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⁾, ³⁾, ²⁾, 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 ⁹⁾, ¹⁰⁾. 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 ¹¹⁾.

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) ¹²⁾. 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 ¹³⁾. Nicotinamide adenine dinucleotide (NAD) is also converted into another active form, the coenzyme nicotinamide adenine dinucleotide phosphate (NADP), in all tissues except skeletal muscle ¹⁴⁾.

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 ¹⁵⁾. 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 ¹⁶⁾.

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 ¹⁷⁾. 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 ¹⁸⁾.

All pathways generate intermediary mononucleotides — either nicotinic acid mononucleotide or nicotinamide mononucleotide ¹⁹⁾. 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 ²⁰⁾. Nicotinamide mononucleotide is also generated by the phosphorylation of nicotinamide riboside, catalyzed by nicotinamide riboside kinases (NRKs) ²¹⁾. 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) ²²⁾. 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 ²³⁾.

When NAD and NADP are consumed in foods, they are converted to nicotinamide in the gut and then absorbed ²⁴⁾. Ingested niacin is absorbed primarily in the small intestine, but some is absorbed in the stomach ²⁵⁾, ²⁶⁾, ²⁷⁾.

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 ²⁸⁾.

As a drug, Niacin or vitamin B3, has two main indications ²⁹⁾:

• 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 ³⁰⁾. 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 ³¹⁾, ³²⁾. 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”) ³³⁾, ³⁴⁾, ³⁵⁾. In the 1700s, pellagra first appeared in Italy, and the name translates into “pella” meaning skin, and “agra” meaning rough ³⁶⁾.  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 ³⁷⁾, ³⁸⁾. 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 ³⁹⁾. Some clinicians prefer niacinamide for the treatment of pellagra because it lacks vasodilating effects ⁴⁰⁾.

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) ⁴¹⁾. 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 ⁴²⁾. 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 ⁴³⁾, ⁴⁴⁾. 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 ⁴⁵⁾.

Even when taken in very high doses of 3–4 g, niacin is almost completely absorbed ⁴⁶⁾. 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 ⁴⁷⁾. Unmetabolized nicotinic acid and nicotinamide might be present in the urine as well when niacin intakes are very high ⁴⁸⁾.

Levels of niacin in the blood are not reliable indicators of niacin status ⁴⁹⁾. 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 ⁵⁰⁾. 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 ⁵¹⁾. An adult has niacin deficiency when urinary-excretion rates are less than 5.8 micromol/day ⁵²⁾. 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 ⁵³⁾. Another measure of niacin status takes into account the fact that NAD levels decline as niacin status deteriorates, whereas NADP levels remain relatively constant ⁵⁴⁾, ⁵⁵⁾, ⁵⁶⁾. A “niacin number” (the ratio of NAD to NADP concentrations in whole blood x 100) below 130 suggests niacin deficiency ⁵⁷⁾, ⁵⁸⁾. 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 ⁵⁹⁾. No functional biochemical tests that reflect total body stores of niacin are available ⁶⁰⁾.

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 ⁶¹⁾, ⁶²⁾. 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 ⁶³⁾. The flushing is accompanied by burning, tingling, and itching sensations ⁶⁴⁾, ⁶⁵⁾. 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 ⁶⁶⁾. 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 ⁶⁷⁾.

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 ⁶⁸⁾, ⁶⁹⁾, ⁷⁰⁾, ⁷¹⁾. 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 ⁷²⁾, ⁷³⁾, ⁷⁴⁾, ⁷⁵⁾, ⁷⁶⁾. Liver injury is more likely to occur with the use of extended-release forms of nicotinic acid ⁷⁷⁾, ⁷⁸⁾, ⁷⁹⁾.

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 ⁸⁰⁾. 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 ⁸¹⁾.

Nicotinamide does not cause skin flushing and has fewer adverse effects than nicotinic acid, and these effects typically begin with much higher doses ⁸²⁾. Nausea, vomiting, and signs of liver toxicity can occur with nicotinamide intakes of 3,000 mg/day ⁸³⁾. 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) ⁸⁴⁾, ⁸⁵⁾, ⁸⁶⁾, ⁸⁷⁾.

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 ⁸⁸⁾. 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 ⁸⁹⁾. 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 ⁹⁰⁾.

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 ⁹¹⁾.

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.

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 ⁹³⁾. 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 ⁹⁴⁾.

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

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 ⁹⁷⁾. 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 ⁹⁸⁾. 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 ⁹⁹⁾, ¹⁰⁰⁾.

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 ¹⁰¹⁾.

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.

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 ¹⁰³⁾. 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 ¹⁰⁴⁾. 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 ¹⁰⁵⁾. In another study, nicotinic acid affected the liver uptake of ApoA1 lipoprotein, thereby reducing high-density lipoprotein (HDL) removal from the circulation ¹⁰⁶⁾. 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 ¹⁰⁷⁾. 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 ¹⁰⁸⁾. 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 ¹⁰⁹⁾.

Calcium mobilization

In humans, CD38 and CD157 belong to a family of NAD+ glycohydrolases or ADP-ribosylcyclases ¹¹⁰⁾. 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 ¹¹¹⁾. 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 ¹¹²⁾. O-acetyl-ADP-ribose generated by the activity of sirtuins also controls calcium entry through TRPM2 channels ¹¹³⁾. 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 ¹¹⁴⁾.

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 ¹¹⁵⁾. 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 ¹¹⁶⁾. Similar observations were made with lipopolysaccharide-activated monocytes ¹¹⁷⁾. Extracellular NAADP+ and ADP-ribose might also bind to P2Y receptors and trigger intracellular NAADP+- and ADP-ribose-dependent calcium mobilization (see Calcium mobilization) ¹¹⁸⁾, ¹¹⁹⁾.

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 ¹²⁰⁾. 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 ¹²¹⁾.

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 ¹²²⁾, ¹²³⁾.

• ARTCs are extracellular enzymes that catalyze the mono ADP-ribosylation of membrane or secreted proteins involved in innate immunity and cell communication ¹²⁴⁾.
• 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 ¹²⁵⁾.

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) ¹²⁶⁾. 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) ¹²⁷⁾. 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 ¹²⁸⁾. 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 2–19 ¹²⁹⁾. 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) ¹³⁰⁾. Among all racial and ethnic groups, Hispanics had the greatest prevalence, 1.3%, of niacin intakes below the Estimated Average Requirement ¹³¹⁾.

According to self-reported data from the 2013-2014 NHANES, 21% of all individuals aged 2 and older took a dietary supplement containing niacin ¹³²⁾. 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) ¹³³⁾.

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

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.

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

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

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 ¹³⁶⁾.
• 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 ¹³⁷⁾, ¹³⁸⁾.
• 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 ¹³⁹⁾.

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 ¹⁴⁰⁾, ¹⁴¹⁾. 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 ¹⁴²⁾. However, the efficiency of the conversion of tryptophan to NAD varies considerably in different people ¹⁴³⁾.

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

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 ¹⁴⁴⁾. 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.

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 ¹⁴⁶⁾.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 ¹⁴⁷⁾. 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 ¹⁴⁸⁾, ¹⁴⁹⁾, ¹⁵⁰⁾. 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 ¹⁵¹⁾. 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 ¹⁵²⁾.

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 ¹⁵³⁾:

• 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 ¹⁵⁴⁾. 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 ¹⁵⁵⁾. 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% ¹⁵⁶⁾. 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 ¹⁵⁷⁾.

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 ¹⁵⁸⁾. 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 ¹⁵⁹⁾. 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 ¹⁶⁰⁾. 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 ¹⁶¹⁾, ¹⁶²⁾.

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 ¹⁶³⁾.

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 ¹⁶⁴⁾, ¹⁶⁵⁾. 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 ¹⁶⁶⁾, ¹⁶⁷⁾. 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 ¹⁶⁸⁾. 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 ¹⁶⁹⁾. 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) ¹⁷⁰⁾. 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 ¹⁷¹⁾. 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 ¹⁷²⁾. Nicotinic acid treatment was associated with a significantly higher risk of gastrointestinal and musculoskeletal adverse events ¹⁷³⁾. 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 ¹⁷⁴⁾.

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 ¹⁷⁵⁾. 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 ¹⁷⁶⁾.

Overall, the evidence indicates that nicotinic acid supplementation improves blood lipid profiles but has no significant effects on risk of cardiovascular events ¹⁷⁷⁾. 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 ¹⁷⁸⁾.

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 ¹⁷⁹⁾. 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 ¹⁸⁰⁾. 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 ¹⁸¹⁾.

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 ¹⁸²⁾. 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 ¹⁸³⁾. Repeated daily doses of 3.5 to 6 g of nicotinamide led to significant increases in frataxin concentration in peripheral white blood cells ¹⁸⁴⁾. 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 ¹⁸⁵⁾. 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 ¹⁸⁶⁾. An increased degradation of tryptophan via the kynurenine pathway appears to coexist with intracellular niacin/NAD deficiency in HIV infection ¹⁸⁷⁾. An explanatory model for these paradoxical observations incriminates the oxidative stress induced by multiple nutrient deficiencies in HIV patients ¹⁸⁸⁾. 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 ¹⁸⁹⁾, ¹⁹⁰⁾. The increased IDO activity has been linked to the altered immune response that contributes to the persistence of HIV ¹⁹¹⁾. Antiretroviral therapy (ART) only partially restores normal IDO activity, without normalizing it, yet induces viral suppression and CD4 T-cell recovery ¹⁹²⁾. 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 ¹⁹³⁾. 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 ¹⁹⁴⁾. Abnormal lipid profiles observed in patients have been attributed to the HIV infection and to the highly active antiretroviral treatment (HAART) ¹⁹⁵⁾. Moreover, insulin resistance has been detected together with dyslipidemia in antiretroviral therapy-treated patients ¹⁹⁶⁾. 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 ¹⁹⁷⁾. 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 ¹⁹⁸⁾. 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 ¹⁹⁹⁾. 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 ²⁰⁰⁾.

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 ²⁰¹⁾. The adjunctive use of nutrients like niacin to correct deficiencies associated with neurologic symptoms is called orthomolecular psychiatry ²⁰²⁾. 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 ²⁰³⁾, ²⁰⁴⁾.

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 ²⁰⁵⁾, ²⁰⁶⁾. An association has been found between the altered niacin sensitivity and greater functional impairment in schizophrenic subjects ²⁰⁷⁾, which supports other findings suggesting that altered lipid metabolism could critically impair brain development and contribute to the disease ²⁰⁸⁾. 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 ²⁰⁹⁾.

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 ²¹⁰⁾. 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 ²¹¹⁾. 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 ²¹²⁾. 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 ²¹³⁾. The expression of p53 was also altered by niacin deficiency in rat bone marrow cells ²¹⁴⁾. Impairment of DNA repair caused by niacin deficiency could lead to genomic instability and drive tumor development in rat models ²¹⁵⁾, ²¹⁶⁾. 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 ²¹⁷⁾, ²¹⁸⁾. 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 ²¹⁹⁾. 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 ²²⁰⁾. 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 ²²¹⁾. 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 ²²²⁾. 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 ²²³⁾. 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 ²²⁴⁾.

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 ²²⁵⁾. 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 ²²⁶⁾, ²²⁷⁾.

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 ²²⁸⁾. 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 ²²⁹⁾. 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 ²³⁰⁾. 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 ²³¹⁾. 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 ²³²⁾.

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 ²³³⁾. 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 ²³⁴⁾. 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 ²³⁵⁾. 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 ²³⁶⁾.

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 ²³⁷⁾. In an experimental animal model of diabetes, high levels of nicotinamide are administered to protect β-cells from damage caused by streptozotocin ²³⁸⁾.

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 ²³⁹⁾. 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 ²⁴⁰⁾. 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 ²⁴¹⁾. Nicotinamide could reduce inflammation-related parameters in these high-risk subjects yet was ineffective to prevent disease onset ²⁴²⁾. 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 ²⁴³⁾.

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 ²⁴⁴⁾:

• 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 ²⁴⁵⁾. 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 ²⁴⁶⁾:

• 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 ²⁴⁷⁾. 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 ²⁴⁸⁾. 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 ²⁴⁹⁾, ²⁵⁰⁾, ²⁵¹⁾. As a result, the body has less available tryptophan to convert to niacin. Hartnup disease management involves supplementation with nicotinic acid or nicotinamide ²⁵²⁾. 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 ²⁵³⁾. 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 ²⁵⁴⁾. In humans, the dose of NAD precursors necessary to avert NAD deficiency-induced congenital VACTERL malformations has yet to be defined ²⁵⁵⁾.

Nicotinamide may also rescue NAD depletion secondary to an ultra-rare inborn error of glutamine metabolism ²⁵⁶⁾. 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 ²⁵⁷⁾.

Finally, many inborn errors of metabolism result from genetic mutations decreasing cofactor binding affinity and, subsequently, enzyme efficiency ²⁵⁸⁾: 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 ²⁵⁹⁾: 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 ²⁶⁰⁾.

Vitamin B3 Niacin side effects

The niacin that food and beverages naturally contain is safe ²⁶¹⁾, ²⁶²⁾. 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 ²⁶³⁾. The flushing is accompanied by burning, tingling, and itching sensations ²⁶⁴⁾, ²⁶⁵⁾. 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 ²⁶⁶⁾. 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 ²⁶⁷⁾.

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.

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 ²⁶⁸⁾, ²⁶⁹⁾, ²⁷⁰⁾, ²⁷¹⁾. 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 ²⁷²⁾, ²⁷³⁾, ²⁷⁴⁾, ²⁷⁵⁾, ²⁷⁶⁾. Liver injury is more likely to occur with the use of extended-release forms of nicotinic acid ²⁷⁷⁾, ²⁷⁸⁾, ²⁷⁹⁾.

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 ²⁸⁰⁾. 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 ²⁸¹⁾.

Nicotinamide does not cause skin flushing and has fewer adverse effects than nicotinic acid, and these effects typically begin with much higher doses ²⁸²⁾. Nausea, vomiting, and signs of liver toxicity can occur with nicotinamide intakes of 3,000 mg/day ²⁸³⁾. 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) ²⁸⁴⁾, ²⁸⁵⁾, ²⁸⁶⁾, ²⁸⁷⁾.

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 ²⁸⁸⁾. 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 ²⁸⁹⁾. 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 ²⁹⁰⁾.

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 ²⁹¹⁾. In addition, isoniazid can interfere with niacin’s conversion to NAD ²⁹²⁾. 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 ²⁹³⁾. 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 ²⁹⁴⁾. 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 ²⁹⁵⁾.

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) ²⁹⁶⁾, ²⁹⁷⁾, ²⁹⁸⁾, ²⁹⁹⁾. In advanced stages, increased pigmentation usually leads to thin varnish-like eruptive scales ³⁰⁰⁾. 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 ³⁰¹⁾, ³⁰²⁾, ³⁰³⁾. 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 ³⁰⁴⁾, ³⁰⁵⁾, ³⁰⁶⁾. As pellagra progresses, anorexia develops, and the affected individual eventually dies if pellagra is left untreated ³⁰⁷⁾, ³⁰⁸⁾, ³⁰⁹⁾.

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 ³¹⁰⁾, ³¹¹⁾. 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 ³¹²⁾, ³¹³⁾. 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 ³¹⁴⁾. 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 ³¹⁵⁾. Pellagra epidemics were also unknown to Native Americans who consumed immature corn that contains predominantly unbound (bioavailable) niacin ³¹⁶⁾.

Although frank niacin deficiencies leading to pellagra are very rare in the United States, some individuals have marginal or low niacin status ³¹⁷⁾, ³¹⁸⁾, ³¹⁹⁾.

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 ³²⁰⁾, ³²¹⁾, ³²²⁾, ³²³⁾. Deficiencies of other B vitamins and some trace minerals may aggravate niacin deficiency ³²⁴⁾, ³²⁵⁾.

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) ³²⁶⁾, ³²⁷⁾, ³²⁸⁾.

Malabsorptive disorders that can lead to pellagra include Crohn’s disease and megaduodenum ³²⁹⁾, ³³⁰⁾. 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 ³³¹⁾. 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 ³³²⁾. Finally, other populations at risk for niacin deficiency include dialysis patients, cancer patients ³³³⁾, ³³⁴⁾, individuals suffering from chronic alcoholism ³³⁵⁾, 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 ³³⁶⁾.

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 ³³⁷⁾.

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

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.

Figure 7. Pellagra tongue

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 ³⁴¹⁾, ³⁴²⁾:

• 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 ³⁴³⁾, ³⁴⁴⁾. 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 ³⁴⁵⁾, ³⁴⁶⁾, ³⁴⁷⁾, ³⁴⁸⁾.

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 ³⁴⁹⁾, ³⁵⁰⁾.

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 ³⁵¹⁾. 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 ³⁵²⁾. Hartnup disease interferes with the absorption of tryptophan in the small intestine and increases its loss in the urine via the kidneys ³⁵³⁾, ³⁵⁴⁾, ³⁵⁵⁾. 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 ³⁵⁶⁾. 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 ³⁵⁷⁾:

• 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 ³⁵⁸⁾. 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 ³⁵⁹⁾. 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 ³⁶⁰⁾. 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 ³⁶¹⁾.

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 ³⁶²⁾. Skin sores may become infected.

Vitamin B3 deficiency diagnosis

Niacin deficiency or pellagra diagnosis is a clinical diagnosis and biochemical testing is rarely used ³⁶³⁾. Investigations such as blood tests and skin biopsy are not diagnostic but may be used to exclude other diagnoses ³⁶⁴⁾. If needed, niacin deficiency can be assessed by two methods ³⁶⁵⁾, ³⁶⁶⁾, ³⁶⁷⁾:

• 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 ³⁶⁸⁾.

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 ³⁶⁹⁾. 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 ³⁷⁰⁾, ³⁷¹⁾, ³⁷²⁾. Because patients with pellagra often display additional vitamin deficiencies, administration of a vitamin B-complex preparation is advised ³⁷³⁾.

Individuals with Hartnup disease who do not develop symptoms will usually not require any treatment ³⁷⁴⁾. 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 ³⁷⁵⁾. Supplementing the diet with nicotinamide or niacin is also of benefit in preventing Hartnup disease episodes ³⁷⁶⁾. 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 ³⁷⁷⁾. 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 ³⁷⁸⁾, ³⁷⁹⁾, ³⁸⁰⁾. The skin changes typically resolve within two weeks. However, a longer recovery may be seen in chronic cases ³⁸¹⁾.

What is total parenteral nutrition

Total parenteral nutrition (TPN) is a way of supplying all the nutritional needs of the body by bypassing the digestive system and dripping nutrient solution directly into a vein. Total parenteral nutrition is used when individuals cannot or should not get their nutrition through eating. Total parenteral nutrition is used when the intestines are obstructed, when the small intestine is not absorbing nutrients properly or a gastrointestinal fistula (abnormal connection) is present. Total parenteral nutrition (TPN) is also used when the bowels need to rest and not have any food passing through them. Bowel rest may be necessary in Crohn’s disease, pancreatitis, ulcerative colitis, and with prolonged bouts of diarrhea in young children. total parenteral nutrition is also used for individuals with severe burns, multiple fractures, and in malnourished individuals to prepare them for major surgery, chemotherapy, or radiation treatment. Individuals with AIDS or widespread infection (sepsis) may also benefit from total parenteral nutrition. Total parenteral nutrition (TPN) is also used for patients who have gastroparesis and cannot digest food properly.

Total parenteral nutrition is normally given through a large central vein, generally through a PICC (peripherally inserted central catheter) line, but can also be administered through a central line or port-a-cath. A catheter is inserted into the vein in the chest area under local anesthesia and sterile conditions. Often the placement is done in an operating room to decrease the chance of infection. Several different types catheters are used based on the reason total parenteral nutrition is needed and the expected length of treatment. Once the catheter is in place, a chest x ray is done to make sure the placement is correct.

Normally total parenteral nutrition is administered in a hospital, but under certain conditions and with proper patient and caregiver education, it may also be used at home for long-term therapy. total parenteral nutrition solution is mixed daily under sterile conditions. Maintaining sterility is essential for preventing infection. For this reason, the outside tubing leading from the bag of solution to the catheter is changed daily, and special dressings covering the catheter are changed every other day.

Patients may be on total parenteral nutrition for many weeks or months until their issues resolve. Throughout the course of therapy, patients may or may not be able to ingest anything orally; whatever the case, they will not get any substantive nutrition via the oral route.

Because patients are not getting any other true form of nutrition, the total parenteral nutrition formula needs to contain all of the essential nutrients a body needs to be healthy. This includes proteins, carbohydrates, fats, electrolytes, vitamins, and minerals. There are standard formulations that are available, and these are often what are used by large hospital systems. Infusion Solutions, however, batches each total parenteral nutrition formula to meet the individual dietary needs of the patient. This leads to optimal nutrition and a better chance of restoring health.

The total parenteral nutrition formulation is a complex mixture containing up to 40 different chemical components that may cause problems with stability and compatibility. Serious harm and death have resulted from improperly compounded parenteral feeding formulations.

The contents of the total parenteral nutrition solution are determined based on the age, weight, height, and the medical condition of the individual. All solutions contain sugar (dextrose) for energy and protein (amino acids). Fats (lipids) may also be added to the solution. Electrolytes such as potassium, sodium, calcium, magnesium, chloride, and phosphate are also included, as these are essential to the normal functioning of the body. Trace elements such as zinc, copper, manganese and chromium are also needed. Vitamins can be included in the total parenteral nutrition solution, and insulin, a hormone that helps the body use sugar, may need to be added. Adults need approximately 2 liters of total parenteral nutrition solution daily, although this amount varies with the age, size, and health of the individual. Special solutions have been developed for individuals with reduced liver and kidney function.

The formula can be adjusted as necessary based on lab markers and the progress of the disease state. The rate of total parenteral nutrition administration can also be changed under some circumstances. Generally, patients are initially started on a continuous cycle and are given their total parenteral nutrition over a 24 hour period. As patients progress, it may be possible to move to an 18, 15, or even a 12-hour infusion cycle. This can certainly improve the quality of life for those patients managing this infusion at home.

The total parenteral nutrition itself comes in a 2-3 liter bag, and most patients infuse one bag per day. The bag itself is connected to a portable infusion pump that has been pre-programmed by the pharmacy team to deliver the total parenteral nutrition over a specified amount of time. The whole system fits nicely into a small backpack that can be worn by the patient or hung nearby throughout the infusion. As with all home infusion therapies, the intent is for the patient to be as mobile as he or she would like to accommodate their lifestyle.

Successful total parenteral nutrition requires frequent, often daily monitoring of the individual’s weight, glucose (blood sugar) level, blood count, blood gasses, fluid balance, urine output, waste products in the blood (plasma urea) and electrolytes. Liver and kidney function tests may also be performed. The contents of the solution are individualized based on the results of these tests.

Total parenteral nutrition calculations

This total parenteral nutrition calculator (https://clincalc.com/TPN/Macronutrients.aspx) provides an empiric dose for the macronutrients included in a total parenteral nutrition formulation. In addition to providing an initial recommended dose, you may alter the contents of each macronutrient while maintaining a specified daily caloric requirement.

• Osmolarity = measure of solute concentration, defined as the number of osmoles (Osm) of solute per liter (L) of solution (Osm/L)
• Osmolality = measure of osmoles of solute per kilogram of solvent (Osm/kg)

Osmolarity of total parenteral nutrition calculations

• Dextrose% X 50
• Amino Acid% X 100
• All electrolytes combined in mEq/L X 2
• Total = TPN Osmolarity

Total parenteral nutrition Osmolarity Calculator (http://www.rxkinetics.com/tpnosmolcalc.html).

Energy requirement

Harris-Benedict equation + activity +infection/fever factor = Energy (Kcal)

The Harris–Benedict equation (also called the Harris-Benedict principle) is a method used to estimate an individual’s basal metabolic rate (BMR). The estimated BMR value may be multiplied by a number that corresponds to the individual’s activity level; the resulting number is the approximate daily kilocalorie intake to maintain current body weight.

Men BMR = (10 × weight in kg) + (6.25 × height in cm) – (5 × age in years) + 5

Women BMR = (10 × weight in kg) + (6.25 × height in cm) – (5 × age in years) – 161

• Scale:
  • Normal need: 25-30 kcal/kg/day
  • Elective surgery: 28-30 kcal/kg/day
  • Severe injury: 30-40 kcal/kg/day
  • Extensive trauma/burn: 45-55 kcal/kg/day

Dextrose

• Primary energy source
• 70% => 70 g/100 ml
• 3.4 kcal/g
• 45 -60% total kcal

Glucose Infusion Rate

Dextrose Infusion Rate (DIR) or Glucose Infusion Rate (GIR)

• Glucose Infusion Rate (GIR) = _____ mg / kg / min
• Steps to calculate Glucose Infusion Rate (GIR):
  • Convert grams to milligrams
  • Divide by patient’s weight in kilogram (kg)
  • Divide by minutes per day

Amino Acid

• Crystalline L-amino acid solution – 100% utilizable
• 10% => 10 g / 100 mL
• 15% => 15 g / 100 mL
• 10-20% total kcal
• Hypertonic
• 4 kcal /gram

Fat

• 20-40% of total kcal
• Most common is 20% soybean oil emulsion
  • 10% fat emulsion = 1.1 kcal/mL
  • 20% fat emulsion = 2 kcal/mL
  • 30% fat emulsion = 3 kcal/mL (only used as ingredient of 3 in 1)

Fat Requirements

• To prevent essential fatty acid deficiency, 2 2-4% of kcal should come from linoleic acid (~10% of total kcal from lipid)
• Fat should generally provide 20 20-40% of total kcal
• Maximal fat dosage should not exceed 60% of total kcal

Lipid dose = ____ g/kg/day

• Convert milliliters to grams lipid
• Divide by weight

Hourly Lipid Infusion Rate = ___ g/kg/hour

• Convert milliliters to grams lipid
• Divide by weight
• Divide by infusion time in hours
• Max 0.11 g/kg/hour

Calculating Parenteral Fluids Volume

• Methods of Calculating Fluids Volume:
  • mL per kcal: 1-1.5 mL/kcal
  • mL per kg:
    • >65 years old, 25mL/kg fluid
    • 55 -65 years old, 30mL/kg fluid
    • 30 -55 years old, 35mL/kg fluid
    • 30 years old, 40mL/kg fluid
  • Holliday-Segar
    • <10 kg, 100 mL/kg
    • 10-20 kg, 1000 mL + 50 mL/kg for every kg between between 10 -20 kg
    • >20 kg, 1500 mL + 20 mL/kg for every kg >20 kg
  • 4-2-1 rule
    • <10 kg, 4 mL/kg/hr
    • 10-20 kg, 40 mL/hr + 2 mL/kg/hr for every kg between 10-20kg
    • >20 kg, 60 mL/hr + 1 mL/kg/hr for every kg >20 kg

Cycling

Initial administration 24 hours (continuous)

• Especially for critically ill patients
• Minimizes glucose, fluid, and electrolyte abnormalities

Eventually may be able to “cycle” total parenteral nutrition

• 8-22 hour infusion time
• Decrease infusion time gradually over several days to weeks depending on patient age/status
• Titrate total parenteral nutrition infusion rate over 1-2 hours (i.e., ramp up and down over 1 1-2 hours to cycle up and cycle down total parenteral nutrition)
  • Helps prevent hyper hyper-and hypoglycemia
• Improves quality of life
• May reduce intestinal failure associated liver disease
• Cycling Example:
  • Cycle 2000 mL total parenteral nutrition over 20 hours: 1 h – 1 h – 16 h – 1 h – 1 h

Total parenteral nutrition procedure

Vascular Access

• Individualize access device selection
  • Risk / benefit
  • Clinical factors
  • Psychosocial considerations
• Fewest lumens possible
• Dedicate 1 lumen to total parenteral nutrition when able
• Position tip in lower third of the superior vena cava near the junction with the right atrium
• Confirm optimal position before initiating total parenteral nutrition

Central-Line

• Distal catheter tip in vena cava or right atrium
• Access sites: subclavian, jugular, femoral, cephalic, and basilic veins
• Provides access for infusion and blood aspiration
• Placement is verified by chest X-ray or fluoroscopy
• Ideal for hyperosmolar solutions

Mid-Line

• 3 to 8 inches in length
• Inserted into main veins of arm
• Tip rests in proximal limb
• Decreased phlebitis
• Increased dwell time

Peripheral-Line

• Access is easy to establish
• Intended for short term use
• Central access is not feasible
• Limited osmolarity (900mOsm/kg)
• Complication – phlebitis
• Extend < 3 inches into vein

Know your total parenteral nutrition fluids

• Read the medicine sheet that comes with the total parenteral nutrition. Be aware of any warnings and side effects.
• Check the label on the total parenteral nutrition bag before starting an IV. Make sure the patient name, total parenteral nutrition fluids, and dose are correct.
• Don’t use total parenteral nutrition with an expired date.
• Don’t use total parenteral nutrition if the bag is leaking.
• Don’t use total parenteral nutrition if it looks lumpy or oily.
• Don’t use total parenteral nutrition if anything is floating in it.

Handle supplies as directed

• Store total parenteral nutrition in the refrigerator. If it’s not kept cold, total parenteral nutrition lasts only 24 hours. Don’t freeze.
• Before using total parenteral nutrition, let it get close to room temperature. Don’t heat.
• If vitamins need to be added to the total parenteral nutrition, do so as directed.
• Put all used needles and syringes in a special container (sharps container).
• When the IV is done, put the used supplies in a plastic bag. Seal the bag and throw it in the trash.

Track your health

• Weigh yourself daily. If you lose or gain weight, your total parenteral nutrition dose may need adjusting.
• Keep track of your urine output as directed. Tell the nurse if the amount increases or decreases a lot.
• Check your blood sugar if directed. A nurse may take a blood sample from you each week. This is to make sure your total parenteral nutrition dose is right for you.

Know these IV basics

• Keep the dressing over the catheter exit site clean and dry. Change the dressing if it comes loose or gets soiled or wet.
• Flush the catheter with saline or heparin as directed.
• Wipe all injection sites with alcohol.
• Be sure all IV supplies are in sealed packets. If sterile packets are open, throw away those supplies.
• Do not stop the pump during an IV infusion unless a nurse tells you to.

Total parenteral nutrition guidelines

Total parenteral nutrition indications

Adults

• “Initiate total parenteral nutrition after 7 days for well well-nourished, stable adult patients who have been unable to receive significant (50% or more of estimated requirements) oral or enteral nutrients”
• “Initiate total parenteral nutrition within 3-5 days in those who are nutritionally nutritionally-at -risk and unlikely to achieve desired oral intake or enteral nutrition”
• “Initiate total parenteral nutrition as soon as is feasible for patients with baseline moderate or severe malnutrition in whom oral intake or enteral nutrition is not possible or sufficient”

Children

• “Consider total parenteral nutrition for neonates in the critical care setting, regardless of diagnosis, when enteral nutrition is unable to meet energy requirements for energy expenditure and growth”
• “Use total parenteral nutrition for children when the intestinal tract is not functional or cannot be accessed or when nutrient needs to provide for growth are greater than that which can be provided through oral intake or enteral nutrition support alone”
• “Initiate total parenteral nutrition within 1 1-3 days in infants and within 4 4-5 days in older children and adolescents when it is evident that they will not tolerate full oral intake or enteral nutrition for an extended period”
• “Begin total parenteral nutrition promptly after birth in the very low birth weight infant (<1500g)”

Figure 1. Total parenteral nutrition guidelines adults

Figure 2. Total parenteral nutrition guidelines for children

Total parenteral nutrition complications

Total parenteral nutrition complications include:

Mechanical complications

Mechanical complications are primarily related to the initial placement of a central venous catheter. Improper placement may cause pneumothorax, vascular injury with hemothorax, brachial plexus injury or cardiac arrhythmia.

Venous thrombosis is one of the two most common problems that occur after central venous access is established. The other is infection. Venous thrombosis is associated with significant morbidity rates. Signs include distended neck veins and swelling of the face and ipsilateral arm. The risk of venous thrombosis is greater if patients are dehydrated, have certain malignancies, have had prolonged bed rest, have venous stasis, have sepsis, or have hypercoagulation. Additional risk factors include morbid obesity, smoking, or ongoing estrogen therapy.

Mechanical complications:

• Hemothorax
• Pneumothorax
• Arterial puncture
• Air embolism
• Nerve damage
• Thoracic duct damage
• Hematoma
• Misplaced catheter

Infections

Total parenteral nutrition imposes a chronic breech in the body’s barrier system. The infusion apparatus from container to catheter tip may prove a source for the introduction of bacterial or fungal organisms.

Infection is one of the two most common problems that arise after central venous access is established. The other is venous thrombosis, discussed earlier. The mortality rate from catheter sepsis may be as high as 15%.

The primary preventive measures include adhering to strict aseptic procedure while establishing access and providing care of the dressing and line, and prohibiting the use of the total parenteral nutrition line for other purposes. Other preventive measures include:

• Changing the dressing routinely (every 48-72 hours) or when it becomes soiled, wet or loose. The care-giver should wear a mask and gloves while changing the dressing.
• Extending the application of antimicrobial solution at least 1 inch beyond the final dressing.
• Placing a sterile sponge over the catheter, then placing an occlusive dressing.
• Inspecting the site for tenderness, erythema, edema, loose sutures, or drainage.
• Changing the total parenteral nutrition intravenous tubing every 48 hours. A 0.22 μm in-line filter should be used whenever fat is not being infused.
• Avoiding violation of total parenteral nutrition catheters for central venous pressure monitoring or the administration of intravenous medications or blood products.

Metabolic complications

Metabolic complications fall into two broad categories: early and late complications. Those in the first category occur early in the process of feeding and may be anticipated. They are avoided by careful monitoring and appropriate adjustment of intake. Late metabolic complications are less predictable. They may be caused by an exacerbation of preexisting abnormalities, unpredictable long-term requirements, inadequate solution composition, or failure to monitor adequately.

Metabolic complications of total parenteral nutrition:

Early complications

• Volume overload
• Hyerglycemia
• Refeeding syndrome
• Hypokalemia
• Hypophosphatemia
• Hypomagnesemia
• Hyperchloremic acidosis

Late complications

• Essential fatty acid deficiency
• Trace mineral deficiency
• Vitamin deficiency
• Metabolic bone disease
• Hepatic steatosis
• Hepatic cholestasis

Fluid and electrolyte imbalance

Electrolyte management is one of the most difficult aspects of total parenteral nutrition therapy. Often electrolytes are outside of the normal range based on an underlying cause rather than directly related to the total parenteral nutrition solution. For this reason, no specific guidance can be given to adjust individual electrolytes based on laboratory serum concentration. Instead, incremental dose adjustments are made concurrent with treatment of the underlying cause of electrolyte abnormality. In general, supplemental electrolyte doses in response to an acute underlying condition are best managed outside of total parenteral nutrition therapy.

Table 1. Sodium – Normal = 135 – 145 mEq/L

Table 2. Potassium – Normal = 3.5 – 5.0 mEq/L

Table 3. Magnesium – Normal = 1.5 – 2.0 mEq/L

Table 4. Calcium – Normal = 8.5 – 10.5 mg/dl

Table 5. Phosphorus – Normal = 3.0 – 4.5 mg/dl

Refeeding syndrome

Refeeding of severely malnourished patients may result in “refeeding syndrome” in which there are acute decreases in circulating levels of potassium, magnesium, and phosphate. The consequences of refeeding syndrome adversely affect nearly every organ system and include cardiac dysrhythmias, heart failure, acute respiratory failure, coma, paralysis, nephropathy, and liver dysfunction.

The primary cause of the metabolic response to refeeding is the shift from stored body fat to carbohydrate as the primary fuel source. Serum insulin levels rise, causing intracellular movement of electrolytes for use in metabolism.

The best advice when initiating nutritional support is to “start low and go slow”.

Recommendations to reduce the risk of refeeding syndrome include:

• Recognize patients at risk
  • Anorexia nervosa
  • Classic kwashiorkor or marasmus
  • Chronic malnutrition
  • Chronic alcoholism
  • Prolonged fasting
  • Prolonged IV hydration
  • Significant stress and depletion
• Correct electrolyte abnormalities before starting nutritional support
• Administer volume and energy slowly
• Monitor pulse, input and output, electrolytes closely
• Provide appropriate vitamin supplementation
• Avoid overfeeding

Total parenteral nutrition side effects

Central-vein total parenteral nutrition is associated with mechanical, metabolic, and infectious complications ³⁾. Such complications are much more common when parenteral nutrition is not properly administered and when current standards of practice are not applied ⁴⁾. Complications such as pneumothorax, bleeding, and thrombus formation can occur owing to the insertion of the central venous catheter, which is typically performed as a component of usual critical care. Catheter-related and non–catheter-related infections are not uncommon and are associated with hyperglycemia ⁵⁾, the use of internal jugular-vein or femoral-vein central venous catheters, and the use of nondedicated infusion ports for parenteral nutrition ⁶⁾.

Overfeeding (the administration of excess dextrose, fat, or calories) and the refeeding syndrome (rapid feeding of patients with preexisting malnutrition) can induce a variety of metabolic complications during parenteral nutrition ⁷⁾. Accelerated carbohydrate metabolism increases the body’s use of thiamine and can precipitate symptoms and signs of thiamine deficiency ⁸⁾. Insulin has an antinatriuretic effect ⁹⁾, which, when coupled with increased sodium and fluid intake during refeeding, can cause a rapid expansion of the volume of extracellular fluid in some patients ¹⁰⁾. Decreased levels of blood electrolytes can induce cardiac arrhythmias. In cases, these result in heart failure, particularly in patients with preexisting cardiac dysfunction ¹¹⁾. Other metabolic effects can include hypercapnia, hepatic steatosis, neuromuscular dysfunction, and immunologic defects.

What is glucomannan

Glucomannan also called Konjac glucomannan is a water-soluble polysaccharide or highly viscous fiber commonly separated from Amorphophallus konjac root ¹⁾. Glucomannan (Konjac glucomannan) is a dietary fiber with a long history in food and traditional Chinese medicine ²⁾. Glucomannan is also known as E 425 ii when used as food additives ³⁾. Glucomannan is marketed as being helpful in reducing body weight. In otherwise healthy overweight or obese children and adults, there is some evidence that in the short term glucomannan may help to reduce body weight, but not body mass index (BMI). In 2010, the European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies ⁴⁾ concluded that a cause and effect relationship has been established between the consumption of glucomannan and the maintenance of normal blood cholesterol concentrations and the reduction of body weight. In order to obtain the claimed effect of reduction of body weight, “at least 3 g of glucomannan should be consumed daily in three doses of at least 1 g each, together with 1–2 glasses of water before meals, in the context of an energy‐restricted diet. The target population is overweight adults” ⁵⁾. The conditions and restrictions of use for the health claims for glucomannan (konjac mannan) to contribute to weight loss and to the maintenance of normal blood cholesterol concentrations are authorized by the Commission Regulation (EU) No 432/2012.

According to European Union Commission Regulation No 231/2012, both konjac gum (E 425 i) and konjac glucomannan (E 425 ii) are defined as water soluble hydrocolloid obtained from konjac flour. Konjac gum is obtained by aqueous extraction, while konjac glucomannan is obtained by washing with water‐containing ethanol. In the European Union Commission Regulation, konjac flour is defined as the unpurified raw product from the tuber of the perennial plant Amorphophallus konjac.

The in vitro degradation and the in vivo digestibility of konjac glucomannan in animals demonstrated that this compound would not be absorbed intact or hydrolyzed by digestive enzymes.

Konjac glucomannan and konjac flour can be regarded as non‐toxic based on the results of acute oral toxicity studies.

Dietary supplements do not require extensive pre-marketing approval from the U.S. Food and Drug Administration. Manufacturers are responsible to ensure the safety, but do not need to prove the safety and effectiveness of dietary supplements before they are marketed. Dietary supplements may contain multiple ingredients, and differences are often found between labeled and actual ingredients or their amounts. A manufacturer may contract with an independent organization to verify the quality of a product or its ingredients, but that does not certify the safety or effectiveness of a product. Because of the above issues, clinical testing results on one product may not be applicable to other products.

Figure 1. Glucomannan chemical structure

The glucomannan main chain is polymerized by d-mannose and d-glucose with a α-1,4-pyranoside bond and a small amount of acetyl groups at the C–6 position of the side chain. These can only be hydrolyzed by α-mannase at the end of the small intestine and the colon of the human body ⁶⁾. Glucomannan has good film-forming ability, biocompatibility, biodegradability, and gelation performance, which is one of its most prominent features ⁷⁾. The preparation methods of glucomannan gel mainly include the alkaline processing ⁸⁾, borate cross-linking ⁹⁾, polymer compounding ¹⁰⁾, high voltage electric field preparation ¹¹⁾, and metal ion cross-linking after modification ¹²⁾. The gel microstructure largely determines the performance of the gel, but glucomannan gels prepared through different methods are significantly different in terms of microstructure ¹³⁾. With good biocompatibility and biodegradability ¹⁴⁾, glucomannan gels have been widely used in food ¹⁵⁾, pharmaceutical carriers ¹⁶⁾, tissue scaffolds ¹⁷⁾, absorbing materials ¹⁸⁾ and other fields.

Glucomannan as food additives

Konjac gum (E 425 i) and konjac glucomannan (E 425 ii) are authorized as food additives in the European Union in accordance with Annex II and Annex III to Regulation (EU) No 1333/2008 on food additives and specific purity criteria have been defined in the Commission Regulation (EU) No 231/2012 ¹⁹⁾. According to this regulation, there are distinct specifications for konjac gum (E 425 i) and konjac glucomannan (E 425 ii). The Joint Food and Agriculture Organization (FAO)/World Health Organisation (WHO) Expert Committee on Food Additives (JECFA) has one specification for konjac flour (INS 425). Konjac gum (E 425 i) and konjac glucomannan (E 425 ii) are distinguished by their grade of purity.

In the European Union, konjac gum (E 425 i) and konjac glucomannan (E 425 ii) have been evaluated by the Scientific Committee on Food in 1996 ²⁰⁾, who could not establish an acceptable daily intake (ADI) for both the substances. For konjac gum (E 425 i), the Scientific Committee on Food ²¹⁾ noted ‘Adequate subchronic and long‐term feeding studies with this material are lacking and a no‐observed‐adverse-effect level (NOAEL) cannot be derived. In addition, it has not been clarified to what extent the main component glucomannan is digested in the human intestine’. For konjac glucomannan (425 ii), the Scientific Committee on Food noted that ‘it was tested adequately in 90‐day feeding studies with rats and beagle dogs. These studies did not reveal any relevant toxic effects and a no‐observed‐effect level of 2.5% glucomannan in the diet can be derived, corresponding to 1.25 g/kg body weight per day. However, a long‐term toxicity/carcinogenicity study is lacking and only gene mutation tests in bacteria were performed with a negative result ²²⁾. In addition, it has not been clarified to what extent the glucomannan is digested in the human intestine’. On the other hand, the Scientific Committee on Food concluded, that ‘the existing data (including genotoxicity studies with konjac glucomannan (E 425 ii) as well as human experience did not give reason for concern. Konjac materials have a long history as traditional food in Asian countries. Apart from diarrhea, abdominal pain and an effect on vitamin absorption after ingestion of high doses, no adverse effects of oral ingestion have been reported in humans’. The Scientific Committee on Food considered therefore that ‘the uses of konjac gum (E 425 i) and konjac glucomannan (E 425 ii) as additives at the intended levels up to 1% in food are acceptable, provided that the total intake from all sources did not exceed 3 g/day. This upper limit should be taken into account when setting the conditions of use. The Scientific Committee on Food noted that directive included a footnote in relation to similar products which points out that these substances should not be used to produce dehydrated foodstuffs intended to rehydrate on ingestion’. The Scientific Committee on Food considered that a similar remark would be applicable to konjac gum (E 425 i) and konjac glucomannan (E 425 ii).

No relevant studies on short‐term and subchronic toxicity for konjac gum and konjac glucomannan are available. However, additional studies on nutritional effects are described; no relevant substance‐induced adverse effects were observed.

Based on the data available, the European Food Safety Authority Panel noted that there is no concern with respect to the genotoxicity of konjac flour.

No relevant studies on chronic toxicity and carcinogenicity for konjac gum (E 425 i) and konjac glucomannan (E 425 ii) were available ²³⁾. The European Food Safety Authority Panel noted that no adverse effects were observed in rats in a long‐term feeding trial over 18 months with 1% refined konjac meal in diet, and in mice receiving 10% of konjac glucomannan with the diet for 10 months.

No reproductive toxicity studies were available ²⁴⁾. The European Food Safety Authority Panel considered that the developmental toxicity studies as referred to by the Joint Food and Agriculture Organization (FAO)/World Health Organisation (WHO) Expert Committee on Food Additives (JECFA) ²⁵⁾ in cats and of Sun Tan et al. ²⁶⁾ in sows were both limited and not sufficient for the evaluation of the developmental toxicity of konjac gum (E 425 i) and konjac glucomannan (E 425 ii).

From both human and animal data, the European Food Safety Authority Panel considered that there was no indication for concern for immunotoxicity or allergenicity with konjac gum (E 425 i) and konjac glucomannan (E 425 ii) used as food additives ²⁷⁾.

In human studies, gastrointestinal discomfort (i.e. laxative effects, flatulence, full stomach, feeling of hungry and abdominal distension) has been reported in several clinical human studies included in two meta‐analyses. In a relevant study, a dosage of 3 g konjac glucomannan (divided in three times 1 g)/person per day corresponding to 33 mg/kg body weight per day based on mean body weight of approximately 90 kg, for 12 weeks, was associated with gastrointestinal effects (diarrhea or constipation).

Konjac (E 425) is authorized in a wide range of foods. Very few reported use levels were made available to the European Food Safety Authority (EFSA). Only three food categories out of 67 were taken into account in the refined scenario. Thus the two refined exposure estimates (brand‐loyal consumer scenario and non‐brand‐loyal scenario) are similarly low (below 0.1 mg/kg body weight per day in any scenario and population).

According to the conceptual framework for the risk assessment of certain food additives re‐evaluated under Commission Regulation No 257/2010, European Food Safety Authority Panel on Food Additives and Nutrient Sources added to Food 2014 ²⁸⁾ and given that:

• Current use of konjac (E 425) was limited in all food categories to maximum permitted level of 10 g/kg;
• An indicative refined exposure assessment has been calculated: for all population groups, it was below 0.1 mg/kg body weight per day for the general population (mean and high level);
• Konjac gum and konjac glucomannan were unlikely to be absorbed intact and were significantly fermented by intestinal microbiota;
• The available database on toxicological studies was considered limited, however no relevant adverse effects were seen in rats and dogs in 90‐day feeding studies according to the Scientific Committee on Food, and the no‐observed‐adverse-effect level (NOAEL) in rats was 1,250 mg konjac glucomannan/kg bw per day;
• Konjac gum and konjac glucomannan would be of no concern with respect to the genotoxicity;
• After a daily dosage of 3,000 mg in adults (corresponding to 33 mg/kg body weight based on mean body weight of approximately 90 kg) for 12 weeks, several individuals experienced abdominal discomfort including diarrhea or constipation,

The European Food Safety Authority Panel concluded that there was no need for a numerical acceptable daily intake (ADI) and that there was no safety concern for the general population at the refined exposure assessment for the reported uses of konjac gum (E 425 i) and konjac glucomannan (E 425 ii) as food additives under the current conditions of use at level of 10 g/kg ²⁹⁾.

The European Food Safety Authority Panel agreed with the conclusions of the Scientific Committee on Food (1997) that the uses of konjac (E 425), comprising konjac gum (E 425 i) and konjac glucomannan (E 425 ii), as an additive at the levels up to 10 g/kg in food are acceptable, provided that the total intake from all sources does stay below 3 g/day ³⁰⁾.

The European Food Safety Authority Panel recommended that the European Commission considers harmonizing the microbiological specifications for polysaccharidic thickening agents, such as gums, and to include criteria for total aerobic microbial count and total combined yeasts and molds count into the EU specifications of konjac gum (E 425 i) and konjac glucomannan (E 425 ii) ³¹⁾.

Although the European Food Safety Authority Panel realized that the exposure to these additives is rather low, the European Food Safety Authority Panel recommended that the European Commission considers revising the current limits for the toxic elements (lead and arsenic) in the European Union specification for konjac gum (E 425 i) and konjac glucomannan (E 425 ii) ³²⁾.

Glucomannan supplement

Glucomannan has no specific lactation-related uses. It is most often used to lower cholesterol, to treat constipation and diabetes, and is contained in products to promote weight loss. No data exist on the safety and efficacy of glucomannan in nursing mothers or infants. However, because glucomannan is not absorbable, it will not reach the breastmilk and is very unlikely to affect the nursing infant.

Glucomannan health benefits

Glucomannan and cholesterol

In 2009, the European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies ³³⁾ prepared a scientific opinion on the scientific substantiation of health claims in relation to glucomannan (konjac mannan) and the maintenance of normal blood cholesterol concentrations. Eight randomized controlled trials, which investigated the effects of glucomannan on LDL “bad” cholesterol and/or total cholesterol at daily glucomannan doses of 3-15 g/day in either healthy, hypercholesterolemic or diabetic adult human subjects were provided ³⁴⁾. In weighing the evidence, the European Food Safety Authority Panel took into account that a statistically significant effect on either total or LDL “bad” cholesterol was not observed following the consumption of glucomannan in all of these studies, that reduction in total and/or LDL “bad” cholesterol concentrations did not always lead to significant reductions in the total/HDL “good” cholesterol ratio, that the vast majority of these studies had small sample sizes, and that no clear dose-response relationship was established between the consumption of glucomannan and the claimed effect. However, the European Food Safety Authority Panel considers that most studies showed a consistent effect in the reduction of serum total and LDL “bad” cholesterol concentrations at doses of about 4 grams/day of glucomannan, that the effect has been observed not only in hypercholesterolemic subjects but also in healthy individuals, and that the mechanisms by which the consumption of the food may exert the claimed effect (biological plausibility) are established. On the basis of the data available, the European Food Safety Authority Panel concluded that “a cause and effect relationship has been established between the consumption of glucomannan and the reduction of blood cholesterol concentrations. In order to bear the claim, a food should provide at least 4 g/day of glucomannan in one or more servings. The target population is the general population” ³⁵⁾. The following wording reflects the scientific evidence: “Regular consumption of glucomannan helps maintain normal blood cholesterol concentrations”.

Glucomannan and weight loss

In 2010, the European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies ³⁶⁾ prepared another scientific opinion on the scientific substantiation of health claims in relation to glucomannan (konjac mannan) and reduction of body weight (weight loss), reduction of post‐prandial glycemic responses, maintenance of normal blood glucose concentrations, maintenance of normal (fasting) blood concentrations of triglycerides, maintenance of normal blood cholesterol concentrations, maintenance of normal bowel function and decreasing potentially pathogenic gastrointestinal microorganisms. In weighing the evidence, the European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies took into account that most of the intervention studies, which were of adequate sample size and duration, found a statistically significant effect of glucomannan on body weight loss in the context of a hypocaloric diet when administered as a pre-load before meals, and that the mechanism by which glucomannan could exert the claimed effect is established. On the basis of the data presented, the European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies concludes that a cause and effect relationship has been established between the consumption of glucomannan and the reduction of body weight in the context of an energy-restricted diet ³⁷⁾. The Panel considers that in order to obtain the claimed effect, at least 3 g of glucomannan should be consumed daily in three doses of at least 1 g each, together with 1-2 glasses of water before meals, in the context of an energy-restricted diet. The target population is overweight adults. The European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies ³⁸⁾ concluded that a cause and effect relationship has been established between the consumption of glucomannan and the maintenance of normal blood cholesterol concentrations and the reduction of body weight. In order to obtain the claimed effect of reduction of body weight, “at least 3 g of glucomannan should be consumed daily in three doses of at least 1 g each, together with 1–2 glasses of water before meals, in the context of an energy‐restricted diet. The target population is overweight adults” ³⁹⁾. A cause and effect relationship has not been established between the consumption of glucomannan and the other claimed effects.

Glucomannan dosage

For weight loss: At least 3 g of glucomannan should be consumed daily in three doses of at least 1 g each, together with 1–2 glasses of water before meals, in the context of an energy‐restricted diet.

For cholesterol: At least 4 g/day of glucomannan in one or more servings.

Glucomannan side effects

In human studies, gastrointestinal discomfort (i.e. laxative effects, flatulence, full stomach, feeling of hungry and abdominal distension) has been reported in several clinical human studies included in two meta‐analyses. In a relevant study, a dosage of 3 g konjac glucomannan (divided in three times 1 g)/person per day corresponding to 33 mg/kg body weight per day based on mean body weight of approximately 90 kg, for 12 weeks, was associated with gastrointestinal effects (diarrhea or constipation).

What is kelp

Kelp (Laminaria japonica or Laminaria japonica) is widely cultivated large seaweeds, belonging to the brown algae and classified in the order Laminariales, and are an important food source in many Asian cultures. Kelp is available worldwide in grocery stores as it is a key ingredient of Japanese miso soup. Kelp (Laminaria japonica) is used for food in daily life and also used in traditional medicine in China, with China being the largest producer ¹⁾. According to the “Compendium of Materia Medica” ²⁾, kelp is cold, salty, has efficacy in clearing water, is soft, firm, dissipating and can dissolve phlegm ³⁾, as well as alleviate edema, and eliminate carbuncle. Kelp belongs to the Phaeophyta Laminariaceae Laminaria, containing laminarin, ammonium alginate, mannitol, vitamins, amino acids and various normal and trace elements, with a variety of 40 active components ⁴⁾. The variety of physiological functions of the kelp relate to the biological activity of polysaccharides which can improve the immunity function, anti-aging, anti-tumor ⁵⁾, anti-atheroscloresis, anti-diabetics ⁶⁾ and other such biological activity.

Kelp nutrition

Table 1. Raw Kelp nutrition facts

Table 2. Dried Kelp nutrition facts

Kelp supplements

Key points

• In the United States, recommended daily allowances (RDA) for iodine intake are 150 μg in adults, 220–250 μg in pregnant women, and 250–290 μg in breastfeeding women ⁹⁾. The U.S. diet generally contains enough iodine to meet these needs, with common sources being iodized salt, dairy products, some breads, and seafood. During pregnancy and lactation, women require higher amounts of iodine for the developing fetus and infant. The American Thyroid Association recommends that women take a multivitamin containing 150 μg of iodine daily in the form of potassium iodide ¹⁰⁾ during preconception, pregnancy, and lactation to meet these needs ¹¹⁾.

• The American Thyroid Association advises against the ingestion of iodine and kelp supplements containing in excess of 500 μg iodine daily for children and adults and during pregnancy and lactation ¹²⁾. Long-term iodine intake in amounts greater than the tolerable upper limits should be closely monitored by a physician. There are only equivocal data supporting the benefit of iodine at higher doses than these, including a possible benefit for patients with fibrocystic breast disease ¹³⁾. There is no known thyroid benefit of routine daily iodine doses in excess of the U.S. recommended daily allowances (RDA).
• Kelp is a rich source of iodine that may interfere with thyroid replacement therapies. Kelp is available as a dietary supplement marketed for thyroid support. Iodine content in kelp varies depending on harvest location and preparation. Its average iodine content has been estimated to be about 1,500 to 2,500 μg/g (microgram per gram) of dried preparation, that is i.e., 10 to 16.7 times the recommended daily allowance of 150 μg (microgram) ¹⁴⁾, ¹⁵⁾. In some individuals, the high iodine load from kelp supplements can result in thyroid dysfunction ¹⁶⁾, ¹⁷⁾. Iodine-induced thyrotoxicosis has been reported after consuming a kelp-containing tea ¹⁸⁾.
• Herbal medicine, including kelp and kelp-containing dietary supplements, are not regulated by the FDA. In a study to evaluate the extent of arsenic contamination in commercially available kelp, nine samples were randomly obtained from local health food stores ¹⁹⁾. Eight of the nine samples showed detectable levels of arsenic higher than the Food and Drug Administration tolerance level of 0.5 to 2 ppm for certain food products ²⁰⁾. Chronic arsenic toxicity may cause peripheral neuropathies, parasthesia, ataxia, cognitive deficits, fatigue, and muscular weakness ²¹⁾. Gastrointestinal complaints include anorexia, hepatomegaly, jaundice, nausea, and vomiting. Skin afflictions may include erythema (skin redness), eczema, pigmentation (arsenic melanosis), diffuse alopecia (hairloss), keratosis (especially of palms and soles), scaling and desquamation, brittle nails, white lines or bands in the nails (Mees lines), and localized subcutaneous edema. White striae in the fingernails are consistent with a diagnosis of arsenical polyneuritis, even though urine and hair arsenic concentrations may be within normal limits ²²⁾.
• Past studies have shown that many herbal remedies are contaminated with potential toxicants including mercury and lead. To prevent more inadvertent poisonings, scientists and physicians recommend that manufacturers be required to prove safety before marketing their products.

Kelp is also available as a dietary supplement in the form of capsules, powder and teas. Kelp is a rich source of iodine that may interfere with thyroid replacement therapies. Kelp is available as a dietary supplement marketed for thyroid support. Iodine content in kelp varies depending on harvest location and preparation. Its average iodine content has been estimated to be about 1,500 to 2,500 μg/g (microgram per gram) of dried preparation, that is i.e., 10 to 16.7 times the recommended daily allowance of 150 μg (microgram) ²³⁾, ²⁴⁾.

In the United States, recommended daily allowances (RDA) for iodine intake are 150 μg in adults, 220–250 μg in pregnant women, and 250–290 μg in breastfeeding women ²⁵⁾. The U.S. diet generally contains enough iodine to meet these needs, with common sources being iodized salt, dairy products, some breads, and seafood. During pregnancy and lactation, women require higher amounts of iodine for the developing fetus and infant. The American Thyroid Association recommends that women take a multivitamin containing 150 μg of iodine daily in the form of potassium iodide ²⁶⁾ during preconception, pregnancy, and lactation to meet these needs ²⁷⁾.

The American Thyroid Association advises against the ingestion of iodine and kelp supplements containing in excess of 500 μg iodine daily for children and adults and during pregnancy and lactation ²⁸⁾. Long-term iodine intake in amounts greater than the tolerable upper limits should be closely monitored by a physician. There are only equivocal data supporting the benefit of iodine at higher doses than these, including a possible benefit for patients with fibrocystic breast disease ²⁹⁾. There is no known thyroid benefit of routine daily iodine doses in excess of the U.S. recommended daily allowances (RDA).

In some individuals, the high iodine load from kelp supplements can result in thyroid dysfunction ³⁰⁾, ³¹⁾. Iodine-induced thyrotoxicosis has been reported after consuming a kelp-containing tea ³²⁾. In that case, the patient suffered from multinodular goiter in an endemic area of moderate iodine deficiency, that turned toxic after ingestion of the iodine-rich kelp and hyperthyroidism did not resolve spontaneously following discontinuation of the kelp-containing tea. In another case, a person with no evidence of pre-existing or underlying thyroid disease consumed for 10 days a daily dose of about 1800 μg iodine. Hyperthyroidism developed shortly, followed by overt hypothyroidism ³³⁾.

The normal thyroid gland of human adults secretes about 50 μg iodine daily, an amount the gland can take up in a dietary iodine intake between 100 and 150 mg per day ³⁴⁾. Iodine excess may be tolerated or may induce thyroid disease with hypothyroidism or hyperthyroidism with or without goiter and autoimmunity. Most individuals with a normal thyroid gland tolerate large iodine excess, maintaining thyroid hormones within the normal range, although serum free T4 and free T3 can usually be moderately reduced, TSH increased and a small goiter can develop ³⁵⁾.

The thyroid gland reacts to excess iodine intakes by different mechanisms the most important of which are the Wolff-Chaikoff effect, the down expression of the sodium–iodide symporter, and the block of hormone secretion from stores. The thyroid gland accumulates iodide from plasma against a concentration gradient up to 1:80. This iodide accumulation is made possible by the sodium–iodide symporter that transports two sodium cations and one iodide anion across the basal cell membrane from the exterior into the interior of the cell.5 TSH strictly regulates sodium–iodide symporter expression so that in iodine deficiency, TSH increases and in turn TSH gene expression is increased ³⁶⁾. In 1948, Wolff and Chaikoff reported that elevated plasma iodide levels was followed by a decreased organic binding of iodide in the thyroid ³⁷⁾. This effect (acute Wolff-Chaikoff effect) was of short duration and escape occurred in approximately 2 days, in the presence of continued high plasma iodide concentrations. The mechanism responsible for the acute Wolff-Chaikoff effect remains unknown and has been hypothesised to be caused by organic iodocompounds formed within the thyroid ³⁸⁾.

Following the escape from the acute Wolff-Chaikoff effect, the biosynthesis of sodium–iodide symporter can be shut down by a TSH-independent mechanism. Chronic excess iodide in rat thyroid cells had no effect on sodium–iodide symporter gene expression, whereas decreased sodium–iodide symporter protein at a post-transcriptional level ³⁹⁾. In rats in vivo, excess iodide administration decreased both sodium–iodide symporter mRNA and protein expression, by a mechanism that is at least in part, transcriptional ⁴⁰⁾. This mechanism has been proposed to account for the escape from the acute Wolff-Chaikoff effect. Excess iodine also blocks secretion of stored preformed hormone, as demonstrated in dog thyroid slices ⁴¹⁾. Large quantity of iodide can also have cytotoxic effects as shown in normal human thyroid cells in vitro where it induces apoptosis, through a mechanism involving generation of free radicals ⁴²⁾. The normal thyroid gland adapts to iodine excess by these mechanisms so that most individuals tolerate a chronic excess of iodide without clinical symptoms.

Sometimes these mechanisms fail and iodine excess causes overt clinical hyperthyroidism or hypothyroidism. In some countries, iodine supplementation through iodised salt resulted in a significant number of cases of severe hyperthyroidism ⁴³⁾. Hyperthyroidism is most commonly encountered in regions of chronic iodine deficiency, in participants with long-standing nodular goiter and in hidden Graves’ disease or toxic adenoma silent because of iodine deficiency.

Because kelp is a nutritional supplement and not a drug, the U.S. Food and Drug Administration (FDA) does not require manufacturers to demonstrate safety or efficacy. Herbal medicine, including kelp and kelp-containing dietary supplements are being used by an increasing number of people ⁴⁴⁾. In a study to evaluate the extent of arsenic contamination in commercially available kelp, nine samples were randomly obtained from local health food stores ⁴⁵⁾. Eight of the nine samples showed detectable levels of arsenic higher than the Food and Drug Administration tolerance level of 0.5 to 2 ppm for certain food products ⁴⁶⁾. None of the kelp supplements contained information regarding the possibility of contamination with arsenic or other heavy metals. Manifestations of chronic arsenic ingestion depend on both the intensity and duration of exposure.

Arsenic occurs naturally in some soils, and can contaminate bodies of water. The metalloid concentrates in fish that eat arsenic-rich algae and can also be found in plants that absorb it from the soil or water in which they are grown. Human exposure typically comes from diet, contaminated drinking water, or occupational exposures, as in smelters; people ingest an average of 40 μg per day.

Chronic arsenic toxicity may cause peripheral neuropathies, parasthesia, ataxia, cognitive deficits, fatigue, and muscular weakness ⁴⁷⁾. Gastrointestinal complaints include anorexia, hepatomegaly, jaundice, nausea, and vomiting. Skin afflictions may include erythema (skin redness), eczema, pigmentation (arsenic melanosis), diffuse alopecia (hairloss), keratosis (especially of palms and soles), scaling and desquamation, brittle nails, white lines or bands in the nails (Mees lines), and localized subcutaneous edema. White striae in the fingernails are consistent with a diagnosis of arsenical polyneuritis, even though urine and hair arsenic concentrations may be within normal limits ⁴⁸⁾.

Now researchers at the University of California, Davis, report the case of a 54 year old woman who received toxic doses of arsenic from kelp supplements ⁴⁹⁾. The patient had started taking kelp to treat minor memory loss and fatigue. She initially took the dose recommended on the bottle, then doubled it when her symptoms failed to improve. She took kelp for one year, during which her fatigue worsened to the point that she had to switch from full- to part-time work. She also experienced rash, diarrhea, vomiting, severe headaches, and hair loss. Three weeks after she abandoned kelp, the woman resumed full-time work. Her urine arsenic concentration dropped more than a third in two months and was undetectable after another two months. Eventually all her symptoms resolved.

Kelp vs Seaweed

Kelps are large brown algae seaweeds that make up the order Laminariales. Kelp grows in “underwater forests” (kelp forests) in shallow oceans, and is thought to have appeared in the Miocene, 23 to 5 million years ago ⁵⁰⁾. Kelp require nutrient-rich water with temperatures between 6 and 14 °C (43 and 57 °F). Kelps are known for their high growth rate—the genera Macrocystis and Nereocystis can grow as fast as half a metre a day, ultimately reaching 30 to 80 meters (100 to 260 ft) ⁵¹⁾.

Through the 19th century, the word “kelp” was closely associated with seaweeds that could be burned to obtain soda ash (primarily sodium carbonate). The seaweeds used included species from both the orders Laminariales and Fucales. The word “kelp” was also used directly to refer to these processed ashes.

“Seaweed” is a colloquial term and lacks a formal definition ⁵²⁾. A seaweed may belong to one of several groups of multicellular algae: the red algae, green algae, and brown algae. As these three groups do not have a common multicellular ancestor, the seaweed are in a polyphyletic group. In addition, some tuft-forming blue-green algae (Cyanobacteria) are sometimes considered to be seaweed.

What is amylase

Amylase is an enzyme that helps digest carbohydrates (starch and glycogen) into simple sugar [glucose (monosaccharide) and maltose (disaccharide)] for energy. Amylase is made in the pancreas and the salivary glands that make saliva. Amylase is also found in microbes, plants and animals. Amylases are broadly classified into α (alpha), β (beta), and γ (gamma) subtypes, of which the first two have been the most widely studied. Alpha amylase (α-Amylase) is a faster-acting enzyme than beta amylase (β-amylase). The amylases act on α-1-4 glycosidic bonds and are therefore also called glycoside hydrolases ¹⁾. Microbial amylases obtained from bacteria, fungi, and yeast have been used predominantly in industrial sectors and scientific research. Microbial enzymes have been generally favored for their easier isolation in high amounts, low-cost production in a short time, and stability at various extreme conditions, and their compounds are also more controllable and less harmful. Microbially produced enzymes that are secreted into the media are highly reliable for industrial processes and applications. Furthermore, the production and expression of recombinant enzymes are also easier with microbes as the host cell. Applications of these enzymes include chemical production, bioconversion (biocatalyst), and bioremediation.

The food enzyme is an alpha amylase (4‐α‐d‐glucan glucanohydrolase; EC 3.2.1.1) produced with the genetically modified Bacillus licheniformis strain NZYM‐AV by Novozymes A/S ²⁾. The European Food Safety Authority 2018 review found genetic modifications do not give rise to safety concerns ³⁾. The food enzyme does not contain the production microorganism or its DNA; therefore, there is no safety concern for the environment. The α‐amylase is intended to be used in starch processing for the production of glucose syrups and distilled alcohol production ⁴⁾. Genotoxicity tests did not raise a safety concern. The subchronic toxicity was assessed by means of a repeated dose 90‐day oral toxicity study in rodents. The European Food Safety Authority Panel derived a no observed adverse effect level (NOAEL) at the highest dose level of 796 mg total organic solids/kg body weight per day. The allergenicity was evaluated by comparing the amino acid sequence to those of known allergens and one match was found. The European Food Safety Authority Panel considered that, under the intended condition of use, the risk of allergic sensitization and elicitation reactions by dietary exposure cannot be excluded, but the likelihood is considered low ⁵⁾. Based on the microbial source, the genetic modifications, the manufacturing process, the compositional and biochemical data, the removal of total organic solids during the intended food production processes and the toxicological and genotoxicity studies, the European Food Safety Authority Panel concluded that this food enzyme does not give rise to safety concerns under the intended conditions of use ⁶⁾.

Figure 1. Amylase enzyme function – hydrolysis of starch. Starch is a polysaccharide made up of simple sugars (glucose). Upon the action of amylase, either glucose (a monosaccharide) or maltose (a disaccharide with two glucose molecules) is released.

In human, amylase enzyme is secreted through the pancreatic duct into the first part of the small intestine (duodenum), where it helps break down dietary carbohydrates. Amylase is usually present in the blood and urine in small quantities. When cells in the pancreas are injured, as happens with pancreatitis, or when the pancreatic duct is blocked by a gallstone or by a pancreatic tumor in rare cases, increased amounts of amylase are released into the blood. This increases concentrations of amylase in the blood and also in the urine as amylase is eliminated from the blood through the urine. A test can be done to measure the level of amylase enzyme in your blood. Amylase may also be measured with an amylase 24 hour urine test.

The blood amylase test is used to help diagnose and monitor acute pancreatitis. It is often ordered along with a lipase test. It may also be used to diagnose and monitor chronic pancreatitis and other disorders that may involve the pancreas.

A urine amylase test may also be ordered. Typically, its level will mirror blood amylase concentrations, but both the rise and fall will occur later. Sometimes a urine creatinine clearance may be ordered along with the urine amylase to help evaluate the ratio of amylase to creatinine that is filtered by the kidneys. This ratio is used to assess kidney function because improper function can result in a slower rate of amylase clearance.

In certain cases, for example when there is an accumulation of fluid in the abdomen (ascites), an amylase test may be performed on peritoneal fluid to help make a diagnosis of pancreatitis.

Amylase tests are sometimes used to monitor treatment of cancers involving the pancreas and after the removal of gallstones that have caused gallbladder attacks.

• The normal amylase enzyme range is 40 to 140 units per liter (U/L) or 0.38 to 1.42 microkat/L (µkat/L).

Note: Normal value ranges may vary slightly among different laboratories. Talk to your provider about the meaning of your specific test results.

The examples above show the common measurements for results for these tests. Some laboratories use different measurements or may test different specimens.

A blood amylase test may be ordered when a person has symptoms of a pancreatic disorder, such as:

• Severe abdominal or back pain
• Fever
• Loss of appetite
• Nausea

A urine amylase test may be ordered along with or following a blood amylase test. One or both may also be ordered periodically when a health practitioner wants to monitor a person to evaluate the effectiveness of treatment and to determine whether amylase levels are increasing or decreasing over time.

A high amylase level in the blood may indicate the presence of a condition affecting the pancreas. Urine and blood amylase levels may also be moderately elevated with a variety of other conditions, such as ovarian cancer, lung cancer, tubal pregnancy, acute appendicitis, diabetic ketoacidosis, mumps, intestinal obstruction, or perforated ulcer, but amylase tests are not generally used to diagnose or monitor these disorders.

High levels of amylase may indicate:

• Acute pancreatitis, a sudden and severe inflammation of the pancreas. When treated promptly, it usually gets better within a few days.
• Pancreatic or bile duct blockage
• Cancer of the pancreas, ovaries, or lungs
• Cholecystitis
• Gallbladder attack caused by disease
• Gastroenteritis (severe)
• Infection of the salivary glands (such as mumps) or a blockage
• Intestinal blockage
• Macroamylasemia. Macroamylasemia is the presence of an abnormal substance called macroamylase in the blood. Macroamylase is a substance that consists of an enzyme, called amylase, attached to a protein. Because it is large, macroamylase is filtered very slowly from the blood by the kidneys.
• Perforated ulcer
• Tubal pregnancy (may have burst open)

Low levels of amylase can indicate:

• Chronic pancreatitis, an inflammation of the pancreas that gets worse over time and can lead to permanent damage. Chronic pancreatitis is most often caused by heavy alcohol use.
• Liver disease
• Cystic fibrosis
• Cancer of the pancreas
• Damage to the pancreas
• Kidney disease
• Toxemia of pregnancy

Drugs that can increase amylase measurements include:

• Asparaginase
• Aspirin
• Birth control pills
• Cholinergic medicines
• Ethacrynic acid
• Methyldopa
• Opiates (codeine, meperidine, and morphine)
• Thiazide diuretics

In acute pancreatitis, amylase in the blood often increases to 4 to 6 times higher than the highest reference value, sometimes called the upper limit of normal. The increase occurs within 4 to 8 hours of injury to the pancreas and generally remains elevated until the cause is successfully treated. Then the amylase values will return to normal in a few days.

In chronic pancreatitis, amylase levels initially will be moderately elevated but often decrease over time with progressive pancreas damage. In this case, levels returning to normal may not indicate that the source of damage has been resolved. The magnitude of increase in amylase level does not indicate severity of pancreatic disease.

Amylase levels may also be significantly increased in people with pancreatic duct obstruction and pancreatic cancers.

In general, urine amylase levels rise in proportion to blood amylase levels and will stay elevated for several days after blood levels have returned to normal.

An increased level of amylase in peritoneal fluid can occur in acute pancreatitis but may also occur in other abdominal disorders, such as obstructed intestine or decreased blood flow to the intestines (infarct).

A low amylase level in blood and urine in a person with pancreatitis symptoms may indicate permanent damage to the amylase-producing cells in the pancreas. Decreased levels can also be due to kidney disease and toxemia of pregnancy.

Increased blood amylase levels with normal to low urine amylase levels may indicate the presence of a macroamylase, a benign complex of amylase and other proteins that accumulates in the blood.

Where is amylase produced?

Amylase or alpha amylase (α-amylase) is an exocrine enzyme that is synthesized by pancreatic acinar cells and secreted into the duodenum as a major component of pancreatic fluid ⁸⁾. The elevated serum amylase levels are widely used as screening test for acute pancreatitis in clinical practice ⁹⁾. Moreover, serum amylase levels are also elevated in other conditions, including diabetic ketoacidosis ¹⁰⁾ and renal insufficiency ¹¹⁾. Low serum amylase levels are observed in individuals with chronic pancreatitis ¹²⁾.

Recent studies showed that the serum amylase levels may be associated with endocrine and metabolic diseases ¹³⁾. Low serum amylase levels were associated with increased risks of metabolic abnormalities, metabolic syndrome and diabetes. A previous study by Muneyuki et al. ¹⁴⁾ of asymptomatic middle-aged adults showed that low serum amylase levels were associated with decreased basal insulin levels and insulin secretion, as well as increased insulin resistance. The nature of these associations remains to be elucidated in further studies.

What does amylase do

A typical and well known function of pancreatic alpha amylase is the digestion of starch and glycogen into sugar [glucose (monosaccharide) and maltose (disaccharide)] for energy. In the duodenum, alpha amylase (α-amylase) digests starch to maltose or maltooligosaccharides, which are subsequently hydrolyzed by brush-border membrane (BBM)2 enzymes, such as sucrase-isomaltase ¹⁵⁾. Amylase or alpha amylase can specifically cleave the O-glycosidic bonds in starch, glycogen and several oligosaccharides ¹⁶⁾. The final glucose product is then carried into the enterocytes by Na+/glucose cotransporter 1 (SGLT1) at the brush-border membrane ¹⁷⁾. The small intestine brush-border membrane is heavily glycosylated ¹⁸⁾.

Mammalian pancreatic alpha amylase (α-amylase) binds specifically to glycoprotein N-glycans in the brush-border membrane to activate starch digestion, whereas it significantly inhibits glucose uptake by Na⁺/glucose cotransporter 1 (SGLT1) at high concentrations ¹⁹⁾. However, how the inhibition is stopped was unknown. This study provides novel and significant insights into the control of blood sugar during the absorption stage in the intestine ²⁰⁾.

Recently, it was reported that when the blood glucose level is high in type 2 diabetes mellitus, serum amylase activity is significantly low ²¹⁾. Not only type 2 but also type 1 diabetes mellitus patients have been reported to show a high prevalence of exocrine pancreatic insufficiency ²²⁾. Compared with diabetes mellitus patients, healthy individuals have a higher α-amylase level in the serum and a lower blood glucose level. These phenomena may be explained by the fact that the inhibition of glucose uptake by Na⁺/glucose cotransporter 1 (SGLT1) cannot be achieved by a low concentration of alpha amylase (α-amylase), due to the exocrine dysfunction in diabetes, which results in a high blood glucose level. This suggests that modulation of sugar assimilation via glucose uptake by Na⁺/glucose cotransporter 1 (SGLT1) activity by altering the concentration of pancreatic α-amylase in the intestine might be important for stabilizing blood glucose levels ²³⁾. Recovery of exocrine secretion might therefore be a therapeutic strategy for postprandial hyperglycemia in diabetes mellitus patients.

Amylase supplement

Pancreatic enzyme supplements are used by people whose bodies do not make enough amylase enzyme to digest their food such as patients with cystic fibrosis or chronic pancreatitis; or patients who have had their pancreas removed or who have had gastrointestinal bypass surgery or suffer from ductal obstruction. The amylase enzyme is usually extracted from pig pancreas.

Amylase supplement is approved for the uses listed above. If you would like more information, ask your doctor.

What is ribose

Ribose or D-Ribose is a naturally occurring pentose monosaccharide present in all living cells including the blood and is an essential component for biological energy production ¹⁾. D-Ribose is also a product of dietary nucleic acid digestion ²⁾. Ribose or D-Ribose is a key component of many important biomolecules including ribonucleic acid (RNA) ³⁾, adenosine triphosphate (ATP) ⁴⁾ and Riboflavin (vitamin B2) ⁵⁾. Many foods, such as wheat bran, eggs, meat, cheese and yeast, contain reasonable high concentrations of ribonucleic acid (RNA) and Riboflavin (vitamin B2). The pentose phosphate pathway can convert hexose to D-Ribose. Besides food, D-Ribose is orally administered to improve athletic performance and the ability to exercise by boosting muscle energy as a readily available source of energy.

Previous studies indicated that ribose is a promising supplement in patients with advanced heart failure in improving heart and skeletal muscle performances ⁶⁾. Ribose has shown to replenish low myocardial energy levels, improving cardiac dysfunction following ischemia, and improving ventilation efficiency in patients with heart failure ⁷⁾.

Figure 1. Ribose and D-ribose

Footnote: Note the absence of the hydroxyl (-OH) group on the 2’ carbon in the deoxy-ribose sugar in DNA as compared with the ribose sugar in RNA.

D-Ribose is a popular dietary supplement for humans and horses because of its crucial role in cellular bioenergetics. It is also used to improve symptoms of diseases such as chronic fatigue syndrome, fibromyalgia ⁸⁾ and coronary artery disease ⁹⁾.

The available data indicate that in humans, D-Ribose is rapidly and nearly completely absorbed when administered at 200 mg/kg body weight per hour for 5 hours ¹⁰⁾. In humans, at dose levels above 3 g (about 40 mg/kg body weight), absorption was faster than metabolism. Application of D-Ribose with meals decreases absorption. In the body, D-Ribose is converted mainly to glucose via the pentose phosphate pathway, rather than nucleic acid precursors, which then is further used in the metabolism/biosynthesis. Part of the ribose and its metabolites is excreted via the urine and the percentage increases with increasing dose.

Several human studies which were not designed to assess the safety of D-Ribose found the administration of single oral doses of 2–87 g D-Ribose consistently report transient decreases of glucose concentrations within 1–3 hours. The transient decrease of glucose concentration was not associated with clinical symptoms of hypoglycaemia, except for one case, where a low‐weight female experienced short‐term symptoms of hypoglycaemia after ingesting 10 g of ribose in the fasted state ¹¹⁾. While in this and in most of the other studies, blood glucose levels did not fall below 2.8 mmol/L, a temporary significant decline of blood glucose to 2.6 mmol/L was observed in one study following a single oral dose of 10 g D-Ribose ¹²⁾. The decrease in blood glucose comes along with increases in insulin levels. The glucose‐lowering effect occurs also if meals rich in carbohydrate or fat are ingested before uptake of D-Ribose.

No studies have investigated intake of D-Ribose in infants, young children and adolescents. Whether young age may be of special concern with regard the glucose‐lowering effects of D-Ribose is not known. However, the European Food Safety Authority Panel considers that children could be particularly vulnerable to glucose‐lowering effects of d‐ribose ¹³⁾.

The European Food Safety Authority notes that there is a lack of understanding of the mechanisms responsible for the short‐term decrease in blood glucose reported in the human studies, only limited data on the dose–response relationship between D-Ribose and blood glucose levels, and uncertainty about the risk of symptomatic hypoglycaemia conditions, especially in susceptible persons.

Because the decrease in glucose levels and/or the occurrence of transient symptomatic hypoglycaemia (as reported in one case) is considered adverse, based on the human studies, the lowest observed adverse effect level (LOAEL) would be at intakes of 10 g of D-Ribose. Concerning the human data, taking the above issues into account, the European Food Safety Authority concludes that 5 g per day, equivalent to 70 mg/kg body weight per day, would be the No Observed Adverse Effect Level (NOAEL) with respect to hypoglycaemia that can be considered applicable for adults. For children, the European Food Safety Authority acknowledges the lack of human data directly relevant for this population group.

Based on the No Observed Adverse Effect Level (NOAEL) of 3,600 mg/kg body weight per day derived from the subchronic toxicity study in rats, an acceptable level of intake would be up to 36 mg/kg body weight per day. This is half the NOAEL value identified in the human studies for adults with respect to hypoglycaemia. The European Food Safety Authority concludes that 36 mg/kg body weight per day would also take into account the potentially increased sensitivity of certain population groups to hypoglycaemia, including children.

The body weight therefore concludes that the D-Ribose is safe for the general population at intake levels up to 36 mg/kg body weight per day ¹⁴⁾.

Fenstad et al. ¹⁵⁾ found significantly higher levels of uric acid (which were, however, still in the normal range) following oral administration of 10 g D-Ribose when compared to the dose of 2 g at 30 and 60 min, no changes in serum uric acid concentrations were reported by Thompson et al. ¹⁶⁾ following ingestion of 10 g d‐ribose and in the study of Gross et al. ¹⁷⁾, during or after treatment with 27–89 g d‐ribose. Gastrointestinal symptoms were noted at single intakes of around 70 g ¹⁸⁾.

The occurrence of gastrointestinal problems, short‐term hypoglycaemia and hyperuricemia in some of the studies presented and the lack of long‐term studies analyzing the effect of high doses of D-Ribose, does not allow determining the safety and tolerance of a long‐term intake of D-Ribose ¹⁹⁾.

D-ribose health concerns

As a reducing monosaccharide, Ribose has the ability to react with proteins to produce glycated derivatives ²⁰⁾. Glycation with Ribose (ribosylation) gives rise to advanced glycation end products (AGEs) more rapidly than glycation with D-glucose which requires a relatively long time ²¹⁾. Ribosylation (glycation with Ribose) rapidly induces alpha synuclein to form highly cytotoxic molten globules of advanced glycation end products. Alpha synuclein (α-Syn) is the main component of Lewy bodies which are associated with several neurodegenerative diseases such as Parkinson’s disease ²²⁾. D-Ribose, however, is also closely associated with many fundamental processes in cellular metabolism. Seuffer ²³⁾ has determined the concentration of D-ribose (0.01–0.1 mM) present in cerebrospinal fluid (CSF) in the brain. D-Ribose is used to synthesize nucleotides, nucleic acids, glycogen, and other important metabolic products. D-Ribose is also formed in the body from conversion of D-glucose via the pentose phosphate pathway. Thus, D-Ribose is present both intracellularly and extracellularly, and has opportunities to react with proteins and produce glycated derivatives. For this reason, glycation of Alpha synuclein protein with D-ribose needs to be investigated.

In vitro studies showed that D-Ribose induces protein misfolding rapidly leading to globular-like aggregations that are cytotoxic to neuronal cells ²⁴⁾. Intraperitoneal injection of D-Ribose for 30 days revealed high levels of glycated proteins and advanced glycation end products (AGEs) in the blood and brain of wild type mice. The mice also exhibited impairment of spatial learning and memory ²⁵⁾. More recently, D-Ribose was found to be increased in the urine of type 2 diabetic patients ²⁶⁾, suggesting that diabetic patients may be suffered from metabolic imbalance of not only D-Glucose but also D-Ribose ²⁷⁾.

Ribose intake from the diet

Ribose is reported to be present in meat in varying amounts, e.g. 1–524 mg/100 g beef meat ²⁸⁾ and 6.4–39.5 mg/100 g chicken meat ²⁹⁾, with these differences probably attributable not only to the origin of the meat but also to differences in sampling or analytical methods. Lilyblade and Peterson ³⁰⁾ reported that the content of ribose increases post‐mortem during storage of chicken meat. The cooking process is reported to reduce the quantity of free ribose as this is involved in Maillard reactions.

RNA and free nucleotides are reported to be degraded in the intestinal tract and free ribose may partially be released by the action of nucleosidases ³¹⁾.

Due to the lack of data in the literature, the intake levels of d‐ribose from the diet are largely unknown.

Ribose inside the body production

Based on the estimated mean daily intake of carbohydrates in the UK, i.e. 252 and 198 g in men and women, respectively, ³²⁾ and assuming (i) that 2/3 of these would be composed of glucose, and (ii) that 2–9% of glucose is utilised via the pentose phosphate pathway ³³⁾, it is estimated that the daily endogenous production of d‐ribose through the pentose phosphate pathway ranges from approximately 3–15 g/day. Additional information on the extent of the daily endogenous production of d‐ribose in the literature is lacking. The information is insufficient to draw conclusions on the extent of the daily endogenous production of d‐ribose.

D-ribose dosage

Fibromyalgia and chronic fatigue syndrome patients were given 5 grams three times daily ³⁴⁾.

Based on the No Observed Adverse Effect Level (NOAEL) of 3,600 mg/kg body weight per day derived from the subchronic toxicity study in rats, an acceptable level of intake would be up to 36 mg/kg body weight per day. This is half the NOAEL value identified in the human studies for adults with respect to hypoglycaemia. The European Food Safety Authority concludes that 36 mg/kg body weight per day would also take into account the potentially increased sensitivity of certain population groups to hypoglycaemia, including children.

The body weight therefore concludes that the D-Ribose is safe for the general population at intake levels up to 36 mg/kg body weight per day ³⁵⁾.

D-ribose side effects

While oral administration of ribose is generally safe, studies also revealed that high dose ribose may induce diarrhea ³⁶⁾. During a post‐marketing surveillance programme the adverse reactions reported, ordered by frequency, were upset stomach (5); transient‐elevated blood sugar in diabetic customers (4); transient racing heart (3); rash (3); itching (3); diarrhoea (3); constipation (2); swollen leg (2); felt funny (1); weakness/fatigue (1); headache (1); light‐headedness (1); excess gas (1); muscle tightness (1) ³⁷⁾.

A study Wu et al. ³⁸⁾ showed that feeding D-Ribose daily through gavage to mice for 6 months is correlated with cognitive impairment. Mice treated with D-Ribose (3.75 g/kg per day) exhibited learning and memory decline and anxiety-like behavior, accompanied by Aβ-like deposition and Tau hyperphosphorylation in their brain, especially the hippocampus. These features are Alzheimer’s disease-like, both with regards to pathology (abnormal modifications and aggregations of Tau protein and Aβ peptide) and pathophysiology (memory loss accompanied by anxiety-like behavior). This suggests that D-Ribose-gavaged mouse model may be useful to study age-related cognitive impairment ³⁹⁾ and diabetic encephalopathy, conditions in which Aβ deposition and Tau hyperphosphorylation are found ⁴⁰⁾.

The D-Ribose-induced high level of Aβ-like deposition in the hippocampus demonstrates that mice can develop Aβ-like deposits even though the APP gene sequence of mice differs from that of humans ⁴¹⁾. Previously, other scientists employed mice in a methanol-gavage experiment and found that methanol can distinctly promote hyperphosphorylation of Tau, but not Aβ deposition ⁴²⁾. However, by oral administration of D-Ribose, Aβ-like deposition can be induced under the experimental conditions. Amyloid β deposit is clear and robust.

D-Ribose is significantly increased in the brain of D-Ribose-treated mice. However, it did not markedly increase advanced glycation end levels in the brain, serum, liver and kidney under the experimental conditions. However, intraperitoneal injection of similar concentrations of D-Ribose for 30 days, as described ⁴³⁾, resulted in advanced glycation end accumulation in the mouse blood and brain. Whether D-Ribose elevates levels of advanced glycation ends in mice or not depends on the mode of administration. Thus, impairment of cognitive ability by oral administration of D-Ribose is probably not related to brain advanced glycation end accumulation, but rather the abnormally high levels of Aβ-like deposition and Tau hyperphosphorylation in mouse brain.

To compare the effects between D-Ribose and D-Glucose, oral administration of D-Glucose did not affect cognition. Even though D-Glucose showed elevated pS396 levels in the hippocampus and AT8 reactivity in the cortex, the elevations were not clearly seen by immunohistochemical staining of sections using antibodies AT8, pS396, p214 and T181. D-Glucose was found to reduce the percentage of open arm entries of mice in the elevated plus-maze test. However, the D-Glucose-gavaged mice did not show an abnormal behavior in the open field test, indicating that D-Glucose-gavaged mice may not be anxious. Oral administration of D-Glucose did not cause high levels of Aβ-like deposits. In contrast, gavage of D-Ribose resulted not only in high levels of Aβ-like deposition and Tau phosphorylation in the hippocampus, but also in memory loss and anxiety-like behavior.

The long-term administration of D-Ribose did not cause any significant changes in the body weight compared to mice treated with D-Glucose. Fasting blood sugar levels and advanced glycation end levels did not differ between the groups. Except for memory loss and anxiety, both D-Ribose- and D-Glucose-gavaged mice did not show additional abnormal behavior such as motor dysfunction, reduced muscle strength and impaired co-ordination.

As described by Segal and colleagues ⁴⁴⁾, D-Ribose can cause insulin release and decrease blood D-Glucose. Our results are similar to their findings. Since mice were gavaged with the sugar, it needs more insulin to regulate it. The secreted insulin induced lower level of blood sugar ⁴⁵⁾.

In Alzheimer’s disease, memory disorder is known as the most important symptom. Behavioral and psychiatric symptoms like anxiety and depression may also follow the memory loss. In this study ⁴⁶⁾, D-Ribose-treated mice exhibit an anxious symptom in open field test and elevated plus maze. The anxiety-like effect of D-Ribose on mice should be further investigated. Forced swim test showed that the mice under D-Ribose treatment behave more immobile, which indicates the depression state. While tail suspension test did not show any difference in the immobility time. Administration of D-Glucose as a control did not show anxiety-like behavior and significant depression state. Take all those results, oral administration of D-Ribose induces not only memory impairment but also anxious behavior in mice ⁴⁷⁾.

Oral administration of D-Ribose to mice also causes impaired memory functions, Tau hyperphosphorylation and Aβ-like deposition ⁴⁸⁾. These data suggest that an imbalance of D-Ribose metabolism may play a role in diabetic encephalopathy ⁴⁹⁾.

In summary, oral administration of D-Ribose leads to the impairment of cognitive ability and anxious behavior in mice ⁵⁰⁾. Meanwhile, D-Ribose-gavaged mice suffer from both Aβ-like deposition and Tau hyperphosphorylation in their brain, especially in the hippocampus ⁵¹⁾. These abnormal modifications and the pathological aggregation of these proteins are probably correlated with the memory loss and anxiety-like behavior after D-Ribose treatment ⁵²⁾.

What is shilajit

Shilajit also known as mumijo, mumie and momia, is a pale‐brown to blackish‐brown exudation (asphaltum) of variable consistency, exuding from layers of rocks as they become warm in the summer months in many mountain ranges of the world, especially the Himalayas and Hindukush ranges of the Indian subcontinent ¹⁾. Shilajit is derived from long-term humification of Euphorbia and Trifolium (clover) plants ²⁾. Common people describe it from their knowledge as pahar‐ki‐pasina (sweat of mountains), paharki‐khoon (mountain blood), shilaras (rock juice), asphalt, bitumen, etc ³⁾. Shilajit is composed of rock humus, rock minerals and organic substances that have been compressed by layers of rock mixed with marine organisms and microbial metabolites ⁴⁾. Shilajit has been found to consist of a complex mixture of organic humic substances and plant and microbial metabolites occurring in the rock rhizospheres of its natural habitat ⁵⁾. A derivative of Shilajit, fulvic acid complex, consists of naturally occurring low- and medium-molecular-weight compounds, including oxygenated dibenzo-alpha-pyrones and acylated dibenzo-alpha-pyrones ⁶⁾. It is believed dibenzo-alpha-pyrone, fulvic acid and their derivatives are the principal constituents of Shilajit contributing to these effects ⁷⁾. The fulvic acid stimulates blood formation, energy production, and prevents cold exposure and hypoxia ⁸⁾. Fulvic acid actively takes part in the transportation of nutrients into deep tissues and helps to overcome tiredness, lethargy, and chronic fatigue ⁹⁾. It also works effectively as a tonic for cardiac, gastric, and nervous systems, adaptogen and antistress agent ¹⁰⁾.

Shilajit has been used as a rejuvenator and an adaptogen for thousands of years, in one form or another, as part of traditional systems of medicine in a number of countries. Shilajit is widely used in the preparation of Ayurvedic medicines and is regarded as one of the most important ingredients in Ayurvedic system of medicine, the traditional Indian system of medicine ¹¹⁾. Shilajit is used as an adaptogen ¹²⁾.

Early Ayurvedic writings from the Charaka Samhita ¹³⁾ describe Shilajit as a cure for all diseases as well as a Rasayana (rejuvenator) that promises to increase longevity.

Traditional uses of Shilajit primarily focus not only on diabetes and diseases of the urinary tract, but also on edema, tumors, muscle wasting, epilepsy and even insanity ¹⁴⁾. Modern indications extend to all systems of the human body with a significant number of additions in the reproductive and nervous system ¹⁵⁾.

Several toxicological studies, both acute and subchronic, have already been performed on Shilajit throughout the world. Oral LD50 (lethal dose 50 where 50% of the test subjects die) was found to be >2000 mg/kg ¹⁶⁾ and Shilajit was proved to be safe at doses of 0.2–1.0 g per kg body weight when used chronically ¹⁷⁾. Clinical evaluation of spermatogenic activity of processed shilajit in oligospermia ¹⁸⁾ revealed that there was no alteration on objective features related to any systemic toxicities such as serum urea, uric acid, serum bilirubin, total protein, serum globulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) ¹⁹⁾. Besides, it was also observed that there was a significant improvement in semen volume (+37.6%), total sperm count (+61.4%), motility (12.4–17.4% after different time intervals), normal sperm count (+18.9%) and total testosterone (+23.5%) with concomitant decrease in pus and epithelial cell count compared with baseline value in 28 patients of oligospermia after 90 days of treatment with purified shilajit at a dose of 100 mg twice daily ²⁰⁾. An unpublished human safety study of purified Shilajit from Natreon, Inc., New Brunswick, NJ, USA by the present authors has demonstrated the safety of this product at 250 mg twice a day dosing ²¹⁾ and an unpublished animal study in rats with 100 mg/kg body weight (equivalent to human dose of 850 mg) by Natreon showed a significant increase in testosterone levels ²²⁾. Processed Shilajit containing biologically active component di‐benzo‐alpha‐pyrone is earlier reported to increase the spermatogenic activity in selected patients of oligospermia ²³⁾.

Figure 1. Shilajit (asphaltum)

Shilajit traditional medicine uses

Shilajit is an Ayurvedic drug with a long history of human use and has been used in nervous, diabetic, urinary, immune, cardiac, and digestive disorders, and is also used as a performance enhancer ²⁴⁾. Traditionally, it has been recommended for the cure of almost all kinds of human diseases. Shilajit other uses are as a lithotriptic (an agent that effects the dissolution of a calculus), antiseptic ²⁵⁾, analgesic, anti asthmatic agent ²⁶⁾, and in the treatment of AIDS ²⁷⁾, parasitic infections ²⁸⁾, chronic fever, jaundice ²⁹⁾, obesity ³⁰⁾, sexual disorders ³¹⁾, and thyroid disorders ³²⁾. Astanga Hradaya also states that it is the best rejuvenator ³³⁾. Ancient works such as the Hindu Materia Medica, Charaka Samhita, and Susruta Samhita also describe the medicinal properties of Shilajit.

Shilajit can be very useful in the treatment of high-altitude cerebral edema-like conditions of the brain as it maintains the extracellular volume in the body through its diuretic action, and removes the excess fluid and toxins from the brain as well as the body ³⁴⁾. It improves memory and enhances confidence for better handling of stress ³⁵⁾; it also has very good antioxidant properties ³⁶⁾.

Shilajit may play a potential role in the treatment of Alzheimer’s and Parkinson’s diseases ³⁷⁾ as it is an immunostimulant and has been found to be very effective in treating immune, nervous, and urinary disorders ³⁸⁾. Jaiswal et al. ³⁹⁾ revealed its anxiolytic activity and its usefulness in the treatment of disinclination to work. Shilajit is also used as a tonic in the ayurvedic system of medicine due to the presence of humic acid, fulvic acid, coumarins, and triterpenes ⁴⁰⁾.

Shilajit benefits

Eastern European weightlifters have been using Shilajit as part of an “herbal anabolic stack” to promote better strength, recovery, and muscular hypertrophy ⁴¹⁾. Traditional Ayurvedic use of shilajit as a tonic has some support from studies of the humic acids, fulvic acids, coumarins, and triterpenes that have shown antistress effects in animals ⁴²⁾. However, human data on this and other adaptogenic herbs are sorely lacking. Therefore, based on current clinical studies, shilajit has not been shown to be of any benefit for any human conditions.

Because consumers have access to a wide variety of herbal dietary supplements, future studies would be most pertinent if they would focus on outcomes important to male and female consumers.

Shilajit dosage

250 mg of oral Shilajit supplementation twice daily has been used in some clinical trials ⁴³⁾, ⁴⁴⁾.

Another study recommended dose of Shilajit for maintenance of optimal health is 300-500 mg/day ⁴⁵⁾. Shilajit is slowly metabolized and reaches a maximum level in the blood after 12-14 hours of consumption ⁴⁶⁾.

Shilajit side effects

Shilajit is safe and has been found to be quite safe for up to 3 g/kg body weight in mice ⁴⁷⁾. Shilajit should not be used with horse gram, meat of pigeon, Solanum nigrum (black nightshade) ⁴⁸⁾, ⁴⁹⁾. Raw and unprocessed Shilajit should not be used as it contains a significant amount of free radicals and has been found to be contaminated with different fungal organisms such as Aspergillus niger, A. ochraceous, and Trichothecium roseum ⁵⁰⁾.

What is red clover

Red clover (Trifolium pratense L) is a high-quality fodder crop belonging to the family of plants called legumes (just like peas and beans) that is widely cultivated in most temperate regions both within Europe and worldwide. Red clover is sown as a companion crop and a green manure crop to increase soil fertility ¹⁾. Red clover is the second most widely grown forage legume in the United States, after alfalfa, and is considered a high-value feed for livestock because of its digestibility, and protein content ²⁾. Being a nitrogen-fixing forage crop, red clover has a great potential in sustainable agriculture ³⁾. Red Clover is also widely used as a herbal supplement for the reduction of menopausal symptoms, as an alternative to the conventional hormonal replacement therapy, because Red clover contains phytoestrogens called isoflavones—compounds similar to the female hormone estrogen. Red clover extract isoflavones are metabolized to genistein and daidzein after consumption. Potential adverse effects of phytoestrogens have included deficits in sexual behaviour in rats and impaired fertility in livestock (Bennetts 1946). No specific examples of toxicity among humans have been noted in countries in which soy is consumed regularly ⁴⁾. It is generally considered difficult for humans to consume the quantity of isoflavones from natural soy foods needed to reach toxicological levels that induce pathological effects, as recorded in animals. Asian people consume more isoflavones from their regular diet than Western people. Daily isoflavones intake in Chinese and Japanese people was estimated to be 15 to 50 mg/day ⁵⁾, whereas it was likely to be less than 3 mg/day in European and US populations ⁶⁾.

In folk medicine, red clover was used for a variety of conditions including asthma, whooping cough, cancer, and gout. Today, isoflavone extracts from red clover are most often used as dietary supplements for menopausal symptoms, high cholesterol, or osteoporosis. The flowering tops of the red clover plant are used to prepare extracts available in tablets or capsules, as well as in teas and liquid forms.

What scientists know about red clover

• Red clover has not been clearly shown to be helpful for any health condition.
• Most research indicates that taking red clover does not relieve menopause symptoms such as hot flashes.
• A 2015 meta-analysis and systematic review of 15 randomized controlled trials ⁷⁾ found no significant treatment effect of phytoestrogen on menopausal symptoms as compared with placebo. However, an analysis of the ten studies that reported hot flash data indicated that phytoestrogens result in a significantly greater reduction in frequency of hot flashes compared to placebo.
• A 2014 systematic review ⁸⁾ concluded that studies of isoflavones had significant reductions on hot flashes and co-occurring symptoms during menopause and post-menopause, but replication of studies with larger sample sizes are needed.
• A 2013 Cochrane review ⁹⁾ of 43 randomized controlled trials involving a total of 4,084 participants with hot flashes found some trials reported a slight reduction in hot flashes and night sweats with phytoestrogen-based treatment; however many of the trials included in the review were small, of short duration and of poor quality. The phytoestrogens containing high levels of genistein (a substance derived from soy) appeared to reduce the number of daily hot flashes, but needs to be further investigated. Overall, there was no indication suggesting that other types of phytoestrogens work any better than no treatment.
• Because red clover contains estrogen-like compounds, there’s a possibility that long-term use would increase the risk of women developing cancer of the endometrium (the lining of the uterus). However, short-term studies of women who have taken red clover have not shown harmful changes in the uterine lining.
• Red clover may not be safe for women who are pregnant or breastfeeding, for children, or for women who have breast cancer or other hormone-sensitive cancers.
• Red clover supplementation is not advised in children younger than 12 years.
• The main chemical classes contained in red clover are carbohydrates, isoflavones, flavonins, and saponins. Other constituents include coumaric acid, fats, minerals, and vitamins. A volatile oil that includes methyl salicylate is distilled from the flowers ¹⁰⁾. Isoflavones are often termed phytoestrogens because of their functional similarity to estrogens. The major isoflavones in red clover are biochanin A, formononetin, daidzein, and genistein; total phytoestrogen content is approximately 0.17%.
• Clinical practice guidelines issued in 2011 by the American Association of Clinical Endocrinologists ¹¹⁾ for the diagnosis and management of menopause state that phytoestrogens, including soy-derived isoflavonoids, result in inconsistent relief of symptoms. The guidelines advise that women with a personal or strong family history of hormone-dependent cancers, thromboembolic events, or cardiovascular events should not use soy-based therapies. Likewise, guidelines from the American College of Obstetricians and Gynecologists state that phytoestrogens and herbal supplements have not been shown to be useful for treating hot flashes.

The red clover plant is low and bushy with several hairy stems arising from a taproot. Dense terminal heads of up to 125 fragrant red-to-purple flowers are borne at the end of the branched stems. The leaves occur in groups of 3 ovate leaflets; a characteristic lighter water mark in the shape of an inverted V is visible at the center of the group.

Figure 1. Red clover (Trifolium pratense L.)

Red clover traditional medicine uses

Dried red clover flowers have been used in traditional medicine to treat a wide variety of ailments, including jaundice, cancer, breast tissue infections, joint disorders, and respiratory conditions (e.g, whooping cough, bronchial asthma), and as a sedative. The plant was thought to purify the blood by promoting urine and mucus production, improving circulation, and stimulating secretion of bile. Red clover ointments have been used topically to speed wound healing and to treat psoriasis, eczema, and rashes. Respiratory complaints have been treated with an infusion; poultices of the whole plant have been used as topical applications for cancerous growths.

However, there is no clinical evidence to support any of these uses. Safety of use in treating breast cancer has not been determined, and protection against prostate cancer has not yet been confirmed by clinical trials.

Red clover health benefits

There have been several studies of red clover in people, but their results haven’t provided clear evidence of any beneficial effects.

Red clover flowers have been used traditionally as a sedative, to purify the blood, and to treat respiratory conditions; topical preparations have been used for psoriasis, eczema, and rashes, and to accelerate wound healing. More recently, clinical trials have been conducted examining red clover’s use in the treatment of menopausal symptoms, but with minimal to no possible effects. A few additional studies have shown positive effects on cardiovascular health and bone density, although they have included only a small number of subjects.

Much of the interest in red clover originated from observations of positive health benefits derived from the use of soy products. Both soy and red clover are sources of isoflavones and have similar estrogenic activity; in test tube studies have shown this to be approximately 1/400th that of 17-β-estradiol ¹²⁾.

Red clover for menopause

According to the North American Menopause Society ¹³⁾, in five controlled studies, no consistent or conclusive evidence was found that red clover leaf extract reduces hot flashes. As with black cohosh, however, some women claim that red clover has helped them ¹⁴⁾. Studies report few side effects and no serious health problems with use. But studies in animals have raised concerns that red clover might have harmful effects on hormone-sensitive tissue.

A wide range of products containing plant or phytoestrogens, including soy products, are available as over the counter remedies for hot flushes. Studies have varied widely in the dose and nature of compounds tested and the active product of these is thought to be isoflavones. Varied outcomes have been demonstrated with some short term studies suggesting that there may be some benefit in using these products early in menopause but we are still lacking good long term studies. The available evidence suggests that isoflavones do not relieve long term menopausal vasomotor symptoms any better than placebo ¹⁵⁾.

There is some evidence that questions the safety of these products in patients with breast cancer and phytoestrogen supplements may interfere with treatments for breast cancer ¹⁶⁾.

Cardiovascular effects

Beneficial effects of soy protein on blood lipid profiles have been demonstrated. However, results from studies of red clover have been mixed, with either no effects on plasma lipids ¹⁷⁾ or with only modest improvements observed ¹⁸⁾. Results from studies investigating vascular effects of red clover have been more encouraging.

No improvements in cardiovascular risk factors were associated with the 1-year use of a red clover-derived isoflavone supplement by women aged 49 to 65 years. However, a trend toward potentially beneficial changes in triglycerides was observed in perimenopausal women ¹⁹⁾. A small but significant decrease in triglyceride levels was observed in another study of women receiving Promensil or Rimostil . Women with elevated baseline triglyceride levels showed greatest improvement ²⁰⁾. However, the effect was probably too small to be clinically important. These studies suggest that isoflavones may not be responsible for the well-documented effects of soy protein on blood lipids.

Arterial compliance, an index of the elasticity of large arteries, improved in a small, short-term study of postmenopausal women receiving Promensil ²¹⁾. These results were confirmed by a larger study of normotensive men and postmenopausal women ²²⁾. Ambulatory blood pressure remained unchanged but total peripheral resistance improved in these patients. Subjects received 80 mg/day of a red clover-derived isoflavone supplement containing mostly biochanin A or formononetin; improvements were greatest in the formononetin group.

Effects on bone density

Diets rich in soy protein have been associated with reduced incidence of hip fracture and attenuation of bone loss. Because of this, red clover has been investigated also.

Isoflavone supplementation was associated with reduced losses of bone mineral content and bone mineral density at the lumbar spine in a large study (N = 205) ²³⁾. Markers of bone formation were also increased in women, 49 to 65 years of age, who received Promensil for 12 months. Postmenopausal women appeared to gain most advantage. Between-group differences in bone mineral density at the hip were not significant. Another trial showed no differences in markers of bone turnover among menopausal women receiving Rimostil, Promensil, or placebo ²⁴⁾. However, the validity of the results may have been affected by the short study duration (12 weeks).

Other uses

Biochanin A has been reported to inhibit carcinogenic activity in cell cultures ²⁵⁾. Men with low- to moderate-grade prostate carcinoma who received isoflavonoid supplements prior to radical prostatectomy showed no changes in serum prostate-specific antigen, serum testosterone, or biochemical factors ²⁶⁾. However, analysis of prostatectomy specimens showed an increase in apoptosis, particularly in regions of low- to moderate-grade cancer, when compared with historical controls.

Red clover dosage

The traditional dose of red clover blossoms for sedation is 4 grams. Red clover is now used primarily as a source of isoflavones. The usual dose is 40 to 80 mg/day of standardized isoflavones, typically containing biochanin A, formononetin, genistein, and daidzein. Several commercial preparations are available.

Extracts standardized for isoflavone content (eg, Promensil and Rimostil ; Novogen Laboratories , North Sydney, Australia) have been used frequently in clinical trials. These tablets contain biochanin A, formononetin, genistein, and daidzein; Promensil contains a higher proportion of biochanin A and genistein and lower proportions of formononetin and daidzein than Rimostil ²⁷⁾. The usual dosage is 40 to 80 mg/day of total isoflavones (1 to 2 tablets).

Red clover side effects

No serious side effects have been reported in studies that evaluated red clover for various health conditions for up to a year. High doses of isoflavones have been associated with loss of appetite, pedal edema, and abdominal tenderness.

The role of clover species in causing intracranial hemorrhage has been known since the 1920s with the discovery of sweet clover hemorrhagic syndrome in cattle which proved to be the first step in the development of warfarin. In addition to coumarin derivates, Red Clover contains phenolic compounds which inhibit platelet adhesion and reduce platelet factor 4 release ²⁸⁾. The literature contains one case of intracranial bleeding due to Red Clover where a patient suffered a spontaneous, nonaneurysmal subarachnoid hemorrhage ²⁹⁾. In another case a 65-year-old woman who suffered a spontaneous acute-on-chronic subdural hemorrhage with a significant postoperative re-hemorrhage after taking Red Clover supplements for her postmenopausal symptoms ³⁰⁾. Further questioning into her history revealed that she had been taking Red Clover for the preceding 8–10 years (364 mg per day of standardized Red Clover extract containing 40 mg isoflavones, as recommended by the manufacturer) as an over-the-counter herbal preparation for relief of menopausal symptoms. These cases highlight another risk factor for intracranial hemorrhage and the mechanism of Red Clover induced coagulopathy appears to be mediated through anti-platelet actions, assumed to be due to the coumarin derivatives, hence the contraindication for Red Clover use alongside warfarin; however, in-vitro evidence has shown Red Clover’s role in preventing platelet adhesion ³¹⁾.

Contraindications

Red Clover is contraindicated in patients with a history of breast cancer and during pregnancy or lactation.

The phytoestrogens in red clover may be expected to act through estrogenic mechanisms with the associated risk of estrogen-like adverse effects, including increased incidence of endometrial, ovarian, and breast cancers.

The finding from a 2015 systematic review and meta-analysis suggests that red clover consumption may have breast cancer-promoting effects ³²⁾. An earlier 2002 meta-analysis showed a positive relationship between levels of estradiol and increased risk of breast cancer ³³⁾. The 2015 systematic review and meta-analysis study showed that red clover may increase the risk of estrogen-dependent cancers as estradiol showed a borderline increase in the red clover groups in comparison with control group base on three trials ³⁴⁾.

Pregnancy/Lactation

Red clover has estrogenic activity. Avoid use.

Interactions

Isoflavonoids may interfere with hormonal agents; avoid use with oral contraceptives, estrogen, or progesterone therapies.

Red clover contains coumarin derivatives; there is little risk of anticoagulant abnormalities ³⁵⁾.

Toxicology

The phytoestrogens in red clover may be expected to act through estrogenic mechanisms with the associated risk of estrogen-like adverse effects, including increased incidence of endometrial, ovarian, and breast cancers. Red clover induced a proliferation of estrogen-sensitive breast cancer cells in an in vitro study ³⁶⁾. However, another study showed that mammographic breast density, a marker for estrogenic and antiestrogenic effects, was unaffected by administration of Promensil for 1 year in women 49 to 65 years of age ³⁷⁾. A small pilot study found no antiproliferative effects on the endometrium associated with use of red clover isoflavones ³⁸⁾. Three trials ³⁹⁾, ⁴⁰⁾, ⁴¹⁾, assessed the effect of red clover on the endometrial thickness. Overall, it seems that red clove showed a range of null effect to non-significant decrease in postmenopausal period. However, further studies with control group are required to confirm this data.

Infertility and growth disorders have been observed in grazing animals receiving high proportions of red clover in their feed. This has been attributed to the estrogenic activity of red clover. A syndrome characterized by infertility, abnormal lactation, dystonia, and prolapsed uterus, known as clover disease, has been described in sheep.

What is Coenzyme Q10

Coenzyme Q10 (CoQ10) also called ubiquinone or ubidecarenone, is a substance that is naturally present in the human body in most body tissues, with the highest levels in the heart, liver, kidneys, and pancreas. The lowest amounts are found in the lungs. CoQ10 decreases in the body as people get older. Your body uses Coenzyme Q10 for cell growth and to protect cells from damage. Coenzyme Q10 is a lipid-soluble benzoquinone that has 10 isoprenyl units in its side chain and is a key component of the mitochondrial respiratory chain for adenosine triphosphate (ATP) synthesis by acting as an electron carrier in mitochondria and as a co-enzyme for mitochondrial enzymes ¹⁾, ²⁾. Studies has indicated that coenzyme Q10 is an intracellular antioxidant can protects membrane phospholipids, mitochondrial membrane protein, and low density lipoprotein-cholesterol (LDL-C) from free radical-induced oxidative damage ³⁾. In vitro or in vivo studies have demonstrated that coenzyme Q10 not only plays an antioxidant, but also has anti-inflammation effects ⁴⁾ by modulating the expression of cyclooxygenase-2 and nuclear factor-κB (NF-κB) in the liver tissue of rats with hepatocellular carcinoma ⁵⁾.

A coenzyme helps an enzyme do its job. An enzyme is a protein that speeds up the rate at which chemical reactions take place in cells of the body. The body’s cells use coenzyme Q10 to make energy needed for the cells to grow and stay healthy. The body also uses coenzyme Q10 as an antioxidant. An antioxidant protects cells from chemicals called free radicals.

Figure 1. Coenzyme Q10

A coenzyme Q10 deficiency occurs with age; however, certain drugs can cause depletion of coenzyme Q10 levels, particularly hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, or statins ⁶⁾. Statins are prescribed to reduce cholesterol levels and work by inhibiting HMG-CoA reductase and the mevalonate metabolic pathway ⁷⁾. Mevalonate is used to synthesize cholesterol as well as coenzyme Q10 ⁸⁾, therefore, when statin drugs lower cholesterol levels they simultaneously lower coenzyme Q10 levels. Statins are known to block coenzyme Q10 biosynthesis and reduce serum concentrations of coenzyme Q10 by up to 40% ⁹⁾. Furthermore, statin use is often associated with a variety of muscle-related symptoms or myopathies. Research has suggested that coenzyme Q10 supplementation may decrease muscle pain associated with statin treatment ¹⁰⁾.

Coenzyme Q10 is sold in the United States as a dietary supplement. Supplementary oral administration of coenzyme Q10 has been shown to increase coenzyme Q10 levels in plasma, platelets, and white blood cells ¹¹⁾. Because CoQ10 has important functions in the body and because people with some diseases have reduced levels of this substance, researchers have been interested in finding out whether CoQ10 supplements might have health benefits. Studies suggest that CoQ10 deficiency may be associated with a multitude of diseases as diverse as coronary artery disease and congestive heart failure, Parkinson’s disease, diabetes, and breast cancer, as well as the risk factor, hypertension ¹²⁾. It has been suggested that Coenzyme Q10 has the potential to lower blood pressure without significant adverse events in hypertensive patients ¹³⁾.

There are also a number of ways that Coenzyme Q10 could act favorably to reduce blood pressure. Coenzyme Q10 could act directly on vascular endothelium and decrease total peripheral resistance by acting as an antagonist of vascular superoxide, by either scavenging it, or suppressing its synthesis ¹⁴⁾. Further to this, a recent meta-analysis has associated CoQ10 supplementation with a significant improvement in arterial endothelial function in patients with and without cardiovascular disease ¹⁵⁾. Coenzyme Q10’s antioxidant properties may also result in the quenching of free radicals that cause inactivation of endothelium-derived relaxing factor or fibrosis of arteriolar smooth muscle, or both ¹⁶⁾. In addition, CoQ10 has been found to decrease blood viscosity and improve blood flow to cardiac muscle in patients with ischemic heart disease; therefore it may reduce blood pressure ¹⁷⁾.

Dietary supplementation with coenzyme Q10 results in increased levels of ubiquinol-10 (the reduced form of coenzyme Q10) within circulating lipoproteins. In its reduced form the coenzyme Q10 molecule acts as a powerful intracellular antioxidant due to its ability to hold electrons rather loosely, and will quite easily give up one or both electrons. The antioxidant and free radical scavenger effects of coenzyme Q10 can therefore help to prevent lipid peroxidation and thus the progression of atherosclerosis ¹⁸⁾. Furthermore, coenzyme Q10 has also been found to modulate the amount of ß-integrin levels on the surface of blood monocytes, strongly suggesting that the anti-atherogenic effects of coenzyme Q10 are mediated by other mechanisms beside its antioxidant properties ¹⁹⁾.

Coenzyme Q10 (CoQ10) key facts

• Coenzyme Q10 (CoQ10) has not been shown to be of value in treating cancer, but it may reduce the risk of heart damage caused by one type of cancer chemotherapy drug.
• Only a few studies have looked at whether CoQ10 might help prevent heart disease, and their results are inconclusive. Research on the effects of CoQ10 in heart failure is also inconclusive. However, there is evidence that CoQ10 may reduce the risk of some complications of heart surgery.
• Although results of individual studies have varied, the overall scientific evidence does not support the idea that CoQ10 can reduce muscle pain caused by the cholesterol-lowering drugs known as statins.
• The small amount of evidence currently available suggests that CoQ10 probably doesn’t have a meaningful effect on blood pressure.
• Guidelines from the American Academy of Neurology and the American Headache Society say that coenzyme Q10 is “possibly effective” in preventing migraines, but this conclusion is based on limited evidence.
• A major study showed that coenzyme Q10, even in higher-than-usual doses, didn’t improve symptoms in patients with early Parkinson’s disease. A 2017 evaluation of this study and several other, smaller studies concluded that coenzyme Q10 is not helpful for Parkinson’s symptoms.
• Coenzyme Q10 (CoQ10) has also been studied for a variety of other conditions, including amyotrophic lateral sclerosis (Lou Gehrig’s disease), Down syndrome, Huntington’s disease, and male infertility, but the research is too limited for any conclusions to be drawn.

Coenzyme Q10 (CoQ10) supplement benefits

The U.S. Food and Drug Administration (FDA) does not approve dietary supplements as safe or effective. The company that makes the dietary supplements is responsible for making sure that they are safe and that the claims on the label are true and do not mislead the patient. The way that supplements are made is not regulated, so all batches and brands of coenzyme q10 supplements may not be the same.

Coenzyme Q10 for cancer

There have been few clinical trials that study the use of CoQ10 in patients with cancer. A trial of 236 breast cancer patients were randomized to receive either Coenzyme q10 or placebo, each combined with vitamin E, for 24 weeks. The study found that levels of fatigue and quality of life were not improved in patients who received Coenzyme q10 compared to patients who received the placebo.

A randomized trial of 20 children treated for acute lymphoblastic leukemia or non-Hodgkin lymphoma looked at whether Coenzyme q10 would protect the heart from the damage caused by doxorubicin. The results reported that CoQ10 decreased the harmful effects of doxorubicin on the heart.

Clinical trials have been limited to small numbers of people, and it is not clear if the benefits reported were from the Coenzyme q10 therapy, other dietary supplements, or standard treatments used before or during the CoQ10 therapy.

Reversal of statin-induced myopathy

Statins (HMG-CoA reductase inhibitors) deplete circulating coenzyme Q10 levels by interfering with its biosynthesis ²⁰⁾. Most studies indicate a correlation between the decrease in serum coenzyme Q10 and decreases of total and low-density lipoprotein cholesterol levels. This effect may be particularly important in elderly patients, in whom coenzyme Q10 levels are already compromised, and is also associated with higher dosages (lower dosages do not seem to affect intramuscular levels of coenzyme Q10) ²¹⁾. The use of ezetimibe alone or in combination with a statin does not offer protection against depletion of coenzyme Q10 ²²⁾. No correlation has been established for decreased serum coenzyme Q10 and cardiovascular events ²³⁾. Supplemental coenzyme Q10 increased circulating levels of the compound. However, results from randomized clinical trials are inconsistent in showing an effect on statin-associated myopathy ²⁴⁾, ²⁵⁾.

Neurological disorders

The case for coenzyme Q10 as a treatment option in neurological (mitochondrial-related) disease is not as strong ²⁶⁾. The role of coenzyme Q10 in Parkinson, Alzheimer, and Huntington diseases; amyotrophic lateral sclerosis; and Friedreich ataxia is postulated but not established ²⁷⁾.

Studies in Friedreich and non-Friedreich ataxia have largely shown a continued worsening of disease, as measured by the International Cooperative Ataxia Group rating scale, irrespective of coenzyme q10 use (5 mg/kg/day) ²⁸⁾.

A link between mitochondrial dysfunction and Parkinson disease has been established, but the relationship with coenzyme Q10 has not ²⁹⁾. A multicenter clinical trial found a decrease in worsening of symptoms in patients with early Parkinson disease receiving coenzyme Q10 1,200 mg/day, but not at lower dosages ³⁰⁾. Effects were not apparent at 1 month, but were evident at 8 months. Changes in daily living factors were more pronounced than clinical disease progression changes ³¹⁾. Increases in plasma coenzyme Q10 were recorded. A larger trial using higher dosages (coenzyme Q10 600 mg chewable wafers 4 times a day) found a mean change in total rating score high enough to warrant a phase 3 trial ³²⁾; however, the trial was not designed to evaluate efficacy ³³⁾. A multicenter trial of patients receiving anti-Parkinson medication found no difference in symptoms over placebo ³⁴⁾.

The role of mitochondrial stress in Alzheimer disease led to more studies of coenzyme Q10 ³⁵⁾. Multicenter clinical trials using idebenone dosages of up to 360 mg 3 times a day found no effect on the rate of decline over placebo. Analyses using various rating scales showed some differences that were not considered clinically important, mirroring other older trials ³⁶⁾. Similarly, no slowing of decline was noted in Huntington disease ³⁷⁾.

Other uses

Coenzyme Q10 has been evaluated in migraine versus placebo in small trials. Decreases in attack frequency, days with headache, and days with nausea were found for a daily dose of 300 mg ³⁸⁾. The coadministration of ubiquinone with tamoxifen mitigated the hyperlipidemia associated with tamoxifen, and tumor marker levels indicated an antiangiogenesis effect ³⁹⁾. An Agency for Healthcare Research and Quality review of clinical trials reported no evidence to support the use of ubiquinone in the prevention or treatment of cancer ⁴⁰⁾.

Deficiencies of coenzyme Q10 have been described, predominantly affecting children, in a spectrum of diseases including infantile-onset, multisystem diseases, as well as adult-onset cerebellar ataxia and pure myopathies ⁴¹⁾. Lymphocyte and platelet coenzyme Q10 levels were lower in Down syndrome ⁴²⁾, while lowered serum levels are associated with phenylketonuria and mevalonic aciduria ⁴³⁾.

In infants with Prader-Willi syndrome, coenzyme Q10 had no effect on lean mass versus growth hormone ⁴⁴⁾.

Coenzyme Q10 for blood pressure and cardiovascular disease

Considering the key role of coenzyme Q10 in cellular energy production, and the high energy requirements of cardiac cells, coenzyme Q10 has a potential role in the prevention and treatment of heart ailments by improving cardiac bioenergetics ⁴⁵⁾.

Studies have shown that a coenzyme Q10 deficiency is associated with cardiovascular disease ⁴⁶⁾; however, it is uncertain whether a coenzyme Q10 deficiency is the cause or the effect of disease, especially in observational studies ⁴⁷⁾. Patients with ischemic heart disease (coronary heart disease) and dilated cardiomyopathy have been found to have significantly lower levels of coenzyme Q10 compared to healthy controls ⁴⁸⁾. In addition, the concentrations of coenzyme Q10 in blood and heart tissue decline with increasing severity of heart disease ⁴⁹⁾. Coenzyme Q10 deficiency has also been observed in patients with hypertension; enzymatic deficiency of coenzyme Q10 has been reported in 39% of hypertensive patients compared with only 6% of healthy controls ⁵⁰⁾.

Congestive heart failure

Much of the research on coenzyme Q10 is related to the secondary prevention of cardiovascular disease and results of clinical trials support the use of coenzyme Q10 in the treatment of congestive heart failure ⁵¹⁾. Several meta-analyses and systematic reviews of clinical trials in congestive heart failure have been published, with results generally being more consistent for congestive heart failure than with other disease states. The inclusion of 2 trials in which coenzyme Q10 failed to show an effect greater than placebo in these analyses, results in only a trend in favor of coenzyme Q10 in improving cardiac function (an increase in resting ejection fraction of 1.9% ⁵²⁾. In a meta-analysis that included trials with a crossover or parallel-arm design, a 3.7% absolute difference in resting ejection fraction was found for coenzyme Q10 ⁵³⁾. In other trials, coenzyme Q10 has been used in combination with other micronutrients ⁵⁴⁾. The studies, however, either do not evaluate or are underpowered to evaluate mortality outcomes ⁵⁵⁾. Because differing Coenzyme Q10 preparations were used in the studies, both the bioavailability of the compound ⁵⁶⁾ and the adequacy of dosing to reach sufficient plasma coenzyme Q10 levels for effect have been questioned ⁵⁷⁾.

Hypertension

In primary prevention, a meta-analysis of observational studies and clinical trials (12 studies, total of 362 patients) has shown that coenzyme Q10 supplementation reduces blood pressure ⁵⁸⁾. Rosenfeldt et al. conducted a meta-analysis, comprising three randomized trials ⁵⁹⁾, ⁶⁰⁾, ⁶¹⁾, one randomized crossover study ⁶²⁾ and eight open-label studies ⁶³⁾, ⁶⁴⁾, ⁶⁵⁾ in 362 hypertensive patients, most of whom had essential hypertension or isolated systolic hypertension ⁶⁶⁾. They reported that coenzyme Q10 therapy had the potential to reduce BP by up to 17/10 mm Hg ⁶⁶⁾. The meta-analysis was however, limited by the inclusion of studies which were open-labeled and not placebo-controlled. Furthermore, there were considerable differences in patient populations with respect to age, underlying disease and comorbidities, coenzyme Q10 dose and duration, and use of concomitant antihypertensive therapy between the trials. Finally, the meta-analysis did not make use of individual patient data from the component studies, which would have provided a more robust assessment of any effect of coenzyme Q10 on arterial pressure.

On the other hand, a recent 2016 Cochrane systematic review of randomized controlled trials in participants with primary hypertension dispute these findings ⁶⁷⁾. The 2016 Cochrane Review provides moderate-quality evidence that coenzyme Q10 does not have a clinically significant effect on blood pressure. Due to the small number of individuals and studies available for analysis, more well-conducted trials are needed ⁶⁸⁾.

The additional findings from Young et al. ⁶⁹⁾, showing no effect of coenzyme q10 on the 24-hour ambulatory monitoring systolic BP, diastolic BP, or heart rate compared to placebo provide supporting evidence for the conclusion that coenzyme Q10 has no clinically significant effect on BP (blood pressure). The 24-hour measurements are done using an automatic machine, and thus are free from observer bias that could occur with clinic measurements done by a physician or nurse.

These findings concur with another double-blind, placebo-controlled intervention trial by Mori et al. ⁷⁰⁾ who found 8 weeks of coenzyme Q10 administration had no effect on 24-h ambulatory BP in patients with chronic kidney disease. In that study, treated BP levels were 125/73 mm Hg before randomization. As noted above, however, any antihypertensive action of coenzyme Q10 is likely to be less obvious the lower the baseline level of BP. In this regard, it has been shown that coenzyme Q10 does not have vasodilatory effects in normotensive animals or humans ⁷¹⁾.

In conclusion, randomized controlled studies demonstrated that compared with placebo, coenzyme Q10 does not result in clinically significant reductions in systolic or diastolic 24-h ambulatory BP or heart rate in patients with the metabolic syndrome and inadequately treated hypertension, although there was a significant reduction in daytime diastolic BP loads. Coenzyme Q10 was well tolerated and was not associated with any clinically relevant changes in safety parameters.

Cardiac surgery and cardiac arrest

The use of coenzyme Q10 in improving mitochondrial function has been evaluated in cardiac surgery. A review was published of 8 studies, in which improvements in contractility of the myocardial tissue were demonstrated in association with increases in serum coenzyme Q10 ⁷²⁾. Doses of coenzyme Q10 300 mg daily for 2 weeks prior to surgery were evaluated versus placebo ⁷³⁾. A randomized, placebo-controlled trial evaluated coenzyme Q10 450 mg in divided doses in conjunction with hypothermia after cardiac arrest. Increased survival was shown for the coenzyme Q10 group ⁷⁴⁾.

Coenzyme Q10 dosage

Several dosage forms exist, including compressed and chewable tablets, powder-filled and gel-filled capsules, liquid syrups, and newer solubilized formulations. The reduced form of coenzyme Q10, ubiquinol, is also commercially available. It may also be given by injection into a vein (IV).

Pharmacokinetic studies suggest split dosing is superior to single daily dosing; for tissue uptake and crossing the blood-brain barrier, plasma coenzyme Q10 levels should be higher than normal ⁷⁵⁾.

Usual adult dose of Coenzyme-Q10 is 30 to 200 mg/day oral.

In observational studies and clinical trials (12 studies, total of 362 patients) has shown that coenzyme Q10 supplementation reduces blood pressure ⁷⁶⁾. Dose of coenzyme Q10 ranged between 34 and 225 mg/day and duration of individual studies from one to 56 weeks.

Cardiovascular and neurologic trials predominately use coenzyme Q10 dosages of 300 mg/day or coenzyme Q10 dosages of 5 mg/kg/day.

High-dose coenzyme Q10 (1,200 mg/day) was used in patients with early Parkinson disease ⁷⁷⁾, while dosages of 2,700 to 3,000 mg/day were used in amyotrophic lateral sclerosis trials ⁷⁸⁾. An open-label study that included children evaluated tolerability of high-dose coenzyme Q10. Daily dosages of 60 mg/kg given in 3 divided doses were used for 1 month ⁷⁹⁾.

Coenzyme Q10 side effects

No serious side effects of CoQ10 have been reported. Mild side effects such as insomnia or digestive upsets may occur.

Reported side effects from the use of Coenzyme-Q10 include the following:

• High levels of liver enzymes.
• Nausea.
• Heartburn.
• Headache.
• Pain in the upper part of the abdomen.
• Dizziness.
• Rashes.
• Unable to fall sleep or stay asleep.
• Feeling very tired.
• Feeling irritable.
• Sensitive to light.

It is important to check with health care providers to find out if CoQ10 can be safely used with other drugs. Certain drugs, such as those that are used to lower cholesterol, blood pressure, or blood sugar levels, may decrease the effects of Coenzyme-Q10. CoQ10 may change the way the body uses warfarin (a drug that prevents the blood from clotting) and insulin.

Coenzyme-Q10 may interact with the anticoagulant (blood thinner) warfarin and the diabetes drug insulin, and it may not be compatible with some types of cancer treatment.

What other drugs will affect Coenzyme Q10?

Do not take Coenzyme Q10 without medical advice if you are using any of the following medications:

• omega-3 fatty acids;
• vitamins (especially A, C, E, or K);
• blood pressure medicine;
• cancer medicine; or
• warfarin (Coumadin, Jantoven).

This list is not complete. Other drugs may affect Coenzyme Q10, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible drug interactions are listed here.

Toxicology

A review of animal experiments and clinical trials has estimated an acceptable daily intake for coenzyme Q10 to be 12 mg/kg (ie, 720 mg/day for a 60 kg person) based on a no-observed-adverse-effect level in rats of 1,200 mg/kg/day. An observed safety level based on clinical data is given as 1,200 mg/day. No accumulation in plasma or tissue following cessation of coenzyme Q10 consumption was noted and endogenous biosynthesis was not affected ⁸⁰⁾.

Coenzyme Q10 are a class of lipid-soluble benzoquinones that are involved in mitochondrial electron transport. They are found in the majority of aerobic organisms, from bacteria to mammals, hence the name ubiquinone (“ubiquitous quinone”).

What is serrapeptase

Serrapeptase is an extracellular metalloprotease enzyme isolated from enterobacterium Serratia marcescens Serratia sp. strain E-15 (one of the enteric bacilli in silk worm) ¹⁾. The microorganism Serratia marcescens Serratia sp. strain E-15 was originally isolated in the late 1960s from silk worm Bombyx mori L ²⁾. Serrapeptase is presented in the silk worm intestine and allows the emerging moth to dissolve its cocoon. It is produced by purification mainly from fermentation of Serratia marcescens or Serratia sp. E 15. The Serrapeptase  enzyme belongs to Serralysin group of enzymes and is known to cleave the peptides with linkages of Asn-Gln, CysSO3H-Gly, Arg-Gly, and Tyr-tyr as well as the bond between His-Leu, Gly-Ala, Ala-Leu, Tyr-leu, Gly-Gly, Phen-Tyr, and Tyr-Thr, showing broad substrate specificity ³⁾. The Serrapeptase enzyme is absorbed through the intestine and transported directly into the blood stream ⁴⁾. Serrapeptase should be enterically coated or else it may get destroyed by acid in the stomach before it gets into small intestine ⁵⁾. Serrapeptase enzyme is believed to induce degradation of insoluble protein products like fibrin and inflammatory mediators. It reduces the viscosity of exudates facilitating drainage and alleviates pain by inhibiting the release of bradykinin ⁶⁾.

Serrapeptase is also known as Serratiopeptidase (Serratia E-15 protease), serralysin, serratiapeptase, serratia peptidase or serrapeptidase, is a proteolytic enzyme preparation used is used either alone or in combination with other drugs to treat inflammation. Serrapeptase has been used in Europe and Asia for over 30 years, but is relatively new in the United States and Canada ⁷⁾. Serrapeptase has powerful anti-inflammatory properties. Clinical studies have shown that Serrapeptase is effective in reducing swelling and edema and metabolizing scar tissues in the body ⁸⁾ and particularly useful for post-traumatic swelling, breast engorgement during lactation ⁹⁾ and bronchitis ¹⁰⁾. Serrapeptase can digest dead tissue, blood clots, cysts, and arterial plaques ¹¹⁾. The anti-inflammatory properties of serrapeptase was first studied in Japan in 1967. Later during the 1970s these parenteral enzyme formulations were replaced by their enteric coated successors. During the 1980s and 1990s it was proposed by separate research conducted in Europe and Japan that serrapeptase is the most effective agent in reducing inflammation among all enzyme preparations.

Serrapeptase is used either alone or in combination with other drugs to treat inflammation. It is proved to be a superior alternative to traditional NSAIDS like diclofenac sodium and ketoprofen which have pronounced side effects.

Serrapeptase mechanism of anti-inflammatory effect is because of hydrolysis of histamine, bradykinin, and serotonin ¹²⁾. Serrapeptase also has a proteolytic and fibrinolytic effect. This is achieved by dissolving the complement (specific proteins responsible for inflammation) and increasing the plasmin activity by inhibiting the plasmin inactivators ¹³⁾. This anti-inflammatory activity of serrapeptase can be evaluated by Rat Paw Edema model, wherein edema is induced by Aerosil and the decrease in the thickness of the inflamed rat paw is measured using plethysmometer ¹⁴⁾.

Serrapeptase contains 450 amino acids cleaved with the peptide bond having molecular weight of approximately 60 kDa. Serrapeptase is labile to heat, moisture, and pH of the environment. The enzyme has maximal activity at pH 9.0 and at temperature 40°C. Serrapeptase shows excellent stability at lower temperatures in the pH range from 5 to 10. Serrapeptase is unstable at 37°C in alkaline conditions. The enzyme is completely inactivated by heating at 55°C for 15 min.

What is serrapeptase good for?

Serrapeptase has been used to treat chronic sinusitis ¹⁵⁾, carpal tunnel syndrome ¹⁶⁾, sprains, torn ligaments, serous otitis media ¹⁷⁾, osteoarthritis of the knee ¹⁸⁾, osteoarticular infections ¹⁹⁾, and postoperative inflammation ²⁰⁾. Serrapeptase was found to produce some relief in breast pain, induration and swelling, when compared to placebo in women with breast engorgement during lactation, with a fewer number of women experiencing slight to no improvement in overall breast engorgement, swelling and breast pain ²¹⁾. However, the overall quality of the studies was found to be low due to limitations in study design and the small number of women in the included studies, thus there is insufficient evidence from published trials on Serrapeptase to justify widespread implementation as treatment for breast engorgement during lactation. More robust research is urgently needed on the treatment of breast engorgement during lactation.

Esch et al. ²²⁾ used serrapeptase for reduction of postoperative swelling in upper ankle joint surgery and concluded that significant reduction in swelling had been achieved post- operatively with the use of serrapeptase.

Al-Khateeb and Nusair ²³⁾ investigated the ability of serrapeptase to reduce post-operative pain, swelling and trismus after third molar surgery. There was a significant reduction in the pain intensity and extent of cheek swelling in the serrapeptase group at the 2nd, 3rd and 7th post-operative days. Another study by Chappi et al. ²⁴⁾ also indicated similar results in which the serrapeptase group showed significantly reduced trismus and swelling on the day 1, 3 and 5 post-operatively. However, this enzyme preparation did not exert an appreciable analgesic effect post-operatively ²⁵⁾. In the same study by Chappi et al. ²⁶⁾ showed serratiopeptidase 10 mg orally produced an appreciable anti-edema effect and had no apparent effect on rate of wound healing. Murugesan et al. ²⁷⁾ found that dexamethasone was more effective in reducing swelling and pain when compared with serratiopeptidase, however both had same effect on trismus.

Serrapeptase uses

Serrapeptase is a potent anti-inflammatory enzyme. Supplementing serrapeptase with NSAIDs has shown to have a favorable anti-inflammatory effect on the tissues of the body ²⁸⁾.

Possibly effective for:

• Facial swelling after surgery to clear the sinuses.

Insufficient evidence for:

• Chronic bronchitis. Developing research suggests that serrapeptase can significantly reduce coughing and thin secretions in people with chronic bronchitis after about 4 weeks of treatment.
• Sinus pain (sinusitis). Early research suggests that people with sinusitis who take serrapeptase have significantly reduced pain, nasal secretions, and nasal obstruction after 3-4 days of treatment.
• Hoarseness (laryngitis). Early research suggests that serrapeptase can significantly reduce pain, secretions, difficulty swallowing, and fever in people with laryngitis after 3-4 days of treatment.
• Sore throat (pharyngitis). Early research suggests that serrapeptase can significantly reduce pain, secretions, difficulty swallowing, and fever in people with sore throat after 3-4 days of treatment.
• Back pain.
• Osteoarthritis.
• Rheumatoid arthritis.
• Osteoporosis.
• Carpel tunnel syndrome.
• Diabetes.
• Leg ulcers.
• Migraine headache.
• Tension headache.
• Asthma.
• Pus accumulation (empyema).
• Thrombophlebitis.
• Fibromyalgia.
• Fibrocystic breast disease.
• Inflammatory bowel disease (IBD) including ulcerative colitis and Crohn’s disease.
• Breast engorgement.
• Heart disease.
• Ear infections.
• Other conditions e.g. weight loss.

More evidence is needed to rate the effectiveness of serrapeptase for these uses.

Serrapeptase dosage

For reducing swelling of the inside of the cheek after sinus surgery: 5-10 mg of serrapeptase 3 times on the day before surgery, once in the evening after surgery, and then 3 times daily for 5 days following surgery.

Serrapeptase side effects

Serrapeptase seems to be safe for adults when taken by mouth, short-term (up to 4 weeks). The long-term safety of serrapeptase is not known.

According to a review of the literature, Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported as being associated exclusively with serrapeptase ²⁹⁾.

Special Precautions and Warnings

Pregnancy and breast-feeding: Not enough is known about the use of serrapeptase during pregnancy and breast-feeding. Stay on the safe side and avoid use.

Bleeding disorders: Serrapeptase might interfere with blood clotting, so some researchers worry that it might make bleeding disorders worse. If you have a bleeding disorder, check with your healthcare provider before using serrapeptase.

Surgery: Serrapeptase might interfere with blood clotting. There is a concern that it might increase bleeding during and after surgery. Stop using serrapeptase at least 2 weeks before a scheduled surgery.

Drug interactions

Medications that slow blood clotting (Anticoagulant/Antiplatelet drugs interacts with serrapeptase

Serrapeptase might decrease blood clotting. Therefore, taking serrapeptase along with medications that also slow clotting might increase the chances of bruising and bleeding. Some medications that slow blood clotting include aspirin, clopidogrel (Plavix), diclofenac (Voltaren, Cataflam, others), ibuprofen (Advil, Motrin, others), naproxen (Anaprox, Naprosyn, others), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, warfarin (Coumadin), and others.