid (0.5-2 g/day), and lifestyle changes (low-fat diet and exercise) for 24 weeks was effective in normalizing lipid parameters in a cohort of 191 antiretroviral therapy-treated patients. Increased risk of liver dysfunction was detected in subjects receiving both fibrates and niacin, but insulin sensitivity was not affected by nicotinic acid treatment given alone or when combined with fibrates ⁹⁰. Another 24-week, open-label, uncontrolled trial in 99 antiretroviral therapy-treated patients found that randomization to extended-release nicotinic acid (0.5-2 g/day) or fenofibrates increased blood HDL-cholesterol but did not reduce inflammatory markers or improve endothelial function when compared to baseline ⁹¹.

Schizophrenia

Schizophrenia is a neurologic disorder with unclear etiology that is diagnosed purely from its clinical presentation. Because neurologic disorders associated with pellagra resemble acute schizophrenia, niacin-based therapy for the condition was investigated during the 1950s-70s ⁹². The adjunctive use of nutrients like niacin to correct deficiencies associated with neurologic symptoms is called orthomolecular psychiatry ⁹³. Such an approach has not been included in psychiatric practice; practitioners have instead relied solely on antipsychotic drugs to eliminate the clinical symptoms of schizophrenia. Nevertheless, recent scientific advances and new hypotheses on the benefit of nutrient supplementation in the treatment of psychiatric disorders have suggested the re-assessment of orthomolecular medicine by the medical community ⁹⁴, ⁹⁵.

Skin flushing is one major side effect of the therapeutic use of nicotinic acid and the primary reason for non-adherence to treatment (see side effects). Flushing is caused by the activation of phospholipase A2, an enzyme that stimulates the production of a specific lipid from the prostanoid family called prostaglandin D2. Prostaglandin D2, synthesized by antigen-presenting cells of the skin and mucosa (i.e., the Langerhans cells), can induce the dilation of blood vessels and trigger a flushing response. Interestingly, patients with schizophrenia tend not to flush following treatment with nicotinic acid. This blunted skin flushing response suggests abnormal prostanoid signaling in schizophrenic patients ⁹⁶, ⁹⁷. An association has been found between the altered niacin sensitivity and greater functional impairment in schizophrenic subjects ⁹⁸, which supports other findings suggesting that altered lipid metabolism could critically impair brain development and contribute to the disease ⁹⁹. Interestingly, blunted skin flushing responses are more prevalent in first-degree relatives of people with schizophrenia than in the general population, suggesting that reduced niacin sensitivity is a heritable trait within affected families ¹⁰⁰.

Cancer prevention

Studies of cultured cells (in vitro) provide evidence that NAD content influences mechanisms that maintain genomic stability. Loss of genomic stability, characterized by a high rate of damage to DNA and chromosomes, is a hallmark of cancer ¹⁰¹. The current understanding is that the pool of NAD is decreased during niacin deficiency and that it affects the activity of NAD-consuming enzymes rather than redox and metabolic functions ¹⁰². Among NAD-dependent reactions, poly ADP-ribosylations catalyzed by PARP enzymes (ARTDs) are critical for the cellular response to DNA injury. After DNA damage, PARPs are activated; the subsequent poly ADP-ribosylations of a number of signaling and structural molecules by PARPs were shown to facilitate DNA repair at DNA strand breaks ¹⁰³. Cellular depletion of NAD has been found to decrease levels of the tumor suppressor protein p53, a target for poly ADP-ribosylation, in human breast, skin, and lung cells ¹⁰⁴. The expression of p53 was also altered by niacin deficiency in rat bone marrow cells ¹⁰⁵. Impairment of DNA repair caused by niacin deficiency could lead to genomic instability and drive tumor development in rat models ¹⁰⁶, ¹⁰⁷. Both PARPs and sirtuins have been recently involved in the maintenance of heterochromatin, a chromosomal domain associated with genome stability, as well as in transcriptional gene silencing, telomere integrity, and chromosome segregation during cell division ¹⁰⁸, ¹⁰⁹. Neither the cellular NAD content nor the dietary intake of NAD precursors necessary for optimizing protective responses following DNA damage has been determined, but both are likely to be higher than that required for the prevention of pellagra.

Bone marrow

Cancer patients often suffer from bone marrow suppression following chemotherapy, given that bone marrow is one of the most proliferative tissues in the body and thus a primary target for chemotherapeutic agents. Niacin deficiency was found to decrease bone marrow NAD and poly-ADP-ribose levels and increase the risk of chemically induced leukemia in rats ¹¹⁰. Conversely, a pharmacologic dose of either nicotinic acid or nicotinamide was able to increase NAD and poly ADP-ribose in bone marrow and decrease the development of leukemia in rats ¹¹¹. It has been suggested that niacin deficiency often observed in cancer patients could sensitize bone marrow tissue to the suppressive effect of chemotherapy. However, little is known regarding cellular NAD levels and the prevention of DNA damage or cancer in humans. One study in two healthy individuals involved elevating NAD levels in blood lymphocytes by supplementation with 100 mg/day of nicotinic acid for eight weeks. Compared to non-supplemented individuals, the supplemented individuals had reduced DNA strand breaks in lymphocytes exposed to free radicals in a test tube assay ¹¹². However, nicotinic acid supplementation of up to 100 mg/day for 14 weeks in 21 healthy smokers failed to provide any evidence of a decrease in cigarette smoke-induced genetic damage in blood lymphocytes compared to placebo ¹¹³. More recently, the frequency of chromosome translocation was used to evaluate DNA damage in peripheral blood lymphocytes of 82 pilots chronically exposed to ionizing radiation, a known human carcinogen. In this observational study, the rate of chromosome aberrations was significantly lower in subjects with higher (28.4 mg/day) compared to lower (20.5 mg/day) dietary niacin intake ¹¹⁴. Higher availability of NAD in x-ray treated peripheral blood lymphocytes was found to favor DNA repair by enhancing survival, particularly through SIRT-mediated p53 deacetylation ¹¹⁵.

Upper digestive tract cancer

Generally, relationships between dietary factors and cancer are established first in epidemiological studies and followed up by basic cancer research at the cellular level. In the case of niacin, research on biochemical and cellular aspects of DNA repair has stimulated an interest in the relationship between niacin intake and cancer risk in human populations ¹¹⁶. A large case-control study found increased consumption of niacin, along with antioxidant nutrients, to be associated with decreased incidence of oral (mouth), pharyngeal (throat), and esophageal cancers in northern Italy and Switzerland. An increase in daily niacin intake of 6.2 mg was associated with about a 40% decrease in cases of cancers of the mouth and throat, while a 5.2 mg increase in daily niacin intake was associated with a similar decrease in cases of esophageal cancer ¹¹⁷, ¹¹⁸.

Skin cancer

Niacin deficiency can lead to severe sunlight sensitivity in exposed skin. Given the implication of NAD-dependent enzymes in DNA repair, there has been some interest in the effect of niacin on skin health. In vitro and animal experiments have helped gather information, but human data on niacin/NAD status and skin cancer are very limited. One study reported that niacin supplementation decreased the risk of ultraviolet light (UV)-induced skin cancers in mice, despite the fact that mice convert tryptophan to NAD more efficiently than rats and humans and thus do not get severely deficient ¹¹⁹. Hyper-proliferation and impaired differentiation of skin cells can alter the integrity of the skin barrier and increase the occurrence of pre-malignant and malignant skin conditions. A protective effect of niacin was suggested by topical application of myristyl nicotinate, a niacin derivative, which successfully increased the expression of epidermal differentiation markers in subjects with photodamaged skin ¹²⁰. The activation of the nicotinic acid receptors, GPR109A and GPR109B, by pharmacologic doses of niacin could be involved in improving skin barrier function. Conversely, differentiation defects in skin cancer cells were linked to the abnormal cellular localization of defective nicotinic acid receptors ¹²¹. Nicotinamide restriction with subsequent depletion of cellular NAD was shown to increase oxidative stress-induced DNA damage in a precancerous skin cell model, implying a protective role of NAD-dependent pathways in cancer ¹²². Altered NAD availability also affects sirtuin expression and activity in UV-exposed human skin cells. Along with PARPs, NAD-consuming sirtuins could play an important role in the cellular response to photodamage and skin homeostasis ¹²³.

A pooled analysis of two large US prospective cohort studies that followed 41,808 men and 72,308 women for up to 26 years suggested that higher versus lower intake of niacin (from diet and supplements) might be protective against squamous-cell carcinoma but not against basal-cell carcinoma and melanoma ¹²⁴. A phase 3, randomized, double-blind, placebo-controlled trial in 386 subjects with a history of nonmelanoma skin cancer recently examined the effect of daily nicotinamide supplementation (1 g) for 12 months on skin cancer recurrence at three-month intervals over an 18-month period ¹²⁵. Nicotinamide effectively reduced the rate of premalignant actinic keratose (-11%), squamous-cell carcinoma (-30%), and basal-cell carcinoma (-20%) compared to placebo after 12 months, yet this protection was not sustained during the six-month post-supplementation period ¹²⁵. Larger trials are needed to assess whether nicotinamide could reduce the risk of melanomas, which are not as common as other skin cancer but are more deadly ¹²⁶.

Type 1 diabetes mellitus

Type 1 diabetes mellitus in children is caused by the autoimmune destruction of insulin-secreting β-cells in the pancreas. Prior to the onset of symptomatic diabetes, specific antibodies, including islet cell autoantibodies (ICA), can be detected in the blood of high-risk individuals ¹²⁷. In an experimental animal model of diabetes, high levels of nicotinamide are administered to protect β-cells from damage caused by streptozotocin ¹²⁸.

Yet, pharmacologic doses of nicotinamide (up to 3 g/day) have not been found to be effective in delaying or preventing the onset of type 1 diabetes in at-risk subjects. An analysis of 10 trials, of which five were placebo-controlled, found evidence of improved β-cell function after one year of treatment with nicotinamide, but the analysis failed to find any clinical evidence of improved glycemic control ¹²⁹. A large, multicenter randomized controlled trial of nicotinamide in islet cell autoantibodies-positive siblings (ages, 3-12 years) of type 1 diabetic patients also failed to find a difference in the incidence of type 1 diabetes after three years ¹²⁹. A randomized, double-blind, placebo-controlled multicenter trial of nicotinamide (maximum of 3 g/day) was conducted in 552 islet cell autoantibodies (ICA)-positive relatives of patients with type 1 diabetes. The proportion of relatives who developed type 1 diabetes within five years was comparable whether they were treated with nicotinamide or placebo ¹³⁰. Nicotinamide could reduce inflammation-related parameters in these high-risk subjects yet was ineffective to prevent disease onset ¹³¹. More recently, case reports of the combined use of nicotinamide (25 mg/kg/day) and acetyl-L-carnitine (50 mg/kg/day) in children at risk for type 1 diabetes showed promising results, warranting further investigation ¹³².

Vitamin B3 Niacin uses

Niacin is used with diet changes (restriction of cholesterol and fat intake) to reduce the amount of cholesterol (a fat-like substance) and other fatty substances in your blood (hyperlipidemia) and to increase the amount of high density lipoprotein (HDL; ”good cholesterol”). Niacin can be used in a number of situations including the following ¹³³:

alone or in combination with other medications, such as HMG-CoA inhibitors (statins) or bile acid-binding resins to treat high cholesterol and triglyceride (fat-like substances) levels in the blood;
to decrease the risk of another heart attack in patients with high cholesterol who have had a heart attack;
to prevent worsening of atherosclerosis (buildup of cholesterol and fats along the walls of the blood vessels) in patients with high cholesterol and coronary artery disease;
to reduce the amount of triglycerides (other fatty substances) in the blood in patients with very high triglycerides who are at risk of pancreatic disease (conditions affecting the pancreas, a gland that produces fluid to break down food and hormones to control blood sugar);
may help prevent the development of pancreatitis (inflammation of the pancreas) and other problems caused by high levels of cholesterol and triglycerides in the blood.

Niacin is also used to prevent and treat pellagra (niacin deficiency), a disease caused by inadequate niacin or tryptophan in your diet and other medical problems ¹³³. Niacin is a B-complex vitamin. At therapeutic doses, only with your doctor’s prescription, niacin is a cholesterol-lowering medication.

Results of a clinical study in people with heart disease and well-controlled cholesterol levels that compared people who took niacin and simvastatin with people who took simvastatin alone and found similar results for the two groups in the rate of heart attacks or strokes. Taking niacin along with simvastatin or lovastatin also has not been shown to reduce the risk of heart disease or death compared with the use of niacin, simvastatin, or lovastatin alone. Talk to your doctor if you have questions about the risks and benefits of treating increased amounts of cholesterol in your blood with niacin and other medications.

Before taking niacin ¹³³:

tell your doctor and pharmacist if you are allergic to niacin, any other medications, or any of the ingredients in niacin tablets. Ask your pharmacist or check the manufacturer’s information for the patient for a list of the ingredients.
tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: anticoagulants (‘blood thinners’) such as warfarin (Coumadin); aspirin; insulin or oral medications for diabetes; medications for high blood pressure; nutritional supplements or other products containing niacin; or other medications for lowering cholesterol or triglycerides. If you take insulin or oral diabetes medication, your dose may need to be changed because niacin may increase the amount of sugar in your blood and urine.
if you are taking a bile acid-binding resin such as colestipol (Colestid) or cholestyramine (Questran), take it at least 4 to 6 hours before or 4 to 6 hours after niacin.
tell your doctor if you drink large amounts of alcohol and if you have or have ever had diabetes; gout; ulcers; allergies; jaundice (yellowing of the skin or eyes); bleeding problems; or gallbladder, heart, kidney, or liver disease.
tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. If you become pregnant while taking niacin, stop taking niacin and call your doctor.
if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking niacin.
ask your doctor about the safe use of alcoholic beverages while you are taking niacin. Alcohol can make the side effects from niacin worse.
you should know that niacin causes flushing (redness, warmth, itching, tingling) of the face, neck, chest, or back. This side effect usually goes away after taking the medicine for several weeks. Avoid drinking alcohol or hot drinks or eating spicy foods around the time you take niacin. Taking aspirin or another nonsteroidal anti-inflammatory drug such as ibuprofen (Advil, Motrin) or naproxen (Aleve, Naprosyn) 30 minutes before niacin may reduce the flushing. If you take extended-release niacin at bedtime, the flushing will probably happen while you are asleep. If you wake up and feel flushed, get up slowly, especially if you feel dizzy or faint.

Niacin-responsive genetic disorders

Congenital NAD deficiency-related disorders can result from mutations in genes involved in the uptake and transport of the various dietary NAD precursors or in the distinct metabolic pathways leading to NAD production ³. Some of these disorders might respond to niacin supplementation. For example, defective transport of tryptophan into cells results in Hartnup disease, which features signs of severe niacin deficiency ¹³⁴. Hartnup disease is due to mutations in the SLCA19 gene, which codes for a sodium-dependent neutral amino acid transporter expressed primarily in the kidneys and intestine. Hartnup disease interferes with the absorption of tryptophan in the small intestine and increases its loss in the urine via the kidneys ¹³⁵, ⁶, ¹³⁶. As a result, the body has less available tryptophan to convert to niacin. Hartnup disease management involves supplementation with nicotinic acid or nicotinamide ¹³⁷. Recessive mutations in genes coding for enzymes of the kynurenine pathway — namely kynureninase and 3-hydroxyanthranilic-acid 3,4-dioxygenase — lead to combined vertebral, anal, cardiac, tracheo-esophageal, renal, and limb (VACTERL) congenital malformations ¹³⁸. Depletion of NAD, rather than accumulation of intermediate metabolites in the kynurenine pathway, was found to be responsible for these malformations. Niacin supplementation throughout pregnancy ensured adequate levels of NAD and prevented congenital anomalies in mice with kynurenine pathway mutations ¹³⁸. In humans, the dose of NAD precursors necessary to avert NAD deficiency-induced congenital VACTERL malformations has yet to be defined ¹³⁹.

Nicotinamide may also rescue NAD depletion secondary to an ultra-rare inborn error of glutamine metabolism ¹⁴⁰. Glutamine is required for the conversion of nicotinic acid adenine dinucleotide to NAD catalyzed by NAD synthetase (Figure 2). Thus, inherited glutamine synthetase deficiency specifically affects the synthesis of NAD from the NAD precursors, tryptophan and nicotinic acid. If the combined deficiencies of glutamine and NAD are responsible for the severe clinical phenotype of subjects with inherited glutamine synthetase deficiency, it is likely that supplementation with both glutamine and nicotinamide would provide some relief ¹⁴⁰.

Finally, many inborn errors of metabolism result from genetic mutations decreasing cofactor binding affinity and, subsequently, enzyme efficiency ¹⁴¹: relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002 Apr;75(4):616-58. doi: 10.1093/ajcn/75.4.616)). In many cases, the administration of high doses of the vitamins serving as precursors of cofactors can restore enzymatic activity — at least partially — and lessen signs of the genetic diseases ¹⁴¹: relevance to genetic disease and polymorphisms. Am J Clin Nutr. 2002 Apr;75(4):616-58. doi: 10.1093/ajcn/75.4.616)). Given the large number of enzymes requiring NAD, it is speculated that many of the conditions due to defective enzymes might be rescued by niacin supplementation ³⁸.

Vitamin B3 Niacin side effects

The niacin that food and beverages naturally contain is safe ⁴, ⁶. However, dietary supplements with 30 mg or more of nicotinic acid can make the skin on your face, arms, and chest turn reddish color because of vasodilation of small subcutaneous blood vessels ⁴. The flushing is accompanied by burning, tingling, and itching sensations ²⁸, ²⁹. These signs and symptoms are typically transient and can occur within 30 minutes of nicotinic acid intake or over days or weeks with repeated dosing; they are considered an unpleasant, rather than a toxic, side effect ⁴. However, the flushing can be accompanied by more serious signs and symptoms, such as headache, rash, dizziness, and/or a decrease in blood pressure. Supplement users can reduce the flushing effects by taking nicotinic acid supplements with food, slowly increasing the dose over time, or simply waiting for the body to develop a natural tolerance ⁴.

If you take nicotinic acid as a medication in doses of 1,000 or more mg/day, it can cause more severe side effects. These include:

Low blood pressure (which can increase the risk of falls)
Extreme tiredness
High blood sugar levels
Nausea, heartburn, and abdominal pain
Blurred or impaired vision and fluid buildup in the eyes

Long-term treatment, especially with extended-release forms of nicotinic acid, can cause liver problems, including hepatitis and liver failure.

Niacin in the form of nicotinamide has fewer side effects than nicotinic acid. However, at high doses of 500 mg/day or more, nicotinamide can cause diarrhea, easy bruising, and can increase bleeding from wounds. Even higher doses of 3,000 mg/day or more can cause nausea, vomiting, and liver damage.

The Food and Nutrition Board at the National Academies of Sciences, Engineering, and Medicine has established Tolerable Upper Intake Level (maximum daily intake unlikely to cause adverse health effects) for niacin that apply only to supplemental niacin for healthy infants, children, and adults ⁶. The daily Tolerable Upper Intake Level for niacin from dietary supplements are listed in Table 2 above. These Tolerable Upper Intake Levels (ULs) are based on the levels associated with skin flushing. The Food and Nutrition Board acknowledges that although excess nicotinamide does not cause flushing, a Tolerable Upper Intake Level for nicotinic acid based on flushing can prevent the potential adverse effects of nicotinamide ⁶. The Tolerable Upper Intake Level, therefore, applies to both forms of supplemental niacin. However, the Tolerable Upper Intake Level does not apply to individuals who are receiving supplemental niacin under medical supervision ⁶.

Interactions with Medications

Niacin can interact with certain medications, and several types of medications might adversely affect niacin levels. A few examples are provided below. Individuals taking these and other medications on a regular basis should discuss their niacin status with their doctors.

Isoniazid and pyrazinamide

Isoniazid and pyrazinamide (together in Rifater), used to treat tuberculosis, are structural analogs of niacin and interrupt the production of niacin from tryptophan by competing with a vitamin B6-dependent enzyme required for this process ¹⁴². In addition, isoniazid can interfere with niacin’s conversion to NAD ⁴. Although pellagra can occur in patients with tuberculosis treated with isoniazid, it can be prevented with increased intakes of niacin.

Antidiabetes medications

Large doses of nicotinic acid can raise blood glucose levels by causing or aggravating insulin resistance and increasing hepatic production of glucose ⁴. Some studies have found that nicotinic acid doses of 1500 mg/day or more are most likely to increase blood glucose levels in individuals with or without diabetes ³². People who take any antidiabetes medications should have their blood glucose levels monitored if they take high-dose nicotinic acid supplements concomitantly because they might require dose adjustments ⁴.

Vitamin B3 deficiency

Severe vitamin B3 or Niacin deficiency or tryptophan (an amino acid) deficiency leads to pellagra, a disease characterized by a pigmented rash or brown discoloration on skin exposed to sunlight; the skin also develops a roughened, sunburned-like appearance (Figure 5) ⁹, ⁶, ¹⁹, ¹⁴³. In advanced stages, increased pigmentation usually leads to thin varnish-like eruptive scales ¹⁹. The characteristic skin rash has a typical photosensitive distribution with welldefined borders, and is mostly observed on the face, the neck – forming the so-called Casal’s necklace -, the dorsa of the hands and the extensor surface of the forearms ¹⁶, ¹⁷, ¹⁸. In addition to skin changes, pellagra can cause a bright red tongue (glossitis) and changes in the digestive tract that lead to vomiting, constipation, or intractable diarrhea. The neurological symptoms of pellagrous encephalopathy can include depression; apathy; headache; fatigue; loss of memory that can progress to aggressive, paranoid, and suicidal behaviors; and auditory and visual hallucinations ⁶, ⁷, ⁹. As pellagra progresses, anorexia develops, and the affected individual eventually dies if pellagra is left untreated ⁷, ¹⁷, ¹⁴⁴.

Pellagra is uncommon in industrialized populations and is mostly limited to people living in poverty, such as refugees and displaced people who eat very limited diets low in niacin and protein ¹⁴², ¹⁴³. Pellagra was common in the early 20th century among individuals living in poverty in the southern United States and parts of Europe whose limited diets consisted mainly of corn or sorghum ⁷, ⁶. Pellagra was also common in the southern United States during the early 1900s where income was low and corn products were a major dietary staple ¹⁴⁵. Interestingly, pellagra was not known in Mexico, where corn was also an important dietary staple and much of the population was also poor. In fact, if corn contains appreciable amounts of niacin, it is present in a bound form that is not nutritionally available to humans. The traditional preparation of corn tortillas in Mexico involves soaking the corn in a lime (calcium oxide) solution, prior to cooking. Heating the corn in an alkaline solution results in the release of bound niacin, increasing its bioavailability ¹⁴⁶. Pellagra epidemics were also unknown to Native Americans who consumed immature corn that contains predominantly unbound (bioavailable) niacin ¹⁴⁵.

Although frank niacin deficiencies leading to pellagra are very rare in the United States, some individuals have marginal or low niacin status ¹³⁶, ¹⁹, ¹⁴².

Niacin deficiency or pellagra may result from inadequate dietary intake of NAD precursors, including tryptophan. Niacin deficiency — often associated with malnutrition — is observed in the homeless population, in individuals suffering from anorexia nervosa or obesity, and in consumers of diets high in maize and poor in animal protein ¹⁴⁷, ¹⁴⁸, ¹⁴⁹, ¹⁵⁰. Deficiencies of other B vitamins and some trace minerals may aggravate niacin deficiency ¹⁵¹, ¹⁵².

Niacin deficiency should especially be suspected in the following conditions: i) malnutrition (homelessness, anorexia nervosa or severe comorbid conditions like end-stage malignancy or HIV); ii) malabsorption (e.g. Crohn’s or Hartnup disease); iii) chronic alcoholism; iv) hemodialysis or peritoneal dialysis; v) drugs like isoniazid, ethionamide, 6-mercaptopurine and estrogens; vi) carcinoid syndrome (due to excess turnover of tryptophan, precursor of niacin, to serotonin) ¹⁶, ¹⁷, ¹⁴⁴.

Malabsorptive disorders that can lead to pellagra include Crohn’s disease and megaduodenum ¹⁵³, ¹⁵⁴. Patients with Hartnup’s disease, a hereditary disorder resulting in defective tryptophan absorption, have developed pellagra. Carcinoid syndrome, a condition of increased secretion of serotonin and other catecholamines by carcinoid tumors, may also result in pellagra due to increased utilization of dietary tryptophan for serotonin rather than niacin synthesis. Furthermore, prolonged treatment with the anti-tuberculosis drug isoniazid has resulted in niacin deficiency ¹⁵⁵. Other pharmaceutical agents, including the immunosuppressive drugs azathioprine (Imuran) and 6-mercaptopurine, the anti-cancer drug 5-fluorouracil (5-FU, Adrucil), and levodopa/carbidopa (Sinemet; two drugs given to people with Parkinson’s disease), are known to increase the reliance on dietary niacin by interfering with the tryptophan-kynurenine-niacin pathway ³. Finally, other populations at risk for niacin deficiency include dialysis patients, cancer patients ¹⁵⁶, ¹⁵⁷, individuals suffering from chronic alcoholism ¹⁷, and people with HIV/AIDS. Furthermore, chronic alcohol intake can lead to severe niacin deficiency through reducing dietary niacin intake and interfering with the tryptophan-to-NAD conversion ¹⁵².

The World Health Organization (WHO) recommends treating pellagra with 300 mg/day nicotinamide in divided doses for 3-4 weeks along with a B-complex or yeast product to treat likely deficiencies in other B vitamins ¹⁴³.

Figure 5. Skin lesions of niacin deficiency (pellagra) involving face, neck, hand and forearm (A), after treatment with niacin for 2 weeks (B)

[Source ¹⁵⁸ ]

Figure 6. Pellagra rash

Footnote: This is a classical case of pellagra. A 42 year old woman was admitted to hospital with a one month history of progressive forgetfulness, irritability and confusion. There was no history of tremor or confabulation. Reportedly, she also had fever two weeks prior to admission. There was no history of headache, neck-ache or neck stiffness. Further inquiry revealed she had developed rash around her neck and in the distal parts of all four limbs a month prior to the onset of the altered mental status. There was no history of rash involving the mucosae or of having taken any drugs in the period preceding the rash.

[Source ¹⁵⁹ ]

Figure 7. Pellagra tongue

[Source ¹⁶⁰ ]

Vitamin B3 deficiency causes

Niacin deficiency or pellagra is caused by having too little niacin or tryptophan in your diet. It can also occur if your body fails to absorb niacin or tryptophan.

Half of your body’s niacin requirement comes from dietary intake of niacin. The other half is synthesized in your body from the amino acid tryptophan. Niacin is found in many animal products (as nicotinamide) and plants (as nicotinic acid). A varied diet including milk, eggs, red meat, poultry, fish, peanuts, legumes, and seeds provides sufficient niacin and tryptophan.

Niacin deficiency or pellagra may also develop due to ¹⁶¹, ¹⁶²:

Gastrointestinal diseases (chronic colitis, severe ulcerative colitis and regional ileitis)
Prolonged diarrhea
Weight loss (bariatric) surgery
Gastric cancer surgery
Anorexia nervosa
Excessive alcohol use or chronic alcoholism
Carcinoid syndrome (group of symptoms associated with carcinoid tumors of the small intestine, colon, appendix, and bronchial tubes in the lungs)
Certain medicines, such as isoniazid, 5-fluorouracil, 6-mercaptopurine, pyrazinamide, hydantoin, ethionamide, phenobarbital, azathioprine, and chloramphenicol
HIV infection
Tuberculosis of the gastrointestinal tract
Hepatic cirrhosis
Hartnup disease.

Pellagra is most common among poor and food-limited populations. The disease is more common in parts of the world (such as certain parts of Africa) where people have a lot of untreated corn in their diet. Corn is a poor source of tryptophan, and niacin in corn is tightly bound to other components of the grain. Niacin is released from corn if soaked in limewater overnight. This method is used to cook tortillas in Central America where pellagra is rare. Pellagra is rare in the United States and may be associated with severe alcoholism or medical causes of malnutrition.

Groups at Risk of Vitamin B3 deficiency

Niacin inadequacy usually arises from insufficient intakes of foods containing niacin and tryptophan. It can also be caused by factors that reduce the conversion of tryptophan to niacin, such as low intakes of other nutrients ⁶, ¹⁴². The following groups are among those most likely to have inadequate niacin status.

People with undernutrition

People who are undernourished because they live in poverty or have anorexia, alcohol use disorder, AIDS, inflammatory bowel disease, or liver cirrhosis often have inadequate intakes of niacin and other nutrients ⁶, ¹⁴², ¹³⁶, ¹⁹.

People with inadequate riboflavin (vitamin B2), pyridoxine (vitamin B6) and/or iron intakes

People who do not consume enough riboflavin (vitamin B2), pyridoxine (vitamin B6), or iron convert less tryptophan to niacin because enzymes in the metabolic pathway for this conversion depend on these nutrients to function ⁶, ¹⁴².

People with Hartnup disease

Hartnup disease is a rare genetic disorder caused by mutations in the SLC6A19 gene and is inherited in an autosomal recessive manner ¹³⁵. The SLC6A19 gene produces a protein known as an amino acid transporter, which serves to assist the movement (or transport) of specific amino acids within the body. The amino acid transporter protein is especially active within the kidneys and the intestines, although these organs are otherwise unaffected and function normally. The amino acids affected include tryptophan, alanine, asparagine, glutamine, histidine, isoleucine, leucine, phenylalanine, serine, threonine, tyrosine, and valine ¹³⁵. Hartnup disease interferes with the absorption of tryptophan in the small intestine and increases its loss in the urine via the kidneys ¹³⁵, ⁶, ¹³⁶. As a result, the body has less available tryptophan to convert to niacin.

The symptoms of Hartnup disease vary greatly from one person to another. The majority of affected individuals do not have any apparent symptoms (asymptomatic). When symptoms do develop, they most often occur between the ages of 3-9. In rare instances, symptoms first appear in adulthood.

The most common symptom are red, scaly light-sensitive (photosensitive) rashes on the face, arms, extremities, and other exposed areas of skin.

A wide variety of neurological abnormalities can occur including sudden episodes of impaired muscle coordination (ataxia), an unsteady walk (gait), impaired articulation of speech (dysarthria), occasional tremors of the hands and tongue, and spasticity, a condition marked by increased muscle tone and stiffness of the muscles, particularly those of the legs.

There have been reports of delayed cognitive development and, in rare instances, mild intellectual disability in some children. It is, however, unclear whether these symptoms are related to Hartnup disorder or incidentally occurred in the same individual and were therefore attributed to Hartnup disorder. Similarly, seizures, fainting, trembling, lack of muscle tone (hypotonia), headaches, dizziness and/or vertigo, and delays in motor development have been observed but may be unrelated. Some affected individuals may experience psychiatric abnormalities including emotional instability such as rapid mood changes, depression, confusion, anxiety, delusions, and/or hallucinations.

Some children experience growth delays and may be shorter than would be expected based upon age and gender (short stature). In some instances, the eyes may be affected and individuals may experience double vision (diplopia), involuntary rhythmic movements of the eyes (nystagmus), and droopy upper eyelids (ptosis).

Diarrhea may precede or follow an episode of this disorder. Some adults with Hartnup disease have been reported whose initial symptom was the onset of seizures during adulthood. Heartburn has been reported in adults with the disorder.

Hartnup disease has a good prognosis with treatment and symptoms tend to improve with age.

People with carcinoid syndrome

Carcinoid syndrome is caused by slow-growing tumors in the gastrointestinal tract that release serotonin and other substances. It is characterized by facial flushing, diarrhea, and other symptoms. In those with carcinoid syndrome, tryptophan is preferentially oxidized to serotonin and not metabolized to niacin ⁶. As a result, the body has less available tryptophan to convert to niacin.

Vitamin B3 deficiency prevention

Pellagra can be prevented by following a well-balanced diet.

Get treated for health problems that may cause pellagra.

Vitamin B3 deficiency symptoms

Symptoms of niacin deficiency or pellagra include ²¹:

Delusions or mental confusion
Diarrhea
Weakness
Loss of appetite
Pain in abdomen
Inflamed mucous membrane
Scaly skin sores, especially in sun-exposed areas of the skin

The most common symptoms of niacin deficiency involve the skin, the digestive system, and the nervous system ³. The symptoms of pellagra are commonly referred to as the 4 “Ds”: sun-sensitive dermatitis, diarrhea, and dementia. A fourth “D,” death, occurs if pellagra is left untreated ³⁸. In the skin, a thick, scaly, darkly pigmented rash develops symmetrically in areas exposed to sunlight. In fact, the word “pellagra” comes from “pelle agra,” the Italian phrase for rough skin. Symptoms related to the digestive system include inflammation of the mouth and tongue (“bright red tongue”), vomiting, constipation, abdominal pain, and ultimately, diarrhea. Gastrointestinal disorders and diarrhea contribute to the ongoing malnourishment of the patients. Neurologic symptoms include headache, apathy, fatigue, depression, disorientation, and memory loss and are more consistent with delirium than with the historically described dementia ¹⁷. Disease presentations vary in appearance since the classic triad rarely presents in its entirety. The absence of dermatitis, for example, is known as pellagra sine pellagra ³.

Vitamin B3 deficiency complication

Left untreated, niacin deficiency or pellagra can result in malnutrition and cachexia (wasting of the body), nerve damage, particularly in the brain. Progression of the neuropsychiatric symptoms can lead to delusions, hallucinations, psychosis, and eventually coma and death ¹⁹. Skin sores may become infected.

Vitamin B3 deficiency diagnosis

Niacin deficiency or pellagra diagnosis is a clinical diagnosis and biochemical testing is rarely used ¹⁶⁰. Investigations such as blood tests and skin biopsy are not diagnostic but may be used to exclude other diagnoses ¹⁶³. If needed, niacin deficiency can be assessed by two methods ¹⁶⁴, ¹⁶², ¹⁹:

Biochemical assessment. This approach is not widely used. Measurement of urinary N-methylnicotinamide or erythrocyte NAD: NADP (ratio) can be obtained to evaluate the metabolic rate of niacin in the body. The combined urinary excretion of N methylnicotinamide and pyridone of less than 1.5 mg in 24 hours indicates severe niacin deficiency. Low urinary levels of N-methylnicotinamide and pyridone suggest niacin deficiency and support the diagnosis of pellagra.
- Low serum niacin, tryptophan, NAD, and NADP levels can reflect niacin deficiency and confirm the diagnosis of pellagra.
- Blood counts (anemia), findings of hypoproteinemia, higher levels of serum calcium and lower levels of serum kalium and phosphorus, liver function test results, and serum porphyrin levels can help in diagnosing pellagra.
Clinical assessment. It is more widely used by assessing for diarrhea, glossitis, and dermatitis. The skin is assessed for hyperpigmentation, dryness and scaling, facial butterfly sign, and/or Casal’s collar (necklace) in sun-exposed areas. It is important to note that diarrhea and dementia may not always be present.

The rapid response to niacin supplementation usually confirms the diagnosis.

Hartnup disease is diagnosed on the detection of neutral amino acids in the urine. Molecular genetic testing can confirm a diagnosis of Hartnup disease in some cases. Molecular genetic testing can detect genetic alterations in the SLC19A6 gene known to cause the disorder, but usually is not necessary to obtain a diagnosis ¹³⁵.

Vitamin B3 deficiency treatment

To treat niacin deficiency or pellagra, the World Health Organization (WHO) recommends administering nicotinamide to avoid the flushing commonly caused by nicotinic acid ¹⁴³. Treatment guidelines suggest using 300 mg/day of oral nicotinamide in divided doses, or 100 mg/day administered parenterally in divided doses, for three to four weeks ¹⁵⁷, ¹⁴³, ¹⁶⁵. Because patients with pellagra often display additional vitamin deficiencies, administration of a vitamin B-complex preparation is advised ¹⁴³.

Individuals with Hartnup disease who do not develop symptoms will usually not require any treatment ¹³⁵. Low protein diets (vegan or similar) may trigger symptomatic episodes, which can be reduced or avoided by maintaining good nutrition including a high protein diet, avoiding excess exposure the sun, and avoiding certain drugs such as sulphonamide drugs ¹³⁵. Supplementing the diet with nicotinamide or niacin is also of benefit in preventing Hartnup disease episodes ¹³⁵. In some instances, during a symptomatic episode, treatment with nicotinamide may be recommended. According to the medical literature, at least one individual showed an improvement of symptoms after treatment with the compound L-tryptophan ethyl ester, which restored tryptophan levels in both the serum and cerebrospinal fluid ¹³⁵. Other treatment is symptomatic and supportive. Genetic counseling may be helpful for affected families.

Vitamin B3 deficiency prognosis

Diarrhea and glossitis are the first to improve within days usually improve in 2 to 3 days, while recovery from dementia and dermatitis is seen within 7 days of treatment ¹⁶⁶, ¹⁶⁷, ¹⁶². The skin changes typically resolve within two weeks. However, a longer recovery may be seen in chronic cases ¹⁶⁸.

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Pantothenic acid

Pantothenic acid also known as vitamin B5, is a water-soluble vitamin that is naturally present in some foods (i.e., eggs, milk, vegetables, beef, chicken, and whole grains), added to others, and available as a dietary supplement ¹. The main function of pantothenic acid (vitamin B5) is a precursor in the biosynthesis of coenzyme A (CoA) and acyl carrier protein (Figure 1) ², ³. Coenzyme A (CoA) is essential for fatty acid synthesis and degradation, transfer of acetyl and acyl groups, and a multitude of other anabolic and catabolic processes ⁴, ⁵. Acyl carrier protein’s main role is in fatty acid synthesis ³. Coenzyme A (CoA) reacts with acyl groups, giving rise to thioester derivatives, such as acetyl-CoA, succinyl-CoA, malonyl-CoA, and 3-hydroxy-3-methylglutaryl (HMG)-CoA. Coenzyme A (CoA) and its acyl derivatives are required for reactions that generate energy from the degradation of dietary fat, carbohydrates, and proteins ⁶. In addition, coenzyme A (CoA) in the form of acetyl-CoA and succinyl-CoA is involved in the citric acid cycle, in the synthesis of essential fats, cholesterol, steroid hormones, vitamins A and D, the neurotransmitter acetylcholine, and in the fatty acid beta-oxidation pathway ⁶. Coenzyme A (CoA) derivatives are also required for the synthesis of the hormone, melatonin, and for a component of hemoglobin called heme. Furthermore, metabolism of a number of drugs and toxins by the liver requires coenzyme A ⁷.

A wide variety of plant and animal foods contain pantothenic acid (vitamin B5) ². About 85% of dietary pantothenic acid (vitamin B5) is in the form of coenzyme A (CoA) or phosphopantetheine ³, ⁵. These forms are converted to pantothenic acid (vitamin B5) by digestive enzymes (nucleosidases, peptidases, and phosphorylases) in the intestinal lumen and intestinal cells. Pantothenic acid (vitamin B5) is absorbed in the intestine and delivered directly into the bloodstream by active transport (and possibly simple diffusion at higher doses) ⁵, ². Pantetheine, the dephosphorylated form of phosphopantetheine, however, is first taken up by intestinal cells and converted to pantothenic acid before being delivered into the bloodstream ³. The intestinal flora also produces pantothenic acid, but its contribution to the total amount of pantothenic acid that the body absorbs is not known ⁵. Red blood cells carry pantothenic acid throughout the body ⁵. Most pantothenic acid in tissues is in the form of coenzyme A (CoA), but smaller amounts are present as acyl carrier protein or free pantothenic acid ⁵.

Few data on pantothenic acid (vitamin B5) intakes in the United States are available. However, a typical mixed diet in the United States provides an estimated daily intake of about 6 mg, suggesting that most people in the United States consume adequate amounts ⁸. Some pantothenic acid (vitamin B5) intake information is available from other Western populations. For example, a 1996–1997 study in New Brunswick, Canada, found average daily pantothenic acid (vitamin B5) intakes of 4.0 mg in women and 5.5 mg in men ⁹.

Pantothenic acid status is not routinely measured in healthy people ¹. Microbiologic growth assays, animal bioassays, and radioimmunoassays can be used to measure pantothenic concentrations in blood, urine, and tissue, but urinary concentrations are the most reliable indicators because of their close relationship with dietary intake ⁵. With a typical American diet, the urinary excretion rate for pantothenic acid is about 2.6 mg/day ¹⁰, ⁴. Excretion of less than 1 mg pantothenic acid per day suggests deficiency ¹¹, ². Like urinary concentrations, whole-blood concentrations of pantothenic acid correlate with pantothenic acid intake, but measuring pantothenic acid in whole blood requires enzyme pretreatment to release free pantothenic acid from coenzyme A (CoA) ². Normal blood concentrations of pantothenic acid range from 1.6 to 2.7 mcmol/L, and blood concentrations below 1 mcmol/L are considered low and suggest deficiency ². Unlike whole-blood concentrations, plasma levels of pantothenic acid do not correlate well with changes in intake or status ².

Pantothenic acid (vitamin B5) deficiency is generally rare since the vitamin is present in many foods. However, pantothenic acid (vitamin B5) deficiency can present in people with severe malnutrition ¹². An individual with pantothenic acid (vitamin B5) deficiency commonly has deficiencies in other nutrients, which can make it challenging to identify the effects that are specific to pantothenic acid (vitamin B5) deficiency. An experimental pantothenic acid (vitamin B5) deficiency study associated the deficiency with symptoms such as fatigue, headache, malaise, personality changes, numbness, muscle cramps, paresthesia, muscle/ abdominal cramps, nausea, and impaired muscle coordination ¹¹.

Pantothenic acid kinase 2 (PANK2) catalyzes the initial step of phosphorylation of pantothenic acid to 4’-phosphopantothenic acid. Individuals with a mutation in their pantothenate kinase 2 (PANK2) gene are likely to have a pantothenic acid inadequacy as well. Enough PANK2 mutations reduce the activity of pantothenate kinase 2, which can potentially decrease the conversion of pantothenic acid to coenzyme A (CoA) and lead to reduced CoA levels. PANK2 gene mutations also cause pantothenate kinase-associated neurodegeneration (PKAN). A common hallmark of individuals with pantothenate kinase-associated neurodegeneration (PKAN) is an accumulation of iron in the brain that forms a pattern called the “eye of the tiger” sign ¹³. Pantothenate kinase-associated neurodegeneration (PKAN) disease also presents with a progressive movement disorder, and other symptoms may vary significantly from case to case. Symptoms include dysarthria, dystonia, poor balance, spasticity, and muscle rigidity. Treatment of pantothenate kinase-associated neurodegeneration (PKAN) focuses mainly on reducing symptoms. A few anecdotal reports indicate that vitamin B5 supplements can reduce symptoms, but the benefits of the general use of this supplement in PKAN are not known ¹⁴.

Figure 1. Coenzyme A (CoA) synthesis from pantothenic acid (vitamin B5)

[Source ¹⁵ ]

Figure 2. Structure of pantothenic acid and its derivatives (pantetheine, pantethine, and acetyl-CoA).

[Source ¹⁶ ]

Pantothenic Acid function

Pantothenic acid or Vitamin B5 is essential for synthesis of coenzyme A (CoA) and acyl-carrier protein (ACP) and phosphopantetheine, which are crucial to fatty acid metabolism ¹⁷. Coenzyme A (CoA) plays a vital role in many catabolic and anabolic reactions. It is necessary for synthesis of fatty acids, cholesterol, acetylcholine, bile acids, and others ¹⁶. Coenzyme A (CoA) also plays a role in regulation of metabolism and gene expression. Coenzyme A (CoA) is required for processing large organic molecules, such as lipids, carbohydrates, and proteins. These reactions generate energy with formation of acylated forms of CoA, such as acetyl-CoA, succinyl-CoA, propionyl-CoA, isovaleryl-CoA, isobutyryl-CoA, α-methylbutyryl-CoA, and fatty acyl-CoA ¹⁸. The structure of pantothenic acid and its derivatives is shown in Figure 2.

Acyl-carrier protein (ACP) is important for synthesis of fatty acids ¹⁶. Acyl-carrier protein (ACP) is expressed in the inactive form, apo-ACP. Its activation to holo-ACP requires the attachment of a prosthetic group (the 4′-phosphopantetheinyl moiety). This happens during the reaction with coenzyme A (CoA) catalyzed by 4′-phosphopantetheinyl transferase ¹⁹.

Coenzyme A

Pantothenic acid is a precursor in the biosynthesis of coenzyme A (CoA) (Figure 1), an essential coenzyme in a variety of biochemical reactions that sustain life ⁶. Pantothenic acid kinase 2 (PANK2) catalyzes the initial step of phosphorylation of pantothenic acid to 4’-phosphopantothenic acid. Coenzyme A (CoA) and its derivatives inhibit the synthesis of 4’-phosphopantothenic acid, but the inhibition can be reversed by carnitine, required for the transport of fatty acids into the mitochondria ²⁰. The subsequent reactions in this biosynthetic pathway include the synthesis of the intermediate 4’-phosphopantetheine, as well as the recycling of coenzyme A to 4’-phosphopantetheine (Figure 1).

Coenzyme A (CoA) reacts with acyl groups, giving rise to thioester derivatives, such as acetyl-CoA, succinyl-CoA, malonyl-CoA, and 3-hydroxy-3-methylglutaryl (HMG)-CoA ⁶. Coenzyme A (CoA) and its acyl derivatives are required for reactions that generate energy from the degradation of dietary fat, carbohydrates, and proteins. In addition, coenzyme A (CoA) in the form of acetyl-CoA and succinyl-CoA is involved in the citric acid cycle, in the synthesis of essential fats, cholesterol, steroid hormones, vitamins A and D, the neurotransmitter acetylcholine, and in the fatty acid beta-oxidation pathway ⁶. Coenzyme A (CoA) derivatives are also required for the synthesis of the hormone, melatonin, and for a component of hemoglobin called heme ⁶. Furthermore, metabolism of a number of drugs and toxins by the liver requires coenzyme A (CoA) ⁷.

Coenzyme A was named for its role in acetylation reactions ⁶. Most acetylated proteins in the body have been modified by the addition of an acetate group that was donated by the coenzyme A thioester derivative, acetyl-CoA. Protein acetylation alters the overall charge of proteins, modifying their three-dimensional structure and, potentially, their function ⁶. For example, acetylation is a mechanism that regulates the activity of peptide hormones, including those produced by the pituitary gland ²¹. Also, protein acetylation, like other posttranslational modifications, has been shown to regulate the subcellular localization, the function, and the half-life of many signaling molecules, transcription factors, and enzymes. Notably, the acetylation of histones plays a role in the regulation of gene expression by facilitating transcription (i.e., mRNA synthesis), while deacetylated histones are usually associated with chromatin compaction and gene silencing. The acetylation of histones was found to result in structural changes of the chromatin, which affect both DNA-protein and protein-protein interactions. Crosstalk between acetylation marks and other posttranscriptional modifications of the histones also facilitate the recruitment of transcriptional regulators to the promoter of genes that are subsequently transcribed ²².

Finally, a number of signaling molecules are modified by the attachment of long-chain fatty acids donated by coenzyme A (CoA). These modifications are known as protein acylation and have central roles in cell-signaling pathways ⁷.

Acyl-carrier protein

Lipids are fat molecules essential for normal physiological function and, among other types, include sphingolipids (essential components of the myelin sheath that enhances nerve transmission), phospholipids (important structural components of cell membranes), and fatty acids ⁶. Fatty acid synthase (FAS) is a multi-enzyme complex that catalyzes the synthesis of fatty acids ⁶. Within the fatty acid synthase complex, the acyl-carrier protein (ACP) requires pantothenic acid in the form of 4′-phosphopantetheine for its activity as a carrier protein ²⁰. A group, such as the 4’-phosphopantetheinyl moiety for acyl-carrier protein (ACP), is called a prosthetic group; the prosthetic group is not composed of amino acids and is a tightly bound cofactor required for the biological activity of some proteins (Figure 3). Acetyl-CoA, malonyl-CoA, and acyl-carrier protein (ACP) are all required for the synthesis of fatty acids in the cytosol ⁶. During fatty acid synthesis, the acyl groups of acetyl-CoA and malonyl-CoA are transferred to the sulfhydryl group (-SH) of the 4’-phosphopantetheinyl moiety of acyl-carrier protein (ACP). The prosthetic group is used as a flexible arm to transfer the growing fatty acid chain to each of the enzymatic centers of the type 1 fatty acid synthase complex ²³. In the mitochondria, 4′-phosphopantetheine also serves as a prosthetic group for an acyl-carrier protein (ACP) homolog present in mitochondrial type 2 fatty acid synthase complex ²³.

Figure 3. Acyl-carrier protein (ACP) function

[Source ⁶ ]

10-formyltetrahydrofolate dehydrogenase

The enzyme 10-formyltetrahydrofolate dehydrogenase (FDH) catalyzes the conversion of 10-formyltetrahydrofolate to tetrahydrofolate, an essential cofactor in the metabolism of nucleic acids and amino acids (Figure 4) ⁶. Similar to acyl-carrier protein (ACP), 10-formyltetrahydrofolate dehydrogenase requires a 4’-phosphopantetheine prosthetic group for its biological activity ⁶. The prosthetic group acts as a swinging arm to couple the activities of the two catalytic domains of 10-formyltetrahydrofolate dehydrogenase ²⁴, ²⁵. A homolog of 10-formyltetrahydrofolate dehydrogenase in mitochondria also requires 4’-phosphopantetheinylation to be biologically active ²⁶.

Figure 4. Formyltetrahydrofolate dehydrogenase function

[Source ⁶ ]

Alpha-aminoadipate semialdehyde synthase

4’-phosphopantetheinylation is required for the biological activity of the apo-enzyme alpha-aminoadipate semialdehyde synthase (AASS) ⁶. Alpha-aminoadipate semialdehyde synthase (AASS) catalyzes the initial reactions in the mitochondrial pathway for the degradation of lysine — an essential amino acid for humans ⁶. Alpha-aminoadipate semialdehyde synthase (AASS) is made of two catalytic domains. The lysine-ketoglutarate reductase domain first catalyzes the conversion of lysine to saccharopine. Saccharopine is further converted to α-aminoadipate semialdehyde in a reaction catalyzed by the saccharopine dehydrogenase domain (Figure 5).

Figure 5. Alpha-aminoadipate semialdehyde synthase (AASS) function

[Source ⁶ ]

Pantothenic acid health benefits

Scientists are studying pantothenic acid or vitamin B5 to understand how it affects health. Here is what research have shown.

High cholesterol and triglyceride levels

Because of pantothenic acid’s role in triglyceride synthesis and lipoprotein metabolism, experts have hypothesized that vitamin B5 or pantothenic acid supplementation might reduce lipid levels in patients with hyperlipidemia ²⁷. The form of pantothenic acid called pantethine is being studied to see if it helps lower total cholesterol, low-density lipoprotein (LDL or “bad”) cholesterol, and triglyceride levels. It’s also being studied to see if it raises levels of high-density lipoprotein (HDL or “good”) cholesterol. The results of these studies so far are promising, but more research is needed to understand the effects of pantethine dietary supplements taken alone or combined with a heart-healthy diet.

Several clinical trials have shown that the form of pantothenic acid known as pantethine reduces lipid levels when taken in large amounts ²⁸, but pantothenic acid itself does not appear to have the same effects ². A 2005 review included 28 small clinical trials (average sample size of 22 participants) that examined the effect of pantethine supplements (median daily dose of 900 mg for an average of 12.7 weeks) on serum lipid levels in a total of 646 adults with hyperlipidemia ²⁸. On average, the supplements were associated with triglyceride declines of 14.2% at 1 month and 32.9% at 4 months. The corresponding declines in total cholesterol were 8.7% and 15.1%, and for low-density lipoprotein (LDL) cholesterol were 10.4% and 20.1%. The corresponding increases in high-density lipoprotein (HDL) cholesterol were 6.1% and 8.4% ²⁸.

A few additional clinical trials have assessed pantethine’s effects on lipid levels since the publication of the 2005 review. A double-blind trial in China randomly assigned 216 adults with hypertriglyceridemia (204–576 mg/dl) to supplementation with 400 U/day coenzyme A (CoA) or 600 mg/day pantethine ²⁹. All participants also received dietary counseling. Triglyceride levels dropped by a significant 16.5% with pantethine compared with baseline after 8 weeks. Concentrations of total cholesterol and non–HDL cholesterol also declined modestly but significantly from baseline. However, these declines might have been due, at least in part, to the dietary counseling that the participants received ²⁹.

Two randomized, blinded, placebo-controlled studies by the same research group in a total of 152 adults with low to moderate cardiovascular disease risk found that 600 mg/day pantethine for 8 weeks followed by 900 mg/day for 8 weeks plus a therapeutic lifestyle change diet resulted in small but significant reductions in total cholesterol, LDL cholesterol, and non-HDL cholesterol compared with placebo after 16 weeks ²⁷, ³⁰. Increasing the amount of pantethine from 600 to 900 mg/day did not increase the magnitude of reduction in the lipid measures.

Additional studies are needed to determine whether pantethine supplementation has a beneficial effect on hyperlipidemia independently of, and together with, eating a heart-healthy diet. Research is also needed to determine the mechanisms of pantethine’s effects on lipid levels.

Wound healing

The addition of calcium D-pantothenate and/or pantothenol to the medium of cultured skin fibroblasts given an artificial wound was found to increase cell proliferation and migration, thus accelerating wound healing in vitro (test tube studies) ³¹, ³². Likewise, in vitro (test tube studies) deficiency in pantothenic acid induced the expression of differentiation markers in proliferating skin fibroblasts and inhibited proliferation in human keratinocytes ³³. The application of ointments containing either calcium D-pantothenate or pantothenol — also known as D-panthenol or dexpanthenol — to the skin has been shown to accelerate the closure of skin wounds and increase the strength of scar tissue in animals ²⁰.

The effects of dexpanthenol on wound healing are unclear. In a placebo-controlled study that included 12 healthy volunteers, the application of dexpanthenol-containing ointment (every 12 hours for 1 to 6 days) in a model of skin wound healing was associated with an enhanced expression of markers of proliferation, inflammation, and tissue repair ³⁴. However, the study failed to report whether these changes in response to topical dexpanthenol improved the wound-repair process compared to placebo ³⁴. Some studies have shown no effects. Early randomized controlled trials in patients undergoing surgery for tattoo removal found that daily co-supplementation with 1 gram or 3 grams of vitamin C and 200 mg or 900 mg of pantothenic acid (vitamin B5) for 21 days did not significantly improve the wound-healing process ³⁵, ³⁶. Yet, in a recent randomized, double-blind, placebo-controlled study, the use of dexpanthenol pastilles (300 mg/day for up to 14 days post surgery) was found to accelerate mucosal healing after tonsillectomy in children ³⁷.

Facial acne

A randomized, double-blind, placebo-controlled study of adults (average age of 31.8 ± 8.4 years) previously diagnosed with mild to moderate acne vulgaris was performed over over 12-weeks ³⁸, ³⁹. Subjects were randomized to the study agent, a pantothenic acid-based dietary supplement (2.2 g of pantothenic acid twice a day with food), or a placebo for 12 weeks ³⁹. The primary outcome of the study was the difference in total lesion count between the study agent group versus the placebo group from baseline to endpoint. Secondary measurements included differences in mean non-inflammatory and inflammatory lesions, Investigators Global Assessment and Dermatology Life Quality Index (DLQI) scores between the two groups. The results from this study indicate that the administration of a pantothenic acid-based dietary supplement in healthy adults with facial acne lesions is safe, well tolerated and reduced total facial lesion count versus placebo after 12 weeks of administration ³⁹. Secondary analysis shows that the study agent significantly reduced area-specific and inflammatory blemishes ³⁹. Further randomized, placebo-controlled trials are needed to confirm these findings.

Skin conditions

The usage of vitamin B5 is prevalent within the field of dermatology. This interest has led to a study that compares the effectiveness of reduced form of vitamin B5 dexpanthenol (D-panthenol) as an alternative treatment to atopic dermatitis against a standard treatment of hydrocortisone. Overall, the study found that dexpanthenol can potentially treat mild to moderate childhood atopic dermatitis therapy ⁴⁰. Other research suggests that dexpanthenol cream can be useful in managing mucocutaneous side effects that occur during isotretinoin therapy ⁴¹. Isotretinoin therapy is used as a treatment for acne, and its mucocutaneous side effects include dryness of mucous membranes, cheilitis, and xerosis.

The reduced form of vitamin B5 dexpanthenol (D-panthenol) effects are, however, likely not related to the physiological function of vitamin B5 but are mediated by its moisturizing effect, which is based on its hygroscopic property ¹⁶. Vitamin B5 dexpanthenol (D-panthenol) could be used topically as a cream, emollient, drops, gel, lotion, oil, ointment, solution, and spray in concentration of 2–5% ⁴². Dexpanthenol protects epithelium and promotes cellular proliferation. During the wound healing, it helps to recover the epidermal barrier function, has anti-inflammatory activity, and supports wound closure ⁴³.

The healing properties of dexpanthenol-containing cream (5%) were confirmed on superficial skin lesions caused by application of 5% sodium lauryl sulfate solution for 4 hours. One week, twice daily dexpanthenol-containing cream (5%) application led to a significant enhancement of stratum corneum hydration, as well as reduction in skin roughness and inflammation ⁴⁴. Other studies confirmed the effect of dexpanthenol containing emollient on sodium dodecyl sulfate (0.5%) induced skin barrier dysfunction. Dexpanthenol improved skin hydration and increased ceramide 3, as well as free fatty acid and cholesterol content, in the stratum corneum, and it also supported recolonization of the skin with commensal bacteria ⁴⁵.

Dexpanthenol in ointment with petroleum jelly led to a significantly faster and pronounced reduction of skin lesions size and better re-epithelialization of ablative CO2 laser photo-damaged skin than the petroleum-jelly cream itself ⁴⁶. Protective effect of an ointment with dexpanthenol (5%) was also seen in combination with zinc oxide in irritant diaper dermatitis in comparison to the control ointment base ⁴⁷. Two-week administration of dexpanthenol 5% water-oil formulations 4 to 8 times daily restored the skin barrier of freshly tattooed skin. The disadvantage of this study is that the effect was not compared with a control group ⁴⁸.

In treatment of atopic dermatitis in children, dexpanthenol (5%) ointment exerted equal effectiveness to hydrocortisone (1%) ointment and, therefore, can be used as alternative to treatment of mild and moderate atopic dermatitis ⁴⁰.

Use of dexpanthenol cream (5%) on treatment of traumatic nipples of breastfeeding mothers had the same therapeutic effect in comparison with pure lanolin or 0.2% peppermint oil creams administered every 8 hours for 14 days ⁴⁹.

The application of 2% dexpanthenol drops on corneal epithelial wounds after surface laser ablation only induced little effect on corneal epithelial regeneration, and, in general, the effect was of minimal clinical relevance after 2 months of use ⁵⁰. However, dexpanthenol has been found to be effective in treatment of dry eye, where it exerted superior improvement in disturbances of corneal epithelium permeability comparing with dexpanthenol-free drops ⁵¹.

Dexpanthenol is also added to topical nasal decongestant (sprays and droplets) containing α-sympathomimetics to treat acute allergic or non-allergic rhinitis or after nasal surgery. A combined preparation of oxymethazoline (0.05%) with dexpanthenol (5%) showed a better efficacy than xylomethazoline (0.1%) alone in patients with acute allergic rhinitis or with post-nasal surgery. The relief in nasal congestion was significantly better, recovery time was shorter, and significant improvements in sneezing, nasal discharge, and irritation were also observed ⁵². Similarly, addition of dexpanthenol to xylometazoline significantly reduced nasal obstruction, rhinorrhea, hyperplasia of nasal concha, and redness of the nasal mucous membrane compared with xylometazoline alone ⁵³, ⁵⁴.

Graying of hair

Mice that are deficient in pantothenic acid (vitamin B5) developed skin irritation and graying of the fur, which is reversed by pantothenic acid administration. In humans, there is no evidence that taking pantothenic acid (vitamin B5) as supplements or using shampoos containing pantothenic acid can prevent or restore hair color ⁵⁵.

How much pantothenic acid do I need?

The amount of pantothenic acid or vitamin B5 you need depends on your age and sex. Average daily recommended amounts are listed below in milligrams (mg).

Few data on vitamin B5 or pantothenic acid intakes in the United States are available ¹. However, a typical mixed diet in the United States provides an estimated daily intake of about 6 mg, suggesting that most people in the United States consume adequate amounts ⁸. Some intake information is available from other Western populations. For example, a 1996–1997 study in New Brunswick, Canada, found average daily pantothenic acid intakes of 4 mg in women and 5.5 mg in men ⁹.

Table 1. Adequate Intakes for Pantothenic Acid (vitamin B5)

Life Stage	Recommended Amount
Birth to 6 months	1.7 mg
Infants 7–12 months	1.8 mg
Children 1–3 years	2 mg
Children 4–8 years	3 mg
Children 9–13 years	4 mg
Teens 14–18 years	5 mg
Adults 19 years and older	5 mg
Pregnant teens and women	6 mg
Breastfeeding teens and women	7 mg

Footnote:

Adequate Intake (AI) = Intake at this level is assumed to ensure nutritional adequacy; established when evidence is insufficient to develop an Recommended Dietary Allowance (RDA).
Recommended Dietary Allowance (RDA) = Average daily level of intake sufficient to meet the nutrient requirements of nearly all (97%–98%) healthy individuals; often used to plan nutritionally adequate diets for individuals.

[Source ⁴ ]

What foods have Pantothenic acid?

Pantothenic acid or Vitamin B5 is naturally present in almost all plant- and animal-based foods ⁵. Vitamin B5 or pantothenic acid is also added to some foods, including some breakfast cereals and beverages (such as energy drinks) ⁵. Limited data indicate that the body absorbs 40%–61% (or half, on average) of pantothenic acid from foods ¹⁰.

The U.S. Department of Agriculture’s (USDA’s) FoodData Central (https://fdc.nal.usda.gov) lists the nutrient content of many foods and provides a comprehensive list of foods containing pantothenic acid arranged by nutrient content (https://www.nal.usda.gov/sites/www.nal.usda.gov/files/pantothenic_acid.pdf).

You can get recommended amounts of vitamin B5 (pantothenic acid) by eating a variety of foods, including the following:

Beef, poultry, seafood, and organ meats
Eggs and milk
Vegetables such as mushrooms (especially shiitakes), avocados, potatoes, and broccoli
Whole grains, such as whole wheat, brown rice, and oats
Peanuts, sunflower seeds, and chickpeas.

Food processing may alter the content of vitamin B5 or pantothenic acid ⁵⁶, ⁵⁷. The milling of cereals, in which grains, such as wheat, rice, and corn, are dehulled and ground into smaller pieces or flours to improve palatability, reduce cooking time, and create food products, but remove grain parts rich in micronutrients, resulting in considerable losses of vitamin B5 or pantothenic acid ⁵⁸, ⁵⁹, ⁶⁰, ⁶¹, ⁶². Milling reduces vitamin B5 or pantothenic acid contents, in comparison to whole cereals, by 50–55% and 64–88% in wheat and maize, respectively ⁵⁸, ⁶³, ⁶⁴. Vitamin B5 or pantothenic acid losses are 50–67% and 18–25% in non-parboiled and parboiled white rice, respectively, compared to brown rice ⁵⁸, ⁶⁵, ⁶¹, ⁶⁴.

Vitamin B5 or pantothenic acid is quite stable during thermal processing at pH levels of 5–7; losses of pantothenic acid during the preparation and cooking of foods are normally not very large ⁶⁶, ⁵⁶, but substantial losses of pantothenic acid can occur through leaching into the cooking liquids, such as water, soup, gravy, or drippings; when these are consumed along with the cooked food, a great part of the vitamin is retained ⁶⁷, ⁶⁸, ⁶⁹, ⁷⁰, ⁷¹. Vitamin B5 or pantothenic acid content in pork, beef, and chicken is reduced owing to steaming, braising, and, in particular, by boiling, by 15–50% solely in meat due to leaching. In the whole dish, the losses are only 10–20%. Frying decreases the vitamin level by 20%, and it only decreases by 10% when the meat is breaded ⁶⁷. Similarly, a decrease in pantothenic acid in fish during cooking by different methods comes about ⁶⁷, ⁷², ⁷³. Steaming, boiling, baking, and frying of potatoes with the peel bring on pantothenic acid losses of 10% in all cases, but the losses might reach 30% in peeled potatoes when boiled ⁶⁷, ⁶⁸. In addition, in vegetables, boiling and steaming usually causes declines of 10% in the total dish, and those of 30–40% and 15%, respectively, in vegetables alone ⁶⁷, ⁶⁸, ⁷⁴, ⁷⁵. Stewing, frying, and baking lessen pantothenic acid amounts in vegetables by 10% ⁶⁷, ⁶⁸. Vitamin B5 or pantothenic acid losses of 24–67% in legumes during boiling are influenced by the pre-soaking method and cooking times ⁶⁹, ⁷⁶, ⁷⁷. Boiling of rice results in a decrease of 59–66% in pantothenic acid content ⁵⁸. That is why steaming is preferred to boiling, in particular, when cooked vegetables are eaten without cooking liquids ⁶⁷, ⁷⁴, ⁷⁵. Poached, boiled, and fried eggs lose, due to cooking, 4%, 7%, and 9% of their pantothenic acid, respectively ⁷⁸. In milk, pantothenic acid is stable during pasteurization, since the normal pH of milk is within the optimal pH stability range; milk generally loses less than 10% during processing ⁶⁹, ⁵⁶, ⁷⁹.

In breadmaking, no significant difference of vitamin B5 or pantothenic acid was observed during the kneading phase, while a mild decrease of 12% was documented during baking. This indicates that pantothenic acid is more sensitive to heat than to light and oxygen ⁸⁰. The roasting of peanuts at 160 °C and 180 °C decreases the amount of pantothenic acid by 24% and 92%, respectively; so, peanuts can be an excellent source if properly processed ⁸¹.

Canning leads to various reductions in vitamin B5 or pantothenic acid content: 1–43% in pork luncheon meat, depending on times and temperatures used during thermal processing ⁸²; 20–35%, 46–78%, and 51%, in foods of animal origin (such as meats, fish, and dairy products), vegetables, and fruits and fruit juices, respectively ⁶⁴. Thermal degradation kinetics of pantothenic acid in extracts of Averrhoa bilimbi fruits showed that increasing the temperature speeds up the decomposition, which was also linearly time-dependent ⁸³. Treatment of food with ionizing radiation used as a method for its preservation has insignificant effects on pantothenic acid content ⁸⁴, ⁸⁵. Less vitamin B5 or pantothenic acid is in food products based on nixtamalized (i.e., alkali-treated) maize ⁸⁶, ⁸⁷.

Lower contents of vitamin B5 or pantothenic acid in frozen foods, compared to those in raw ones, have been reported; decreases were 18–63% in vegetables, 29–71% in legumes, 7% in fruits and fruit juices, and 4–55% in fish ⁸⁸, ⁶⁴, ⁸⁹. After thawing frozen meat, pantothenic acid, together with other B vitamins, transfer in a drip; amounts of pantothenic acid from defrosted meat found in the drip were 7% and 33% in pork and in beef, respectively. For prevention of the loss of the vitamin, collection and use of the drip is recommended ⁷⁰, ⁹⁰, ⁹¹.

Regarding fortification of foods using vitamin B5 or pantothenic acid, adult human intake of that vitamin has generally been considered adequate in view of the absence of deficiency in normal populations and the fact that the daily requirement for vitamin B5 or pantothenic acid is easily fulfilled from most natural dietary sources owing to its ubiquitous distribution ⁵⁸, ⁹². Pantothenic acid (as calcium pantothenate or sodium pantothenate or dexpanthenol) is added to various foods (such as milk-based products, breakfast cereals, and rice powders) to prevent deficiency due to incorrect nutrition or malnutrition or for certain nutritional requirements (baby foods, e.g., for non-breastfed infants; athletes’ products; low-calorie, reduced-calorie, and vitamin-rich foods) ⁹³, ⁹⁴, ⁹⁵, ⁹⁶, ⁹², ⁹⁷.

Table 2. Pantothenic acid (vitamin B5) content of selected foods

Food	Milligrams (mg) per serving	Percent DV*
Beef liver, boiled, 3 ounces	8.3	166
Breakfast cereals, fortified with 100% of the DV	5	100
Shitake mushrooms, cooked, ½ cup pieces	2.6	52
Sunflower seeds, ¼ cup	2.4	48
Chicken, breast meat, skinless, roasted, 3 ounces	1.3	26
Tuna, fresh, bluefin, cooked, 3 ounces	1.2	24
Avocados, raw, ½ avocado	1	20
Milk, 2% milkfat, 1 cup	0.9	18
Mushrooms, white, stir fried, ½ cup sliced	0.8	16
Potatoes, russet, flesh and skin, baked, 1 medium	0.7	14
Egg, hard boiled, 1 large	0.7	14
Greek yogurt, vanilla, nonfat, 5.3-ounce container	0.6	12
Ground beef, 85% lean meat, broiled, 3 ounces	0.6	12
Peanuts, roasted in oil, ¼ cup	0.5	10
Broccoli, boiled, ½ cup	0.5	10
Whole-wheat pita, 1 large	0.5	10
Chickpeas, canned, ½ cup	0.4	8
Rice, brown, medium grain, cooked, ½ cup	0.4	8
Oats, regular and quick, cooked with water, ½ cup	0.4	8
Cheese, cheddar, 1.5 ounces	0.2	4
Carrots, chopped, raw, ½ cup	0.2	4
Cabbage, boiled, ½ cup	0.1	2
Clementine, raw, 1 clementine	0.1	2
Tomatoes, raw, chopped or sliced, ½ cup	0.1	2
Cherry tomatoes, raw, ½ cup	0	0
Apple, raw, slices, ½ cup	0	0

Footnote: *DV = Daily Value. The Daily Value (DV) for pantothenic acid is 5 mg for adults and children age 4 years and older. The U.S. Food and Drug Administration (FDA) does not require food labels to list pantothenic acid content unless pantothenic acid has been added to the food. Foods providing 20% or more of the DV (Daily Value) are considered to be high sources of a nutrient, but foods providing lower percentages of the DV (Daily Value) also contribute to a healthful diet.

[Source ⁹⁸ ]

Pantothenic acid supplement

Pantothenic acid (vitamin B5) is available in dietary supplements containing only pantothenic acid, in combination with other B-complex dietary supplements and in some multivitamin/multimineral supplements ¹. Pantothenic acid (vitamin B5) in dietary supplements is often in the form of calcium pantothenate or pantethine (a dimeric form of pantetheine) ⁵, ⁸⁹, ⁹⁹. Research has not shown that any form of pantothenic acid is better than the others. The amount of pantothenic acid in dietary supplements typically ranges from about 10 mg in multivitamin/multimineral products to up to 1,000 mg in supplements of B-complex vitamins or pantothenic acid alone ¹. Pantethine is used as a cholesterol-lowering agent in Japan and is available in the US as a dietary supplement ¹⁰⁰.

What happens if I don’t get enough pantothenic acid?

Pantothenic acid or Vitamin B5 deficiency is very rare in the United States because most people in the United States get enough vitamin B5 or pantothenic acid from their diet. However, people with severe malnutrition or people with a rare inherited disorder called pantothenate kinase-associated neurodegeneration mutation (PKAN) can’t use pantothenic acid properly. These disorders can lead to symptoms of pantothenic acid deficiency. Severe vitamin B5 or pantothenic acid deficiency can cause numbness and burning of the hands and feet, headache, extreme tiredness, irritability, restlessness, sleeping problems, stomach pain, heartburn, diarrhea, nausea, vomiting, and loss of appetite.

A common hallmark of individuals with pantothenate kinase-associated neurodegeneration mutation (PKAN) (formerly called Hallervorden-Spatz syndrome) is an accumulation of iron in the brain that forms a pattern called the “eye of the tiger” sign ¹³, ¹⁰¹. Pantothenate kinase-associated neurodegeneration mutation (PKAN) also presents with a progressive movement disorder, and other symptoms may vary significantly from case to case. Symptoms include dysarthria, dystonia, dysphasia, poor balance, spasticity, and muscle rigidity ¹³. Dementia, severe mental retardation and severe movement disability may develop at later stages ¹⁰². Rare clinical features include rigidity, parkinsonism, choreoathetosis, seizures, optic atrophy, and pigmentary retinopathy ¹³. Based on age at onset and rate of progression, PKAN can be classified in two major forms. In the classic form of PKAN, onset is usually in the first decade of life. Visual impairment caused by optic atrophy or retinal degeneration have been described in some classical cases ¹³. Atypical PKAN is presented in the second decade of life with slow progression ¹³. Neurobehavioral disorders and seizure are common in atypical form ¹⁰³. All PKAN cases have mutation in pantothenate kinase 2 (PANK2) gene located on the short arm of chromosome 20 (20p13) ¹⁰⁴. PANK2 encodes a mitochondrial pantothenate kinase which is the key regulatory enzyme in coenzyme A biosynthesis ¹⁰⁵. Treatment of pantothenate kinase-associated neurodegeneration mutation (PKAN) focuses mainly on reducing symptoms. A few anecdotal reports indicate that vitamin B5 supplements can reduce symptoms, but the benefits of the general use of this supplement in PKAN are not known ¹⁰⁶.

Pantothenic acid deficiency

Because some pantothenic acid (vitamin B5) is present in almost all foods, pantothenic acid (vitamin B5) deficiency is very rare in the United States except in people with severe malnutrition ⁵. When someone has a pantothenic acid (vitamin B5) deficiency, it is usually accompanied by deficiencies in other nutrients, making it difficult to identify the effects that are specific to pantothenic acid deficiency ². The only individuals known to have developed pantothenic acid deficiency were fed diets containing virtually no pantothenic acid or were taking a pantothenic acid metabolic antagonist ⁴.

On the basis of the experiences of prisoners of war in World War II and studies of diets lacking pantothenic acid in conjunction with administration of an antagonist of pantothenic acid metabolism, a pantothenic acid (vitamin B5) deficiency is associated with numbness and burning of the hands and feet, headache, fatigue, extreme tiredness, irritability, restlessness, disturbed sleep, and gastrointestinal disturbances such as stomach pain, heartburn, diarrhea, nausea, vomiting, and loss of appetite ², ⁵, ¹⁰⁷, ¹⁰⁸, ¹¹.

The following group is most likely to have inadequate pantothenic acid (vitamin B5) status:

Pantothenate kinase-associated neurodegeneration (PKAN)

Pantothenate kinase-associated neurodegeneration (PKAN) also known as Hallervorden-Spatz syndrome is a rare inherited neurological movement disorder characterized by the progressive degeneration of specific regions in the central nervous system (neurodegenerative disorder) and buildup of iron in the brain ¹⁰⁹. Pantothenate kinase-associated neurodegeneration (PKAN) is characterized by progressive difficulty with movement, typically beginning in childhood. Movement abnormalities include involuntary muscle spasms, rigidity, and trouble with walking that worsens over time ¹¹⁰, ¹¹¹, ¹⁰¹. Many people with pantothenate kinase-associated neurodegeneration (PKAN) also develop problems with speech (dysarthria), and some develop vision loss. Additionally, affected individuals may experience a loss of intellectual function (dementia) and psychiatric symptoms such as behavioral problems, personality changes, and depression.

Pantothenate kinase-associated neurodegeneration (PKAN) is the most common type of neurodegeneration with brain iron accumulation (NBIA), a group of clinical disorders marked by progressive abnormal involuntary movements, alterations in muscle tone, and postural disturbances (extrapyramidal) ¹¹², ¹³, ¹¹⁰, ¹¹³, ¹¹⁴, ¹⁰³. Pantothenate kinase-associated neurodegeneration (PKAN) is also known as neurodegeneration with brain iron accumulation type 1 (NBIA type 1), which accounts for approximately half of the cases of neurodegeneration with brain iron accumulation (NBIA) ¹³. The neurodegeneration with brain iron accumulation (NBIA) disorders show radiographic evidence of iron accumulation in the brain, called the “eye-of-the-tiger sign”, which is typically seen on magnetic resonance imaging (MRI) scans of the brain in people with pantothenate kinase-associated neurodegeneration (PKAN) (Figure 5). The ‘eye of the tiger’ pattern of iron accumulation in the globus pallidus on T2 weighted magnetic resonance imaging (MRI) which is caused by iron deposition in the periphery (hypointensity) and necrosis on its core (hyperintensity) ¹¹⁵, ¹¹⁶.

Pantothenate kinase-associated neurodegeneration (PKAN) is inherited as an autosomal recessive genetic condition caused by mutations in the pantothenate kinase 2 (PANK2) gene, located on the short arm of chromosome 20 (20p13) ¹¹⁰. The PANK2 gene provides instructions for making an enzyme called pantothenate kinase 2 ¹¹⁷. The pantothenate kinase 2 (PANK2) enzyme is active in specialized cellular structures called mitochondria, which are the cell’s energy-producing centers. Within mitochondria, pantothenate kinase 2 regulates the formation of a molecule called coenzyme A (CoA). Coenzyme A (CoA) is found in all living cells, where it is essential for the body’s production of energy from carbohydrates, fats, and some protein building blocks (amino acids).

PANK2 is one of four human genes that provide instructions for making versions of pantothenate kinase. The functions of these different versions probably vary among tissue types and parts of the cell. The version produced by the PANK2 gene is active in cells throughout the body, including nerve cells in the brain.

Vitamin B5 is required for the production of coenzyme A in cells. Disruption of this enzyme affects energy and lipid metabolism and may lead to accumulation of potentially harmful compounds in the brain, including iron. Currently, PANK2 is the only gene known to be associated with pantothenate kinase-associated neurodegeneration (PKAN).

Recessive genetic disorders occur when an individual inherits a non-working gene from each parent ¹¹⁰. If an individual receives one working gene and one non-working gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the non-working gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier, like the parents, is 50% with each pregnancy ¹¹⁰. The chance for a child to receive working genes from both parents is 25% ¹¹⁰. The risk is the same for males and females.

Pantothenate kinase-associated neurodegeneration (PKAN) clinical presentations include dystonia, dysarthria, and dysphasia. Dementia, severe mental retardation and severe movement disability may develop at later stages ¹⁰². Rare clinical features include rigidity, parkinsonism, choreoathetosis, seizures, optic atrophy, and pigmentary retinopathy.

Based on age at onset and rate of progression, pantothenate kinase-associated neurodegeneration (PKAN) is usually classified into two major forms: classic and atypical PKAN.

Classic PKAN causes symptoms in the first 10 years of life, with symptoms that worsen rapidly. Visual impairment caused by optic atrophy or retinal degeneration have been described in some classical cases.
Atypical PKAN usually occurs after the age of 10 and progresses more slowly. Neurobehavioral disorders and seizure are common in atypical form ¹⁰³.
Classic PKAN tends to have onset before 6 years of age, whereas atypical PKAN manifests at a mean age of 14 years ¹⁰⁶. Some people have been diagnosed in infancy or adulthood, and some of those affected have characteristics that are between the two categories.
Signs and symptoms vary, but the atypical PKAN is more likely than the classic PKAN to involve speech defects and psychiatric problems.
Pantothenate kinase-associated neurodegeneration (PKAN) prevalence is estimated around 1 to 3 per million ¹⁰⁶.

All individuals with PKAN have an abnormal buildup of iron in certain areas of the brain. A particular change, called the ‘eye-of-the-tiger sign’, which indicates a buildup of iron, is typically seen on magnetic resonance imaging (MRI) scans of the brain in people with this disorder.

A condition called HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) syndrome, which was historically described as a separate syndrome, is now considered part of pantothenate kinase-associated neurodegeneration (PKAN) ¹⁰¹.

The manifestations of pantothenate kinase-associated neurodegeneration (PKAN) can include dystonia (contractions of opposing groups of muscles), spasticity, and pigmentary retinopathy ³, ⁵, ¹¹⁸. Its progression is rapid and leads to significant disability and loss of function ¹¹⁸. Treatment focuses primarily on reducing symptoms ¹¹⁹.

PKAN is typically diagnosed by molecular genetic testing, most often after a characteristic finding on magnetic resonance imaging (MRI), called the “eye-of-the-tiger” sign, is detected.

There is no specific treatment for individuals with pantothenate kinase-associated neurodegeneration (PKAN) ¹¹⁰. Treatment is directed towards the specific symptoms that appear in each individual and may include medication (such as botulinum toxin), surgery, deep brain stimulation and physical therapy. Whether pantothenate supplementation is beneficial in PKAN is not known, but some anecdotal reports indicate that supplements can reduce symptoms in some patients with atypical PKAN ¹⁰⁶. Research is focusing on a better understanding of the underlying cause of this disorder, which may eventually help to find a more effective treatment.

Figure 6. Eye-of-the-tiger sign (MRI scan of the brain in pantothenate kinase-associated neurodegeneration (PKAN))

Footnote: T2 weighted brain magnetic resonance imaging (MRI) of a patient with pantothenate kinase-associated neurodegeneration (PKAN) which shows a central hyperintensity (bright spots) within substantia nigra and a surrounding area of hypointensity in globus pallidus (eye-of-the-tiger).

[Source ¹²⁰ ]

Pantothenate kinase-associated neurodegeneration (PKAN) causes

Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive genetic condition caused by mutations in the pantothenate kinase 2 (PANK2) gene, located on the short arm of chromosome 20 (20p13) ¹⁰⁴, ¹¹⁰. The PANK2 gene provides instructions for making an enzyme called pantothenate kinase 2 ¹¹⁷. The pantothenate kinase 2 (PANK2) enzyme is active in specialized cellular structures called mitochondria, which are the cell’s energy-producing centers. Within mitochondria, pantothenate kinase 2 regulates the formation of a molecule called coenzyme A (CoA). Coenzyme A (CoA) is found in all living cells, where it is essential for the body’s production of energy from carbohydrates, fats, and some protein building blocks (amino acids).

Individuals with PKAN have abnormal accumulation of iron in certain areas of the brain. This is especially seen in regions of the basal ganglia called the globus pallidus and the substantia nigra ¹¹⁰. The basal ganglia is a collection of structures deep within the base of the brain that assist in regulating movements. The exact relationship between iron accumulation and the symptoms of PKAN is not fully understood ¹¹⁰.

Pantothenate kinase-associated neurodegeneration (PKAN) signs and symptoms

The common feature among all individuals with pantothenate kinase-associated neurodegeneration (PKAN) is iron accumulation in the brain, in a pattern called the ‘eye of the tiger sign,’ along with a progressive movement disorder. Symptoms may vary greatly from case to case. In most cases, progression of the disease extends over several years, leading to death in childhood or early adulthood in classic PKAN cases ¹¹⁰. Some patients experience rapid deterioration and die within 1-2 years ¹¹⁰. Others have a slower progression or can plateau for long periods of time and continue to function into the third decade of life. Atypical individuals often retain a high level of function into later adulthood and some are known to be living in their sixties to seventies ¹¹⁰.

Pantothenate kinase-associated neurodegeneration (PKAN) symptoms include dystonia, (sustained muscle contractions causing repetitive movements), dysarthria (abnormal speech), muscular rigidity, poor balance, and spasticity (sudden involuntary muscle spasms), These features can result in clumsiness, gait (walking) problems, difficulty controlling movement, and speech problems. Another common feature is degeneration of the retina, resulting in progressive night blindness and loss of peripheral (side) vision.

Dystonia is characterized by involuntary muscle contractions that may force certain body parts into unusual, and sometimes painful, movements and positions. In addition, there may be stiffness in the arms and legs because of continuous resistance to muscle relaxing (spasticity) and abnormal tightening of the muscles (muscular rigidity). Spasticity and muscle rigidity usually begin in the legs and later develop in the arms. As affected individuals age, they may eventually lose control of voluntary movements. Muscle spasms combined with decreased bone mass can result in bone fractures (not caused by trauma or accident).

Dystonia affects the muscles in the mouth and throat, which may cause dysarthria and difficulty swallowing (dysphagia). The progression of dystonia in these muscles can result in loss of speech as well as tongue-biting and difficulty with eating.

Specific forms of dystonia that may occur in association with PKAN include blepharospasm and torticollis. Blepharospasm is a condition in which the muscles of the eyelids do not function properly, resulting in excessive blinking and involuntary closing of the eyelids. Torticollis is a condition in which there are involuntary contractions of neck muscles resulting in abnormal movements and positions of the head and neck.

Many of the delays in development pertain to motor skills (movement), although a small subgroup may have intellectual delays. Although intellectual impairment has often been described as a part of the condition in the past, it is unclear if this is a true feature. Intellectual testing may be hampered by the movement disorder; therefore, newer methods of studying intelligence are necessary to determine if there are any cognitive features of this condition.

The symptoms and physical findings associated with PKAN gene mutations can be distinguished between classical and atypical disease. Individuals with classical disease have a more rapid progression of symptoms. In most cases, atypical disease progresses slowly over several years. The symptoms and physical findings vary from case to case.

Classical PKAN develops in the first ten years of life (average age for developing symptoms is three and a half years). These children may initially be perceived as clumsy and later develop more noticeable problems with walking. Speech delay is also common. Eventually, falling becomes a frequent feature. Because of the limited ability to protect themselves during falls, children may have repeated injury to the face and chin. Many individuals with the classic form of PKAN require a wheelchair by their mid-teens (in some cases earlier). Most lose the ability to move/walk independently between 10 and15 years after the beginning of symptoms.

Individuals with classical PKAN are more likely to have specific eye problems. Approximately two-thirds of these patients will have retinal degeneration. This is a progressive degeneration of the nerve-rich membrane lining the eyes (retina), resulting in tunnel vision, night blindness, and loss of peripheral vision. Loss of this peripheral vision may contribute to the more frequent falls and gait disturbances in the early stages. [For more information on this retinopathy (retinitis pigmentosa), choose “retinitis pigmentosa” as your search term in the Rare Disease Database].

The atypical form of PKAN usually occurs after the age of ten years and progresses more slowly. The average age for developing symptoms is 13 years. Loss of independent ambulation (walking) often occurs 15 to 40 years after the initial development of symptoms. The initial presenting symptoms usually involve speech. Common speech problems are repetition of words or phrases (palilalia), rapid speech (tachylalia), and dysarthria. Psychiatric symptoms are more commonly observed and include impulsive behavior, violent outbursts, depression, or a tendency to rapid mood swings. While the movement disorder is a very common feature, it usually develops later. In general, atypical disease is less severe and more slowly progressive than early-onset PKAN.

In cases of neurodegeneration with brain iron accumulation (NBIA) that are not caused by PKAN, the movement-related symptoms (such as dystonia) may be very similar. Nine additional genes causing various subtypes of NBIA have been identified at this time. For those without a specific diagnosis or known cause of NBIA, symptoms are more varied because there are probably several different causes of neurodegeneration in this group. There is a subgroup of patients with moderate to severe intellectual disability. Also, seizure disorders are more common among non-PKAN individuals.

Pantothenate kinase-associated neurodegeneration (PKAN) diagnosis

The diagnosis of pantothenate kinase-associated neurodegeneration (PKAN) is made based upon a detailed patient history, a thorough clinical evaluation, and a variety of specialized tests ¹¹⁰. PKAN is typically suspected when the characteristic brain MRI finding called the “eye-of-the-tiger” sign, which is a dark area indicating accumulation of iron with a bright spot in the center, is observed on T2-weighted MRI. This MRI finding is not seen in other forms of neurodegeneration with brain iron accumulation (NBIA).

Molecular genetic testing for the full gene sequence of the PANK2 gene is the gold standard way to make this diagnosis ¹¹⁰. Approximately 95% of those affected have two identifiable mutations in the PANK2 gene and approximately 5% have only one identifiable mutation. Some PANK2 gene deletions are not detected by sequencing the gene, so for individuals without a detectable mutation or only one detectable mutation, gene deletion/duplication analysis is also recommended ¹¹⁰.

Pantothenate kinase-associated neurodegeneration (PKAN) treatment

There is no specific treatment for individuals with pantothenate kinase-associated neurodegeneration (PKAN) ¹¹⁰. Treatment is directed towards the specific symptoms that appear in each individual. Research is focusing on a better understanding of the underlying cause of this disorder, which may eventually help to find a more comprehensive treatment.

Treatment may require the coordinated efforts of a team of specialists. Physicians that the family may work with include the pediatrician or internist, neurologist, ophthalmologist, physiatrist and geneticist. A team approach to supportive therapy may include physical therapy, exercise physiology, occupation therapy, speech pathology and nutrition/feeding. In addition, many families may benefit from genetic counseling.

The most consistent forms of relief from disabling dystonia are baclofen, trihexyphenidyl, and clonazepam. These medications can be taken orally. Later in disease, a baclofen pump can be used to administer regular doses automatically into the central nervous system. Intramuscular botulinum toxin may also help treat specific regions where dystonia is problematic.
Levodopa/carbidopa does not generally appear to help patients with PKAN, although there may be exceptions. These treatments may have a role in the treatment of other causes of NBIA; however, their overall effectiveness is unknown and the responsiveness in individual cases is unpredictable.

Drugs that reduce the levels of iron in the body (iron chelation) have been attempted to treat individuals with PKAN ¹¹⁰. These early agents were proven ineffective and can cause anemia ¹¹⁰. A clinical trial of the drug deferiprone was completed for PKAN and results were published in 2019. The results suggested a possible modest slowing of disease progression, although the statistical analysis of the data was not able to prove this as significant ¹²¹, ¹²².

Pallidotomy and thalamotomy have been investigational attempts at controlling dystonia. These are both surgical techniques which destroy (ablate) very specific regions of the brain, the globus pallidus and thalamus, respectively. Some families have reported some immediate and temporary relief. However, most patients return to their pre-operative level of dystonia within one year of the operation ¹¹⁰. Deep brain stimulation (DBS) of the globus pallidus has been found to have promising results in some patients with PKAN and NBIA and is now favored over ablative procedures ¹¹⁰.

Individuals experiencing seizures usually benefit from standard anti-convulsive drugs ¹¹⁰. In addition, standard approaches to pain management are generally recommended where there is no identifiable treatment for the underlying cause of pain. Referral to pediatric palliative care specialists can be highly beneficial during later disease stages.

The association between pantothenate kinase and PKAN suggests that supplemental pantothenate (pantothenic acid, calcium pantothenate) taken orally could be beneficial. Pantothenate is another name for vitamin B5, a water soluble vitamin. Theoretically, this is most likely to assist individuals with very low levels of pantothenate kinase activity (atypical PKAN). It is hypothesized that classic PKAN results from complete absence of the enzyme pantothenate kinase, whereas atypical PKAN results from a severe deficiency, although the individuals still may have some level of enzyme activity. Clinical trials are needed to investigate the effectiveness of this treatment ¹¹⁰.

The benefits and limitations of any of the above treatments should be discussed in detail with a physician.

Pantothenic acid deficiency symptoms

Because vitamin B5 or pantothenic acid is widely distributed in nature and deficiency is extremely rare in humans, most information regarding the consequences of vitamin B5 deficiency has been gathered from experimental research in animals ²⁰, ¹⁶. The most common symptoms of vitamin B5 or pantothenic acid in animals are growth problems, skin rash, gastrointestinal and nervous symptoms, such as ataxia, loss of coordination, and muscle weakness ¹⁶. Similar symptoms appeared also in human studies. Symptoms are described in more detail in Table 3. The diversity of symptoms emphasizes the numerous functions of pantothenic acid in its coenzyme forms.

Humans administered with a vitamin B5 antagonist omega-methyl pantothenic acid developed personality changes with irritability, restlessness, and quarrelsomeness ¹⁶. Similar symptoms developed in humans on a diet deficient in vitamin B5 content (8 weeks) ¹²³. An analogous experiment was performed, as well, by Fry et al., in 1976 ¹²⁴, who tested the effect of a diet essentially free from pantothenic acid on human health. In that study, however, no clinical symptoms of deficiency were observed, but some subjects appeared listless and complained of fatigue at the end of diet deficient period (63 days) ¹²⁴.

Lower levels of pantothenic acid were also detected in some brain regions affected by Alzheimer’s disease compared with controls. It is still unknown whether vitamin B5 depletion participates in the pathophysiology or if this is simply a consequence of the underlying neuropathological process ¹²⁵.

Vitamin B5 or pantothenic acid deficiency in rats can cause damage to the adrenal glands, breeding problems and failure of embryo implementation with subsequent resorption ¹²⁶. Vitamin B5 or pantothenic acid deficiency in rats throughout pregnancy has an impact on endocrine function of the placenta, which is linked to a lower production of progesterone and acetylcholine, and underdevelopment of fetuses ¹²⁷. Among the reported abnormalities in rats include: cerebral and eye defects, digital hemorrhages and edema, interventricular septal defects, anomalies of the aortic arch pattern, hydronephrosis and hydroureter, clubfoot, tail defects, cleft palate, and dermal defects ¹²⁶.

While vitamin B5 or pantothenic acid-deficient monkeys developed anemia due to decreased synthesis of heme, a component of hemoglobin ⁶. Dogs with vitamin B5 or pantothenic acid deficiency developed low blood glucose, rapid breathing and heart rates, and convulsions ⁶. Chickens developed skin irritation, feather abnormalities, and spinal nerve damage associated with the degeneration of the myelin sheath ⁶. Pantothenic acid-deficient mice showed decreased exercise tolerance and diminished storage of glucose (in the form of glycogen) in muscle and liver ⁶. Mice also developed skin irritation and graying of the fur, which is reversed by pantothenic acid administration ⁶.

Table 3. Vitamin B5 or pantothenic acid deficiency symptoms

Species	Symptoms	Sources
Humans	Nervous system: headache, irritability, restlessness, quarrelsomeness, excessive fatigue, numbness, paresthesia, muscle cramps, faulty coordination associated with tremor and peculiar gait	¹²³
	Digestive track: abdominal rumbling, diarrhea, epigastric burning, regurgitation
	Glands: loss of eosinophilic response to adrenocorticotropic hormone, increased sensitivity to insulin
Rodents (rats, mice, guinea pigs)	Growth: retardation, decrease in weight	¹²⁸, ¹²⁹, ¹³⁰, ¹³¹, ¹³²
	Skin and mucosa: ruffing and discoloration of the fur, thinning of hair, alopecia, dryness of the skin with scaly desquamation, nasal discharge, watering of the eyes
	Digestive track: diarrhea, duodenal changes (Lieberkühn crypts—enlargement, hyperplasia, increase in space between crypts, atrophy; villi diminution, epithelial changes to cuboid or flat, leading to ulcerations, perforation and chronic lesions), salivation
	Nervous system: muscle weakness of the hind legs, convulsions, coma
	Glands: adrenal lesions
Birds (ducklings and chicks)	Growth: retardation, decrease in weight	¹³⁰, ¹³³, ¹³⁴
	Skin: scaly dermatitis, skin lesions, scabs around beak and eyes, feather depigmentation, dermal edema
	Nervous system: severe ataxia, tendency to fall and inability to rise and laying panting
	Glands: lymphoid cell necrosis in the bursa of Fabricius and the thymus, and a lymphocytic paucity in the spleen
Pigs	Growth: failure to gain in weight, loss of appetite	¹³⁵, ¹³⁶, ¹³⁷
	Skin: loss of hair, roughness of the coat
	Digestive track: diarrhea, severe colonic lesions
	Nervous system: ataxia, lesions in sensory neurons, sudden lifting one of the limbs from the ground, unusual walk, inability to walk or stand
	Respiratory system: cough and nasal secretion
Dogs	Growth: retardation Nervous system: sudden weakness, coma, rapid respiratory and heart rate, convulsions, spasticity of the hind legs	¹³⁸, ¹³⁹
	Digestive track: decreased appetite, gastrointestinal symptoms, gastritis or enteritis
	Glands: fatty liver, mottled thymusis
	Blood: blood level of glucose and chlorides were lower and non-protein nitrogen was elevated
	Urinary system: hemorrhagic kidney degeneration

[Source ¹⁶ ]

Pantothenic acid safety

Pantothenic acid or vitamin B5 is considered safe, even at high doses ¹⁴⁰, ⁵⁹. However, taking very high doses of vitamin B5 or pantothenic acid supplements (such as 10,000 mg to 20,000 mg/day) can cause an upset stomach and diarrhea, but the mechanism for this effect is not known ², ⁵⁹. However, there is one case report of life-threatening eosinophilic pleuropericardial effusion in an elderly woman who took a combination of 10 mg/day of biotin and 300 mg/day of pantothenic acid for two months ¹⁴¹. She was hospitalized with chest pain and breathing problems. Blood tests showed an inflammatory syndrome with a high eosinophil concentration (1200–1500 cells/mm³) ¹⁴². Due to the lack of reports of adverse effects when the Dietary Reference Intakes (DRI) for pantothenic acid were established in 1998, the Food and Nutrition Board of the Institute of Medicine did not establish a tolerable upper intake level (UL) for pantothenic acid ¹⁴³. Pantethine is generally well tolerated in doses up to 1,200 mg/day. However, gastrointestinal side effects, such as nausea and heartburn, have been reported ¹⁰⁰. Also, topical formulations containing up to 5% of dexpanthenol (D-panthenol) have been safely used for up to one month. Yet, a few cases of skin irritation, contact dermatitis, and eczema have been reported with the use of dexpanthenol-containing ointments ¹⁴⁴, ¹⁴⁵.

Pantothenic acid contraindications

Pantothenic acid (vitamin B5) contraindications include patients with hypersensitivity or allergy to the drug or any of its derivatives. A report suggests that pantothenic acid (vitamin B5) intake might correlate with increased cerebral amyloid-beta peptide burden in individuals with cognitive impairment ¹⁴⁶. Although further studies are still needed to confirm the findings and discover the molecular mechanisms of this pathway, the current research suggests those with cognitive impairment to be a potential contraindication ¹⁴⁶.

Interactions with medications or other supplements

Large doses of pantothenic acid (vitamin B5) have the potential to compete with biotin for intestinal and cellular uptake by the human sodium-dependent multivitamin transporter (hSMVT) ¹⁴⁷, ¹⁴⁸.

Oral contraceptives (birth control pills) containing estrogen and progestin may increase the requirement for pantothenic acid ¹⁴⁰. Use of pantethine in combination with cholesterol-lowering drugs called statins (HMG-CoA reductase inhibitors) or with nicotinic acid (niacin) may produce additive effects on blood lipids ¹⁰⁰.

The following drugs have moderate interactions with pantothenic acid (vitamin B5) ¹²:

Azithromycin
Clarithromycin
Erythromycin base
Erythromycin ethylsuccinate
Erythromycin lactobionate
Erythromycin stearate
Roxithromycin

Furthermore, there are at least 60 other drugs that have mild interactions with pantothenic acid (vitamin B5).

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