Dietary Factors

Some of the listed dietary factors (i.e., L-carnitine, coenzyme Q10, and lipoic acid) can be synthesized by the body.



  • Our body produces L-carnitine from the essential amino acid lysine via a specific biosynthetic pathway. Healthy individuals, including strict vegetarians, generally synthesize enough L-carnitine to prevent deficiency. However, certain conditions like pregnancy may result in increased excretion of L-carnitine, potentially increasing the risk for deficiency. (More information)
  • Because of its role in the transport of long-chain fatty acids from the cytosol to the mitochondrial matrix, L-carnitine is critical for mitochondrial fatty acid β-oxidation. (More information)
  • L-Carnitine supplementation is indicated for the treatment of primary systemic carnitine deficiency, which is caused by mutations in the gene that codes for the carnitine transporter, OCTN2. (More information)
  • L-Carnitine is also approved for the treatment of carnitine deficiencies secondary to inherited diseases, such as propionyl-CoA carboxylase deficiency and medium chain acyl-CoA dehydrogenase deficiency, and in patients with end-stage renal disease undergoing hemodialysis. (More information)
  • Evidence from randomized controlled trials suggests that L-carnitine or acylcarnitine esters may be useful adjuncts to standard medical treatment in individuals with cardiovascular disease. (More information)
  • Routine administration of L-carnitine to people with end-stage renal disease undergoing hemodialysis is not recommended unless it is to treat carnitine deficiency. (More information)
  • Acetyl-L-carnitine (ALCAR) may help reduce the severity of chemotherapy-induced peripheral neuropathy. High-quality evidence is needed to evaluate whether ALCAR may benefit the treatment of peripheral neuropathies associated with diabetes or caused by antiretroviral therapy. (More information)
  • There is some low-quality evidence to suggest that supplemental L-carnitine or ALCAR may be beneficial as adjuncts to standard medical therapy of depression, Alzheimer's disease, and hepatic encephalopathy. (More information)
  • There is little evidence that L-carnitine supplementation improves cancer-related fatigue, low fertility, or overall physical health. (More information)
  • If you choose to take L-carnitine supplements, the Linus Pauling Institute recommends acetyl-L-carnitine at a daily dose of 0.5 to 1 g. Note that supplemental L-carnitine (doses, 0.6-7.0 g) is less efficiently absorbed compared to smaller amounts in food. (More information)


L-Carnitine (β-hydroxy-γ-N-trimethylaminobutyric acid) is a derivative of the amino acid, lysine (Figure 1). It was first isolated from meat (carnus in Latin) in 1905. Only the L-isomer of carnitine is biologically active (1). L-Carnitine appeared to act as a vitamin in the mealworm (Tenebrio molitor) and was therefore termed vitamin BT (2). Vitamin BT, however, is a misnomer because humans and other higher organisms can synthesize L-carnitine (see Metabolism and Bioavailability). Under certain conditions, the demand for L-carnitine may exceed an individual's capacity to synthesize it, making it a conditionally essential nutrient (3, 4).

Figure 1. Chemical Structures of L-Carnitine (beta-hydroxy-gamma-N-trimethylaminobutyric acid) and Two Acylcarnitine Derivatives, acetyl-L-carnitine (ALCAR) and propionyl-L-carnitine.

[Figure 1 - Click to Enlarge]


Metabolism and Bioavailability

In healthy people, carnitine homeostasis is maintained through endogenous biosynthesis of L-carnitine, absorption of carnitine from dietary sources, and reabsorption of carnitine by the kidneys (5).

Endogenous biosynthesis

Humans can synthesize L-carnitine from the amino acids lysine and methionine in a multi-step process occurring across several cell compartments (cytosol, lysosomes, and mitochondria) (reviewed in 6). Across different organs, protein-bound lysine is methylated to form ε-N-trimethyllysine in a reaction catalyzed by specific lysine methyltransferases that use S-adenosyl-methionine (derived from methionine) as a methyl donor. ε-N-Trimethyllysine is released for carnitine synthesis by protein hydrolysis. Four enzymes are involved in endogenous L-carnitine biosynthesis (Figure 2). They are all ubiquitous except γ-butyrobetaine hydroxylase is absent from cardiac and skeletal muscle. This enzyme is, however, highly expressed in human liver, testes, and kidney (7).

L-carnitine is primarily synthesized in the liver and transported via the bloodstream to cardiac and skeletal muscle, which rely on L-carnitine for fatty acid oxidation yet cannot synthesize it (8). The rate of L-carnitine biosynthesis in humans was studied in strict vegetarians (i.e., in people who consume very little dietary carnitine) and estimated to be 1.2 µmol/kg of body weight/day (9). The rate of L-carnitine synthesis depends on the extent to which peptide-linked lysines are methylated and the rate of protein turnover. There is some indirect evidence to suggest that excess lysine in the diet may increase endogenous L-carnitine synthesis; however, changes in dietary carnitine intake level or in renal reabsorption do not appear to affect the rate of endogenous L-carnitine synthesis (6).

Figure 2. Carnitine Biosynthetic Pathway. (1) An L-lysine residue is initially methylated by a methyltransferase that uses S-adenosyl methionine as a methyl donor; (2) protein turnover leads to the release of the trimethylated lysine; (3) the enzyme episilon-N-trimethyllysine hydroxylase catalyzes the hydroxylation of episilon-N-trimethyllysine into beta-hydroxy-episilon-N-trimethyllysine; (4) the cleavage of beta-hydroxyl-episilon-N-trimethyllysine into gamma-N-trimethylaminobutyraldehyde and glycine is catalyzed by the enzyme serine dydroxymethyltransferase; (5) gamma-N-trimethylaminobutyraldehyde is then hydroxylated to produce gamma-N-trimethylaminobutyrate in a reaction catalyzed by the enzyme aldehyde dehydrogenase; and (6) the conversion of gamma-N-trimehylaminobutyrate into L-carnitine is catalyzed by the enzyme gamma-butyrobetaine hydroxylase. Mineral element and vitamin derivatives that are used as cofactors in these enzymatic reactions include iron (Fe2+), vitamin C (ascorbate), vitamin B6 (pyridoxal 5;-phosphate), and niacin (NAD+/NADH).

[Figure 2 - Click to Enlarge]

Absorption of exogenous L-carnitine

Dietary L-carnitine

The bioavailability of L-carnitine from food can vary depending on dietary composition. For instance, one study reported that bioavailability of L-carnitine in individuals adapted to low-carnitine diets (i.e., vegetarians) was higher (66%-86%) than in those adapted to high-carnitine diets (i.e., regular red meat eaters; 54%-72%) (10). The remainder is degraded by colonic bacteria.

L-carnitine supplements

While bioavailability of L-carnitine from the diet is quite high (see Dietary L-carnitine), absorption from oral L-carnitine supplements is considerably lower. The bioavailability of L-carnitine from oral supplements (doses, 0.6 to 7 g) ranges between 5% and 25% of the total dose (5). Less is known regarding the metabolism of the acetylated form of L-carnitine, acetyl-L-carnitine (ALCAR); however, the bioavailability of ALCAR is thought to be higher than that of L-carnitine. The results of in vitro experiments suggested that ALCAR might be partially hydrolyzed upon intestinal absorption (11). In humans, administration of 2 g/day of ALCAR for 50 days increased plasma ALCAR concentrations by 43%, suggesting that either ALCAR was absorbed without prior hydrolysis or that L-carnitine was re-acetylated in the enterocytes (5).

Elimination and reabsorption

L-Carnitine and short-chain acylcarnitine derivatives (esters of L-carnitine; see Figure 1) are excreted by the kidneys. Renal reabsorption of free L-carnitine is normally very efficient; in fact, an estimated 95% is thought to be reabsorbed by the kidneys (1). Therefore, carnitine excretion by the kidney is usually very low. However, several conditions can decrease the efficiency of carnitine reabsorption and, correspondingly, increase carnitine excretion. Such conditions include high-fat, low-carbohydrate diets; high-protein diets; pregnancy; and certain disease states (see Primary systemic carnitine deficiency) (12). In addition, when circulating L-carnitine concentration increases, as in the case of oral supplementation, renal reabsorption of L-carnitine may become saturated, resulting in increased urinary excretion of L-carnitine (5). Dietary or supplemental L-carnitine that is not absorbed by enterocytes is degraded by colonic bacteria to form two principal products, trimethylamine and γ-butyrobetaine. γ-Butyrobetaine is eliminated in the feces; trimethylamine is efficiently absorbed and metabolized to trimethylamine-N-oxide, which is excreted in the urine (13).

Biological Activities

Mitochondrial oxidation of long-chain fatty acids

L-Carnitine is synthesized primarily in the liver but also in the kidneys and then transported to other tissues. It is most concentrated in tissues that use fatty acids as their primary fuel, such as skeletal and cardiac muscle. In this regard, L-carnitine plays an important role in energy production by conjugating to fatty acids for transport from the cytosol into the mitochondria (6).

L-Carnitine is required for mitochondrial β-oxidation of long-chain fatty acids for energy production (1). Long-chain fatty acids must be esterified to L-carnitine (acylcarnitine) in order to enter the mitochondrial matrix where β-oxidation occurs (Figure 3). On the outer mitochondrial membrane, CPTI (carnitine-palmitoyl transferase I) catalyzes the transfer of medium/long-chain fatty acids esterified to coenzyme A (CoA) to L-carnitine. This reaction is a rate-controlling step for the β-oxidation of fatty acid (13). A transport protein called CACT (carnitine-acylcarnitine translocase) facilitates the transport of acylcarnitine across the inner mitochondrial membrane. On the inner mitochondrial membrane, CPTII (carnitine-palmitoyl transferase II) catalyzes the transfer of fatty acids from L-carnitine to free CoA. Fatty acyl-CoA is then metabolized through β-oxidation in the mitochondrial matrix, ultimately yielding propionyl-CoA and acetyl-CoA (6). Carnitine is eventually recycled back to the cytosol (Figure 3).

Figure 3. The Mitochondrial Carnitine Shuttling System. Medium- and long-chain fatty acids esterfied to CoA are transesterified to carnitine in a reaction catalyzed by CPTI in the outer mitochondrial membrane. Acylcarnitine can diffuse across the outer mitochondrial membrane and then be transported across the inner membrane by CACT. In the mitochondrial matrix, CPTII catalyzes the re-formation of acyl-CoA from acylcarnitine. Acyl-CoA is catabolized in the beta-oxidation pathway to generate acetyl-CoA, which enters the citric acid cycle. Carnitine can be removed from the mitochondrial matrix via CACT. Alternatively, the enzyme CAT can catalyze the transfer of short-chain fatty acids from CoA to carnitine, and the newly formed acyclarnitine can be exported into the cytosol via CACT. Thus, besides its role in long/medium-chain fatty acid transport and oxidation, carnitine is essential to regulate the availability of nonesterified (unbound) CoA within the mitochondrial matrix and can be used as a reservoir for excess acetyl groups produced during fatty acid and pyruvate oxidation.

[Figure 3 - Click to Enlarge]

Regulation of energy metabolism through modulation of acyl CoA:CoA ratio

Free (nonesterified) CoA is required as a cofactor for numerous cellular reactions. The flux through pathways that require nonesterified CoA, such as the oxidation of glucose, may be reduced if all the CoA available in a given cell compartment is esterified. Carnitine can increase the availability of nonesterified CoA for these other metabolic pathways (6). Within the mitochondrial matrix, CAT (carnitine acetyl transferase) catalyzes the transesterification of short- and medium-chain fatty acids from CoA to carnitine (Figure 3). The resulting acylcarnitine esters (e.g., acetylcarnitine) can remain in the mitochondrial matrix or be exported back into the cytosol via CACT. Free (nonesterified) CoA can then participate in other reactions, such as the generation of acetyl-CoA from pyruvate in a reaction catalyzed by pyruvate dehydrogenase (14). Acetyl-CoA can then be oxidized to produce energy (ATP) in the citric acid cycle.

Other functions in cellular metabolism

In addition to its importance for energy production, L-carnitine was shown to display direct antioxidant properties in vitro (15). Age-related declines in mitochondrial function and increases in mitochondrial oxidant production are thought to be important contributors to the adverse effects of aging. Tissue L-carnitine concentrations have been found to decline with age in humans and animals (16). The expression of most proteins involved in the transport of carnitine (OCTN2) and the acylcarnitine shuttling system across the mitochondrial membrane (CPTIa, CPTII, and CAT; Figure 3) was also found to be much lower in the white blood cells of healthy older adults than of younger adults (17).

Preclinical studies in rodents showed that supplementation with high doses of acetyl-L-carnitine (ALCAR; Figure 1) reversed a number of age-related changes in liver mitochondrial function yet increased liver mitochondrial oxidant production (18). ALCAR supplementation in rats has also been found to improve or reverse age-related mitochondrial declines in skeletal and cardiac muscular function (19, 20). Co-supplementation of aged rats with L-carnitine and α-lipoic acid blunted age-related increases in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and DNA strand breaks in a variety of tissues (heart, skeletal muscle, and brain) (21-30). Co-supplementation for three months improved both the number of total and intact mitochondria and mitochondrial ultrastructure of neurons in the hippocampus (30). Although ALCAR exerts antioxidant activities in rodents, it is not known whether taking high doses of ALCAR will have similar effects in humans.


Nutritional carnitine deficiencies have not been identified in healthy people without metabolic disorders, suggesting that most people can synthesize enough L-carnitine (1). Even strict vegetarians (vegans) show no signs of carnitine deficiency, despite the fact that most dietary carnitine is derived from animal sources (9). Infants, particularly premature infants, are born with low stores of L-carnitine, which could put them at risk of deficiency given their rapid rate of growth. One study reported that infants fed carnitine-free, soy-based formulas grew normally and showed no signs of a clinically relevant carnitine deficiency; however, some biochemical measures related to lipid metabolism differed significantly from infants fed the same formula supplemented with L-carnitine (31). Soy-based infant formulas are now fortified with the amount of L-carnitine normally found in human milk (32).

Carnitine status

Renal filtration maintains plasma concentrations of free carnitine around 40 to 50 micromoles (µmol)/L, while plasma concentrations of acetyl-L-carnitine (ALCAR; the most abundant carnitine ester) are around 3 to 6 µmol/L (8). Regardless of the etiology, plasma concentrations of free carnitine ≤20 µmol/L and increased acylcarnitine/free carnitine ratios (≥0.4) are considered abnormal (6). Low carnitine status is generally due to impaired mitochondrial energy metabolism or to carnitine not being efficiently reabsorbed by the kidneys. The rate of carnitine excretion is not a useful indicator of carnitine status because it can vary with dietary carnitine intake and other physiologic parameters. At present, there is no test that assesses functional carnitine deficiency in humans (6).

Primary systemic carnitine deficiency

Primary systemic carnitine deficiency is a rare, autosomal recessive disorder caused by mutations (including deletions) in the SLC22A5 gene coding for carnitine transporter protein OCTN2 (organic cation transporter novel 2) (33). Individuals with defective carnitine transport have poor intestinal absorption of dietary L-carnitine, impaired L-carnitine reabsorption by the kidneys (i.e., increased urinary loss of L-carnitine), and defective L-carnitine uptake by muscles (4). The clinical presentation can vary widely depending on the type of mutation affecting SLC22A5 and the phenotypic manifestation of the mutation, i.e., age of onset, organ involvement, and severity of symptoms at the time of diagnosis (34). The disorder usually presents in early childhood and is characterized by episodes of hypoketotic hypoglycemia (that can cause encephalopathy), hepatomegaly, elevated liver enzymes (transaminases), and hypoammonemia in infants; progressive cardiomyopathy, elevated creatine kinase, and skeletal myopathy in childhood; or fatigability in adulthood (34, 35). The metabolic and myopathic symptoms in infants and children can be fatal such that treatment should start promptly to prevent irreversible organ damage (34). The diagnosis is established by demonstrating abnormally low plasma free carnitine concentrations, reduced carnitine transport of fibroblasts from skin biopsy, and molecular analysis of the gene coding for OCTN2 (33, 34). Treatment consists of pharmacological doses of L-carnitine that are meant to maintain a normal blood carnitine concentration, thereby preventing the risk of hypoglycemia and correcting metabolic and myopathic manifestations (34).

Secondary carnitine deficiency or depletion

Secondary carnitine deficiency or depletion may result from either genetic or acquired conditions.

Hereditary causes include genetic defects in the metabolism of amino acids, cholesterol, and fatty acids, such as propionyl-CoA carboxylase deficiency (aka propionic acidemia) and medium chain acyl-CoA dehydrogenase deficiency (36). Such inherited disorders lead to a buildup of organic acids, which are subsequently removed from the body via urinary excretion of acylcarnitine esters. Increased urinary losses of carnitine can lead to the systemic depletion of carnitine (6).

Systemic carnitine depletion can also occur in disorders of impaired renal reabsorption. For instance, Fanconi's syndrome is a hereditary or acquired condition in which the proximal tubular reabsorption function of the kidneys is impaired (37). This malfunction consequently results in increased urinary losses of carnitine. Patients with renal disease who undergo hemodialysis are at risk for secondary carnitine deficiency because hemodialysis removes carnitine from the blood (see End-stage renal disease) (38).

One example of an exclusively acquired carnitine deficiency involves chronic use of pivalate-conjugated antibiotics. Pivalate is a branched-chain fatty acid anion that is metabolized to form an acyl-CoA ester, which is transesterified to carnitine and subsequently excreted in the urine as pivaloyl carnitine. Urinary losses of carnitine via this route can be 10-fold greater than the sum of daily carnitine intake and biosynthesis and lead to systemic carnitine depletion (see Drug interactions) (39).

Finally, a number of inherited mutations in genes involved in carnitine shuttling and fatty acid oxidation pathways do not systematically result in carnitine depletion (such that carnitine supplementation may not help mitigate the symptoms) but lead to abnormal profiles of acylcarnitine esters in blood (35, 40).

Nutrient interactions

Endogenous biosynthesis of L-carnitine is catalyzed by the concerted action of four different enzymes (see Metabolism and Bioavailability) (Figure 2). This process requires two essential amino acids (lysine and methionine), iron (Fe2+), vitamin B6 in the form of pyridoxal 5’-phosphate, niacin in the form of nicotinamide adenine dinucleotide (NAD), and may also require vitamin C (ascorbate) (4). One of the earliest symptoms of vitamin C deficiency is fatigue, thought to be related to decreased synthesis of L-carnitine (41).

Disease Treatment

In most studies discussed below, it is important to note that treatment with L-carnitine or acyl-L-carnitine esters (i.e., acetyl-L-carnitine [ALCAR], propionyl-L-carnitine; Figure 1) was generally used as an adjunct to standard medical therapy, not in place of it. It is also important to consider the fact that the bioavailability of L-carnitine and acylcarnitine derivatives administered orally is low (~10-20%) (see Metabolism and Bioavailability). Intravenous administration is more likely to increase plasma carnitine concentration, yet homeostatic mechanisms tightly control blood concentration through metabolism and renal excretion: Up to 90% of 2 g of L-carnitine administered intravenously is excreted into the urine within 12 to 24 hours. Only a fraction of the dose is thought to enter the endogenous carnitine pool — largely found in skeletal muscle (reviewed in 8).

Type 2 diabetes mellitus

Several small clinical trials have explored whether supplemental L-carnitine could improve glucose tolerance in people with impaired glucose metabolism. A potential benefit of L-carnitine in these patients is based on the fact that it can (i) increase the oxidation of long-chain fatty acids which accumulation may contribute to insulin resistance in skeletal muscle, and (ii) enhance glucose utilization by reducing acyl-CoA concentration within the mitochondrial matrix (see Biological Activities) (42). A meta-analysis of five trials in participants with either impaired fasting glucose, type 2 diabetes mellitus, or nonalcoholic steatohepatitis found evidence of an improvement in insulin resistance with supplemental L-carnitine compared to placebo (43). Another meta-analysis of four randomized, placebo-controlled trials found evidence of a reduction in fasting plasma glucose concentration and no improvement of glycated hemoglobin concentration in subjects with type 2 diabetes mellitus supplemented with acetyl-L-carnitine (ALCAR) (44). A third meta-analysis of 16 trials suggested that supplementation with (acyl)-L-carnitine may reduce fasting blood glucose and glycated hemoglobin concentrations, but not resistance to insulin (45). In a recent double-blind, randomized, placebo-controlled trial, the effect of ALCAR was examined in 229 participants treated for type 2 diabetes mellitus, hypertension, and dyslipidemia (46). ALCAR supplementation (1 g/day for 6 months) had no effect on systolic or diastolic blood pressure, markers of kidney function (i.e., glomerular filtration rate and albuminuria), markers of glucose homeostasis (i.e., glucose disposal rate, glycated hemoglobin concentration, and a measure of insulin resistance), and blood lipid profile (i.e., concentrations of triglycerides, lipoprotein (a), LDL-cholesterol, HDL-cholesterol, and total cholesterol) (46).

Cardiovascular disease

In the studies discussed below it is important to note that treatment with L-carnitine or propionyl-L-carnitine was used as an adjunct (in addition) to appropriate medical therapy, not in place of it.

Myocardial infarction

Myocardial infarction (MI) occurs when an atherosclerotic plaque in a coronary artery ruptures and obstructs the blood supply to the heart muscle, causing injury or damage to the heart (see the page on Heart Attack). Several clinical trials have explored whether L-carnitine administration immediately after MI diagnosis could reduce injury to heart muscle resulting from ischemia and improve clinical outcomes. An early trial in 160 men and women diagnosed with a recent MI showed that oral L-carnitine (4 g/day) in addition to standard pharmacological treatment for one year significantly reduced mortality and the occurrence of angina attacks compared to the control (47). In another controlled trial in 96 patients, treatment with intravenous L-carnitine (5 g bolus followed by 10 g/day for three days) following a MI resulted in lower concentrations of creatine kinase-MB and troponin-I, two markers of cardiac injury (48). However, not all clinical trials have found L-carnitine supplementation to be beneficial after MI. For example, in a randomized, double-blind, placebo-controlled trial in 60 participants diagnosed with an acute MI, neither mortality nor echocardiographic measures of cardiac function differed between patients treated with intravenous L-carnitine (6 g/day) for seven days followed by oral L-carnitine (3 g/day) for three months and those given a placebo (49). Another randomized placebo-controlled trial in 2,330 patients with acute MI, L-carnitine therapy (9 g/day intravenously for five days, then 4 g/day orally for six months) did not affect the risk of heart failure and death six months after MI (50).

A 2013 meta-analysis of randomized controlled trials found that L-carnitine therapy in patients who experienced an MI reduced the risks of all-cause mortality (-27%; 11 trials; 3,579 participants), ventricular arrhythmias (-65%; five trials; 229 participants), and angina attacks (-40%; 2 trials; 261 participants), but had no effect on the risks of having a subsequent myocardial infarction or developing heart failure (51). Because about 90% of oral L-carnitine supplements is unlikely to be absorbed, one could ask whether the efficacy is equivalent between protocols using both intravenous and oral administration and those using oral administration only (8). This has not been examined in subgroup analyses.

Heart failure

Heart failure is described as the heart's inability to pump enough blood for all of the body's needs (see the page on Heart Failure). In coronary heart disease, accumulation of atherosclerotic plaque in the coronary arteries may prevent heart regions from getting adequate circulation, ultimately resulting in cardiac damage and impaired pumping ability. Myocardial infarction may also damage the heart muscle, which could potentially lead to heart failure. Further, the diminished heart’s capacity to pump blood in cases of dilated cardiomyopathy may lead to heart failure. Because physical exercise increases the demand on the weakened heart, measures of exercise tolerance are frequently used to monitor the severity of heart failure. Echocardiography is also used to determine the left ventricular ejection fraction (LVEF), an objective measure of the heart's pumping ability. An LVEF of less than 40% is indicative of systolic heart failure (52).

An abnormal acylcarnitine profile and a high acylcarnitine to free carnitine ratio in the blood of patients with heart failure have been linked to disease severity and poor prognosis (53-55). Addition of L-carnitine to standard medical therapy for heart failure has been evaluated in several clinical trials. A 2013 meta-analysis of 17 randomized, placebo-controlled studies in a total of 1,625 participants with heart failure found that oral L-carnitine (1.5-6 g/day for seven days to three years) significantly improved several measures of cardiac functional capacity (including exercise tolerance and markers of the left ventricle function), yet had no impact on all-cause mortality (56).

Angina pectoris

Angina pectoris is chest pain that occurs when the coronary blood supply is insufficient to meet the metabolic needs of the heart muscle (as with ischemic heart disease; see the page on Angina Pectoris) (57). In a prospective cohort study in over 4,000 participants with suspected angina pectoris, elevated concentrations of certain acylcarnitine intermediates in blood were associated with fatal and non-fatal acute myocardial infarction (58). In early studies, the addition of oral L-carnitine or propionyl-L-carnitine to pharmacologic therapy for chronic stable angina modestly improved exercise tolerance and decreased electrocardiographic signs of ischemia during exercise testing in some angina patients (59-61). Another early study examined hemodynamic and angiographic variables before, during, and after administering intravenous propionyl-L-carnitine (15 mg/kg body weight) in men with myocardial dysfunction and angina pectoris (62). In this study, propionyl-L-carnitine decreased myocardial ischemia, evidenced by significant reductions in ST-segment depression and left ventricular end-diastolic pressure (62). No recent and/or large-scale studies have been conducted to further examine the potential benefit of L-carnitine or propionyl-L-carnitine in the management of angina pectoris.

Intermittent claudication in peripheral arterial disease

In peripheral arterial disease, atherosclerosis of the arteries that supply the lower extremities may diminish blood flow to the point that the metabolic needs of exercising muscles are not sufficiently met, thereby leading to ischemic leg or hip pain known as claudication (see the page on Intermittent Claudication in Peripheral Arterial Disease) (63). Several clinical trials have found that treatment with propionyl-L-carnitine improves exercise tolerance in some patients with intermittent claudication. In a double-blind, placebo-controlled, dose-titration study, 1 to 3 g/day of oral propionyl-L-carnitine for 24 weeks was well tolerated and improved maximal walking distance in patients with intermittent claudication (64). In a randomized, placebo-controlled study of 495 patients with intermittent claudication, 2 g/day of propionyl-L-carnitine for 12 months significantly increased maximal walking distance and the distance walked prior to the onset of claudication in patients whose initial maximal walking distance was less than 250 meters (m), but no effect was seen in patients who had an initial maximal walking distance greater than 250 m (65). More recent trials have associated oral propionyl-L-carnitine supplementation (2 g/day for several months) with improved walking distance and claudication onset time (66, 67), as well as with higher pain-free walking distance and higher ankle-brachial index (a diagnostic measure of peripheral arterial disease) (68). Two 2013 systematic reviews of interventions concluded that the modest benefit of propionyl-L-carnitine on walking performance was equivalent or superior to that obtained with drugs approved for claudication in the US (e.g., pentoxyphylline, cilostazol) yet inferior to improvements seen with supervised exercise interventions (69, 70).

End-stage renal disease

L-Carnitine and short/medium-chain acylcarnitine molecules are removed from the circulation during hemodialysis. Both L-carnitine loss into the dialysate and impaired synthesis by the kidneys contribute to a progressive carnitine deficiency in patients with end-stage renal disease (ESRD) undergoing hemodialysis (71). The low clearance of long-chain acylcarnitine molecules leads to a high acylcarnitine-to-L-carnitine ratio that has been associated with a higher risk of cardiovascular mortality (72). Carnitine depletion in patients undergoing hemodialysis may lead to various conditions, such as muscle weakness and fatigue, plasma lipid abnormalities, and refractory anemia. A 2014 systematic review and meta-analysis of 31 randomized controlled trials in a total of 1,734 patients with ESRD found that L-carnitine treatment — administered either orally or intravenously — resulted in reductions of serum C-reactive protein (a marker of inflammation and predictor of mortality in patients undergoing hemodialysis) and LDL-cholesterol, although the latter was not deemed to be clinically relevant (73). There was no effect of L-carnitine on other serum lipids (i.e., total and HDL-cholesterol, triglycerides) and anemia-related indicators (i.e., hemoglobin concentration, hematocrit, albumin, and required dose of recombinant erythropoietin) (73).

The US National Kidney Foundation did not recommend routine administration of L-carnitine to subjects undergoing dialysis yet encouraged the development of trials in patients with select symptoms that do not respond to standard therapy, i.e., persistent muscle cramps or hypotension during dialysis, severe fatigue, skeletal muscle weakness or myopathy, cardiomyopathy, and anemia requiring large doses of erythropoietin (74, 75).

Finally, the use of L-carnitine (10-20 mg/kg body weight given as a slow bolus injection) is approved by the US FDA to treat L-carnitine deficiency in subjects with ESRD undergoing hemodialysis (76).

Peripheral neuropathy

Antiretroviral-related peripheral neuropathy

The use of certain antiretroviral agents (nucleoside analogs) has been associated with an increased risk of developing peripheral neuropathy in HIV-positive individuals (77, 78). Small, uncontrolled, open-label intervention studies have suggested a beneficial effect of acetyl-L-carnitine (ALCAR) in patients with painful neuropathies. An early uncontrolled study found that 10 out of 16 HIV-positive subjects with painful neuropathy reported improvement after three weeks of intravenous or intramuscular ALCAR treatment (79). Results from another uncontrolled intervention in 21 HIV-positive patients suggested that long-term (two to four years) oral ALCAR supplementation (1.5 g/day) may be a beneficial adjunct to antiretroviral therapy to improve neuropathic symptoms in some HIV-infected individuals (80, 81). Additionally, two small studies in participants presenting with antiretroviral-induced neuropathy found significant reduction in subjects' mean pain intensity with oral ALCAR (1-3 g/day) for 4 to 24 weeks, but no effect on objective neurophysiological parameters was found (82, 83).

A double-blind, placebo-controlled trial in 90 HIV-positive patients with symptomatic distal symmetrical polyneuropathy found no benefit of intramuscular injection with 1 g/day of ALCAR for two weeks in the intention-to-treat analysis, but there was some pain relief in the group of 66 patients who completed the trial (84). Large-scale, controlled studies are needed before any conclusions can be drawn.

Diabetic peripheral neuropathy

Peripheral nerve dysfunction occurs in about 50% of people with diabetes mellitus, and chronic neuropathic pain is present in about one-third of people with diabetic peripheral neuropathy (85). Advanced stages of diabetic peripheral neuropathy can lead to recurrent foot ulcers and infections, and eventually amputations (86). A 2019 systematic review (87) identified three placebo-controlled interventions that examined the effect of oral supplementation with acetyl-L-carnitine (ALCAR; 1.5-3.0 g/day for one year) in individuals with diabetic peripheral neuropathy (3, 88). Low-quality evidence suggested a lower level of pain with ALCAR, as measured with a visual scale analog. Low-quality evidence from another trial that compared the effect of ALCAR (1.5 g/day) with that of methylcobalamin (1.5 mg/day) for 24 weeks suggested no difference between treatments regarding the extent of functional disability (using the Neuropathy Disability Scale) or measures of symptom quality and severity (using the Neuropathy Symptom Scale) (89).

Chemotherapy-induced peripheral neuropathy

A few randomized, double-blind, placebo-controlled trials have examined whether ALCAR might help prevent or treat chemotherapy-induced peripheral neuropathy. A trial in 150 participants with either ovarian cancer or castration-resistant prostate cancer found no evidence that ALCAR (1g every 3 days) given with the anticancer drug sagopilone (for up to six cycles of treatment) reduced the overall risk of peripheral neuropathy compared to a placebo (90). However, ALCAR reduced the risk of high-grade sagopilone-induced neuropathy (90). In contrast, another trial in 409 women with breast cancer found that ALCAR (3 g/day for 24 weeks) increased anticancer drug (taxanes)-induced peripheral neuropathy and decreased measures of functional status compared to placebo (91). A follow-up study reported that the negative impact of 24-week treatment with ALCAR was still observed at week 52; however, no  differences between ALCAR and placebo were apparent at week 104 (92). Finally, one trial in 239 participants already suffering from chemotherapy-induced peripheral neuropathy reported a reduction in the severity of neuropathic symptoms with ALCAR (3 g/day for eight weeks) compared to placebo (93). Improvements in electrophysiological parameters were also observed with ALCAR treatment (93).

The results from these trials are conflicting and thus difficult to interpret. The efficacy of ALCAR in the prevention and treatment of chemotherapy-induced peripheral neuropathy remains to be established (94).


A 2018 meta-analysis identified 12 randomized controlled trials, including 791 participants, that examined the effect of ALCAR on symptoms of depression (95). Evidence from nine trials suggested a reduction in depressive symptoms with ALCAR (3 g/day for a median 8 weeks) compared to a placebo. Three trials that compared ALCAR treatment (1-3 g/day for 7-12 weeks) and antidepressant medications found ALCAR was as effective as antidepressants in treating depressive symptoms (95). Another meta-analysis of trials that compared the safety profile of antidepressants found evidence of fewer adverse effects, and consequently, better adherence to treatment with ALCAR compared to placebo and in contrast to classical pharmaceutical agents (96).

Alzheimer's disease

The metabolomic profiling of acylcarnitine molecules showed variations in serum concentrations of subjects along the continuum from cognitively healthy to affected by Alzheimer's disease (97). Changes in the blood concentrations of specific acylcarnitines in subjects with either subjective memory complaints, mild cognitive impairment, or Alzheimer's disease, compared to cognitively healthy peers may reflect changes in the transport of fatty acids into the mitochondria and/or impairments in energy production. Several clinical trials conducted in the 1990s  examined the effect of acetyl-L-carnitine (ALCAR) treatment on the cognitive performance of patients clinically diagnosed with Alzheimer's disease. Early, small trials suggested a beneficial effect of ALCAR with respect to cognitive decline (98-100), whereas later, larger trials found little-to-no effect compared to placebo (101-103). However, a 2003 systematic review highlighted differences in methodologies between early and later studies that make it difficult to compare results (104). Nevertheless, the pooled analysis of 16 trials suggested improvements in the summary measure of patients' global functioning (assessed with the Clinical Global Impressions [CGI-I] scale) after 12 and 24 weeks of (but not after 52 weeks) of ALCAR treatment (1-3 g/day) and in cognitive performance (assessed with the Mini-Mental State Examination [MMSE] scale) after 24 weeks (but not at 12 or 52 weeks) (104). A 2003 meta-analysis of 21 trials found that ALCAR was superior to placebo in several psychometric tests assessing global patient functioning, attention, memory, and some intellectual functions (105).

Hepatic encephalopathy

Hepatic encephalopathy refers to the occurrence of a spectrum of neuropsychiatric signs or symptoms in individuals with acute or chronic liver disease (106). Subclinical hepatic encephalopathy may not feature any symptoms beyond abnormal behavior on psychometric tests or symptoms that are nonspecific in nature. In contract, overt hepatic encephalopathy can present with disorientation, obvious personality change, inappropriate behavior, somnolence, stupor, confusion, and coma (106). Changes in mental status are thought to be caused by the liver failing to detoxify neurotoxic compounds like ammonia. A 2019 systematic review of five placebo-controlled trials conducted by one group of investigators examined the effect of acetyl-L-carnitine (ALCAR) in 398 participants with cirrhosis and portal hypertension (high blood pressure in the portal vein) and presenting with either subclinical or overt hepatic encephalopathy. ALCAR was either administered orally (4 g/day for 90 days) in four trials or intravenously (4 g/day for three days) in one trial. ALCAR was found to significantly reduce blood ammonium concentration compared to placebo. However, none of the trials reported on serious adverse outcomes, including mortality. Additionally, the evidence was too limited to assess the impact on quality of life or mental and physical fatigue.

Cancer-related fatigue

Fatigue is not uncommon in people who have undergone chemotherapy and survived cancer, with fatigue symptoms depending on the specific type of cancer and treatment. Cancer-related fatigue can persist well beyond the end of chemotherapy and be associated with cognitive and functional decline, insomnia, depression, and a reduction in the quality of life (107). A 2017 systematic review and meta-analysis identified 12 intervention studies that assessed the effect of L-carnitine or ALCAR on cancer-related fatigue (reported as a primary or secondary outcome) in cancer survivors (108). Three studies had no control arm, eight studies were open-label, and eight studies included fewer than 100 participants. Overall, only three studies were deemed of good quality. The meta-analysis of these three randomized, double-blind, placebo-controlled trials found no effect of L-carnitine (0.25-4 g/day for 1 week to 3 months) or ALCAR (3 g/day for 6 months) on the level of cancer-related fatigue (108).


L-Carnitine is concentrated in the epididymis, where sperm mature and acquire their motility (109). An early cross-sectional study of 101 fertile and infertile men found that L-carnitine concentrations in semen were positively correlated with the number of sperm, the percentage of motile sperm, and the percentage of normal appearing sperm in the sample (110), suggesting that L-carnitine may play an important role in male fertility. One placebo-controlled, double-blind, cross-over trial in 86 subjects with fertility issues found that supplementation with L-carnitine (2 g/day) for two months improved sperm quality, as evidenced by increases in sperm concentration and motility (111). In another placebo-controlled trial conducted by the same group, similar improvements in sperm motility were observed in participants supplemented with 2g/day of L-carnitine and 1 g/day of acetyl-L-carnitine (ALCAR) for six months (112). In both trials, the effect of carnitine was greater in the most severe cases of asthenozoospermia (reduced sperm motility) at baseline (111, 112). Another placebo-controlled, double-blind, randomized study in 44 men with idiopathic asthenozoospermia found an increase in sperm motility in those given ALCAR alone (3 g/day) or ALCAR (1 g/day) plus L-carnitine (2 g/day) compared to those given L-carnitine alone (2 g/day) or a placebo (113). However, a pooled analysis of the two trials that employed ALCAR found no significant effect of ALCAR and L-carnitine on sperm concentration, motility, and morphology (114). Evidence from larger scale clinical trials is still needed to determine whether L-carnitine and ALCAR could play a role in the treatment of male infertility.

Physical health


Frailty is a syndrome prevalent among geriatric populations and characterized by a functional decline and a loss of independence to perform the activities of daily living. Frailty in individuals may include at least three of the following symptoms: unintentional weight loss, exhaustion (poor endurance), weakness (low grip strength), slowness, and physical inactivity (115). It is believed that early stages of frailty are amenable to interventions that could avert adverse outcomes, including the increased risk of hospitalization and premature death (116). The suggestion that carnitine deficiency may lead to frailty through mitochondrial dysfunction (117) has been examined in one trial. This randomized, double-blind, placebo-controlled trial in 58 older adults identified as "pre-frail" found an decrease in a Frailty Index score and an improvement in the hand grip test in individuals supplemented with L-carnitine (1.5 g/day) over 10 weeks but not in those given a placebo (118). However, there was no difference in Frailty Index and hand grip test scores between supplemental L-carnitine and placebo groups.

Skeletal muscle wasting

Loss of skeletal muscle mass is associated with a decrease in muscle strength and occurs with aging (119), as well as in several pathological conditions (120-122). Based on preclinical studies, it has been suggested that L-carnitine supplementation could limit the imbalance between protein anabolism (synthesis) and catabolism (degradation) that leads to skeletal muscle wasting (42). A randomized, double-blind, placebo-controlled trial in 28 older women (ages, 65-70 years) found no effect of L-carnitine supplementation (1.5 g/day for 24 weeks) on serum pro-inflammatory cytokine concentrations, body mass and composition (lean [fat-free] mass and skeletal muscle mass), or measures of skeletal muscle strength (123). In contrast, a retrospective cohort study in patients with cirrhosis found a reduced rate of skeletal muscle loss over at least six months in those who were administered L-carnitine (N=35; mean dose, 1.02 g/day) compared to those who were not (124). Of note, supplementation with L-carnitine was given in patients with cirrhosis to control hyperammonemia (N=27), to reduce muscle cramps (N=6), or to prevent carnitine deficiency (N=2). One major limitation of this study beyond its retrospective design is that patients who received L-carnitine had a significantly different clinical presentation; in particular, liver dysfunction was significantly more severe in these patients than in those who were not supplemented (124).

Muscle cramps

Muscle cramps are involuntary and painful contractions of skeletal muscles. Two uncontrolled studies conducted in participants with cirrhosis found that L-carnitine supplementation was safe to use at doses of 0.9 to 1.2 g/day for eight weeks (125) and 1 g/day for 24 weeks (126) and might be considered to control the frequency of cramps. However, whether supplemental L-carnitine can be efficacious to limit the incidence of muscle cramps in patients with cirrhosis remains unknown. An open-label, non-randomized trial in 69 patients with either type 1 or type 2 diabetes mellitus found a reduction in the incidence of muscle cramps and an improvement in the quality of life of those prescribed 0.6 g/day of L-carnitine for four months compared to controls (127). In contrast, there is little evidence to date to suggest that supplemental L-carnitine could reduce muscle cramps in patients undergoing hemodialysis (128). Well-designed trials are necessary to examine whether L-carnitine could be helpful in the management of cramps.

Physical performance

Interest in the potential of L-carnitine supplementation to improve athletic performance is related to its important roles in energy metabolism. A number of small, poorly controlled studies have reported that either acute (dose given one hour before exercise bout) or short-term (two to three weeks) supplementation with L-carnitine (2 to 4 g/day) supported energy production, cardiorespiratory fitness, and endurance capacity during physical exercise (reviewed in 129). However, in a double-blind, placebo-controlled trial in 32 healthy adults, propionyl-L-carnitine (1 g/day or 3 g/day) for eight weeks did not improve aerobic or anaerobic exercise performance (130). An intervention study compared the effect of L-carnitine supplementation (2 g/day for 12 weeks) on plasma and skeletal muscle carnitine concentrations and physical performance between 16 vegetarian and 8 omnivorous male participants (131). At baseline, plasma carnitine concentration was about 10% lower in vegetarian compared to omnivorous participants. However, the content carnitine in skeletal muscle, phosphocreatine, ATP, glycogen, and lactate, as well as measures of physical performance during exercise were equivalent between vegetarians and omnivores. While L-carnitine supplementation normalized plasma carnitine concentration in vegetarians to that observed in omnivores, there was no effect on energy metabolism and physical performance compared to no supplementation and between vegetarians and omnivores (131).



The normal rate of L-carnitine biosynthesis in humans ranges from 0.16 to 0.48 mg/kg of body weight/day (4). Thus, a 70 kg (154 1b) person would synthesize between 11 and 34 mg of carnitine per day. This rate of synthesis, combined with efficient (95%) L-carnitine reabsorption by the kidneys, is sufficient to prevent deficiency in generally healthy people, including strict vegetarians (132).

Food sources

Meat, poultry, fish, and dairy products are the richest sources of L-carnitine, while fruit, vegetables, and grains contain relatively little L-carnitine. Omnivorous diets have been found to provide 23 to 135 mg/day of L-carnitine for an average 70 kg person, while strict vegetarian diets may provide as little as 1 mg/day for a 70 kg person (8). Between 54% and 86% of L-carnitine from food is absorbed, compared to 5%-25% from oral supplements (0.6-7 g/day) (13). Non-milk-based infant formulas (e.g., soy formulas) should be fortified so that they contain 11 mg/L of L-carnitine. Some carnitine-rich foods and their carnitine content in milligrams (mg) are listed in Table 1.

Table 1. L-Carnitine Content of Selected Foods
Food Serving L-Carnitine (mg)
Beef steak 3 ounces* 81
Ground beef 3 ounces 80 
Pork 3 ounces  24 
Canadian bacon 3 ounces  20 
Milk (whole) 8 fluid ounces (1 cup) 
Fish (cod) 3 ounces 
Chicken breast 3 ounces 
Ice cream 4 ounces (½ cup) 
Avocado 1 medium 
American cheese 1 ounce 
Whole-wheat bread 2 slices  0.2 
Asparagus 6 spears (½ cup) 0.2
*A three-ounce serving of meat is about the size of a deck of cards.


Intravenous L-carnitine

Intravenous L-carnitine is available by prescription only for the treatment of primary and secondary L-carnitine deficiencies (76).

Oral L-carnitine

Oral L-carnitine is available by prescription for the treatment of primary and secondary L-carnitine deficiencies (76). It is also available without a prescription as a nutritional supplement; supplemental doses usually range from 0.5 to 2 g/day.


Acetyl-L-carnitine (ALCAR) is available without a prescription as a nutritional supplement. In addition to providing L-carnitine, it provides acetyl groups that may be used in the formation of the neurotransmitter, acetylcholine. Supplemental doses usually range from 0.5 to 2 g/day (133).


Propionyl-L-carnitine is not approved by the US FDA for use as a drug to prevent or treat any condition. It is, however, available without prescription as a nutritional supplement.

See Figure 1 for the chemical structures of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine.


Adverse effects

In general, L-carnitine appears to be well tolerated; no toxic effects have been reported in relation to intakes of high doses of L-carnitine. L-Carnitine supplementation may cause mild gastrointestinal symptoms, including nausea, vomiting, abdominal cramps, and diarrhea. Supplements providing more than 3 g/day may cause a "fishy" body odor. Acetyl-L-carnitine (ALCAR) has been reported to increase agitation in some Alzheimer's disease patients (133). Despite claims that L-carnitine or ALCAR might increase seizures in some individuals with seizure disorders (133), these are not supported by any scientific evidence (134). Only the L-isomer of carnitine is biologically active; the D-isomer may actually compete with L-carnitine for absorption and transport, thereby increasing the risk of L-carnitine deficiency (4). Supplements containing a mixture of the D- and L-isomers (D,L-carnitine) have been associated with muscle weakness in patients with kidney disease. Long-term studies examining the safety of ALCAR supplementation in pregnant and breast-feeding women are lacking (133).

Drug interactions

Pivalic acid combines with L-carnitine and is excreted in the urine as pivaloylcarnitine, thereby increasing L-carnitine losses (see also Secondary carnitine deficiency). Consequently, prolonged use of pivalic acid-containing antibiotics, including pivampicillin, pivmecillinam, pivcephalexin, and cefditoren pivoxil (Spectracef), can lead to secondary L-carnitine deficiency (135). The anticonvulsant valproic acid (Depakene) interferes with L-carnitine biosynthesis in the liver and forms with L-carnitine a valproylcarnitine ester that is excreted in the urine. However, L-carnitine supplements are necessary only in a subset of patients taking valproic acid. Risk factors for L-carnitine deficiency with valproic acid include young age (<2 years), severe neurological problems, use of multiple antiepileptic drugs, poor nutrition, and consumption of a ketogenic diet (135). There is insufficient evidence to suggest that nucleoside analogs used in the treatment of HIV infection (i.e., zidovudine [AZT], didanosine [ddI], zalcitabine [ddC], and stavudine [d4T] or certain cancer chemotherapy agents (i.e., ifosfamide, cisplatin) increase the risk of secondary L-carnitine deficiency (135).

Authors and Reviewers

Originally written in 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2012 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2019 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in December 2019 by:
Tory M. Hagen, Ph.D.
Principal Investigator, Linus Pauling Institute
Professor, Dept. of Biochemistry and Biophysics
Helen P. Rumbel Professor for Healthy Aging Research
Oregon State University

Copyright 2002-2024  Linus Pauling Institute


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Coenzyme Q10




Coenzyme Q10 is a member of the ubiquinone family of compounds. All animals, including humans, can synthesize ubiquinones, hence, coenzyme Q10 is not considered a vitamin (1). The name ubiquinone refers to the ubiquitous presence of these compounds in living organisms and their chemical structure, which contains a functional group known as a benzoquinone. Ubiquinones are fat-soluble molecules with anywhere from 1 to 12 isoprene (5-carbon) units. The ubiquinone found in humans, ubidecaquinone or coenzyme Q10, has a "tail" of 10 isoprene units (a total of 50 carbon atoms) attached to its benzoquinone "head" (Figure 1) (1).

Figure 1. The Different Redox Forms of Coenzyme Q10. Coenzyme Q10 exists in three oxidation states: the fully reduced ubiquinol form, the radical semiquinone intermediate, and the fully oxidized ubiquinone form.

[Figure 1 - Click to Enlarge]

Biological Activities

Coenzyme Q10 is soluble in lipids (fats) and is found in virtually all cell membranes, including mitochondrial membranes. The ability of the benzoquinone head group of coenzyme Q10 to accept and donate electrons is a critical feature to its function. Coenzyme Q10 can exist in three oxidation states (Figure 1): (i) the fully reduced ubiquinol form, CoQ10H2; (ii) the radical semiquinone intermediate, CoQ10H·; and (iii) the fully oxidized ubiquinone form, CoQ10.

Mitochondrial ATP synthesis

The conversion of energy from carbohydrates and fats to ATP, the form of energy used by cells, requires the presence of coenzyme Q10 in the inner mitochondrial membrane. As part of the mitochondrial electron transport chain, coenzyme Q10 accepts electrons from reducing equivalents generated during fatty acid and glucose metabolism and then transfers them to electron acceptors. At the same time, coenzyme Q10 contributes to transfer protons (H+) from the mitochondrial matrix to the intermembrane space, creating a proton gradient across the inner mitochondrial membrane. The energy released when the protons flow back into the mitochondrial interior is used to form ATP (Figure 2) (1). In addition to its role in ATP synthesis, mitochondrial coenzyme Q10 mediates the oxidation of dihydroorotate to orotate in the de novo pyrimidine synthesis.

Figure 2. Mitochondrial Electron Transport Chain. Coenzyme Q10 is a lipid-soluble component of the mitochondrial inner membrane that is critical to electron transport (in red) in the mitochondrial respiratory chain. Coenzyme Q10 carries electrons from complexes I and II to complex III, thus participating in ATP production.

[Figure 2 - Click to Enlarge]

Lysosomal function

Lysosomes are organelles within cells that are specialized for the digestion of cellular debris. The digestive enzymes within lysosomes function optimally at an acidic pH, meaning they require a permanent supply of protons. The lysosomal membranes that separate those digestive enzymes from the rest of the cell contain relatively high concentrations of coenzyme Q10. Research suggests that coenzyme Q10 plays an important role in the transport of protons across lysosomal membranes to maintain the optimal pH (2, 3)

Antioxidant functions

In its reduced form (CoQ10H2), coenzyme Q10 is an effective fat-soluble antioxidant that protects cell membranes and lipoproteins from oxidation. The presence of a significant amount of CoQ10H2 in cell membranes, along with enzymes capable of reducing oxidized CoQ10 back to CoQ10H2 (i.e., NAD(P)H oxidoreductases), supports the idea that CoQ10H2 is an important cellular antioxidant (4). CoQ10H2 has been found to inhibit lipid peroxidation when cell membranes and low-density lipoproteins (LDL) are exposed to oxidizing conditions. When LDL is oxidized, CoQ10H2 is the first antioxidant consumed. In isolated mitochondria, coenzyme Q10 can protect membrane proteins and mitochondrial DNA from the oxidative damage that accompanies lipid peroxidation (5). Moreover, when present, CoQ10H2 was found to limit the formation of oxidized lipids and the consumption of α-tocopherol (a form of vitamin E with antioxidant properties) (6). Indeed, in addition to neutralizing free radicals directly, CoQ10H2 is capable of regenerating antioxidants like α-tocopherol and ascorbate (vitamin C) (4). Finally, the role of coenzyme Q10 as an antioxidant is also exemplified by recent evidence showing that mitochondrial coenzyme Q10 deficiency causes an increased production of mitochondrial superoxide radical anion (O2•–) which might be driving insulin resistance in adipose and muscle tissues (7).

Nutrient interactions

Vitamin E

α-Tocopherol (vitamin E) and coenzyme Q10 are the principal fat-soluble antioxidants in membranes and lipoproteins. When α-tocopherol (α-TOH) neutralizes a free radical, such as a lipid peroxyl radical (LOO·), it becomes oxidized itself, forming α-TO·, which can in turn promote the oxidation of lipoproteins under certain conditions in the test tube, thus propagating a chain reaction. However, when the reduced form of coenzyme Q10 (CoQ10H2) reacts with α-TO·, α-TOH is regenerated and the semiquinone radical (CoQ10H·) is formed. It is possible for CoQ10H· to react with oxygen (O2) to produce superoxide anion radical (O2·-), which is a less reactive pro-oxidant than LOO·. However, CoQ10H· can also reduce α-TO· back to α-TOH, resulting in the formation of fully oxidized coenzyme Q10 (CoQ10), which does not react with O2 to form O2·- (Figure 3) (6, 8).

Figure 3. Antioxidant Activity of Coenzyme Q10. The peroxidation of unsaturated lipids leads to the formation of lipid peroxyl radicals that easily diffuse in biological systems. Peroxyl radicals react 1,000 times faster with alpha-tocopherol than with unsaturated lipids. The hydoxyl group in the chromal head of alpha-tocoperol (reduced form) can donate hydrogen to scavenge lipid peroxyl radicals, which halts their propagation in membranes and circulating lipoproteins. The presence of other antioxidants, such as coenzyme Q10 (ubiquinol), is required to regenerate the antioxidant capacity of alpha-tocopherol. 

[Figure 3 - Click to Enlarge]


Coenzyme Q10 deficiency has not been described in the general population, so it is generally assumed that normal biosynthesis, with or without a varied diet, provides sufficient coenzyme Q10 to sustain energy production in healthy individuals (9).

Primary coenzyme Q10 deficiency is a rare genetic disorder caused by mutations in genes involved in coenzyme Q10 biosynthetic pathway. To date, mutations in at least nine of these genes have been identified (1). As a result, primary coenzyme Q10 deficiency is a clinically heterogeneous disorder that includes five major phenotypes: (i) severe infantile multi-systemic disease, (ii) encephalomyopathy, (iii) cerebellar ataxia, (iv) isolated myopathy, and (v) nephrotic syndrome. Whereas most mitochondrial respiratory chain disorders are hardly amenable to treatments, oral coenzyme Q10 supplementation has been shown to improve muscular symptoms in some (yet not all) patients with primary coenzyme Q10 deficiency (10). Neurological symptoms in patients with cerebellar ataxia are only partially relieved by coenzyme Q10 (CoQ10H2) supplementation (10).

Secondary coenzyme Q10 deficiency results from mutations or deletions in genes that are not directly related to coenzyme Q10 biosynthetic pathway. Evidence of secondary coenzyme Q10 deficiency has been reported in several mitochondrial disorders, such as mitochondrial DNA depletion syndrome, Kearns-Sayre syndrome, or multiple acyl-CoA dehydrogenase deficiency (MADD) (10). Secondary coenzyme Q10 deficiency has also been identified in non-mitochondrial disorders, such as cardiofaciocutaneous syndrome and Niemann-Pick-type C disease (11). Because the therapeutic potential of supplemental coenzyme Q10 is limited to its capacity to restore electron transfer in a defective mitochondrial respiratory chain and/or to increase antioxidant defense, patients with secondary coenzyme Q10 deficiency may fail to respond to supplementation (see Disease Treatment).

Coenzyme Q10 concentrations have been found to decline gradually with age in a number of different tissues (5, 12), but it is unclear whether this age-associated decline constitutes a deficiency (see Disease Prevention) (13). Decreased plasma concentrations of coenzyme Q10 have been observed in individuals with diabetes mellitus, cancer, and congestive heart failure (see Disease Treatment). Lipid-lowering medications that inhibit the activity of 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase (statins), a critical enzyme in both cholesterol and coenzyme Q10 biosynthesis, decrease plasma coenzyme Q10 concentrations (see HMG-CoA reductase inhibitors [statins]), although it remains unproven that this has any clinical implications.

Disease Prevention


According to the free radical and mitochondrial theories of aging, oxidative damage of cell structures by reactive oxygen species (ROS) plays an important role in the functional declines that accompany aging (14). ROS are generated by mitochondria as a byproduct of ATP production. If not neutralized by antioxidants, ROS may damage mitochondria over time, causing them to function less efficiently and to generate more damaging ROS in a self-perpetuating cycle. Coenzyme Q10 plays an important role in mitochondrial ATP synthesis and functions as an antioxidant in mitochondrial membranes (see Biological Activities). One of the hallmarks of aging is a decline in energy metabolism in many tissues, especially liver, heart, and skeletal muscle. Tissue concentrations of coenzyme Q10 have been found to decline with age, thereby accompanying age-related declines in energy metabolism (12). Early animal studies have not been able to demonstrate an effect of lifelong dietary supplementation with coenzyme Q10 on the lifespan of rats or mice (15-17). Nonetheless, more recent studies have suggested that supplemental coenzyme Q10 could promote mitochondrial biogenesis and respiration (18, 19) and delay senescence in transgenic mice (19). Presently, there is limited scientific evidence to suggest that coenzyme Q10 supplementation prolongs life or prevents age-related functional declines in humans. In a small randomized controlled trial, elderly individuals (>70 years) who received a combination of selenium (100 µg/day) and coenzyme Q10 (200 mg/day) for four years reported an improvement in vitality, physical performance, and quality of life (20). Further, a 12-year follow-up of these participants showed a reduction in cardiovascular mortality with supplemental selenium and coenzyme Q10 compared to placebo (21).


Oxidative modification of low-density lipoproteins (LDL) in arterial walls is thought to represent an early event leading to the development of atherosclerosis. Reduced coenzyme Q10 (CoQ10H2) inhibits the oxidation of LDL in the test tube (in vitro) and works together with α-tocopherol (α-TOH) to inhibit LDL oxidation by regenerating α-TO· back to α-TOH. In the absence of a co-antioxidant, such as CoQ10H2 or vitamin C, α-TO· can, under certain conditions, promote the oxidation of LDL in vitro (6). Supplementation with coenzyme Q10 increases the concentration of CoQ10H2 in human LDL (22). Studies in apolipoprotein E-deficient mice, an animal model of atherosclerosis, found that coenzyme Q10 supplementation with supra-pharmacological amounts of coenzyme Q10 inhibited lipoprotein oxidation in the blood vessel wall and the formation of atherosclerotic lesions (23). Interestingly, co-supplementation of these mice with α-TOH and coenzyme Q10 was more effective in inhibiting atherosclerosis than supplementation with either α-TOH or coenzyme Q10 alone (24).

Another important step in the development of atherosclerosis is the recruitment of immune cells known as monocytes into the blood vessel walls. This recruitment is dependent in part on monocyte expression of cell adhesion molecules (integrins). Supplementation of 10 healthy men and women with 200 mg/day of coenzyme Q10 for 10 weeks resulted in significant decreases in monocyte expression of integrins, suggesting another potential mechanism for the inhibition of atherosclerosis by coenzyme Q10 (25). Although coenzyme Q10 supplementation shows promise as an inhibitor of LDL oxidation and atherosclerosis, more research is needed to determine whether coenzyme Q10 supplementation can inhibit the development or progression of atherosclerosis in humans.

Disease Treatment

Primary and secondary coenzyme Q10 deficiencies

Inherited coenzyme Q10 deficiencies are rare diseases that are clinically and genetically heterogeneous (see Deficiency). In individuals with primary coenzyme Q10 deficiency, early treatment with high-dose coenzyme Q10 supplementation (10–30 mg/kg/day in children and 1.2–3.0 g/day in adults) may improve the pathological phenotype, yet the effectiveness depends on the type of mutations affecting the coenzyme Q10 biosynthetic pathway (1, 26). Early treatment with pharmacological doses of coenzyme Q10 is essential to limit irreversible organ damage in coenzyme Q10-responsive deficiencies (1).

It is not clear to what extent coenzyme Q10 supplementation might have therapeutic benefit in patients with inherited secondary Q10 deficiencies. For example, multiple acyl-CoA dehydrogenase deficiency (MADD), caused by mutations in genes that impair the activity of enzymes involved in the transfer of electrons from acyl-CoA to coenzyme Q10, is usually responsive to riboflavin monotherapy yet patients with low coenzyme Q10 concentrations might also benefit from co-supplementation with coenzyme Q10 and riboflavin (27). Another study suggested clinical improvements in secondary coenzyme Q10 deficiency with supplemental coenzyme Q10 in patients presenting with ataxia (28). Because the cause of secondary coenzyme Q10 in inherited conditions is generally unknown, it is difficult to predict whether improving coenzyme Q10 status with supplemental coenzyme Q10 would lead to clinical benefits for the patients.

Finally, coenzyme Q10 deficiency can be secondary to the inhibition of HMG-CoA reductase by statin drugs (see Deficiency). A 2015 meta-analysis of six small, randomized controlled trials found no reduction in statin-induced muscle pain with 100 to 400 mg/day of supplemental coenzyme Q10 for one to three months (29). The trials failed to establish a diagnosis of relative coenzyme Q10 deficiency before the intervention started, hence limiting the conclusion of the meta-analysis. While statin therapy may not necessary lead to a reduction in circulating coenzyme Q10 concentrations, further research needs to examine whether secondary coenzyme Q10 deficiency might be predisposing patients to statin-induced myalgia (30).

Cardiovascular disease

Congestive heart failure

Impairment of the heart's ability to pump enough blood for all of the body's needs is known as congestive heart failure. In coronary heart disease (CHD), accumulation of atherosclerotic plaque in the coronary arteries may prevent parts of the cardiac muscle from getting adequate blood supply, ultimately resulting in heart damage and impaired pumping ability. Heart failure can also be caused by myocardial infarction, hypertension, diseases of the heart valves, cardiomyopathy, and congenital heart diseases. Because physical exercise increases the demand on the weakened heart, measures of exercise tolerance are frequently used to monitor the severity of heart failure. Echocardiography is also used to determine the left ventricular ejection fraction, an objective measure of the heart's pumping ability (31).

A study of 1,191 heart failure patients found that low plasma coenzyme Q10 concentration was a good biomarker of advanced heart disease (32). A number of small intervention trials that administered supplemental coenzyme Q10 to congestive heart failure patients have been conducted. A 2014 literature review identified seven small randomized controlled trials examining the effect of coenzyme Q10 supplementation (60-200 mg/day for ≤3 months in most trials) in heart failure patients (33). Pooling data from some of the trials showed an increase in serum coenzyme Q10 concentrations (three studies) but no effect on left ventricular ejection fraction (two studies) or exercise capacity (two studies) (33). However, a recent meta-analysis of 14 randomized, placebo-controlled trials in 2,149 participants with heart failure found that supplemental coenzyme Q10 (30-300 mg/day) resulted in a 39% reduction in mortality (seven studies), improved exercise capacity (four studies), but had no effect on left ventricular ejection fraction (nine studies) compared to placebo (34).

A trial is presently being conducted to assess the value of supplemental coenzyme Q10 and/or D-ribose in the treatment of congestive heart failure in patients with normal left ventricular ejection fraction (35).

Ischemia-reperfusion injury

The heart muscle may become oxygen-deprived (ischemic) as the result of myocardial infarction or during cardiac surgery. Increased generation of reactive oxygen species (ROS) when the heart muscle's oxygen supply is restored (reperfusion) might be an important contributor to myocardial damage occurring during ischemia-reperfusion (36). Pretreatment of animals with coenzyme Q10 has been found to preserve myocardial function following ischemia-reperfusion injury by increasing ATP concentration, enhancing antioxidant capacity and limiting oxidative damage, regulating autophagy, and reducing cardiomyocyte apoptosis (37). Another potential source of ischemia-reperfusion injury is aortic clamping during some types of cardiac surgery, such as coronary artery bypass graft (CABG) surgery. Early placebo-controlled trials found that coenzyme Q10 pretreatment (60-300 mg/day for 7-14 days prior to surgery) provided some benefit in short-term outcome measures after CABG surgery (38, 39). In a small randomized controlled trial in 30 patients, oral administration of coenzyme Q10 for 7 to 10 days before CABG surgery reduced the need for mediastinal drainage, platelet transfusion, and positive inotropic drugs (e.g. dopamine) and the risk of arrhythmia within 24 hours post-surgery (40). In one trial that did not find preoperative coenzyme Q10 supplementation to be of benefit, patients were treated with 600 mg of coenzyme Q10 12 hours prior to surgery (41), suggesting that preoperative coenzyme Q10 treatment may need to commence at least one week prior to CABG surgery to improve surgical outcomes. The combined administration of coenzyme Q10, lipoic acid, omega-3 fatty acids, magnesium orotate, and selenium at least two weeks before CABG surgery and four weeks after was examined in a randomized, placebo-controlled trial in 117 patients with heart failure (42). The treatment resulted in lower concentration of troponin-I (a marker of cardiac injury), shorter length of hospital stay, and reduced risk of postoperative transient cardiac dysfunction compared to placebo (42).

Although trials have included relatively few people and examined mostly short-term, post-surgical outcomes, the results are promising (43).

Periprocedural myocardial injury

Coronary angioplasty (also called percutaneous coronary intervention) is a nonsurgical procedure for treating obstructive coronary heart disease, including unstable angina pectoris, acute myocardial infarction, and multivessel coronary heart disease. Angioplasty involves temporarily inserting and inflating a tiny balloon into the clogged artery to help restore the blood flow to the heart. Periprocedural myocardial injury that occurs in up to one-third of patients undergoing otherwise uncomplicated angioplasty increases the risk of morbidity and mortality at follow-up.

A prospective cohort study followed 55 patients with acute ST segment elevation myocardial infarction (a type of heart attack characterized by the death of some myocardial tissue) who underwent angioplasty (44). Plasma coenzyme Q10 concentration one month after angioplasty was positively correlated with less inflammation and oxidative stress and predicted favorable left ventricular end-systolic volume remodeling at six months (44). One randomized controlled trial has examined the effect of coenzyme Q10 supplementation on periprocedural myocardial injury in patients undergoing coronary angioplasty (45). The administration of 300 mg of coenzyme Q10 12 hours before the angioplasty to 50 patients reduced the concentration of C-reactive protein ([CRP]; a marker of inflammation) within 24 hours following the procedure compared to placebo. However, there was no difference in concentrations of two markers of myocardial injury (creatine kinase and troponin-I) or in the incidence of major adverse cardiac events one month after angioplasty between active treatment and placebo (45). Additional trials are needed to examine whether coenzyme Q10 therapy can improve clinical outcomes in patients undergoing coronary angioplasty.

Angina pectoris

Myocardial ischemia may also lead to chest pain known as angina pectoris. People with angina pectoris often experience symptoms when the demand for oxygen exceeds the capacity of the coronary circulation to deliver it to the heart muscle, e.g., during exercise. Five small placebo-controlled studies have examined the effects of oral coenzyme Q10 supplementation (60-600 mg/day) in addition to conventional medical therapy in patients with chronic stable angina (46). In most of the studies, coenzyme Q10 supplementation improved exercise tolerance and reduced or delayed electrocardiographic changes associated with myocardial ischemia compared to placebo. However, only two of the studies found significant decreases in symptom frequency and use of nitroglycerin with coenzyme Q10 supplementation. Presently, there is only limited evidence suggesting that coenzyme Q10 supplementation would be a useful adjunct to conventional angina therapy. 


Very few high-quality trials have examined the potential therapeutic benefit of coenzyme Q10 supplementation in the treatment of primary hypertension (47). A systematic review identified two small randomized, double-blind, placebo-controlled trials that found little evidence of a reduction in systolic or diastolic blood pressure following the administration of coenzyme Q10 (100-200 mg/day) for three months (47). In contrast, a meta-analysis that used less stringent selection criteria included 17 small trials and found evidence of a blood pressure-lowering effect of coenzyme Q10 in patients with cardiovascular disease or metabolic disorders (48). The effect of coenzyme Q10 on blood pressure needs to be examined in large, well-designed clinical trials.

Cardiovascular risk factors

Endothelial dysfunction: Normally functioning vascular endothelium promotes blood vessel relaxation (vasodilation) when needed (for example, during exercise) and inhibits the formation of blood clots. Atherosclerosis is associated with impairment of vascular endothelial function, thereby compromising vasodilation and normal blood flow. Endothelium-dependent vasodilation is impaired in individuals with elevated serum cholesterol concentrations, as well as in patients with coronary heart disease or diabetes mellitus. A 2012 meta-analysis examining the results of five small randomized controlled trials in 194 subjects in total found that supplemental coenzyme Q10 (150-300 mg/day for 4 to 12 weeks) resulted in a clinically significant, 1.7% increase in flow-dependent endothelial-mediated dilation (49). Evidence from larger studies is needed to further establish the effect of coenzyme Q10 on endothelium-dependent vasodilation. 

Inflammation: Several small randomized controlled trials in patients at increased cardiovascular disease risk or with established cardiovascular disease have examined the effect of supplemental coenzyme Q10 for ≤3 months on circulating inflammation markers i.e., CRP, interleukin-6, and/or tumor necrosis factor-α. Recently published pooled analyses of these trials have given mixed results (50-52). Larger studies are needed to examine the effect of coenzyme Q10 supplementation on low-grade inflammation.

Blood lipids: Elevated plasma lipoprotein(a) concentration is an independent risk factor for cardiovascular disease. A meta-analysis of six controlled trials (of which five were randomized) in 409 participants found a reduction in plasma lipoprotein(a) concentration with coenzyme Q10 supplementation (100-300 mg/day for 4-12 weeks) (53). Other effects of coenzyme Q10 on blood lipids have not been reported (51, 53, 54).

A therapeutic approach combining coenzyme Q10 with other antioxidants might prove to be more effective to target co-existing metabolic disorders in individuals at risk for cardiovascular disease (55).

Diabetes mellitus

Diabetes mellitus is a condition of increased oxidative stress and impaired energy metabolism. Plasma concentrations of reduced coenzyme Q10 (CoQ10H2) have been found to be lower in diabetic patients than healthy controls after normalization to plasma cholesterol concentrations (56, 57). Randomized controlled trials that examined the effect of coenzyme Q10 supplementation found little evidence of benefits on glycemic control in patients with diabetes mellitus. A meta-analysis of six trials in participants with type 2 diabetes and one trial in participants with type 1 diabetes found that 100 to 200 mg/day of coenzyme Q10 for three to six months lowered neither fasting plasma glucose nor levels of glycated hemoglobin ([HbA1c]; a measure of glycemic control). Maternally inherited diabetes mellitus-deafness syndrome (MIDD) is caused by a mutation in mitochondrial DNA, which is inherited exclusively from one's mother. MIDD accounts for less than 1% of all cases of diabetes. Some early evidence suggested that long-term coenzyme Q10 supplementation (150 mg/day) may improve insulin secretion and prevent progressive hearing loss in these patients (58, 59)

Of note, the pathogenesis of type 2 diabetes mellitus involves the early onset of glucose intolerance and hyperinsulinemia associated with the progressive loss of tissue responsiveness to insulin. Recent experimental studies tied insulin resistance to a decrease in coenzyme Q10 expression and showed that supplementation with coenzyme Q10 could restore insulin sensitivity (7). Coenzyme Q10 supplementation might thus be a more useful tool for the primary prevention of type 2 diabetes rather than for its management.

Neurodegenerative diseases

Parkinson's disease

Parkinson's disease is a degenerative neurological disorder characterized by tremors, muscular rigidity, and slow movements. It is estimated to affect approximately 1% of Americans over the age of 65. Mitochondrial dysfunction and oxidative damage in a part of the brain called the substantia nigra may play a role in the development of the disease (60). Decreased ratios of reduced-to-oxidized coenzyme Q10 have been found in platelets of individuals with Parkinson's disease (61, 62). One study also found higher concentrations of oxidized coenzyme Q10 in the cerebrospinal fluid of patients with untreated Parkinson’s disease compared to healthy controls (63). Additionally, a study in postmortem Parkinson’s disease patients found lower concentrations of total coenzyme Q10 in the cortex region of the brain compared to age-matched controls, but no differences were seen in other brain areas, including the striatum, substantia nigra, and cerebellum (64).

A 16-month randomized, placebo-controlled phase II clinical trial evaluated the safety and efficacy of 300, 600, or 1,200 mg/day of coenzyme Q10 in 80 people with early Parkinson's disease (65). Coenzyme Q10 supplementation was well tolerated at all doses and resulted in a slower deterioration of function in Parkinson's disease patients in the group taking 1,200 mg/day. A phase III clinical trial was then designed to further examine the effect of high-dose coenzyme Q10 (1,200-2,400 mg/day) and vitamin E (1,200 IU/day) supplementation on both motor and non-motor symptoms associated with Parkinson’s disease. This trial was prematurely terminated because it was unlikely that such a treatment was effective in treating Parkinson’s disease (66). A smaller placebo-controlled trial showed that oral administration of 300 mg/day of coenzyme Q10 for 48 to 96 months moderately improved motor symptoms in treated patients (with Levodopa) with re-emerging symptoms but not in patients at an early stage of the disease (67). Two recent meta-analyses of randomized, placebo-controlled trials found no evidence that coenzyme Q10 improved motor-related symptoms or delayed the progression of the disease when compared to placebo (68, 69)

Huntington's disease

Huntington's disease is an inherited neurodegenerative disorder characterized by selective degeneration of nerve cells known as striatal spiny neurons. Symptoms, such as movement disorders and impaired cognitive function, typically develop in the fourth decade of life and progressively deteriorate over time. Animal models indicate that impaired mitochondrial function and glutamate-mediated neurotoxicity may be involved in the pathology of Huntington's disease. Some, but not all, studies in mouse models of Huntington’s disease have suggested that coenzyme Q10 supplementation could improve motor performance, overall survival, and various hallmarks of Huntington's disease, i.e., brain atrophy, ventricular enlargement, and striatal neuronal atrophy (70, 71). Interestingly, co-administration of coenzyme Q10 with remacemide (an NMDA receptor antagonist), the antibiotic minocycline, or creatine led to greater improvements in most biochemical and behavioral parameters (70-72).

To date, only two clinical trials have examined whether coenzyme Q10 might be efficacious in human patients with Huntington's disease. A 30-month, randomized, placebo-controlled trial of coenzyme Q10 (600 mg/day), remacemide, or both in 347 patients with early Huntington's disease found that neither coenzyme Q10 nor remacemide significantly altered the decline in total functional capacity, although coenzyme Q10 supplementation (with or without remacemide) resulted in a nonsignificant trend toward a slower decline (73). A 20-week pilot trial examined the safety and tolerability of increasing dosages of coenzyme Q10 (1,200 mg/day, 2,400 mg/day, and 3,600 mg/day) in eight healthy subjects and in 20 patients with Huntington’s disease; 22 of the subjects completed the study (74). All dosages were generally well tolerated, with gastrointestinal symptoms being the most frequently reported adverse effect. Blood concentrations of coenzyme Q10 at the end of the study were maximized with the daily dose of 2,400 mg (74). This dose was tested in a multicenter phase III clinical trial in 609 participants with early-stage Huntington’s disease. Participants were randomized to receive either 2,400 mg/day of coenzyme Q10 or placebo for five years (75). The trial was prematurely halted because it appeared unlikely to demonstrate any health benefit in supplemented patients — about one-third of participants completed the trial at the time of study termination (75). Although coenzyme Q10 is generally well tolerated, there is no evidence that supplementation can improve functional and cognitive symptoms in Huntington's disease patients.

Inherited ataxias

Friedreich's ataxia (FRDA): FRDA is an autosomal recessive neurodegenerative disease caused by mutations in the gene FXN that encodes for the mitochondrial protein, frataxin. Frataxin is 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 (76). Frataxin deficiency is associated with imbalances in iron-sulfur containing proteins, mitochondrial respiratory chain dysfunction and lower ATP production, and accumulation of iron in the mitochondria, which increases oxidative stress and oxidative damage to macromolecules of the respiratory chain (77). Clinically, FRDA is a progressive disease characterized by ataxia, areflexia, speech disturbance (dysarthria), sensory loss, motor dysfunction, cardiomyopathy, diabetes, and scoliosis (77). A pilot study administering coenzyme Q10 (200 mg/day) and vitamin E (2,100 IU/day) to 10 FDRA patients found that energy metabolism of cardiac and skeletal muscle was improved after only three months of therapy (78). Follow-up assessments at 47 months indicated that cardiac and skeletal muscle improvements were maintained and that FRDA patients showed significant increases in fractional shortening, a measure of cardiac function. Moreover, the therapy was effective at preventing the progressive decline of neurological function (79). Another study reported both coenzyme Q10 and vitamin E deficiencies among FRDA patients and suggested that co-supplementation with both compounds, at doses as low as 30 mg/day of coenzyme Q10 and 4 IU/day of vitamin E, might improve disease symptoms (80). Large-scale, randomized controlled trials are necessary to determine whether coenzyme Q10, in conjunction with vitamin E, has therapeutic benefit in FRDA. At present, about one-half of patients use coenzyme Q10 and vitamin E supplements despite the lack of proven therapeutic benefit (77).

Spinocerebellar ataxias (SCAs): SCAs are a group of rare autosomal dominant neurodegenerative diseases characterized by gait difficulty, loss of hand dexterity, dysarthria, and cognitive decline. SCA1, 2, 3, and 6 are the most common SCAs (81). In vitro coenzyme Q10 treatment of forearm skin fibroblasts isolated from patients with SCA2 was found to reduce oxidative stress and normalize complex I and II-III activity of the mitochondrial respiratory chain (82). A multicenter prospective cohort study that followed 319 patients with SCAs (≥15 years) found no difference in the rate of disease progression over two years between those taking supplemental coenzyme Q10 (median dose, 600 mg/day) and nonusers (81).


Early interest in coenzyme Q10 as a potential therapeutic agent in cancer was stimulated by an observational study that found that individuals with lung, pancreas, and especially breast cancer were more likely to have low plasma coenzyme Q10 concentrations than healthy controls (83). Two randomized controlled trials have explored the effect of coenzyme Q10 as an adjunct to conventional therapy for breast cancer. Supplementation with coenzyme Q10 failed to improve measures of fatigue and quality of life in patients newly diagnosed with breast cancer (84) and in patients receiving chemotherapy (85).


Athletic performance

There is little evidence that supplementation with coenzyme Q10 improves athletic performance in healthy individuals. A few placebo-controlled trials have examined the effects of 100 to 150 mg/day of supplemental coenzyme Q10 for three to eight weeks on physical performance in trained and untrained men. Most did not find significant differences between the group taking coenzyme Q10 and the group taking placebo with respect to measures of aerobic exercise performance, such as maximal oxygen consumption (VO2 max) and exercise time to exhaustion (86-90). One study found the maximal cycling workload to be slightly (4%) increased after eight weeks of coenzyme Q10 supplementation compared to placebo, although measures of aerobic power were not increased (91). Two studies actually found significantly greater improvement in measures of anaerobic (87) and aerobic (86) exercise performance with a placebo than with supplemental coenzyme Q10. More recent studies have suggested that coenzyme Q10 could help reduce both muscle damage-associated oxidative stress and low-grade inflammation induced by strenuous exercise (92-95). Studies on the effect of supplementation on physical performance in women are lacking, but there is little reason to suspect a gender difference in the response to coenzyme Q10 supplementation.



Coenzyme Q10 is synthesized in most human tissues. The biosynthesis of coenzyme Q10 involves three major steps: (1) synthesis of the benzoquinone structure from 4-hydroxybenzoate derived from either tyrosine or phenylalanine, two amino acids; (2) synthesis of the polyisoprenoid side chain from acetyl-coenzyme A (CoA) via the mevalonate pathway; and (3) the joining (condensation) of these two structures to form coenzyme Q10. In the mevalonate pathway, the enzyme 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, which converts HMG-CoA into mevalonate, is common to the biosynthetic pathways of both coenzyme Q10 and cholesterol and is inhibited by statins (cholesterol-lowering drugs; see Drug interactions) (1).

Of note, pantothenic acid (formerly vitamin B5) is the precursor of coenzyme A, and pyridoxine (vitamin B6), in the form of pyridoxal-5'-phosphate, is required for the conversion of tyrosine to 4-hydroxyphenylpyruvic acid that constitutes the first step in the biosynthesis of the benzoquinone structure of coenzyme Q10. It is not known to what extent the coenzyme Q10 biosynthetic pathway may be affected by inadequate pantothenic acid and/or vitamin B6 nutritional status.

Food sources

It has been estimated that dietary consumption contributes to about 25% of plasma coenzyme Q10, but there are currently no specific dietary intake recommendations for coenzyme Q10 from the US National Academy of Medicine (formerly the Institute of Medicine) or other agencies (96). The extent to which dietary consumption contributes to tissue coenzyme Q10 concentrations is not clear. 

Based on studies employing food frequency questionnaires, the average dietary intake of coenzyme Q10 is about 3 to 6 mg/day (97). Rich sources of dietary coenzyme Q10 include mainly meat, poultry, and fish. Other good sources include soybean, corn, olive, and canola oils; nuts; and seeds. Fruit, vegetables, eggs, and dairy products are moderate sources of coenzyme Q10 (97). Some dietary sources are listed in Table 1.

Table 1. Coenzyme Q10 Content of Selected Foods (98-100)
Food Serving Coenzyme Q10 (mg)
Beef, fried  3 ounces*  2.6 
Herring, marinated  3 ounces  2.3 
Chicken, fried  3 ounces  1.4 
Soybean oil  1 tablespoon  1.3 
Canola oil  1 tablespoon  1.0 
Rainbow trout, steamed  3 ounces  0.9 
Peanuts, roasted  1 ounce  0.8 
Sesame seeds, roasted  1 ounce  0.7 
Pistachio nuts, roasted  1 ounce  0.6 
Broccoli, boiled  ½ cup, chopped  0.5 
Cauliflower, boiled  ½ cup, chopped  0.4 
Orange  1 medium  0.3 
Strawberries  ½ cup  0.1 
Egg, boiled  1 medium  0.1
*A three-ounce serving of meat or fish is about the size of a deck of cards.


Coenzyme Q10 is available without a prescription as a dietary supplement in the US. Doses in supplements for adults range from 30 to 100 mg/day, which are considerably higher than typically estimated dietary coenzyme Q10 intakes. Coenzyme Q10 is fat-soluble and is best absorbed with fat in a meal. Doses higher than 100 mg/day are generally divided into two or three doses throughout the day (101). Less than 5% of orally administered coenzyme Q10 is thought to reach the circulation (102). Therefore, pharmacological doses of coenzyme Q10 as high as 1,200 to 3,000 mg/day for adults and 30 mg/kg/day for children are usually needed to relieve symptoms in patients with coenzyme Q10 deficiency (26).

Does oral coenzyme Q10 supplementation increase tissue concentrations?

Oral supplementation with coenzyme Q10 is known to increase blood and lipoprotein concentrations of coenzyme Q10 in humans (2, 15, 22). Plasma coenzyme Q10 appears to reach a plateau following supplementation with a dose of 2,400 mg/day (103, 104). Yet, under normal circumstances, uptake of supplemental coenzyme Q10 from peripheral tissues/organs is likely limited because coenzyme Q10 is ubiquitously synthesized (105). Nonetheless, under certain physiological circumstances (e.g., aging) or in pathologies, coenzyme Q10 status might be compromised and it is then presumed that supplementation might increase coenzyme Q10 concentrations in tissues that are deficient (106). For example, a study in 24 older adults supplemented with 300 mg/day of coenzyme Q10 or placebo for at least seven days prior to cardiac surgery found that the coenzyme Q10 content of atrial tissue was significantly increased in those taking coenzyme Q10, especially in patients greater than 70 years of age (38). In another study of patients with left ventricular dysfunction, supplementation with 150 mg/day of coenzyme Q10 for four weeks before cardiac surgery increased coenzyme Q10 concentrations in the heart but not in skeletal muscle (107). Finally, a 2007 review of the literature highlighted that plasma coenzyme Q10 concentrations higher than ‘normal’ were likely needed to promote coenzyme Q10 uptake by peripheral tissues and different tissues may indeed require different plasma thresholds for the uptake of coenzyme Q10 (102).



There have been no reports of significant adverse side effects of oral coenzyme Q10 supplementation at doses as high as 3,000 mg/day for up to eight months (103), 1,200 mg/day for up to 16 months (65), and 600 mg/day for up to 30 months (73). According to the observed safe level (OSL) risk assessment method, evidence of safety is strong with doses up to 1,200 mg/day of coenzyme Q10 (108). Some people have experienced gastrointestinal symptoms, such as nausea, diarrhea, appetite suppression, heartburn, and abdominal discomfort, especially with daily doses ≥200 mg (109). These adverse effects may be minimized if daily doses >100 mg are divided into two or three daily doses (101). During pregnancy, the use of coenzyme Q10 supplements (100 mg twice daily) from 20 weeks' gestation was found to be safe (110). Because reliable data in lactating women are not available, supplementation should be avoided during breast-feeding (110).

Drug interactions


Concomitant use of warfarin (Coumadin) and coenzyme Q10 supplements has been reported to decrease the anticoagulant effect of warfarin in a few cases (111). An individual on warfarin should not begin taking coenzyme Q10 supplements without consulting the health care provider who is managing his or her anticoagulant therapy. If warfarin and coenzyme Q10 are to be used concomitantly, blood tests to assess clotting time (prothrombin time; PT/INR) should be monitored frequently, especially in the first two weeks. 

HMG-CoA reductase inhibitors (statins)

HMG-CoA reductase is an enzyme that catalyzes a biochemical reaction that is common to both cholesterol and coenzyme Q10 biosynthetic pathways (see Biosynthesis). Statins are HMG-CoA reductase inhibitors that are widely used as cholesterol-lowering medications. Statins can thus also reduce the endogenous synthesis of coenzyme Q10. Therapeutic use of statins, including simvastatin (Zocor), pravastatin (Pravachol), lovastatin (Mevacor, Altocor, Altoprev), rosuvastatin (Crestor), and atorvastatin (Lipitor), has been shown to decrease circulating coenzyme Q10 concentrations (112-121). However, because coenzyme Q10 circulates with lipoproteins, plasma coenzyme Q10 concentration is influenced by the concentration of circulating lipids (122, 123). It is likely that circulating coenzyme Q10 concentrations are decreased because statins reduce circulating lipids rather than because they inhibit coenzyme Q10 synthesis (124). In addition, very few studies have examined coenzyme Q10 concentrations in tissues other than blood such that the extent to which statin therapy affects coenzyme Q10 concentrations in the body's tissues is unknown (118, 120, 125). Finally, there is currently little evidence to suggest that secondary coenzyme Q10 deficiency is responsible for statin-associated muscle symptoms in treated patients. In addition, supplementation with coenzyme Q10 failed to relieve myalgia in statin-treated patients (see Disease Treatment) (126, 127).

Authors and Reviewers

Originally written in 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in February 2007 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in March 2012 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2018 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2018 by:
Roland Stocker, Ph.D.
Centre for Vascular Research
School of Medical Sciences (Pathology) and
Bosch Institute
Sydney Medical School
The University of Sydney
Sydney, New South Wales, Australia

Copyright 2003-2024  Linus Pauling Institute


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Lipoic Acid




Lipoic acid (often called α-lipoic acid), also known as thioctic acid, is a naturally occurring organosulfur compound that is synthesized by plants and animals, including humans (1, 2). Lipoic acid is covalently bound to certain proteins, which function as part of essential mitochondrial multienzyme complexes involved in energy and amino acid metabolism (see Biological Activities). In addition to the physiological functions of protein-bound lipoic acid, there is increasing scientific and medical interest in potential therapeutic uses of pharmacological doses of free (unbound) lipoic acid (3).

Lipoic acid contains two thiol (sulfur) groups, which may be oxidized or reduced; dihydrolipoic acid is the reduced form of lipoic acid (Figure 1) (4). Lipoic acid also contains an asymmetric carbon, which means that lipoic acid can exist as one of two possible optical isomers, also called enantiomers. These enantiomers are mirror images of each other: R-lipoic acid and S-lipoic acid (Figure 1). Only the R-enantiomer is endogenously synthesized and covalently bound to protein. R-lipoic acid occurs naturally in food (see Food sources). Free (unbound) lipoic acid supplements may contain either R-lipoic acid or a 50:50 (racemic) mixture of R-lipoic acid and S-lipoic acid (see Supplements).

Figure 1. Chemical Structures of Lipoic Acid and Lipoyllysine Residue. Lipoic acid has an asymmetric carbon such that lipoic acid can exist as one of two optical isomers, called enantiomers: R-lipoic acid and S-lipoic acid, which are mirror  images of each other. Lipoic acid is covalently linked to the E2 component of the alpha-ketoacid dehydrogenase complex (and to the H-protein of the glycine cleavage system) via a lysine residue (forming a lipoyllysine moiety). Because lipoic acid can be oxidized and reduced, it serves as an electron carrier and an acyl/methylamide carrier.

[Figure 1 - Click to Enlarge]

Metabolism and Bioavailability

Endogenous biosynthesis

The synthesis of lipoic acid has been characterized in detail in the yeast Saccharomyces cerevisiae, but not all genes involved in the process have been identified in humans (5). Lipoic acid is synthesized de novo in mitochondria from octanoic acid, an 8-carbon fatty acid (C8:0), bound to the acyl-carrier protein (ACP; see article on Pantothenic Acid) during the process of fatty acid synthesis (Figure 2). An enzyme called lipoyl (octanoyl) transferase 2 catalyzes the transfer of the octanoyl moiety from octanoyl-ACP to a conserved lysine of the H protein of the glycine cleavage system (see also Biological Activities). The next reaction is the insertion of two sulfur atoms at positions 6 and 8 of the protein H-bound octanoyl moiety, thereby producing a dihydrolipoyl moiety. This step is catalyzed by the lipoic acid synthetase (also called lipoyl synthase), an enzyme containing iron-sulfur clusters that act as sulfur donors in the reaction (5). Finally, the enzyme lipoyl transferase 1 catalyzes the transfer of the dihydrolipoyl moiety from the H protein of the glycine cleavage system to conserved lysine residues of the E2 components of the α-ketoacid dehydrogenase multienzyme complexes (5). The oxidation of the dihydrolipoyl moiety is catalyzed by a dihydrolipoamide dehydrogenase (Figure 2).

Figure 2. Endogenous Synthesis of Lipoic Acid. The de novo synthesis of lipoic acid takes place in the mitochondria and starts with the synthesis of an 8-carbon fatty acid called octanoic acid in the acyl-carrier protein (ACP)-dependent mitochondrial fatty acid synthesis pathway. Lipoyl (octanoyl) transferase 2 catalyzes the transfer of the octanoyl moiety from ACP to a conserved lysine within the H protein of the glycine cleavage complex (see Biological Activities and Figure 3). The sulfuration of the octanoyl moiety at positions 6 and 8 is catalyzed by lipoic acid synthetase and generates a dihydrolipoyl moiety (R enantiomer). This moiety is then transferred to a conserved lysine within the E2 component of the alpha-ketoacid dehydrogenase complexes (see Figure 4). This reaction is catalyzed by the enzyme lipoyl transferase 1. A dihydrolipoamide dehydrogenase activity within the glycine cleavage system (L protein) and within the alpha-ketoacid dehydrogenase complexes (protein E3) can catalyze the conversion of the dihydrolipoyl moiety (reduced form) to the lipoyl moiety (oxidized form). Figure adapted from Mayr et al. J Inherit Metab Dis. 2014;37(4):553-563.

[Figure 2 - Click to Enlarge]

Dietary and supplemental lipoic acid

Consumption of lipoic acid from food has not yet been found to result in detectable increases of free lipoic acid in human plasma or cells (3, 6). In contrast, high oral doses of free lipoic acid (≥50 mg) significantly, yet transiently, increase the concentration of free lipoic acid in plasma and cells. Pharmacokinetic studies in humans have found that about 30%-40% of an oral dose of a racemic mixture of R-lipoic acid and S-lipoic acid is absorbed (6, 7). Oral lipoic acid supplements are better absorbed on an empty stomach than with food: taking lipoic acid with food (versus without food) decreased peak plasma lipoic acid concentrations by about 30% and total plasma lipoic acid concentrations by about 20% (8). A liquid formulation of R-lipoic acid was found to be better absorbed and more stable in the plasma, suggesting that it might be more efficacious than the solid form in the management of a condition like diabetic neuropathy (9, 10).

There may also be differences in bioavailability of the two isomers of lipoic acid. Following single oral doses R,S-lipoic acid (racemic mixture), peak plasma concentrations of R-lipoic acid were found to be 40%-50% higher than S-lipoic acid, suggesting a differential absorption in favor of the R-enantiomer (6, 8, 11). Yet, following oral ingestion, both enantiomers are rapidly metabolized and excreted. Plasma lipoic acid concentrations generally peak within one hour or less and decline rapidly (6, 7, 11, 12). In cells, lipoic acid is swiftly reduced to dihydrolipoic acid, and in vitro studies indicate that dihydrolipoic acid is then rapidly exported from cells (3). Moreover, a pilot study in 19 healthy adults suggested that the bioavailability of R,S-lipoic acid and R-lipoic acid may vary with age and gender (13).

Finally, there is no evidence in humans that exogenous lipoic acid can be 'activated' with ATP or GTP and incorporated into lipoic acid-dependent enzymes by a lipoyl transferase (14). As a consequence, a loss of lipoic acid-dependent enzymatic activity caused by defects in endogenous lipoic acid synthesis (see Deficiency) cannot be rescued by the provision of exogenous lipoic acid (5).

Biological Activities

Protein-bound lipoic acid

Enzyme cofactor

R-lipoic acid is an essential cofactor for several mitochondrial multienzyme complexes that catalyze critical reactions related to the catabolism (breakdown) of amino acids and the production of energy (15). R-lipoic acid is covalently bound to a specific lysine residue in at least one of the proteins in each multienzyme complex. Such a non-protein cofactor is known as a "prosthetic group."

R-lipoic acid functions as a prosthetic group for the biological activity of the following multienzyme complexes:

  • The glycine cleavage system that catalyzes the decarboxylation of glycine coupled with the addition of a methylene group (-CH2) to tetrahydrofolate to form 5,10-methylene tetrahydrofolate, an important cofactor in the synthesis of nucleic acids (Figure 3). Within the glycine cleavage system, R-lipoic acid is covalently bound to a conserved lysine of the H protein (Figures 2 and 3).
  • Four α-ketoacid dehydrogenase complexes (Figure 4), including:

(i) the pyruvate dehydrogenase complex that catalyzes the conversion of pyruvate to acetyl-coenzyme A (CoA), an important substrate for energy production via the citric acid cycle;

(ii) the α-ketoglutarate dehydrogenase complex that catalyzes the conversion of α-ketoglutarate to succinyl CoA, another important intermediate of the citric acid cycle;

(iii) the branched-chain α-ketoacid dehydrogenase complex that is involved in the decarboxylation of ketoacids in the catabolic pathway of the branched-chain amino acids, namely leucine, isoleucine, and valine;

(iv) the 2-oxoadipate dehydrogenase complex that catalyzes the decarboxylation of 2-oxoadipate to glutaryl-CoA in the catabolic pathway of lysine, hydroxylysine, and tryptophan.

All four α-ketoacid dehydrogenase complexes contain three enzymatic activities, namely E1, E2, and E3. E1 is a thiamin pyrophosphate (TPP)-dependent α-ketoacid dehydrogenase, R-lipoic acid functions as a prosthetic group essential for E2 transacetylase activity, and E3 is a flavin adenine dinucleotide (FAD)-dependent dihydrolipoamide dehydrogenase (Figure 4). R-lipoic acid is also found in the E3-binding protein (protein X component) of the pyruvate dehydrogenase complex (5).

Figure 3. The Glycine Cleavage System. The glycine cleavage system is a multienzyme coomplex of four protein components: P, T, L, and H. The P protein catalyzes the decarboxylation of glycine and the transfer of the methylamine reside (CH2-NH2) of glycine to the lipoyl moiety of the H protein. The H protein shuttles the methylamine to the T protein. The latter then catalyzes the transfer of the methylene group (CH2) to tetrahydrofolate. In the process, NH3 is released and the lipoyl group of the H protein is reduced (dihydrolipoyl group). Finally, the L protein catalyzes the re-oxidation of the lipoyl moiety of the H protein in an NAD-dependent reaction. Figure Adapted from Douce et al. Trends Plant Sci. 2001;6(4):167-176.

[Figure 3 - Click to Enlarge]

Figure 4. The Alpha-Ketoacid Dehydrogenase Multienzyme Complexes. The alpha-ketoacid dehydrogenase multienzyme complex family includes (1) the pyruvate dehydrogenase complex; (2) the branched-chain alpha-ketoacid dehydrogenase complex; (3) the alpha-ketoglutarate dehydrogenase complex; and (4) the 2-oxoadipate dehydrogenase complex, which all share the same architecture. Each complex is composed of several copies of three enzymes: E1, E2, and E3. E1 is a TPP-dependent dihydrolipoamide dehydrogenase. The E2 unit binds one or two lipoyl groups via a covalent amide linkage to a lysine group. Each complex catalyzes the conversion of specific alpha-ketoacids into carbon dioxide and acyl-CoA.

[Figure 4 - Click to Enlarge]

Unbound lipoic acid

When considering the biological activities of supplemental (unbound) lipoic acid, it is important to keep in mind the limited and transient nature of the increases in plasma and tissue lipoic acid (see Metabolism and Bioavailability) (3).

Antioxidant activities

Scavenging reactive oxygen and nitrogen species: Reactive oxygen species (ROS) and reactive nitrogen species (RNS) are highly reactive compounds with the potential to damage DNA, proteins, and lipids in cell membranes. Both lipoic acid and dihydrolipoic acid can directly scavenge (neutralize) physiologically relevant ROS and RNS in the test tube (reviewed in 3). However, whether direct quenching reactions occur in vivo is unknown. The highest tissue concentrations of free lipoic acid likely to be achieved through oral supplementation are at least 10 times lower than those of other intracellular antioxidants, such as vitamin C and glutathione. Moreover, free lipoic acid is rapidly eliminated from cells, so any increases in direct radical scavenging activity are unlikely to be sustained.

Regeneration of other antioxidants: When an antioxidant scavenges a free radical, it becomes oxidized itself and is not able to scavenge additional ROS or RNS until it has been reduced. In the test tube, dihydrolipoic acid is a potent reducing agent with the capacity to reduce the oxidized forms of several important antioxidants, including coenzyme Q10, vitamin C, and glutathione (Figure 5) (16, 17). Dihydrolipoic acid may also reduce the oxidized form of α-tocopherol (vitamin E) directly or indirectly through regenerating oxidized vitamin C (see the article on Vitamin E) (18) or oxidized coenzyme Q10 (see the article on Coenzyme Q10) (19). Whether dihydrolipoic acid effectively regenerates antioxidants under physiological conditions is unclear (3).

Metal chelation: Redox-active metal ions, such as free iron and copper, can induce oxidative damage by catalyzing reactions that generate highly reactive free radicals (20). Compounds that chelate free metal ions in a way that prevents them from generating free radicals offer promise in the treatment of neurodegenerative diseases and other chronic diseases in which metal-induced oxidative damage may play a pathogenic role (21). Both lipoic acid and dihydrolipoic acid have been found to inhibit copper- and iron-mediated oxidative damage in the test tube (22, 23) and to inhibit excess iron and copper accumulation in animal models (24, 25). Lipoic acid may also be helpful as an adjunct treatment against heavy metal toxicity. No clinical trial has examined the use of lipoic acid as a chelating agent in mercury toxicity, yet it has proven to be effective in several mammalian species (26, 27).

Activation of antioxidant signaling pathways: Glutathione is an important intracellular antioxidant that also plays a role in the detoxification and elimination of potential carcinogens and toxins. Reductions in glutathione synthesis and tissue glutathione concentrations in aged animals (compared to younger ones) are suggestive of a potentially lower ability to respond to oxidative stress or toxin exposure (28). Lipoic acid has been found to increase glutathione concentrations in cultured cells and in the tissues of aged animals fed lipoic acid (29, 30). Lipoic acid might be able to increase glutathione synthesis in aged rats by up-regulating the expression of γ-glutamylcysteine ligase (γ-GCL), the rate-limiting enzyme in glutathione synthesis (31), and by increasing cellular uptake of cysteine, an amino acid required for glutathione synthesis (32). Lipoic acid was found to upregulate the expression of γ-GCL and other antioxidant enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway (31, 33).

Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol. Keap1 responds to oxidative stress signals by freeing Nrf2. Upon release, Nrf2 translocates to the nucleus where it can bind to the antioxidant response element (ARE) located in the promoter region of genes coding for antioxidant enzymes and scavengers. Lipoic acid — but not dihydrolipoic acid — can react with specific sulfhydryl residues of Keap1, causing the release of Nrf2 (34). Nrf2/ARE target genes code for several mediators of the antioxidant response, including γ-GCL, NAD(P)H quinone oxidoreductase 1 (NQO-1), heme oxygenase-1 (HO-1), catalase, and superoxide dismutase (SOD). For example, the upregulation of the Nrf2 pathway by lipoic acid in cultured hepatocytes and in the liver of obese or diabetic rats prevented lipid overload-induced steatosis (35) and cell death (36). Lipoic acid also protected liver from oxidative stress-induced liver injury in methotrexate-treated rats through the activation of Nrf-2 pathway and other anti-inflammatory pathways (37). Pre-treatment and post-treatment with lipoic acid, respectively, prevented and reversed lipopolysaccharide (LPS)-induced lung histopathological alterations in rats through Nrf2-mediated HO-1 upregulation (38).

Inhibition of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX): NOX is a plasma membrane-bound enzymatic complex that catalyzes the production of superoxide from oxygen and NADPH and has been involved in innate immune defense against microbes (39). Lipoic acid prevented NOX-induced superoxide production in a rat model of cerebral ischemia and limited infarct volume and neurological deficiencies through upregulating the insulin-phosphatidylinositide-3 kinase (PI3K)-protein kinase B (PKB/Akt) signaling pathway (40). Treatment of gastric cancer cells with lipoic acid limited NOX-generated ROS production and reduced cancer cell proliferation induced by Helicobacter pylori (H. pylori) infection (41).

Figure 5. Antioxidant Activity of Lipoic Acid. The peroxidation of unsaturated lipids leads to the formation of lipid peroxyl radicals that easily diffuse in biological systems. Peroxyl radicals react 1,000-times faster with alpha-tocopherol than with unsaturated lipids. The hydroxyl group in the chromanol head of alpha-tocopherol (reduced form) can donate hydrogen to scavenge lipid peroxyl radicals, which halts their propagation in membranes and circulating lipoproteins. The presence of other antioxidants, such as coenzyme Q10, vitamin C, and glutathione, is required to regenerate the antioxidant capacity of alpha-tocopherol. When the reduced form of coenzyme Q10 or that of vitamin C, or that of glutathione reacts with oxidized alpha-tocopherol, the reduced form of alpha-tocopherol is generated and the oxidized form of coenzyme Q10 (ubisemiquinone) or that of vitamin C (ascorbate), or that of glutathione (GSSG) is formed. Oxidized forms of coenzyme Q10, vitamin C, and glutathione can be reduced by the reduced form of lipoic acid, dihydrolipoic acid.

[Figure 5 - Click to Enlarge]

Regulation of cellular glucose uptake

The binding of insulin to the insulin receptor stimulates a cascade of protein phosphorylations leading to the translocation of glucose transporters (GLUT4) to the cell membrane and an increased cellular uptake of glucose (3, 42). Lipoic acid has been found to activate the insulin signaling cascade in cultured cells (3, 42, 43), increase GLUT4 translocation to cell membranes, and increase glucose uptake in cultured adipose and muscle cells (44, 45). A computer modeling study suggested that lipoic acid might bind to the intracellular tyrosine kinase domain of the insulin receptor and stabilize the active form of the enzyme (43).

Regulation of other signaling pathways

In addition to Nrf2 and insulin signaling pathways, lipoic acid was found to target other cell-signaling molecules thereby affecting a variety of cellular processes, including metabolism, stress responses, proliferation, and survival. For example, in cultured endothelial cells, lipoic acid was found to inhibit IKK-β, an enzyme that promotes the translocation of redox-sensitive and pro-inflammatory transcription factor, nuclear factor-kappa B (NFκB) from the cytosol to the nucleus (46). Lipoic acid has also been shown to improve nitric oxide (NO)-dependent vasodilation in aged rats by increasing PKB/Akt-dependent phosphorylation of endothelial NO synthase (eNOS) and eNOS-catalyzed NO production (47). Additionally, lipoic acid increased mitochondrial biogenesis through triggering AMP-activated protein kinase (AMPK)-induced transcription factor PGC-1α activation in skeletal muscle of aged mice (48). Several reviews of the literature have described pathways that are potential targets of lipoic acid in various models and under different experimental conditions (49-52).


Lipoic acid deficiency has been described in rare cases of inherited mutations in the lipoic acid biosynthetic pathway. Mutations identified in patients with defective lipoic acid metabolism affect genes involved in the synthesis of iron-sulfur clusters and genes coding for lipoic acid synthetase (LIAS), lipoyl transferase 1 (LIPT1), and dihydrolipoamide dehydrogenase (E3 component of α-ketoacid dehydrogenase complexes; DLD) (5, 53, 54).

Disease Treatment

Diabetes mellitus

Chronically elevated blood glucose concentration is the hallmark of diabetes mellitus. Type 1 diabetes is caused by the autoimmune destruction of the insulin-producing β-cells of the pancreas, leading to an insufficient production of insulin. Exogenous insulin is required to maintain a normal blood glucose concentration (i.e., fasting blood glucose <100 milligram per deciliter [mg/dL]). In contrast, impaired tissue glucose uptake in response to insulin (a phenomenon called insulin resistance) plays a key role in the development of type 2 diabetes (55). Although patients with type 2 diabetes may eventually require insulin, interventions that enhance insulin sensitivity may be used to maintain normal blood glucose concentrations. The term 'prediabetes' is sometimes used to describe early metabolic abnormalities that place individuals at high risk of developing type 2 diabetes. Of note, these patients are also at high risk for cardiovascular disease. According to the American Diabetes Association, prediabetes can be defined by a condition of impaired fasting glucose, characterized by a fasting blood glucose concentration between 100 mg/dL and 125 mg/dL and/or a condition of impaired glucose tolerance, characterized by a 2-hour blood glucose concentration ≥140 mg/dL following an oral glucose tolerance test (56).

Glucose utilization

The effect of high-dose lipoic acid on glucose utilization has been primarily examined in individuals with type 2 diabetes. An early clinical trial in 13 patients with type 2 diabetes found that a single intravenous infusion of 1,000 mg of lipoic acid improved insulin-stimulated glucose disposal (i.e., insulin sensitivity) by 50% compared to a placebo infusion (57). A placebo-controlled study of 72 patients with type 2 diabetes found that oral administration of lipoic acid at doses of 600 mg/day, 1,200 mg/day or 1,800 mg/day improved insulin sensitivity by 25% after four weeks of treatment (58). There were no significant differences among the three doses of lipoic acid, suggesting that 600 mg/day may be the maximum effective dose (55). However, in a more recent randomized, placebo-controlled study in 102 subjects, daily supplementation with 600 mg of lipoic acid (+/- 800 mg of vitamin E [α-tocopherol]) for 16 weeks had no effect on fasting blood glucose, fasting blood insulin, or a measure of insulin resistance called the homeostatic model assessment of insulin resistance (HOMA-IR) index (59). A 2018 systematic review and meta-analysis identified 20 randomized controlled trials (published between 2007 and 2017) that examined the effect of supplemental lipoic acid on markers of glucose utilization in 1,245 subjects with metabolic disorders (not limited to type 2 diabetes) (60). Administration of lipoic acid (200 to 1,800 mg/day for 2 weeks to 1 year), alone or together with other nutrients, was found to lower fasting blood glucose and insulin concentrations, insulin resistance, and blood HbA1c concentration — a marker of glycemic control over the past few months (60).

Endothelial function

The inner lining of blood vessels, known as the vascular endothelium, plays an important role in the maintenance of cardiovascular health. In particular, nitric oxide (NO) regulates vascular tone and blood flow by promoting the relaxation of all types of blood vessels, including arteries — a phenomenon called vasodilation. Alterations in NO-mediated endothelium-dependent vasodilation results in widespread vasoconstriction and coagulation abnormalities and is considered to be an early step in the development of atherosclerosis. The presence of chronic hyperglycemia, insulin resistance, oxidative stress, and pro-inflammatory mechanisms contribute to endothelial dysfunction in patients with diabetes mellitus (61).

The measurement of brachial flow-mediated dilation (FMD) is often used as a surrogate marker of endothelial function. Two techniques are being used to measure endothelium-dependent vasodilation. One technique measures the forearm blood flow by venous occlusion plethysmography during infusion of acetylcholine. Using this invasive technique, intra-arterial infusion of lipoic acid was found to improve endothelium-dependent vasodilation in 39 subjects with type 2 diabetes but not in 11 healthy controls (62). A more recent randomized, double-blind, placebo-controlled study in 30 patients with type 2 diabetes found that intravenous infusion of 600 mg of lipoic acid improved the response to the endothelium-dependent vasodilator acetylcholine but not to the endothelium-independent vasodilator, glycerol trinitrate (63). Another noninvasive technique using ultrasound to measure flow-mediated vasodilation was used in two additional studies conducted by Xiang et al. (64, 65). The results of these randomized, placebo-controlled studies showed that intravenous lipoic acid could improve endothelial function in patients with impaired fasting glucose (64) or impaired glucose tolerance (65).

One randomized placebo-controlled trial that assessed the effect of oral lipoic acid supplementation in 58 patients diagnosed with metabolic syndrome, a condition characterized by abnormal glucose and lipid metabolism, showed that flow-mediated vasodilation improved by 44% with 300 mg/day of lipoic acid for four weeks (66).

Diabetic neuropathy

Peripheral neuropathy: Up to 50% of diabetic patients develop peripheral neuropathy, a type of nerve damage that may result in pain, loss of sensation, and weakness, particularly in the lower extremities (67). Peripheral neuropathy is also a leading cause of lower limb amputation in diabetic patients (68). Several mechanisms have been proposed to explain chronic hyperglycemia-induced nerve damage, such as intracellular accumulation of sorbitol, glycation reactions, and oxidative and nitrosative stress (reviewed in 69). The results of several large randomized controlled trials indicated that maintaining blood glucose at near normal concentrations was the most important step in limiting the risk of diabetic neuropathy and lower extremity amputation (70-72). However, evidence of the efficacy of enhanced control of glycemia in preventing neuropathy is stronger in patients with type 1 diabetes than in those with type 2 diabetes (73). Moreover, this glucose control intervention increased the risk of hypoglycemic episodes (73).

The efficacy of lipoic acid, administered either intravenously or orally, in the management of neuropathic symptoms has been examined in patients with diabetes. Meta-analyses of randomized controlled trials suggest that infusion of 300 to 600 mg/day of lipoic acid for two to four weeks significantly reduced the symptoms of diabetic neuropathy to a clinically meaningful degree (55, 74). Regarding the efficacy of oral lipoic acid supplementation, an initial short-term study in 24 patients with type 2 diabetes mellitus found that the symptoms of peripheral neuropathy improved in those who took 600 mg of lipoic acid three times a day for three weeks compared to those who took a placebo (75). A larger clinical trial randomly assigned more than 500 patients with type 2 diabetes and symptomatic peripheral neuropathy to one of the following treatments: (i) 600 mg/day of intravenous lipoic acid for three weeks followed by 1,800 mg/day of oral lipoic acid for six months, (ii) 600 mg/day of intravenous lipoic acid for three weeks followed by oral placebo for six months, or (iii) intravenous placebo for three weeks followed by oral placebo for six months (76). Evidence of improvements in sensory and motor deficits — assessed by physicians — could be observed after three weeks of intravenous lipoic acid therapy, yet not at the end of six months of oral lipoic acid therapy. However, another randomized, double-blind, placebo-controlled trial in 181 patients with diabetic neuropathy found that oral supplementation with either 600 mg/day, 1,200 mg/day, or 1,800 mg/day of lipoic acid for five weeks significantly improved neuropathic symptoms (77). In this study, the 600 mg/day dose was as effective as the higher doses. Finally, a four-year, multicenter, clinical trial in 421 diabetic patients with distal symmetric sensorimotor polyneuropathy found no difference between oral administration of 600 mg/day of lipoic and placebo on the primary endpoint, a composite score that assessed neuropathic impairment of the lower limbs and nerve conduction (78). Yet, measures of specific neuropathic impairments (secondary outcomes) improved with lipoic acid supplementation (78). A post-hoc analysis suggested that oral lipoic acid supplementation may reduce neuropathic symptoms particularly in subjects with a high burden of cardiovascular disease, diabetes, and neuropathy yet with normal body mass index (BMI) and blood pressure (79).

Autonomic neuropathy: Another neuropathic complication of diabetes mellitus is cardiac autonomic neuropathy (CAN), which occurs in as many as 25% of diabetic patients (55). CAN is characterized by damage to the nerve fibers that innervate the heart and blood vessels, leading to reduced heart rate variability (variability in the time interval between heartbeats) and increased risk of mortality (80). In a randomized controlled trial of 72 patients with type 2 diabetes and reduced heart rate variability, oral supplementation with 800 mg/day of lipoic acid for four months resulted in significant improvement in two out of four measures of heart rate variability compared to placebo (81).

Summary: Overall, the available research suggests that treatment with intravenous or oral lipoic acid may help reduce symptoms of diabetic peripheral neuropathy. The use of lipoic acid is currently approved for the treatment of diabetic neuropathy in Germany (4). It is important to note that many of the studies that examined the efficacy of lipoic acid in the treatment of diabetic neuropathy have been primarily conducted by one German research group and funded by the manufacturer of lipoic acid in Germany (82).

Diabetic retinopathy

Chronic hyperglycemia can damage blood vessels in the retina and cause a potentially sight-threatening condition called diabetic retinopathy (83). One placebo-controlled study examined the effect of lipoic acid on the visual capability of 80 participants of whom 12 had type 1 diabetes, 48 had type 2 diabetes, and 20 were diabetes-free. The result showed that daily oral administration of 300 mg of lipoic acid for three months prevented the deterioration of contrast sensitivity in patients with diabetes and improved it in healthy patients compared to placebo (84).

Multiple sclerosis

Multiple sclerosis is an autoimmune disease of unknown etiology that is characterized by the progressive destruction of myelin and nerve fibers in the central nervous system, causing neurological symptoms in affected individuals (85). There are four main types of multiple sclerosis defined according to the disease course: (i) clinically isolated syndrome, (ii) relapsing-remitting multiple sclerosis, (iii) secondary progressive multiple sclerosis, and (iv) primary progressive multiple sclerosis (for more information, visit the National Multiple Sclerosis Society website) (86). Lipoic acid was found to effectively slow disease progression when administered either orally (87), intraperitoneally (88), or subcutaneously (89) to mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. In vitro and animal studies have found that lipoic acid exhibits immunomodulatory properties through mechanisms that stimulate the production of cyclic AMP (cAMP) (90, 91) — a central regulator of innate immune functions — and inhibits the migration of immune cells into the brain and spinal cord (92), possibly by decreasing endothelial expression of cell adhesion molecules, inhibiting expression of enzymes like matrix metalloproteinases (MMP), and/or reducing the permeability of the blood-brain barrier (87, 89, 93, 94).

Only a few studies have examined lipoic acid supplementation in humans. A small pilot study designed to evaluate the safety of lipoic acid in 30 people with relapsing or progressive multiple sclerosis found that treatment with 1,200 to 2,400 mg/day of oral lipoic acid for two weeks was generally well tolerated (see Safety) (95). In this study, higher serum concentrations of lipoic acid were associated with the lowest serum concentrations of MMP-9 — a marker of inflammation (95). Another study suggested that an oral dose of 1,200 mg of lipoic acid in subjects with multiple sclerosis could help achieve serum lipoic acid concentrations similar to those found to be therapeutic in mice (96). A randomized, placebo-controlled study in 52 subjects (mean age, 30 years) with relapsing-remitting multiple sclerosis found an increase in total antioxidant capacity in blood with lipoic acid supplementation (1,200 mg/day for 12 weeks) yet not in the activity of specific antioxidant enzymes (superoxide dismutase and glutathione peroxidase) (97). Supplemental lipoic acid also decreased the serum concentrations of some (IFN-γ, ICAM-1, TGF-γ, IL-4), but not all markers (TNF-γ, IL-6, MMP-9), cytokines and other inflammation (98). In addition, lipoic acid supplementation did not reduce the severity of multiple sclerosis symptoms, as assessed by the Expanded Disability Status Scale (EDSS) scoring system (98, 99).

A two-year clinical trial designed to assess the effect of lipoic acid (1,200 mg/day) on loss of mobility and changes in brain volume in patients with progressive multiple sclerosis is ongoing (85).

Cognitive impairments and dementia

Studies in animal models of aging and neurodegenerative disease have indicated that lipoic acid administration might improve measures of spatial memory, learning capacity, and/or motor function (reviewed in 100).

It is not known whether oral lipoic acid supplementation can slow cognitive decline related to aging or pathological conditions in humans. An uncontrolled, open-label trial in nine patients with probable Alzheimer’s disease and related dementias, who were also taking acetylcholinesterase inhibitors, reported that oral supplementation with 600 mg/day of lipoic acid appeared to stabilize cognitive function over a one-year period (101). A subsequent study that followed 43 patients for up to four years found those with mild dementia or moderate-early dementia who took lipoic acid (600 mg/day), in addition to acetylcholinesterase inhibitors, experienced slower cognitive decline compared to the typical cognitive decline of Alzheimer’s patients as reported in the literature (102). However, the significance of these findings is difficult to assess without a control group for comparison. A randomized controlled trial found that oral supplementation with 1,200 mg/day of lipoic acid for 10 weeks was of no benefit in treating HIV-associated cognitive impairment (103). The results of another randomized trial in 39 patients with Alzheimer’s disease suggested that supplementation with fish oil concentrate (high in omega-3 fatty acids) with or without lipoic acid (600 mg/day) for one year could delay the progression in cognitive and functional impairments assessed by the Instrumental Activities of Daily Living (IADL) scoring system compared to placebo (104). Interestingly, patients who took fish oil concentrate together with lipoic acid showed no worsening of global cognitive function (as assessed by the Mini-Mental State Examination [MMSE] score system) over 12 months as opposed to those who took either the fish oil concentrate alone or a placebo (104). Larger trials are needed to confirm these preliminary findings and further evaluate the usefulness of supplemental lipoic acid in the prevention and/or management of neurodegenerative diseases.

Weight management

A 2018 meta-analysis of randomized, placebo-controlled trials found that lipoic acid supplementation in those with high body mass index (BMI) resulted in significant, yet modest, reductions in weight (9 studies) and BMI (11 studies) in the absence of caloric restriction (except in one study) (105). Subgroup analyses revealed that weight loss was greater in overweight versus obese participants, in unhealthy versus healthy participants, with daily doses ≤600 mg, and for intervention period shorter than 10 weeks. There was no reduction in waist circumference with supplemental lipoic acid (5 studies) (105). Substantial weight and BMI reductions with lipoic acid supplementation in overweight or obese subjects were also reported in a prior meta-analysis (106).


Endogenous biosynthesis

R-lipoic acid is synthesized endogenously by humans (see Metabolism and Bioavailability).

Food sources

R-lipoic acid occurs naturally in food covalently bound to lysine in proteins (lipoyllysine; see Figure 1). Although lipoic acid is found in a wide variety of foods from plant and animal sources, quantitative information on the lipoic acid or lipoyllysine content of food is limited; published databases are lacking. Animal tissues with high lipoyllysine content (~1-3 μg/g dry wt) include kidney, heart, and liver, while lipoyllysine-rich vegetables include spinach and broccoli (107). Somewhat lower amounts of lipoyllysine (~0.5 μg/g dry wt) have been measured in tomatoes, peas, and Brussels sprouts.


Unlike lipoic acid in foods, lipoic acid in supplements is not bound to protein. Moreover, the amounts of lipoic acid available in dietary supplements (50-600 mg) are likely as much as 1,000 times greater than the amounts that could be obtained from the diet. In Germany, lipoic acid is approved for the treatment of diabetic neuropathies and is available by prescription (108). Lipoic acid is available as a dietary supplement without a prescription in the US. Most lipoic acid supplements contain a racemic mixture of R-lipoic acid and S-lipoic acid (sometimes noted d,l-lipoic acid). Supplements that claim to contain only R-lipoic acid are usually more expensive, and information regarding their purity is not publicly available (109). Since taking lipoic acid with a meal decreases its bioavailability, it is generally recommended that lipoic acid be taken 30 min prior to a meal (see also Metabolism and Bioavailability) (8).

Racemic mixture versus R-lipoic acid only

R-lipoic acid is the isomer that is synthesized by plants and animals and functions as a cofactor for mitochondrial enzymes in its protein-bound form (see Biological Activities). Direct comparisons of the bioavailability of the oral racemic mixture and R-lipoic acid supplements have not been published. Following the ingestion of R,S-lipoic acid, peak plasma concentrations of R-lipoic acid were found to be 40%-50% higher than S-lipoic acid, suggesting better absorption of R-lipoic acid. Both isomers were nonetheless rapidly metabolized and eliminated (6, 8, 11). In rats, R-lipoic acid was more effective than S-lipoic acid in enhancing insulin-stimulated glucose transport and metabolism in skeletal muscle (110), and R-lipoic acid was more effective than R,S-lipoic acid and S-lipoic acid in preventing cataracts (111). However, all of the published human studies have used R,S-lipoic acid (racemic mixture). It has been suggested that the presence of S-lipoic acid in the racemic mixture may limit the polymerization of R-lipoic acid and enhance its bioavailability (52). At present, it remains unclear which supplemental form is best to use in clinical trials.


Adverse effects

In general, high-dose lipoic acid administration has been found to have few serious side effects. Intravenous administration of lipoic acid at doses of 600 mg/day for three weeks (112) and oral lipoic acid at doses as high as 1,800 mg/day for six months (113) and 1,200 mg/day for two years (76) did not result in serious adverse effects when used to treat diabetic peripheral neuropathy. There was no significant difference in the incidence of adverse events and serious adverse events in patients with diabetic neuropathy who took 600 mg/day of lipoic acid for four years compared to those in the placebo group (78). Oral intake of 2,400 mg/day for two weeks was also found to be safe in a pilot study that included participants with multiple sclerosis (95). Two mild anaphylactoid reactions and one severe anaphylactic reaction, including laryngospasm, were reported after intravenous lipoic acid administration (55). The most frequently reported side effects of oral lipoic acid supplementation are allergic reactions affecting the skin, including rashes, hives, and itching. Abdominal pain, nausea, vomiting, diarrhea, and vertigo have also been reported, and one trial found that the incidence of nausea, vomiting, and vertigo was dose-dependent (77). Further, malodorous urine has been noted by people taking 1,200 mg/day of lipoic acid orally (95).

Pregnancy and lactation

A retrospective observational study reported that daily oral supplementation with 600 mg of lipoic acid (racemic mixture) during pregnancy and without interruption from a period spanning between week 10 and week 30 of gestation and until the end of week 37 was not associated with any adverse effect in mothers and their newborns (114). In absence of further evidence, lipoic acid supplementation during pregnancy should only be considered under strict medical supervision. The safety of lipoic acid supplements in lactating women has not been established and should thus be discouraged (115).


A case of intoxication was reported in a 20-month old child (10.5 kg bw) after the accidental ingestion of four 600-mg tablets of lipoic acid (116). The child was admitted to hospital with seizure, acidosis, and unconsciousness. Symptomatic management and rapid elimination of lipoic acid led to a full recovery without sequelae within five days. The non-accidental ingestion of a very high dose of lipoic acid led to multi-organ failure and subsequent death of an adolescent girl (117).

Drug interactions

In theory, because lipoic acid supplementation may improve insulin-mediated glucose utilization (see Diabetes mellitus), there is a potential risk of hypoglycemia in diabetic patients using insulin or oral anti-diabetic agents (118). Consequently, blood glucose concentrations should be monitored closely when lipoic acid supplementation is added to diabetes treatment regimens. Yet, one study in 24 healthy volunteers reported no significant drug interactions with the co-administration of a single oral dose of lipoic acid (600 mg) and the oral anti-diabetic agents, glyburide (also called glybenclamide) or acarbose (Precose/Prandase/Glucobay) (119).

Nutrient interactions


The chemical structure of biotin is similar to that of lipoic acid, and there is some evidence that high concentrations of lipoic acid can compete with biotin for transport across cell membranes (120, 121). The administration of high doses of lipoic acid by injection to rats decreased the activity of two biotin-dependent enzymes by about 30%-35% (122), but it is not known whether oral or intravenous lipoic acid supplementation substantially increases the requirement for biotin in humans (123).

Authors and Reviewers

Originally written in 2002 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2003 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in April 2006 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2012 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in October 2018 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in January 2019 by:
Tory M. Hagen, Ph.D.
Principal Investigator, Linus Pauling Institute
Professor, Dept. of Biochemistry and Biophysics
Helen P. Rumbel Professor for Healthy Aging Research
Oregon State University

Copyright 2002-2024  Linus Pauling Institute


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Phytochemicals can be defined, in the strictest sense, as chemicals produced by plants. However, the term is generally used to describe chemicals from plants that may affect health, but are not essential nutrients. While there is ample evidence to support the health benefits of diets rich in fruit, vegetables, legumes, whole grains, and nuts, evidence that these effects are due to specific nutrients or phytochemicals is limited. Because plant-based foods are complex mixtures of bioactive compounds, information on the potential health effects of individual phytochemicals is linked to information on the health effects of foods that contain those phytochemicals.

Select a phytochemical from the list for more information.

The information on dietary phytochemicals from the Linus Pauling Institute's Micronutrient Information Center is now available in a book titled, An Evidence-based Approach to Phytochemicals and Other Dietary Factors. The book can be purchased from the Linus Pauling Institute or Thieme Medical Publishers.


α-Carotene, β-Carotene, β-Cryptoxanthin, Lycopene, Lutein, and Zeaxanthin



  • Carotenoids are yellow, orange, and red pigments synthesized by plants. The most common carotenoids in North American diets are α-carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene. (More information)
  • Provitamin A carotenoids, α-carotene, β-carotene, and β-cryptoxanthin, can be converted by the body to retinol (vitamin A). In contrast, no vitamin A activity can be derived from lutein, zeaxanthin, and lycopene. (More information)
  • Dietary lutein and zeaxanthin are selectively taken up into the macula of the eye, where they absorb up to 90% of blue light and help maintain optimal visual function. (More information)
  • At present, it is unclear whether the biological effects of carotenoids in humans are related to their antioxidant activity and/or other non-antioxidant activities. (More information)
  • Although the results of observational studies suggest that diets high in carotenoid-rich fruit and vegetables are associated with reduced risks of cardiovascular disease and some cancers, high-dose β-carotene supplements did not reduce the risk of cardiovascular disease or cancer in large randomized controlled trials. (More information)
  • Two randomized controlled trials found that high-dose β-carotene supplementation increased the risk of lung cancer in smokers and former asbestos workers. (More information)
  • Meta-analyses of observational studies have reported an inverse association between dietary lycopene intake or blood lycopene concentration and risk of developing prostate cancer. To date, most small-scale intervention studies have found little-to-no benefit of lycopene supplements in reducing the incidence or severity of prostate cancer in high-risk patients. (More information)
  • Observational studies have suggested that diets rich in lutein and zeaxanthin may help slow the development of age-related macular degeneration (AMD). Randomized controlled trials in subjects with AMD have found that lutein and zeaxanthin supplementation improves visual acuity and slows the progression to advanced AMD in subjects with AMD. (More information)
  • Evidence is lacking to suggest a role for lutein and zeaxanthin in the management of other eye conditions, including cataracts, diabetic retinopathy, and retinopathy of maturity. (More information)
  • Carotenoids are best absorbed with fat in a meal. Chopping, puréeing, and cooking carotenoid-containing vegetables in oil generally increase the bioavailability of the carotenoids they contain. (More information)


Carotenoids are a class of more than 750 naturally occurring pigments synthesized by plants, algae, and photosynthetic bacteria (1). These richly colored molecules are the sources of the yellow, orange, and red colors of many plants. Fruit and vegetables provide most of the 40 to 50 carotenoids found in the human diet. α-Carotene, β-carotene, β-cryptoxanthin, lutein, zeaxanthin, and lycopene are the most common dietary carotenoids (1). α-Carotene, β-carotene and β-cryptoxanthin are provitamin A carotenoids, meaning they can be converted by the body to retinol (Figure 1). Lutein, zeaxanthin, and lycopene are nonprovitamin A carotenoids because they cannot be converted to retinol (Figure 2).

Carotenoids Figure 1. All-trans Chemical Structures of Provitamin A Carotenoids. Beta-carotene, alpha-carotene, and beta-cryptoxanthin are potential sources of vitamin A. All three carotenoids have a long carbon chain terminated at each end by a ionone ring. Carotenoids with oxygen added to ionone rings like beta-cryptoxanthin are known as xanthophyll carotenoids. Other xanthophylls commonly in the human diet are non-provitamin A lutein and zeaxanthin.

Carotenoids Figure 2. All-trans Chemical Structures of Nonprovitamin A Carotenoids: lutein, zeaxanthin, and lycopene.

Absorption, Metabolism, and Bioavailability

For dietary carotenoids to be absorbed intestinally, they must be released from the food matrix and incorporated into mixed micelles (mixtures of bile salts and several types of lipids). Food processing and cooking help release carotenoids embedded in their food matrix and increase intestinal absorption (1). Moreover, carotenoid absorption requires the presence of fat in a meal. As little as 3 to 5 g of fat in a meal appears sufficient to ensure carotenoid absorption (2, 3), although the minimum amount of dietary fat required may be different for each carotenoid. The type of fat (e.g., medium-chain vs. long-chain triglycerides), the presence of soluble fiber, and the type and amount of carotenoids (e.g., esterified vs. non-esterified) in the food also appear to influence the rate and extent of carotenoid absorption (reviewed in 4). Because they do not need to be released from the plant matrix, carotenoid supplements (in oil) are more efficiently absorbed than carotenoids in food (3, 5). Although carotenoids were initially thought to be absorbed within the cells that line the intestine (enterocytes) only by passive diffusion, carotenoids are also actively absorbed via the apical membrane transporters, Scavenger Receptor-class B type I (SR-BI), Cluster Determinant 36 (CD36), and Niemann-Pick C1 like intracellular transporter 1 (NPC1L1) (6-8).

Within the enterocytes, provitamin A carotenoids may be cleaved by either β-carotene 15,15’-oxygenase 1 (BCO1) or by β-carotene 9’,10’-oxygenase 2 (BCO2) (Figure 3). BCO1 catalyzes the cleavage of provitamin A carotenoids into retinal, which is further reduced to retinol (vitamin A) or oxidized to retinoic acid (the biologically active form of vitamin A). β-Apocarotenal derived from the cleavage of β-carotene by BCO2 can be cleaved further by BCO1 to produce retinal. Although provitamin A carotenoids can be converted into apocarotenals by BCO2, the activity of this enzyme is higher toward nonprovitamin A carotenoids. Conversely, BCO1 shows limited affinity toward nonprovitamin A carotenoids (1).

Within the enterocytes, uncleaved carotenoids and retinyl esters (derived from retinol) are incorporated into triglyceride-rich lipoproteins called chylomicrons, secreted into lymphatic vessels, and then released into the bloodstream (1). Triglycerides are depleted from circulating chylomicrons through the activity of an enzyme called lipoprotein lipase, resulting in the formation of chylomicron remnants. Chylomicron remnants are taken up by the liver, where carotenoids can be cleaved by BCO1/BCO2 or incorporated into lipoproteins and secreted back into the circulation for delivery to extrahepatic tissues. Of note, more hydrophilic molecules in the enterocytes like retinoic acid and apocarotenals can be transported directly to the liver through the portal blood system.

The conversion of provitamin A carotenoids to retinol is influenced by the vitamin A status of the individual (9). The regulatory mechanism involving the intestine-specific homeobox (ISX) transcription factor can block carotenoid uptake and vitamin A production by inhibiting the expression of SR-BI and BCO1. ISX is under the control of retinoic acid and retinoic acid receptor (RAR)-dependent mechanisms such that, when vitamin A stores are high, ISX is activated and both provitamin A carotenoid absorption and conversion to retinol are inhibited. Conversely, during vitamin A insufficiency, the expression of both SR-BI and BCO1 is no longer repressed by ISX, allowing for provitamin A carotenoid absorption and conversion to retinol (1).

Interindividual variations in blood and tissue concentrations of carotenoids have been attributed to genetic differences among individuals. Specifically, a number of single nucleotide polymorphisms (SNPs) — corresponding to changes of one nucleotide in the sequence of genes — have been identified in genes coding for proteins involved in intestinal uptake, transport, and metabolism of carotenoids (10). Specifically, SNPs within genes coding for SR-BI, CD36, and BCO1 are suspected to affect the expression and/or activity of these proteins and, in turn, individual carotenoid status (10). For more information genetic variants affecting carotenoid status, see the review by Moran et al. (5).

Carotenoids Figure 3. Metabolic Pathways of Carotenoids.

Biological Activities

Provitamin A function

Vitamin A is essential for normal growth and development, immune system function, and vision (see the article on Vitamin A). Currently, the only essential function of carotenoids recognized in humans is that of the provitamin A carotenoids, α-carotene, β-carotene, and β-cryptoxanthin, to serve as a source of vitamin A (11).

Retinol activity equivalents (RAEs)

Provitamin A carotenoids are less easily absorbed than preformed vitamin A and must be converted to retinol and other retinoids by the body (see Figure 3). The efficiency of conversion of provitamin A carotenoids into retinol is highly variable, depending on factors like food matrix, food preparation, and one’s digestive and absorptive capacities (12).

The most recent international standard of measure for vitamin A is retinol activity equivalent (RAE), which represents vitamin A activity as retinol. It has been determined that 2 micrograms (µg) of β-carotene in oil provided as a supplement could be converted by the body to 1 µg of retinol, giving it an RAE ratio of 2:1. However, 12 µg of β-carotene from food are required to provide the body with 1 µg of retinol, giving dietary β-carotene an RAE ratio of 12:1. Other provitamin A carotenoids in food are less easily absorbed than β-carotene, resulting in RAE ratios of 24:1. RAE ratios are shown in Table 1.

Table 1. Retinol Activity Equivalent (RAE) Ratios for Preformed Vitamin A and Provitamin A Carotenoids
Quantity Consumed Quantity Bioconverted to Retinol RAE Ratio
1 µg of dietary or supplemental preformed vitamin A 1 µg of retinol 1:1
2 µg of supplemental β-carotene 1 µg of retinol 2:1
12 µg of dietary β-carotene 1 µg of retinol 12:1
24 µg of dietary α-carotene 1 µg of retinol 24:1
24 µg of dietary β-cryptoxanthin 1 µg of retinol 24:1

Antioxidant activity

In plants, carotenoids have the important antioxidant function of quenching (deactivating) singlet oxygen, an oxidant formed during photosynthesis (13). Test tube studies indicated that lycopene is one of the most effective quenchers of singlet oxygen among carotenoids (14). They also suggested that carotenoids could inhibit the oxidation of fats (i.e., lipid peroxidation) under certain conditions, but their actions in humans appear to be more complex (15). Although important for plants, the relevance of singlet oxygen quenching to human health is less clear (1).

Nrf2-dependent antioxidant pathway

Some evidence suggests that carotenoids and/or their metabolites may upregulate the expression of antioxidant and detoxifying enzymes via the activation of the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent pathway (reviewed in 16). Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol. Keap1 responds to oxidative stress signals by freeing Nrf2. Upon release, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE) located in the promoter of genes coding for antioxidant/detoxifying enzymes and scavengers. Nrf2/ARE-dependent genes code for numerous mediators of the antioxidant response, including glutamate-cysteine ligase (GCL), glutathione S-transferases (GSTs), thioredoxin, NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) (17). One study showed an increase in the level of the major antioxidant glutathione and a protection against TNFα-induced oxidative stress in retinal pigment epithelial cells (RPE) following lycopene-mediated Nrf2 activation and GCL induction (18). Nrf2 activation by lycopene also protected RPE against TNFα-mediated proinflammatory signaling involving nuclear factor-κB (NF-κB) activation and intercellular adhesion molecule-1 (ICAM-1) expression (18). Lycopene was shown to trigger Nrf2-mediated antioxidant pathway in various cell types (19-21). At present, evidence from animal and human studies is very limited (16).

Blue light filtering

The long system of alternating double and single bonds common to all carotenoids allows them to absorb light in the visible range of the spectrum (13). This feature has particular relevance to the eye, where lutein, zeaxanthin, and meso-zeaxanthin (derived from in vivo conversion from lutein) efficiently absorb blue light. Depending on the carotenoid pigment density at the center of the eye’s retina (macula), up to 90% of blue light can be absorbed by these pigments. Reducing the amount of short-wavelength light that reaches the critical visual structures of the eye may protect them from light-induced oxidative damage (22). Because the only source of these plant pigments in the eye is diet, a number of observational and intervention studies have examined the potential of dietary and supplemental lutein and zeaxanthin to protect against age-related eye diseases (see Age-related macular degeneration and Cataracts). Supplemental lutein, alone or with zeaxanthin, was found to improve contrast sensitivity and protect against visual fatigue in young and/or healthy individuals (23-26). Lutein has also been suggested to improve visual function through stimulating neuronal signaling efficiency in the eye (27).

Intercellular communication

Carotenoids can facilitate communication between neighboring cells grown in culture by stimulating the synthesis of connexin proteins (28). Connexins form pores (gap junctions) in cell membranes, allowing cells to communicate through the exchange of small molecules. This type of intercellular communication is important for maintaining cells in a differentiated state and is often lost in cancer cells. Carotenoids facilitate intercellular communication by increasing the expression of the gene encoding a connexin protein, an effect that appears unrelated to the vitamin A or antioxidant activities of various carotenoids (29) and involving a retinoic acid receptor (RAR)-independent mechanism (30).

Immune function

Because vitamin A is essential for normal immune system function, it is difficult to determine whether the effects of provitamin A carotenoids are related to their vitamin A activity or other activities of carotenoids. Although some clinical trials have found that β-carotene supplementation improves several biomarkers of immune function (31-33), increasing intakes of lycopene and lutein — carotenoids without vitamin A activity — have not resulted in similar improvements in biomarkers of immune function (34-36).


Although consumption of provitamin A carotenoids (α-carotene, β-carotene, and β-cryptoxanthin) can prevent vitamin A deficiency (see the article on Vitamin A), no overt deficiency symptoms have been identified in people consuming low-carotenoid diets if they consume adequate vitamin A (11). After reviewing the published scientific research in 2000, the Food and Nutrition Board of the Institute of Medicine concluded that the existing evidence was insufficient to establish a recommended dietary allowance (RDA) or adequate intake (AI) for carotenoids. The Board has set an RDA for vitamin A (see the article on Vitamin A). Recommendations by the National Cancer Institute, American Cancer Society, and American Heart Association to consume a variety of fruit and vegetables daily are aimed, in part, at increasing intakes of carotenoids.

Disease Prevention


Lung cancer

In the US, lung cancer is the leading cause of death by cancer among adults, representing about 20% of all cancer-related deaths (37).

Dietary carotenoids: Several large prospective cohort studies, including the Nurses’ Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), have examined potential associations between carotenoid intake and/or blood concentrations and lung cancer (38). In a meta-analysis of eight prospective cohort studies, including NHS and HPFS, the highest versus lowest quantile of total carotenoid intake was significantly associated with a 21% reduced risk of lung cancer. For the individual carotenoids, the risk of lung cancer was estimated to be 20% and 14% lower with the highest versus lowest intakes of β-cryptoxanthin and lycopene, respectively. In contrast, dietary intakes of β-carotene, α-carotene, and lutein/zeaxanthin were not found to be significantly linked to a reduced risk of developing lung cancer (38). In addition, an analysis of the pooled results of 11 nested case-control and four prospective cohort studies found no association between serum concentrations of total carotenoids, β-carotene, α-lycopene, β-cryptoxanthin, and lutein/zeaxanthin and lung cancer. Only high versus low serum lycopene concentrations could be linked to a 29% lower risk of lung cancer (38). Any protective effect of dietary carotenoids against the development of lung cancer is likely small and not statistically significant (38).

Supplemental β-carotene: The effect of β-carotene supplementation on the risk of developing lung cancer has been examined in large randomized, placebo-controlled trials. In Finland, the Α-Tocopherol Βeta-Carotene (ATBC) cancer prevention trial evaluated the effects of 20 mg/day of β-carotene and/or 50 mg/day of α-tocopherol on more than 29,000 male smokers (39), and in the United States, the β-Carotene And Retinol Efficacy Trial (CARET) evaluated the effects of a combination of 30 mg/day of β-carotene and 25,000 IU/day of retinol (preformed vitamin A) in 18,314 men and women who were smokers, former smokers, or had a history of occupational asbestos exposure (40). Unexpectedly, the risk of lung cancer in the groups taking β-carotene supplements was increased by 16% after six years in the ATBC participants and by 28% after four years in the CARET participants. In contrast, the Physicians’ Health Study (PHS) examined the effect of β-carotene supplementation (50 mg every other day) on cancer risk in 22,071 male physicians in the United States, of whom only 11% were current smokers (41). In that lower risk population, β-carotene supplementation for more than 12 years was not associated with an increased risk of lung cancer. In addition, in the Linxian General Population trial conducted in about 29,000 Chinese participants, randomization to 15 mg/day of β-carotene, 30 mg/day of α-tocopherol, and 15 µg/day of selenium, was not found to be associated with lung cancer mortality 10 years after the intervention ended (42). Moreover, five-year follow-up of the Age-Related Eye Disease Study 2 (AREDS2) trial found that β-carotene supplementation nearly doubled the risk of developing lung cancer in former smokers compared to nonsmokers (current smokers did not receive β-carotene supplements) (43). AREDS2 was a multicenter, randomized double-blind, placebo-controlled trial that evaluated the effects of supplementation with antioxidant vitamins and minerals for five years to treat age-related macular degeneration (see below). Finally, a meta-analysis of four randomized controlled trials, including but not limited to trials in high-risk populations like smokers, found β-carotene supplementation (alone or with retinol; 3.7 to 12 years) increased the risk of lung cancer by 20% compared to control (OR, 1.20; 95% CI, 1.01-1.42) (44).  

Although the reasons for the increase in lung cancer risk are not yet clear, several mechanisms have been proposed (45). Baseline β-carotene status might be one factor that influences whether with β-carotene supplementation promotes carcinogenesis in the lungs of smokers (46). The US Preventive Services Task Force estimated that the risks of high-dose β-carotene supplementation outweigh any potential benefits for cancer prevention and recommended against supplementation, especially in smokers or other high-risk populations (44, 47).

Prostate cancer

Prostate cancer is the one of the most prevalent cancers among US men, second only to non-melanoma skin cancer (48).

Dietary lycopene: Several early prospective cohort studies suggested that lycopene-rich diets were associated with significant reductions in the risk of prostate cancer, particularly more aggressive forms (49). Several pooled data analyses of observational studies that examining potential links between dietary intakes and/or circulating concentrations of lycopene and risk of prostate cancer have been completed. A 2015 meta-analysis of observational studies found no association of prostate cancer risk with dietary lycopene intakes (10 case-cohort and two prospective cohort studies) but an inverse association with blood lycopene concentrations (two case-control, nine nested case-control, and one cohort studies) (50, 51). Additionally, a meta-analysis of 15 nested case-control studies conducted by the Endogenous Hormones, Nutritional Biomarkers, and Prostate Cancer Collaborative Group showed an inverse association between circulating lycopene concentrations and risk of advanced stage and/or aggressive prostate cancer, while no association was found with risk of non-aggressive or localized disease (52). A 2017 meta-analysis of observational studies found inverse associations between both dietary (6 cohort/case-cohort and 15 case-control studies) and circulating (1 cohort study, 4 case-control studies, and 12 nested case-control studies) lycopene and prostate cancer risk; risk reductions were 12% in both analyses (RR, 0.88; 95% CI, 0.78-0.98) (53). However, this meta-analysis found no associations between dietary lycopene (5 studies) or circulating lycopene (6 studies) and advanced prostate cancer (53).

While there is considerable scientific interest in the potential for lycopene to help prevent prostate cancer, it is not yet clear whether the prostate cancer risk reduction observed in some observational studies is related to lycopene itself, other compounds in tomatoes, or other factors associated with lycopene-rich diets (54). Experimental studies in rodents suggest that lycopene is protective against prostate cancer but not the only protective compound found in tomatoes (reviewed in 5). Of note, the 2014 World Cancer Research Fund International report on Diet, Nutrition, Physical Activity, and Prostate Cancer suggested the need for better designed studies to establish whether consumption of lycopene-containing foods could be linked to a lower risk of prostate cancer (55).

Supplemental lycopene: To date, a few short-term, dietary intervention studies using lycopene in patients with precancerous prostate lesions (high grade prostatic intraepithelial neoplasia; HGPIN) or prostate cancer have been completed. Specifically, two small randomized controlled studies examined the effect of lycopene supplementation for up to six months in men with HGPIN (56, 57). The consumption of 30 to 35 mg/day of supplemental lycopene in the form of tomato extract (56), or together with selenium (55 mg/day) and green tea catechins (600 mg/day) (57), showed no benefit on the rate of progression to prostate cancer at six-month (56, 57) and 37-month follow-ups (57). Earlier small trials in men with HGPIN led to similar conclusions (reviewed in 58). Additionally, a randomized controlled trial in men with localized prostate cancer found that supplementation with 15, 30, or 45 mg of lycopene (until prostatectomy) did not significantly increase plasma lycopene concentration, modify the ratio of steroid hormones in blood, or reduce the concentration of markers of proliferation (i.e., prostate-specific antigen [PSA] and Ki-67) compared to placebo (59). In another trial, 54 patients with metastatic prostate cancer were randomized to orchidectomy alone or orchidectomy plus 4 mg/day of lycopene (60). The proportion of complete clinical response to treatment — assessed by serum PSA and/or bone scan returning to normal — and patient survival rate were found to be significantly higher in patients supplemented with lycopene (60).

Moreover, a meta-analysis of six randomized controlled trials in patients with non-metastatic prostate cancer found that supplemental lycopene (15-30 mg/day for 3 to 24 weeks) had no effect on circulating PSA concentrations (61). Yet, a subgroup analysis revealed a benefit of PSA reduction in patients with higher concentrations at baseline (PSA ≥6.5 µg/L) (61).

Large-scale, controlled clinical trials are needed to further examine the safety and efficacy of long-term use of lycopene supplements for prostate cancer prevention or treatment.

Other types of cancer

In a meta-analysis of 12 prospective cohort studies, no association was found between total and individual carotenoid intake and risk of breast cancer, except with β-carotene for which a 5% reduction in breast cancer risk was estimated for every 5 mg/day increment in consumption (62). In a pooled analysis of 14 nested case-control studies and one follow-up study of a clinical trial, reductions in breast cancer risk were found to be associated with blood concentrations of total carotenoids (-26%), α-carotene (-20%), and lutein (-30%) (62). Another study that recalibrated data for consistency across eight large prospective cohorts before pooled analysis found reduced breast cancer risk to be associated with the highest versus lowest quintile of blood concentrations of total carotenoids (-21%), β-carotene (-17%), and lycopene (-22%) (63). Further analyses found an inverse association between the blood concentrations of β-carotene and α-carotene and risk of estrogen receptor-negative (ER-), but not estrogen receptor-positive (ER+), breast tumors (63). A similar result was reported in a case-control study nested within the multicenter, large, European Prospective Investigation into Cancer and Nutrition (EPIC) study (64). In a nested case-control study of the Nurses’ Health Study (NHS) and NHSII, a 20% reduction in risk of breast cancer was seen in those with the highest total plasma carotenoids (≥142.1 µg/dL) compared to the lowest (<84.6 µg/dL), and this association was strongest in those presumed to be at higher risk of breast cancer (65). Protective associations were observed for higher circulating levels of the carotenoids, α-carotene (-20%), β-carotene (-18%), as well as lutein and zeaxanthin (-17%) (65). In contrast to the abovementioned pooled analysis (63), this study found a protective association between higher circulating carotenoids and ER+, but not ER-, breast tumors (65).

A case-control study nested within the EPIC study found a 31% lower risk of colorectal cancer with the highest versus lowest quartile of β-carotene intake, while no associations were shown with blood concentrations of other carotenoids or total carotenoids (66). The nested case-control study was included in a meta-analysis of 22 observational studies that failed to find associations between carotenoid intakes and colorectal cancer (67). A meta-analysis of 15 observational studies (11 case-control and 4 prospective cohort studies) reported no association between lycopene intake and colorectal cancer (68).

Pooled data also suggested that higher intakes of individual carotenoids, especially β-cryptoxanthin and lycopene, might be associated with a reduced risk of cancers of the mouth, pharynx, and larynx (69), but most of the data come from case-control control studies (70). The results of case-control studies are more likely to be distorted by bias than results of prospective cohort studies.

Examining blood concentrations of each carotenoid in relation to cancer subsites may help overcome limitations associated with dietary data and differences in carotenoid absorption. In a recent dose-response meta-analysis of observational studies, higher blood concentrations of several carotenoids, including α-carotene (3 studies), β-carotene (4 studies), as well as combined lutein and zeaxanthin (3 studies), were linked to a lower risk of developing bladder cancer (71).

Eye diseases

Age-related macular degeneration

In Western countries, degeneration of the macula, the center of the eye’s retina, is a leading cause of blindness among older adults. Long-term blue light exposure and oxidative damage in the outer segments of photoreceptors may lead to drusen and/or pigment abnormalities in the macula, increasing the risk of age-related macular degeneration (AMD) and central blindness.

Dietary lutein and zeaxanthin: The carotenoids found in the retina are lutein and zeaxanthin, which are both of dietary origin, and meso-zeaxanthin, which is derived in vivo conversion from lutein. These three carotenoids are present in high concentrations in the macula (known as macular pigment), where they are efficient absorbers of blue light. They may prevent a substantial amount of the blue light entering the eye from reaching the underlying structures involved in vision and protect against light-induced oxidative damage, which is thought to play a role in the pathology of age-related macular degeneration (reviewed in 22). It is also possible, though not proven, that lutein, zeaxanthin, and meso-zeaxanthin, act directly to neutralize oxidants formed in the retina.

Increasing dietary consumption of lutein and zeaxanthin was shown to raise their serum concentration and macular pigment density (72, 73). Some, but not all, observational studies have provided evidence that higher intakes of lutein and zeaxanthin are associated with lower risk of age-related macular degeneration (AMD) (74). While cross-sectional and retrospective case-control studies found that higher levels of lutein and zeaxanthin in the diet (75-77), blood (78, 79), and retina (80, 81) were associated with a lower incidence of AMD, several prospective cohort studies found no relationship between baseline dietary intakes or serum concentrations of lutein and zeaxanthin and the risk of developing AMD over time (82-85). One report examined the association between the incidence of AMD and calculated dietary intakes and predicted plasma concentrations of lutein and zeaxanthin in older adults (≥50 years) from two large prospective cohorts, the Nurses’ Health Study (NHS; 63,443 women) and the Health Professionals Follow-up Study (HPFS; 38,603 men), followed for 26 years and 24 years, respectively (86). The highest versus lowest quintile of predicted plasma lutein and zeaxanthin scores was associated with a 41% lower risk of advanced AMD, yet no association was found with intermediate AMD. Evidence has suggested that the consumption of about 6 mg/day of lutein and zeaxanthin from fruit and vegetables (compared with less than 2 mg/day) may decrease the risk of advanced AMD (77, 86). In a small population-based prospective study among 609 older adults in France, followed for a median of 7.6 years, found an inverse association between plasma lutein concentration at baseline and advanced AMD (HR, 0.63; 95% CI, 0.41-0.97) (87). No association was observed for circulating zeaxanthin and advanced AMD (87).

Supplemental lutein and zeaxanthin: The first randomized controlled trial in patients with atrophic AMD found that supplementation with 10 mg/day of lutein slightly improved visual acuity after one year compared to a placebo (88). The effects of long-term lutein supplementation on atrophic AMD were further investigated in combination with antioxidant vitamins and minerals in the Age-Related Eye Disease Study 2 (AREDS2), a multicenter, randomized, double-blind, placebo-controlled trial. In AREDS, oral supplementation with β-carotene (15 mg/day), vitamin C (500 mg/day), vitamin E (400 IU/day), zinc (80 mg/day as zinc oxide), and copper (2 mg/day as cupric oxide) for five years reduced the risk of developing advanced AMD by 25% (89). In the AREDS2 study conducted in 4,203 participants at risk for developing late AMD, supplemental lutein (10 mg/day) and zeaxanthin (2 mg/day), in combination with β-carotene, vitamin C, vitamin E, zinc, and copper (the ‘AREDS’ formulation), did not slow the progression to advanced AMD, although subgroup analyses revealed a benefit in those with the lowest dietary intakes of lutein + zeaxanthin (89). A total of 3,036 subjects were further randomized to various combinations of carotenoids; supplementation with lutein and zeaxanthin significantly reduced the risk of progression to late AMD and to neovascular AMD compared to supplementation with β-carotene (90)

Several smaller (n=30-433) randomized controlled trials also suggested that supplementation with xanthophyll carotenoids would be beneficial in the management of AMD (reviewed in 91). A meta-analysis of eight trials that examined the effect of supplemental lutein (6 to 20 mg/day) or/and zeaxanthin (0 to 10 mg/day) in 1,176 AMD subjects for up to 36 months found improvements in visual acuity and contrast sensitivity with increased levels of xanthophyll carotenoids (92). More recently, a randomized, placebo-controlled trial found daily consumption of a buttermilk drink with egg yolks enriched with lutein (1.4 mg), zeaxanthin (0.2 mg), and an omega-3 polyunsaturated fatty acid (DHA; 160 mg) for one year improved visual acuity and macular pigment optical density in subjects with drusen and/or retinal pigment abnormalities (about half of them being classified as having early AMD) (93). In a randomized, placebo-controlled trial in 74 patients with intermediate AMD, daily supplementation with lutein (10 mg/day) and zeaxanthin (2 mg) for two years, along with daily astaxanthin (4 mg), vitamin C (90 mg), vitamin E (30 mg), zinc (22.5 mg), copper (1 mg), and fish oil (containing 185 mg EPA and 140 mg DHA), resulted in a lower incidence of disease progression (2.1% of patients) when compared to placebo (15.4% of patients) (94).

Supplemental β-carotene: The first randomized controlled trial designed to examine the effect of a carotenoid supplement on AMD used β-carotene in combination with vitamin C, vitamin E, and zinc because lutein and zeaxanthin were not commercially available as supplements at the time the trial began (95). Although the combination of antioxidants and zinc lowered the risk of developing advanced macular degeneration in individuals with signs of moderate-to-severe macular degeneration in at least one eye, it is unlikely that the benefit was related to β-carotene since it is not present in the retina. Supplementation of male smokers in Finland with 20 mg/day of β-carotene for six years did not decrease the risk of AMD compared to placebo (96). A placebo-controlled trial in a cohort of 22,071 healthy US men found that β-carotene supplementation (50 mg every other day) had no effect on the incidence of age-related maculopathy — an early stage of AMD (97). Recent systematic reviews of randomized controlled trials have concluded that there is no evidence that β-carotene supplementation prevents or delays the onset of AMD (98, 99).

Other retinopathies

Retinopathy of prematurity

Preterm infants have an immature retinal vascular system that places them at risk of developing retinopathy of prematurity (ROP). Basically, preterm birth halts the normal development of retinal vascular system, which results in a retina that is poorly vascularized and highly susceptible to hyperoxia. In order to meet metabolic demand, the hypoxic retina induces the production of proangiogenic factors like VEGF (vascular endothelial growth factor). These factors stimulate the development of new blood vessels (angiogenesis), causing aberrant vessels sprouting from the retina into the vitreous. It is thought that an imbalance between the production of reactive oxygen species (ROS) and the reduced levels of antioxidants in preterm infants contributes to ROP pathogenesis and causes additional damage to the retina (reviewed in 100).

Supplemental lutein and zeaxanthin: A randomized controlled trial in 62 preterm infants (≤32 weeks of gestational age) failed to observe any benefits regarding ROP incidence and severity with lutein (0.5 mg/kg/day) and zeaxanthin (0.02 mg/kg/day) supplemented from the seventh day post birth until about 10 weeks of age (101). In two other multicenter, placebo-controlled trials in a total of 343 preterm infants, a daily oral dose of 0.14 mg of lutein and 0.006 mg of zeaxanthin administered from the first week after birth did not significantly reduce ROP incidence or the rate of progression from early to more advanced stages of ROP occurrence (102, 103). A fourth multicenter, randomized controlled trial in 203 preterm infants found that administration of a formula containing carotenoids (lutein/zeaxanthin, lycopene, and β-carotene) had no effect on ROP incidence but limited the progression to severe ROP stages in infants with mild ROP compared to a carotenoid-free formula (104). Compared with the control formula, preterm infants free of ROP fed the carotenoid-containing formula had significantly increased plasma carotenoid concentrations, which were correlated with greater rod photoreceptor sensitivity (104). More research is needed to examine whether carotenoid supplementation might promote normal photoreceptor development and prevent ROP in preterm infants.

Diabetic retinopathy

Supplementation with lutein and zeaxanthin has been shown to help preserve retinal integrity in diabetic rodents by reducing oxidative stress and inflammatory mediators (100). A higher ratio of plasma nonprovitamin A carotenoids (lutein, zeaxanthin, and lycopene) to vitamin A carotenoids (α-carotene, β-carotene, β-cryptoxanthin) was associated with a reduced risk of diabetic retinopathy in a cross-sectional analysis in 111 individuals with type 2 diabetes mellitus (105). A small observational study also found lower macular pigment optical density in those with type 2 diabetes (n=17) or mild nonproliferative diabetic retinopathy (n=12) compared to those without either condition (n=14) (106). Data from 1,430 individuals participating in the Atherosclerosis Risk In Communities (ARIC) study found no association between lutein intake and diabetic retinopathy after adjustment for confounding variables (107).

It is not known if supplementation with lutein and zeaxanthin might prevent or help treat diabetic retinopathy; well-designed, placebo-controlled studies would be needed to address these questions.


The primary function of the eye’s lens is to collect and focus light on the retina. Ultraviolet light and oxidants can damage proteins in the lens, causing structural changes that result in the formation of opacities known as cataracts. As people age, cumulative damage to lens proteins often results in cataracts that are large enough to interfere with vision (13). Risk factors other than aging and sunlight exposure include smoking, diabetes mellitus, higher body mass index, and use of estrogen replacement therapy. An estimated 50 million US adults are projected to be affected by age-related cataracts by 2050 (108).

Dietary lutein and zeaxanthin: The observation that lutein and zeaxanthin are the only carotenoids in the human lens has stimulated interest in the potential for increased intakes of lutein and zeaxanthin to prevent or slow the progression of cataracts (109). Large prospective cohort studies have found that men and women with the highest intakes of foods rich in lutein and zeaxanthin, particularly spinach, kale, and broccoli, were 18%-50% less likely to require cataract extraction (110, 111) or develop cataracts (112-114). Moreover, plasma concentrations of lutein and zeaxanthin have been found to be inversely associated to the progression of nuclear cataract. Additional research is required to determine whether these findings are related specifically to lutein and zeaxanthin intake or to other factors associated with diets high in carotenoid-rich foods (74).

Supplemental lutein and zeaxanthin: The Age-related Eye Disease Study 2 (AREDS2) failed to show an effect of supplemental lutein (10 mg/day) and zeaxanthin (2 mg/day; supplementation for a median of 4.7 years) on the risk of developing cataract, on the progression to severe cataract or to cataract surgery, and on visual acuity (115). However, the results might have been confounded by the fact that most participants were better nourished than the general population and/or used multivitamins that have been found to decrease the risk of developing cataract (116). Additional limitations to consider in interpreting the results have been reviewed elsewhere (115). Additional interventions are required to study whether supplemental lutein and zeaxanthin might be helpful in the prevention of cataract.

Supplemental β-carotene: Evidence from observational studies that cataracts were less prevalent in people with high dietary intakes and blood concentrations of carotenoids led to the inclusion of β-carotene supplements in several large randomized controlled trials of antioxidants. The results of those trials have been somewhat conflicting. β-Carotene supplementation (20 mg/day) for more than six years did not affect the prevalence of cataracts or the frequency of cataract surgery in male smokers living in Finland (96). In contrast, a 12-year study of male physicians in the US found that β-carotene supplementation (50 mg every other day) decreased the risk of cataracts in smokers but not in nonsmokers (117). Note that use of β-carotene supplements have been shown to increase the risk of lung cancer in smokers (see Supplemental β-carotene in lung cancer). Three randomized controlled trials examined the effect of an antioxidant combination that included β-carotene, vitamin C, and vitamin E on the progression of cataracts. Two trials found no benefit after supplementation for five years (118) or more than six years (119), but one trial found a small decrease in the progression of cataracts after three years of supplementation (120). Overall, the results of randomized controlled trials suggest that the benefit of β-carotene supplementation in slowing the progression of age-related cataracts does not outweigh the potential risks.

Cardiovascular disease

Dietary carotenoids: Because carotenoids are very soluble in fat and very insoluble in water, they circulate in lipoproteins, along with cholesterol and other fats. Evidence that low-density lipoprotein (LDL) oxidation plays a role in the development of atherosclerosis led scientists to investigate the role of antioxidant compounds like carotenoids in the prevention of cardiovascular disease (121). The thickness of the inner layers of the carotid arteries can be measured noninvasively using ultrasound technology. This measurement of carotid intima-media thickness is considered a reliable marker of atherosclerosis (122). A number of case-control and cross-sectional studies have found higher blood concentrations of carotenoids to be associated with significantly lower measures of carotid artery intima-media thickness (123-128). Additionally, higher plasma carotenoids at baseline have been associated with significant reductions in risk of cardiovascular disease in some prospective cohort studies (129-133) but not in others (134-137).

In a US national survey, National Health And Nutrition Examination Survey (NHANES) 2003-2006, serum total carotenoid concentration was inversely associated with blood concentrations of two cardiovascular risk factors, C-reactive protein (CRP) and total homocysteine (138). HDL-cholesterol concentration was found to be positively associated with α-carotene, β-cryptoxanthin, and lutein/zeaxanthin concentrations, but only the latter was inversely associated with LDL-cholesterol (138). NHANES 2007-2014 also found an inverse association between total dietary carotenoid intake (sum of α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin) and risk of hypertension (139). Finally, a meta-analysis of observational studies reported lower risks of coronary heart disease (-12%) and stroke (-18%) in individuals in the highest versus lowest tertile of blood lutein concentration (140). In a recent meta-analysis, higher lycopene intake — from diet and/or supplements — was not associated with improvements in blood pressure or concentrations of blood lipids; the included studies were heterogeneous with respect to lycopene delivery (i.e., as a supplement or as food, varying tomato-containing products or extracts) and dose, characteristics of participants (healthy or with disease), and study duration (141).

While the results of several prospective studies indicate that people with higher intakes of carotenoid-rich fruit and vegetables are at lower risk of cardiovascular disease (137, 142-144), it is not yet clear whether this effect is a result of carotenoids or other factors associated with diets high in carotenoid-rich fruit and vegetables.

Supplemental β-carotene: In contrast to the results of observational studies suggesting that high dietary intakes of carotenoid-rich fruit and vegetables may decrease cardiovascular disease risk, four randomized controlled trials found no evidence that β-carotene supplements in doses ranging from 20 to 50 mg/day were effective in preventing cardiovascular disease (39, 41, 145, 146). Based on the results of these randomized controlled trials, the US Preventive Health Services Task Force found good evidence to suggest that β-carotene supplements provided no benefit in the prevention of cardiovascular disease in healthy adults (47). Moreover, a recent meta-analysis of 12 randomized, placebo-controlled trials found that β-carotene supplementation increased mortality related to cardiovascular disease (RR, 1.12; 95% CI, 1.04-1.19) (147). Thus, although diets rich in β-carotene have generally been associated with reduced cardiovascular disease risk in observational studies, there is no evidence that β-carotene supplementation reduces cardiovascular disease risk (148).

Supplemental lycopene: Several randomized controlled trials have examined whether supplementation with lycopene, tomato products, or tomato extracts might benefit cardiovascular health by improving blood pressure, lipid profiles, or function of the vascular endothelium. A recent meta-analysis of eight trials found no effect of supplemental lycopene on systolic or diastolic blood pressure; no benefits were found in healthy subjects or in hypertensive subjects (141). The meta-analysis also showed no effect of lycopene supplementation on total cholesterol (10 trials), LDL cholesterol (11 trials), or HDL (11 trials) cholesterol (141). Moreover, some, but not all (149, 150) short-term trials have indicated supplemental lycopene might improve function of the vascular endothelium in healthy subjects (151, 152); however, large, long-term placebo-controlled studies are needed.


An experimental study found that the administration of β-cryptoxanthin to ovariectomized mice limited bone resorption by inhibiting osteoclast differentiation but had no effect on osteoblast-driven bone formation (153). Yet, evidence of a protective role of β-cryptoxanthin — and other individual carotenoids — against bone loss in humans is scarce. In the prospective Framingham Osteoporosis Study, data analysis of 603 participants found no association between β-cryptoxanthin intake and changes in bone mineral density (BMD) over a four-year period (154). In contrast, intakes of total and individual carotenoids (β-carotene, lycopene, and lutein/zeaxanthin) were positively associated with proximal femur BMD in men over a four-year period, while lycopene intake was positively linked to lumbar spine BMD in women (154). The 17-year follow-up of participants in the Framingham Osteoporosis Study (946 participants) showed those in the highest tertile of total carotenoid intake (median intake: 23.7 mg/day) had a 51% lower risk of hip fracture compared to those in the lowest tertile (median intake: 7.3 mg/day) (155). In a much larger prospective study — the Singapore Chinese Health Study — in 63,257 men and women followed for 10 years, the highest versus lowest quartile of total carotenoid intake was associated with a 37% lower risk of hip fracture in men, but no association was observed in women (156). Dietary intakes of α- and β-carotene — but not of β-cryptoxanthin, lycopene, and lutein/zeaxanthin — were inversely associated with hip fracture risk in men (156). Nevertheless, in a small, four-year, Japanese prospective cohort study in 457 adults, the risk of osteoporosis was 93% lower in postmenopausal women in the highest versus lowest tertile of serum β-cryptoxanthin concentration (157). No such association was reported with serum concentrations of other individual carotenoids. More recently, in a cross-sectional analysis of the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort, higher dietary intakes of β-carotene and combined lutein and zeaxanthin were linked to higher bone density at the heel in women (158). No associations of dietary carotenoid intake and heel bone density were found in men, and serum concentration of carotenoids was not linked to heel bone density in either men or women (158).

While a few studies have found a protective association between higher carotenoid intake and osteoporosis or bone fracture, the available studies are observational. Whether carotenoid supplementation may help prevent bone loss and reduce the risk of osteoporosis in older individuals is currently unknown; randomized controlled trials would be needed to address this question. It is important to note that high-dose supplementation with preformed vitamin A (retinol) has been associated with adverse effects on bone health (see the article on Vitamin A).

Cognitive function

Observational studies have suggested that dietary lutein may be of benefit in maintaining cognitive health (159-162), and a cross-sectional study of 4,076 older adults associated higher blood lutein concentrations with improved cognition, including memory and executive function (163). As stated above, among the carotenoids, lutein and its isomer zeaxanthin are the only two that cross the blood-retina barrier to form macular pigment in the eye. Lutein also preferentially accumulates in the brain (164, 165). A few studies have suggested that lutein and zeaxanthin concentrations in the macula correlate with brain lutein and zeaxanthin status and therefore might be used as a biomarker of cognitive health (165-168). Additionally, in the Georgia Centenarian Study, the analysis of cross-sectional data from 47 centenarian decedents showed a positive association between post-mortem measures of brain lutein concentrations and pre-mortem measures of cognitive function (164). Brain lutein concentrations were found to be significantly lower in individuals with mild cognitive impairment compared to those with normal cognitive function (164). In a small, four-month, double-blind, placebo-controlled study in older women (ages, 60 to 80 years) without cognitive impairment, supplementation with lutein (12 mg/day) and zeaxanthin (~0.5 mg/day) significantly improved cognitive test performance (169). Two small trials in younger adults found supplementation with lutein (10 mg/day) and zeaxanthin (2 mg/day) for one year improved some measures of cognitive function, including memory (170, 171). However, the Age-related Eye Disease Study 2 (AREDS2) failed to show an effect of supplemental lutein (10 mg/day) and zeaxanthin (2 mg/day; supplementation for a median of 4.7 years) on the cognitive test scores of 3,741 older participants (mean age, 72.7 years) (172), perhaps because the trial was conducted in a highly educated and well-nourished population.


Food sources

The most prevalent carotenoids in the human diet are α-carotene, β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin (11). Most carotenoids in foods are found in the all-trans form (see Figure 1 and Figure 2 above), although cooking may result in the formation of other isomers. The relatively low bioavailability of carotenoids from most foods compared to supplements is partly due to the fact that they are associated with proteins in the plant matrix (173). Chopping, homogenizing, and cooking disrupt the plant matrix, increasing the bioavailability of carotenoids (3). For example, the bioavailability of lycopene from tomatoes is substantially improved by heating tomatoes in oil (174, 175). For information on other factors that affect carotenoid bioavailability, see above and the Moran et al. review (5).

α-Carotene and β-carotene

α-Carotene and β-carotene are provitamin A carotenoids, meaning they can be converted in the body to vitamin A. The vitamin A activity of β-carotene in food is 112 that of retinol (preformed vitamin A). Thus, it would take 12 µg of β-carotene from food to provide the equivalent of 1 µg (0.001 mg) of retinol. The vitamin A activity of α-carotene from foods is 124 that of retinol, so it would take 24 µg of α-carotene from food to provide the equivalent of 1 µg of retinol. Orange and yellow vegetables like carrots and winter squash are rich sources of α- and β-carotene. Spinach is also a rich source of β-carotene, although the chlorophyll in spinach leaves hides the yellow-orange pigment. Some foods that are good sources of α-carotene and β-carotene are listed in Table 2 and Table 3 (176).

Table 2. α-Carotene Content of Selected Foods
Food Serving α-Carotene (mg)
Pumpkin, canned 1 cup 11.8
Plantain, yellow, raw 1 plantain 11.8
Carrot juice, canned 1 cup (8 fl. oz.) 10.2
Carrots, cooked 1 cup 5.9
Carrots, raw 1 medium 4.3
Mixed vegetables, frozen, cooked 1 cup 1.8
Winter squash, baked 1 cup 1.4
Collards, frozen, cooked 1 cup 0.2
Tomatoes, red, raw 1 medium 0.1
Tangerine, raw 1 medium 0.09
Peas, edible-podded, frozen, cooked 1 cup 0.08
Table 3. β-Carotene Content of Selected Foods
Food Serving β-Carotene (mg)
Carrot juice, canned 1 cup (8 fl. oz.) 21.9
Pumpkin, canned 1 cup 17.0
Spinach, frozen, cooked 1 cup 13.8
Sweet potato, baked 1 medium 13.1
Carrots, cooked 1 cup 13.0
Collards, frozen, cooked 1 cup 11.6
Carrots, raw 1 medium 10.1
Pumpkin pie 1 piece 7.4
Turnip greens, cooked 1 cup 6.6
Winter squash, cooked 1 cup 5.7
Cantaloupe, raw 1 cup 4.5
Kale, cooked 1 cup 2.0

Like α- and β-carotene, β-cryptoxanthin is a provitamin A carotenoid. The vitamin A activity of β-cryptoxanthin from food was estimated to be 124 that of retinol, so it would take 24 µg of β-cryptoxanthin from food to provide the equivalent of 1 µg of retinol. Orange and red fruit and vegetables like sweet red peppers and oranges are particularly rich sources of β-cryptoxanthin. Some foods that are good sources of β-cryptoxanthin are listed in Table 4 (176).

Table 4. β-Cryptoxanthin Content of Selected Foods
Food Serving β-Cryptoxanthin (mg)
Papaya, raw 1 medium 0.9
Sweet red peppers, sautéed 1 cup 0.8
Sweet red peppers, raw 1 medium 0.5
Orange juice, fresh 1 cup (8 fl. oz.) 0.4
Tangerine, raw 1 medium 0.4
Carrots, frozen, cooked 1 cup 0.3
Yellow corn, frozen, cooked 1 cup 0.2
Watermelon, raw 1 cup 0.2
Paprika, dried 1 teaspoon 0.1

Lycopene gives tomatoes, pink grapefruit, watermelon, and guava their red color. It has been estimated that 80% of the lycopene in the US diet comes from tomatoes and tomato products like tomato sauce, tomato paste, and ketchup (catsup) (177). Lycopene is not a provitamin A carotenoid because it cannot be converted to retinol. Some foods that are good sources of lycopene are listed in Table 5 (176).

Table 5. Lycopene Content of Selected Foods
Food Serving Lycopene (mg)
Tomato paste, canned 1 cup 75.5
Tomato purée, canned 1 cup 54.5
Tomato juice, canned 1 cup 22.0
Vegetable juice cocktail, canned 1 cup 17.3
Tomato soup, canned, condensed 1 cup 16.1
Watermelon, raw 1 cup 6.9
Tomato, raw 1 medium 3.2
Ketchup (catsup) 1 tablespoon 2.1
Pink or red grapefruit, raw ½ grapefruit 1.8
Baked beans, canned 1 cup 1.3
Lutein and zeaxanthin

Although lutein and zeaxanthin are different compounds, they are both classified as xanthophylls and nonprovitamin A carotenoids (see Figure 2 above). Some methods used to quantify lutein and zeaxanthin in food do not separate the two compounds, so they are typically reported as lutein and zeaxanthin or lutein + zeaxanthin. Both pigments are present in a variety of fruit and vegetables. Dark green leafy vegetables like spinach and kale are particularly rich sources of lutein but poor sources of zeaxanthin (178). Although relatively low in lutein, egg yolks and avocados are highly bioavailable sources of lutein. Good sources of dietary zeaxanthin include yellow corn, corn-based products, bell peppers, and egg yolk (179). Some foods containing lutein and zeaxanthin are listed in Table 6 (176).

Table 6. Lutein + Zeaxanthin Content of Selected Foods
Food Serving Lutein + Zeaxanthin (mg)
Spinach, frozen, cooked 1 cup 29.8
Turnip greens, frozen, cooked 1 cup 19.5
Collards, frozen, cooked 1 cup 18.5
Mustard greens, cooked 1 cup 14.6
Dandelion greens, cooked 1 cup 9.6
Kale, frozen, cooked 1 cup 5.9
Summer squash, cooked 1 cup 4.1
Peas, frozen, cooked 1 cup 3.8
Winter squash, baked 1 cup 2.9
Pumpkin, cooked 1 cup 2.5
Brussels sprouts, frozen, cooked 1 cup 2.4
Broccoli, frozen, cooked 1 cup 2.0
Sweet yellow corn, boiled 1 cup 1.4
Avocado, raw 1 fruit 0.5
Egg, cooked 1 large 0.2
Red sweet pepper, raw 1 cup 0.08

For more information on the carotenoid content of certain foods, search USDA's FoodData Central database


Dietary supplements providing purified carotenoids and combinations of carotenoids are commercially available in the US without a prescription. Carotenoids are best absorbed when taken with a meal containing fat.


Supplements containing a mixture of carotenoids may include α-carotene. As a provitamin A carotenoid, supplemental α-carotene can contribute to fulfill vitamin A requirements. It is not known whether the relative bioavailability of supplemental α-carotene is greater than that of dietary α-carotene.


Supplements containing a mixture of carotenoids may include α-cryptoxanthin. As a provitamin A carotenoid, supplemental α-cryptoxanthin can contribute to fulfill vitamin A requirements. It is not known whether the relative bioavailability of supplemental α-cryptoxanthin is greater than that of dietary α-cryptoxanthin.


β-Carotene is sold as individual supplements and also found in supplements marketed to promote visual health (180). Commercially available β-carotene supplements usually contain between 1.5 mg and 15 mg of either synthetic β-carotene or natural β-carotene (mainly from the algae Dunaliella salina) per softgel capsule (178). As a provitamin A carotenoid, β-carotene may be used to provide all or part of the vitamin A in multivitamin supplements. The provitamin A activity of β-carotene from supplements is much higher than that of β-carotene from food: it takes only 2 micrograms [µg] (0.002 mg) of β-carotene from supplements to provide 1 µg of retinol (preformed vitamin A) compared to 12 µg of dietary β-carotene.

Of note, the β-carotene content of supplements is often listed in international units (IU) rather than µg: 3,000 µg (3 mg) of supplemental β-carotene provides 5,000 IU of vitamin A.


Lycopene has no provitamin A activity. Synthetic lycopene and lycopene from natural sources, mainly tomatoes, are available as nutritional supplements containing up to 15 mg of lycopene per softgel capsule (178).

Lutein and zeaxanthin

Lutein and zeaxanthin are not provitamin A carotenoids. Lutein and zeaxanthin supplements are available as free carotenoids (non-esterified) or as esters (esterified to fatty acids). Both forms appear to have comparable bioavailability (181). Many commercially available lutein and zeaxanthin supplements have much higher amounts of lutein than zeaxanthin (178). Supplements containing only lutein or zeaxanthin are also available.




Although β-carotene can be converted to vitamin A, the conversion of β-carotene to vitamin A decreases when body stores of vitamin A are high (see Absorption, Metabolism, and Bioavailability). This may explain why high doses of β-carotene have never been found to cause vitamin A toxicity. High doses of β-carotene (up to 180 mg/day) have been used to treat erythropoietic protoporphyria, a photosensitivity disorder, without toxic side effects (11).

Lycopene, lutein, and zeaxanthin

No toxicities have been reported (182).

Adverse effects


Increased lung cancer risk: Two randomized controlled trials in smokers and former asbestos workers found that supplementation with 20 to 30 mg/day of β-carotene for 4 to 6 years was associated with significant 16%-28% increases in the risk of lung cancer compared to placebo (see Supplemental β-carotene in lung cancer). Although the reasons for these findings are not yet clear, the potential risk of lung cancer in smokers and other high-risk groups supplemented with high-dose β-carotene outweigh any possible benefits for chronic disease prevention (47). It should be noted that there is no evidence that β-carotene supplementation may harm nonsmokers.

Carotenodermia: High doses of β-carotene supplements (≥30 mg/day) and the consumption of large amounts of carotene-rich food have resulted in a yellow discoloration of the skin (xanthoderma) known as carotenodermia, also called carotenemia. Carotenodermia is not associated with any underlying health problems and resolves when supplementation with β-carotene is discontinued or dietary carotene intake is reduced.


Lycopenodermia: High intakes of lycopene-rich food or supplements may result in a deep orange discoloration of the skin known as lycopenodermia. Because lycopene is more intensely colored than the carotenes, lycopenodermia may occur at lower doses than carotenodermia (11).

Lutein and zeaxanthin

A risk assessment analysis of 11 human studies concluded that lutein is likely safe at intake levels below 20 mg/day (183). A more recent case report documented "foveal sparkles" (eye crystals) in an older woman with glaucoma taking 20 mg/day of lutein for eight years; the patient also had very high dietary lutein intake, and total daily intake of lutein was not known (184).


A double-blind, placebo controlled trial in 90 young healthy women found that β-cryptoxanthin supplementation up to 6 mg/day for eight weeks was well tolerated (185).

Safety in pregnancy and lactation


Unlike vitamin A, high doses of β-carotene taken by pregnant women have not been associated with increased risk of birth defects (11). However, the safety of high-dose β-carotene supplements in pregnancy and lactation has not been well studied. Although there is no reason to limit dietary β-carotene intake, pregnant and breast-feeding women should avoid consuming more than 3 mg/day (1,500 µg RAE/day; 5,000 IU/day) of β-carotene from supplements unless they prescribed under medical supervision.

Other carotenoids

The safety of carotenoid supplements other than β-carotene in pregnancy and lactation has not been established, so pregnant and breast-feeding women should obtain carotenoids from food rather than supplements. There is no reason to limit the consumption of carotenoid-rich fruit and vegetables during pregnancy (178).

Drug interactions

The cholesterol-lowering agents, cholestyramine (Questran) and colestipol (Colestid), can reduce absorption of fat-soluble vitamins and carotenoids, as can mineral oil and Orlistat (Xenical), a drug used to treat obesity (178). Colchicine, a drug used to treat gout, can cause intestinal malabsorption. However, long-term use of 1 to 2 mg/day of colchicine did not affect serum β-carotene concentrations in one study (186). Increasing gastric pH through the use of proton-pump inhibitors (Omeprazole, Lansoprazole) may decrease the absorption of a single dose of a β-carotene supplement, but the effect is unlikely to be clinically significant (187).

Antioxidant supplements and statins (3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase inhibitors)

A three-year randomized controlled trial in 160 patients with documented coronary heart disease (CHD) and low serum high density lipoprotein (HDL) concentrations found that a combination of simvastatin (Zocor) and niacin increased HDL2 levels, inhibited the progression of coronary artery stenosis, and decreased the frequency of cardiovascular events, including myocardial infarction and stroke (188). Surprisingly, when an antioxidant combination of 1,000 mg of vitamin C, 536 mg of RRR-α-tocopherol (vitamin E), 100 µg of selenium, and 25 mg of β-carotene daily was taken with the simvastatin-niacin combination, the protective effects were diminished. Since the antioxidants were taken together in this trial, the individual contribution of β-carotene cannot be determined. In contrast, a much larger randomized controlled trial of simvastatin and an antioxidant combination of 297 mg of RRR-α-tocopherol, 250 mg of vitamin C, and 20 mg of β-carotene daily in more than 20,000 men and women with CHD or diabetes mellitus found that the antioxidant combination did not diminish the cardioprotective effects of simvastatin therapy over a five-year period (189). These contradictory findings indicate that further research is needed on potential interactions between antioxidant supplements and cholesterol-lowering agents, such as niacin and statins.

Interactions with food

Fat substitute Olestra

In a controlled feeding study, consumption of 18 g/day of the fat substitute Olestra (sucrose polyester; Olean) resulted in a 27% decrease in serum carotenoid concentrations after three weeks (190). Studies in people before and after the introduction of Olestra-containing snacks to the marketplace found that total serum carotenoid concentrations decreased by 15% in those who reported consuming at least 2 g/day of Olestra (191). One study in adults found that those who consumed more than 4.4 g of Olestra weekly experienced a 9.7% decline in total serum carotenoids compared to those not consuming Olestra (192).

Plant sterol- or stanol-containing foods

Some studies found that the regular use of plant sterol-containing spreads resulted in modest, 10%-20% decreases in the plasma concentrations of some carotenoids, particularly α-carotene, β-carotene, and lycopene (see the article on Phytosterols) (193, 194). However, advising people who use plant sterol- or stanol-containing margarines to consume an extra serving of carotenoid-rich fruit or vegetables daily prevented decreases in plasma carotenoid concentrations (195).


The relationships between alcohol consumption and carotenoid metabolism are not well understood. There is some evidence that regular alcohol consumption inhibits the conversion of β-carotene to retinol (196). Increases in lung cancer risk associated with high-dose β-carotene supplementation in two randomized controlled trials were enhanced in those with higher alcohol intakes (40, 197).

Interactions among carotenoids

The results of metabolic studies suggested that high doses of β-carotene compete with lutein and lycopene for absorption when consumed at the same time (198-200). However, the consumption of high-dose β-carotene supplements did not adversely affect serum carotenoid concentrations in long-term clinical trials (201-204).

Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in May 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in July 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2023 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in October 2023 by:
Elizabeth J. Johnson, Ph.D., F.A.C.N., F.I.C.S.
Associate Professor,
Friedman School of Nutrition and Science & Policy
Tufts University

Copyright 2004-2024  Linus Pauling Institute


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Chlorophyll and Metallo-Chlorophyll Derivatives


  • Chlorophyll a and chlorophyll b are natural, fat-soluble chlorophylls found in plants. (More information)
  • Sodium copper chlorophyllin (SCC) is a semi-synthetic mixture of water-soluble sodium copper salts derived from chlorophyll. (More information)
  • SCC has been used orally as an internal deodorant and topically in the treatment of slow-healing wounds for more than 50 years without any serious side effects. (More information)
  • Chlorophylls and SCC form tight molecular complexes with some chemicals known or suspected to cause cancer, and in doing so, may block carcinogenic effects. Carefully controlled studies have not been undertaken to determine whether a similar mechanism might limit uptake of required nutrients. (More information)
  • Supplementation with SCC before meals substantially decreased a urinary biomarker of aflatoxin-induced DNA damage in a Chinese population at high risk of liver cancer due to unavoidable, dietary aflatoxin exposure from moldy grains and legumes. (More information)
  • Scientists are hopeful that SCC supplementation will be helpful in decreasing the risk of liver cancer in high-risk populations with unavoidable, dietary aflatoxin exposure. However, it is not yet known whether SCC or natural chlorophylls will be useful in the prevention of cancers in people who are not exposed to significant levels of dietary aflatoxin. (More information)


Chlorophyll is the pigment that gives plants and algae their green color. Plants use chlorophyll to trap light needed for photosynthesis (1). The basic structure of chlorophyll is a porphyrin ring similar to that of heme in hemoglobin, although the central atom in chlorophyll is magnesium instead of iron. The long hydrocarbon (phytol) tail attached to the porphyrin ring makes chlorophyll fat-soluble and insoluble in water. Chlorophyll a and chlorophyll b represent about 99% of the chlorophyll species found in edible plants (Figure 1; 2), while some algae and microalgae contain minor quantities of chlorophyll c pigments (e.g., Laminaria ochroleuca, Undaria pinnatifida) (3). Chlorophyll a and b only have a small difference in one of the side chains but an intact phytol tail, while the common characteristic of chlorophyll c isoforms is the absence of a phytol tail. These structural differences cause each type of chlorophyll to absorb light at slightly different wavelengths.

Metallo-chlorophyll derivatives, including chlorophyllins, can be chemically synthesized or produced in industrial food processing; these compounds contain zinc, iron, or copper in place of the central magnesium atom (2). The most studied chlorophyllin, sodium copper chlorophyllin (SCC), is a semi-synthetic mixture of sodium copper salts derived from chlorophyll (4, 5). SCC is often simply called ‘chlorophyllin’ in the older scientific literature, with newer publications specifying whether iron, zinc, copper, or magnesium chlorophyllin were studied. During its synthesis, the magnesium atom at the center of the ring is replaced with copper (or other metals), and the phytol tail is lost. Unlike natural chlorophyll, chlorophyllins (regardless of the metal used) are water-soluble. Although the content of different SCC mixtures may vary, two compounds commonly found in commercial SCC are trisodium copper chlorin e6 and disodium copper chlorin e4 (Figure 2).

Figure 1. Chemical structures of natural chlorophylls: chlorophyll a and chlorophyll b.

Figure 2. Chemcical structures of two compounds found in commercial sodium copper chlorophyllin: trisodium copper chlorin e6 and disodium copper chlorin e4.

Metabolism and Bioavailability

Little is known about the bioavailability and metabolism of chlorophyll in humans, although it is known that chlorophyll undergoes extensive metabolism once consumed. Animal model studies show only about 1%-3% of chlorophyll is absorbed, while the rest is excreted in the feces, primarily as pheopytin and pyropheophytin metabolites, indicating that significant transformation and microbial metabolism occur in the gastrointestinal tract (reviewed in 2). A recent study in eight healthy adults found pheophytin and pheophorbide derivatives in the blood of most subjects following consumption of 1.2 kg boiled spinach, a concentrated source of chlorophyll (6).

Sodium copper chlorophyllin was originally thought to be poorly absorbed because of its lack of apparent toxicity. However, a placebo-controlled clinical trial found that significant amounts of copper chlorin e4 in the serum of people taking chlorophyllin tablets (300 mg/day) (7), indicating that it is indeed absorbed. In vitro studies have found chlorin e4 to have a higher stability than chlorin e6 (2).

More research, however, is needed to understand the bioavailability and metabolism of natural chlorophylls and chlorin compounds in synthetic chlorophyllin.

Biological Activities

Complex formation with other molecules

Chlorophyll and sodium copper chlorophyllin are able to form tight molecular complexes with certain chemicals known or suspected to cause cancer, including polyaromatic hydrocarbons found in tobacco smoke (8), some heterocyclic amines found in cooked meat (9), and aflatoxin-B1 (10). The binding of chlorophyll or SCC to these potential carcinogens may interfere with gastrointestinal absorption of potential carcinogens, reducing the amount that reaches susceptible tissues (11). This has been demonstrated in humans: a cross-over study in three volunteers that used accelerator mass spectrometry to study the pharmacokinetics of an ultra-low dose of aflatoxin-B1 found a 150-mg dose of either SCC or chlorophyll could decrease absorption of aflatoxin-B1 (12).

Antioxidant effects

SCC can neutralize several physically relevant oxidants in vitro (13-16), and limited data from animal studies suggest that SCC supplementation may decrease oxidative damage induced by chemical carcinogens and radiation (17, 18). While chlorophyll and its derivatives have demonstrated antioxidant activity in in vitro assays (15, 19), the relevance of these findings to humans is not clear.

Modification of the metabolism and detoxification of carcinogens

To initiate the development of cancer, some chemicals (procarcinogens) must first be metabolized to active carcinogens that are capable of damaging DNA or other critical molecules in susceptible tissues. Since enzymes in the cytochrome P450 family are required for the activation of some procarcinogens, inhibition of cytochrome P450 enzymes may decrease the risk of some types of chemically induced cancers. In vitro studies indicate that SCC may decrease the activity of cytochrome P450 enzymes (8, 20, 21). Phase II biotransformation enzymes promote the elimination of potentially harmful toxins and carcinogens from the body. Limited data from animal studies indicate that SCC may increase the activity of the phase II enzyme quinone reductase (22).

Therapeutic effects

One in vitro study showed that human colon cancer cells undergo cell cycle arrest after treatment with SCC (23). The mechanism involved inhibition of ribonucleotide reductase activity. Ribonucleotide reductase plays a pivotal role in DNA synthesis and repair and is a target of currently used cancer therapeutic agents, such as hydroxyurea (23). While this may provide a potential avenue for SCC in the clinical setting, sensitizing cancer cells to DNA damaging agents, in vivo studies are needed.

Metal absorption

The porphyrin structure of chlorophyll is analogous to the heme structure found in blood and muscle tissue. Because heme-bound iron has higher bioavailability than nonheme iron (the most common form of iron in plant-based sources, e.g., legumes, spinach), iron uptake from iron chlorophyll is of interest. Toxicity studies in rats suggest iron chlorophyllin is generally safe for mammalian consumption (24). In vitro studies demonstrate that iron chlorophyllin is as good as heme in delivering iron to intestinal cells, and significantly better than the most common supplemental form of iron (i.e., ferrous sulfate) when incorporated into most food matrices (25). However, work in this area is nascent and has not yet been validated in humans. It is also not known if metallo-chlorophyll derivatives of copper or zinc increase absorption of these essential divalent metals.

Disease Prevention

Aflatoxin-associated liver cancer

Aflatoxin-B1 (AFB1), a liver carcinogen produced by certain species of fungus, is found in moldy grains and legumes, including corn, peanuts, and soybeans (4, 11). In hot, humid regions of Africa and Asia with improper grain storage facilities, high levels of dietary AFB1 are associated with increased risk of hepatocellular carcinoma. Moreover, the combination of hepatitis B infection and high dietary AFB1 exposure increases the risk of hepatocellular carcinoma still further. In the liver, AFB1 is metabolized to a carcinogen capable of binding DNA and causing mutations. In animal models of AFB1-induced liver cancer, administration of SCC at the same time as dietary AFB1 exposure significantly reduces AFB1-induced DNA damage in the livers of rainbow trout and rats (26-28) and dose-dependently inhibits the development of liver cancer in trout (29). Likewise, natural chlorophyll has also been found to inhibit AFB1-induced liver cancer in the rat (28). Collectively, this evidence supports a role for SCC and/or chlorophyll itself in limiting cancer initiation. In contrast, data suggest a limited role for SCC in influencing cancer progression. For example, one rat study found that SCC did not protect against aflatoxin-induced liver damage when given after tumor initiation (30).

Because of the long time period between AFB1 exposure and the development of cancer in humans, an intervention trial might require as long as 20 years to determine whether SCC supplementation can reduce the incidence of hepatocellular carcinoma in people exposed to high levels of dietary AFB1. However, a biomarker of AFB1-induced DNA damage (AFB1-N7-guanine) can be measured in the urine, and high urinary levels of AFB1-N7-guanine have been associated with significantly increased risk of developing hepatocellular carcinoma (31). In order to determine whether chlorophyllin could decrease AFB1-induced DNA damage in humans, a randomized, placebo-controlled intervention trial was conducted in 180 adults residing in a region in China where the risk of hepatocellular carcinoma is very high due to unavoidable, dietary AFB1 exposure and a high prevalence of chronic hepatitis B infection (32). Participants took either 100 mg of SCC or a placebo before meals three times daily. After 16 weeks of treatment, urinary levels of AFB1-N7-guanine were 55% lower in those taking SCC than in those taking the placebo, suggesting that SCC supplementation before meals can substantially decrease AFB1-induced DNA damage. Although a reduction in hepatocellular carcinoma has not yet been demonstrated in humans taking SCC, scientists are hopeful that supplementation will provide some protection to high-risk populations with unavoidable, dietary AFB1 exposure (11).

It is not known whether SCC will be useful in the prevention of cancers in people who are not exposed to significant levels of dietary AFB1, as is the case for most people living in the US. Many questions remain to be answered regarding the exact mechanisms of cancer prevention by SCC, the implications for the prevention of other types of cancer, and the potential for natural chlorophylls in the diet to provide cancer protection.

Therapeutic Uses of Chlorophyllin

Internal deodorant

Observations in the 1940s and 1950s that topical SCC had deodorizing effects on foul-smelling wounds led clinicians to administer SCC orally to patients with colostomies and ileostomies in order to control fecal odor (33). While early case reports indicated that SCC doses of 100 to 200 mg/day were effective in reducing fecal odor in ostomy patients (34, 35), a placebo-controlled trial found that 75 mg of oral SCC three times daily was no more effective than placebo in decreasing fecal odor assessed by colostomy patients 36. Several case reports have been published indicating that oral SCC (100-300 mg/day) decreased subjective assessments of urinary and fecal odor in incontinent patients (33, 37).

Trimethylaminuria is a hereditary disorder characterized by the excretion of trimethylamine, a compound with a “fishy” or foul odor. One study in a small number of Japanese patients with trimethylaminuria found that oral SCC (60 mg three times daily) for three weeks significantly decreased urinary trimethylamine concentrations (38).

Wound healing

Research in the 1940s indicated that chlorophyllin slowed the growth of certain anaerobic bacteria in the test tube and accelerated the healing of experimental wounds in animals. These findings led to the use of topical SCC solutions and ointments in the treatment of persistent open wounds in humans (39). During the late 1940s and 1950s, a series of largely uncontrolled studies in patients with slow-healing wounds, such as vascular ulcers and pressure (decubitus) ulcers, reported that the application of topical SCC promoted healing more effectively than other commonly used treatments (40, 41). In the late 1950s, SCC was added to papain and urea-containing ointments used for the chemical debridement of wounds in order to reduce local inflammation, promote healing, and control odor (33). SCC-containing papain/urea ointments are still available in the US by prescription (42). Several studies have reported that such ointments are effective in wound healing (43). A spray formulation of the papain/urea/SCC therapy is also available (44).

Skin conditions

A few small studies have investigated SCC as a topical treatment for various skin conditions. In a pilot study of 10 adults (ages 18-30 years) who had mild-to-moderate acne vulgaris and enlarged facial pores, twice daily application of a 0.1% liposomal SCC gel for three weeks improved a number of clinical parameters of the Global Acne Assessment Scale (i.e., facial oiliness, facial blotchiness, presence and size of facial pores, and number of acne lesions) compared to baseline (45). Additionally, a pilot study in 10 women (ages 40 years or older) with noticeable photodamage and solar lentigines found that twice daily topical application of a gel containing 0.66% SCC complex salts for eight weeks improved various clinical measures, including tactile and visual roughness of facial skin, skin radiance, fine lines, pore size, and overall photodamage (46). A few case reports have also observed some improvement in facial redness and rosacea with application of topical SCC (47).

While the reports from these studies are interesting, placebo-controlled clinical trials are needed to determine whether SCC may have utility in treating various skin conditions.



Chlorophylls are the most abundant pigments in plants, with chlorophyll a being two to four times as prevalent as chlorophyll b (6, 48). Dark-green leafy vegetables like spinach are rich sources of natural chlorophylls. The chlorophyll content of selected vegetables are presented in Table 1 (49).

Table 1. Chlorophyll Content of Selected Raw Vegetables
Food Serving Chlorophyll (mg)
Spinach 1 cup 23.7
Parsley ½ cup 19.0
Cress, garden 1 cup 15.6
Green beans 1 cup 8.3
Arugula 1 cup 8.2
Leeks 1 cup 7.7
Endive 1 cup 5.2
Sugar peas 1 cup 4.8
Chinese cabbage 1 cup 4.1

Food and supplements


Green algae like chlorella are often marketed as supplemental sources of chlorophyll. Because natural chlorophyll is not as stable as SCC and is much more expensive, most over-the-counter chlorophyll supplements actually contain sodium copper chlorophyllin.

Sodium copper chlorophyllin

Oral preparations of sodium copper chlorophyllin (also called chlorophyllin copper complex) are available as a dietary supplement and as an over-the-counter drug (Derifil) used to reduce odor from colostomies and ileostomies, or to reduce fecal odor due to incontinence (50). Oral doses of 100 to 300 mg/day in three divided doses have been used to control fecal and urinary odor (see Therapeutic Uses of Chlorophyllin).

In the US, SCC is found in minor quantities in some types of green table olives (51). It is also used as a green color additive in foods like chewing gum (52), as well as in drugs and cosmetics (53).

Zinc chlorophyll derivatives

In US supermarkets, canned green beans thermally processed in a zinc chloride solution to produce zinc chlorophyll derivatives within the green beans themselves are sold under the trademarked name "veri-green" (54). Because zinc chlorophyll derivatives are more robust to heat and acid treatment, they better retain a bright green color as compared to native magnesium-bound chlorophyll (48).


Natural chlorophylls are not known to be toxic, and no toxic effects have been attributed to chlorophyllin despite more than 50 years of clinical use in humans (11, 33, 39). When taken orally, supplemental chlorophyll or sodium copper chlorophyllin may cause green discoloration of urine or feces, or yellow or black discoloration of the tongue (55). There have also been occasional reports of diarrhea related to oral SCC use. When applied topically to wounds, SCC has been reported to cause mild burning or itching in some cases (56). Oral chlorophyllin may result in false positive results on guaiac card tests for occult blood (57). Since the safety of chlorophyll or chlorophyllin supplements has not been tested in pregnant or lactating women, they should be avoided during pregnancy and lactation.

Authors and Reviewers

Originally written in 2004 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in September 2021 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2022 by:
Rachel E. Kopec, Ph.D.
Assistant Professor of Human Nutrition
The Ohio State University

Copyright 2004-2022  Linus Pauling Institute


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  • Curcumin is a biologically active polyphenolic compound found in turmeric, a spice derived from the rhizomes of the plant Curcuma longa Linn. Commonly consumed in Asian countries, turmeric has been used for medicinal purposes for centuries. (More information)
  • Mounting evidence from preclinical studies shows that curcumin modulates numerous molecular targets and exerts antioxidant, anti-inflammatory, anticancer, and neuroprotective activities. (More information)
  • In humans, curcumin taken orally is poorly absorbed and rapidly metabolized and eliminated. Therefore, the potential of curcumin as a therapeutic agent is limited by its poor bioavailability. (More information)
  • Current evidence suggesting that curcumin may help prevent and/or treat colorectal cancer and type 2 diabetes mellitus is very limited. Yet, several clinical trials designed to assess the safety and efficacy of curcumin alone or with first-line treatment in patients with breast, prostate, pancreatic, lung, or colorectal cancer are under way. (More information)
  • While a few preliminary trials suggested that curcumin may have anti-inflammatory activities in humans, larger randomized controlled trials are still needed to establish the efficacy of curcumin as an anti-inflammatory agent against rheumatoid arthritis, ulcerative colitis, and radiotherapy-induced dermatitis. (More information)
  • There is currently no substantial evidence showing that curcumin may improve cognitive performance in older adults with or without cognitive impairments. Yet, some preclinical studies have found curcumin prevented or reversed certain pathological features of Alzheimer’s disease (AD). A number of clinical trials designed to assess whether curcumin might help prevent or treat AD are under way. (More information)
  • Long-term clinical trials are required to confirm whether curcumin could exhibit long-lasting antidepressant effects in patients suffering from major depressive disorder. (More information)
  • Oral supplementation with curcumin is generally regarded as safe, especially because of its low bioavailability. However, use of curcumin supplements may affect the efficacy or increase the toxicity of a wide range of drugs when taken concurrently. (More information)


Turmeric is a spice derived from the rhizomes of the tropical plant Curcuma longa Linn, which is a member of the ginger family (Zingiberaceae). Rhizomes are horizontal underground stems that send out shoots, as well as roots. The bright yellow-orange color of turmeric comes mainly from fat-soluble, polyphenolic pigments known as curcuminoids. Curcumin, the principal curcuminoid found in turmeric, is generally considered its most active constituent (1). Other curcuminoids found in turmeric include demethoxycurcumin and bisdemethoxycurcumin (Figure 1). In addition to its use as a spice and pigment, turmeric has been used in India for medicinal purposes for centuries (2). More recently, evidence that curcumin may have anti-inflammatory and anticancer activities has renewed scientific interest in its potential to prevent and treat disease.

Figure 1. Major Turmeric-derived Curcuminoids. Curcuminoids in turmeric roots are a mixture of three main compounds: curcumin (~77%), demethoxycurcumin (~17%), and bisdemethoxycurcumin (~3%). Curcumin exists in two molecular configurations (known as tautomers): the bis-keto form is predominatly found in neutral and acidic conditions and in a solid phase, while the enolate form is predominately found in alkaline conditions. 

Metabolism and Bioavailability

Clinical trials in humans indicate that the systemic bioavailability of orally administered curcumin is relatively low (3-5) and that mostly metabolites of curcumin, instead of curcumin itself, are detected in plasma or serum following oral consumption (6, 7). In the intestine and liver, curcumin is readily conjugated to form curcumin glucuronide and curcumin sulfate or, alternately, reduced to tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin (Figure 2) (4). An early clinical trial conducted in Taiwan indicated that serum curcumin concentrations peaked at 0.41 to 1.75 micromoles/liter (μM) one hour after oral doses of 4 to 8 g of curcumin (8). Another clinical trial conducted in the UK found that plasma concentrations of curcumin, curcumin sulfate, and curcumin glucuronide were in the range of 0.01 μM one hour after a 3.6 g oral dose of curcumin (9). Curcumin and its metabolites could not be detected in plasma at doses lower than 3.6 g/day. There is some evidence that orally administered curcumin accumulates in gastrointestinal tissues. For instance, when colorectal cancer patients took 3.6 g/day of curcumin orally for seven days prior to surgery, curcumin was detected in both malignant and normal colorectal tissue (10). In contrast, curcumin was not detected in the liver tissue of patients with liver metastases of colorectal cancer after the same oral dose of curcumin (11), suggesting that oral curcumin administration may not effectively deliver curcumin to tissues outside the gastrointestinal tract.

The safety and efficacy of several curcumin formulations are currently being explored in (pre)clinical settings with the aim of increasing the absorption, bioavailability, and tissue-targeted delivery of curcumin (12-16). Examples of approaches include conjugation to peptide carriers (e.g., to polylactic-co-glycolic acid [PLGA]); complexation with essential oils; coadministration with piperine; and encapsulation into nanoparticles, liposomes, phytosomes, polymeric micelles, and cyclodextrins (reviewed in 17).

Figure 2. Curcumin Metabolites. Chemical structures of the curcumin metabolites: curcumin sulfate, curcumin glucuronide, dihydrocurcumin, tetrahydrocurcumin, hexahydrocurcumin, and octahydrocurcumin (hexahydrocurcuminol).

Biological Activities

Antioxidant activity

Curcumin is an effective scavenger of reactive oxygen species (ROS) and reactive nitrogen species in the test tube (18, 19). However, it is not clear whether curcumin acts as a direct antioxidant in vivo. Due to its limited oral bioavailability in humans (see Metabolism and Bioavailability), plasma and tissue curcumin concentrations are likely to be much lower than those of other fat-soluble antioxidants like α-tocopherol (vitamin E). Yet, curcumin taken orally may reach sufficient concentrations in the gastrointestinal tract and protect the intestinal mucosa against oxidative DNA damage (11). In addition to a potentially direct antioxidant activity, curcumin can induce the expression of phase II antioxidant enzymes, including glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis. Glutathione (GSH) is an important intracellular antioxidant that plays a critical role in cellular adaptation to stress (20). Curcumin was found to upregulate the expression of GCL through the activation of different signaling pathways (21). In particular, curcumin increases the expression of GCL and other detoxifying enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway.

Nrf2-dependent antioxidant pathway

Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol. Keap1 responds to oxidative stress signals by freeing Nrf2. Upon release, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE) located in the promoter of genes coding for antioxidant/detoxifying enzymes and scavengers. Nrf2/ARE-dependent genes code for numerous mediators of the antioxidant response, including GCL, glutathione S-transferases (GSTs), thioredoxin, NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) (22). Nrf2-dependent upregulation of HO-1 in curcumin-treated renal tubular epithelial cells challenged with high glucose concentrations was shown to prevent phenotype changes resembling fibrosis and known to occur at an early stage of diabetic renal injury (23). Curcumin also inhibited the progression of fibrosis in liver and lung in animal models of chronic inflammatory diseases (24, 25). Curcumin mitigated the effect of chronic ethanol intake on mouse liver, partly by upregulating Nrf2 target genes coding for NQO-1, HO-1, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) (26). Curcumin treatment also counteracted oxidative damage induced by heavy ion irradiation by upregulating Nrf2 downstream genes for GCL, HO-1, NQO-1, and SOD in the brain of rats (27). Additional studies have demonstrated the ability of curcumin to reduce oxidative stress in different experimental settings via the induction of Nrf2/ARE pathway (reviewed in 22).

Anti-inflammatory activity

Curcumin has been shown to inhibit mediators of the inflammatory response, including cytokines, chemokines, adhesion molecules, growth factors, and enzymes like cyclooxygenase (COX), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS). Nuclear factor-kappa B (NF-κB) is a transcription factor that binds DNA and induces the transcription of the COX-2 gene, other pro-inflammatory genes, and genes involved in cell proliferation, adhesion, survival, and differentiation. The anti-inflammatory effects of curcumin result from its ability to inhibit the NF-κB pathway, as well as other pro-inflammatory pathways like the mitogen-activated protein kinase (MAPK)- and the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT)-dependent signaling pathways (28). Inhibition of dextran sulfate sodium (DSS)-induced colitis by curcumin in mice has been associated with a downregulation of the expression of p38-MAPK and pro-inflammatory cytokine TNF-α and a reduction of myeloperoxidase (MPO) activity, a marker of neutrophil infiltration in intestinal mucosa (29). Curcumin has also been shown to improve colitis by preventing STAT3 activation and STAT3-dependent induction of cell proliferation in mouse colon (30). Moreover, curcumin was shown to attenuate the immune response triggered by collagen injections in a mouse model of rheumatoid arthritis, partly by blocking the proliferation of T lymphocytes in mouse splenocytes (31). In addition, curcumin has been found to reduce the secretion of TNF-α and IL-1β and the production of COX-2-induced prostaglandin G2. In one study, curcumin inhibited the secretion of matrix metalloproteins (MMPs) — responsible for the degradation of the synovial joints — in human fibroblast-like synoviocytes (31) and in human articular chondrocytes (32). Curcumin has also been found to alleviate neuro-inflammation in a mouse model of traumatic brain injury, reducing macrophage and microglial activation and increasing neuronal survival (33).

Anticancer activity

Effects on biotransformation enzymes

Some compounds are not carcinogenic until they are metabolized in the body by phase I biotransformation enzymes, such as enzymes of the cytochrome P450 (CYP) family (34). Primarily based on evidence from rodent studies, it is thought that curcumin may inhibit procarcinogen bioactivation and help prevent cancer by inhibiting the activity of multiple CYP enzymes in humans (35-37). Curcumin may also increase the activity of phase II detoxification enzymes, such as GSTs and quinone reductase (QR) (see also Nrf2-dependent antioxidant pathway) (35, 38, 39). However, it is important to note that the effect of curcumin on biotransformation enzymes may vary depending on the route of administration, the dose, and the animal model. In addition, curcumin intakes ranging from 0.45 to 3.6 g/day for up to four months did not increase leukocyte GST activity in humans (9).

Inhibition of proliferation and induction of apoptosis

Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or for activation of pathways leading to programmed cell death (apoptosis) if the damage is irreparable (40). Defective cell-cycle regulation may result in the propagation of mutations that contribute to the development of cancer. Unlike normal cells, cancer cells proliferate rapidly and are unable to respond to cell death signals that initiate apoptosis. Curcumin has been found to induce cell-cycle arrest and apoptosis by regulating a variety of cell-signaling pathways (3, 41-45). For example, the inhibition of cell proliferation by curcumin has been associated with the Nrf2-dependent downregulation of DNA repair-specific flap endonuclease 1 (Fen1) in breast cancer cells in culture (46). Curcumin has been shown to induce p53-dependent or -independent apoptosis depending on the cancer cell type (47). In a panel of cancer cell lines, p53-independent apoptosis induced by curcumin was mediated by the rapid increase of ROS and the activation of MAPK and c-jun kinase (JNK) signaling cascades (48). Inhibition of NF-κB signaling by curcumin also suppresses proliferation and induces apoptosis in cancer cells (47).

Inhibition of tumor invasion and angiogenesis

Malignant and aggressive forms of cancer can invade surrounding tissues and spread to distant tissues once cancer cells have acquired the ability to leave the primary site (reduced cell-to-cell adhesion and loss of polarity), migrate, and disseminate. Epithelial-mesenchymal transition (EMT) is the process by which epithelial cells acquire the ability to migrate and invade through downregulating proteins like E-cadherin and γ-catenin and expressing mesenchymal markers like MMPs, N-cadherin, and vimentin. In breast cancer cells, curcumin prevented EMT-associated morphological changes induced by lipopolysaccharide (LPS) while upregulating E-cadherin and downregulating vimentin. It was further shown that curcumin inhibited NF-κB/Snail signaling involved in LPS-induced EMT (49). In another study, curcumin increased the expression of the small non-coding RNA miR181b, which then downregulated proinflammatory cytokines, CXCL1 and CXCL2, as well as MMPs, thereby reducing the metastatic potential of breast cancer cells. Curcumin inhibited IL-6-induced proliferation, migration, and invasiveness of human small cell lung cancer (SCLC) cells by reducing JAK/STAT3 phosphorylation (i.e., activation) and downstream genes coding for cyclin B1, survivin, Bcl-XL, MMPs, intercellular adhesion molecule 1 (ICAM-1), and vascular endothelial growth factor (VEGF) (30).

Curcumin was found to exert its anticancer activities in many different types of cancer cells by regulating a variety of signaling pathways (reviewed in 2, 47).

Neuroprotective activity

In Alzheimer’s disease (AD), a peptide called β-amyloid (Aβ peptide) aggregates into oligomers and fibrils and forms deposits known as amyloid (or senile) plaques outside neurons in the hippocampus and cerebral cortex of patients. Another feature of AD is the accumulation of intracellular neurofibrillary tangles formed by phosphorylated Tau protein (50). Abnormal microglial activation, oxidative stress, and neuronal death are also associated with the progression of the disease. Curcumin has been found to inhibit Aβ fibril formation and extension and to destabilize preformed fibrils in vitro (51-53). Metal chelation by curcumin might interfere with metal ion (Cu2+/Zn2+)-induced Aβ aggregation. Curcumin might also affect the trafficking of Aβ peptide precursor (APP) and the generation of Aβ peptides from APP (54, 55). Abnormally activated microglia and hypertrophic astrocytes around amyloid plaques in AD brains release cytotoxic molecules, such as proinflammatory cytokines and ROS, which enhance Aβ formation and deposition and further damage neurons. Curcumin was found to reduce the inflammatory response triggered by Aβ peptide-induced microglial activation and increase neuronal cell survival (56). When injected into the carotid artery of a transgenic mouse model of AD, curcumin was found to cross the blood-brain barrier, bind to amyloid plaques, and block the formation of Aβ oligomers and fibrils (53). In other animal models of AD, dietary curcumin decreased biomarkers of inflammation and oxidative damage, increased Aβ peptide clearance by macrophages, dismantled amyloid plaques in the brain, stimulated neuronal cell growth in the hippocampus, and improved Aβ-induced memory deficits (reviewed in 57).

Note: It is important to keep in mind that some of the biological activities discussed above were observed in cultured cells and animal models exposed to curcumin at concentrations unlikely to be achieved in cells of humans consuming curcumin orally (see Metabolism and Bioavailability).

Disease Prevention


Oral curcumin administration has been found to inhibit the development of chemically-induced cancer in animal models of oral (58, 59), stomach (60, 61), liver (62), and colon (63-65) cancer. ApcMin/+ mice have a mutation in the Apc (adenomatous polyposis coli) gene similar to that in humans with familial adenomatous polyposis, a genetic condition characterized by the development of numerous colorectal adenomas (polyps) and a high risk for colorectal cancer. Oral curcumin administration has been found to inhibit the development of intestinal adenomas in ApcMin/+ mice (66, 67). Despite promising results in animal studies, there is presently little evidence that high intakes of curcumin or turmeric are associated with decreased cancer risk in humans. A 30-day phase II clinical trial in 40 smokers with at least eight rectal aberrant crypt foci (ACF; precancerous lesions) found that the number of ACF was significantly lower with a daily supplementation with 4 g/day of curcumin compared to 2 g/day (68). Several controlled clinical trials in humans designed to evaluate the effect of oral curcumin supplementation on precancerous colorectal lesions, such as adenomas, are under way (69).

Type 2 diabetes mellitus

Oxidative stress and inflammation have been implicated in the pathogenesis of type 2 diabetes mellitus and related vascular complications. A large body of preclinical evidence suggests that the antioxidant, anti-inflammatory, and glucose-lowering activities of curcumin and its analogs may be useful in the prevention and/or treatment of type 2 diabetes (70). In a nine-month, randomized, double-blind, placebo-controlled study in 237 subjects with impaired glucose tolerance (pre-diabetes), no progression to overt diabetes was reported with a daily ingestion of a mixture of curcuminoids (0.5 g), while 16.4% of placebo-treated participants developed diabetes (71). In addition, curcumin supplementation was shown to reduce insulin resistance and improve measures of pancreatic β-cell function and glucose tolerance. In an eight-week, randomized, placebo-controlled study in 67 individuals with type 2 diabetes, oral curcumin (a mixture of all three major curcuminoids; 0.6 g/day) failed to significantly lower the level of glycated hemoglobin A1c (HbA1c; a measure of glycemic control), plasma fasting glucose, total serum cholesterol, LDL-cholesterol, and serum triglycerides (72). Yet, supplemental curcumin was found to be as effective as lipid-lowering drug atorvastatin (10 mg/day) in reducing circulating markers of oxidative stress (malondialdehyde) and inflammation (endothelin-1, TNFα, IL-6) and in improving endothelial function. Another randomized controlled trial also reported that oral curcumin supplementation (1.5 g/day) for six months improved endothelial function, insulin sensitivity, and metabolic markers associated with atherogenesis (plasma triglycerides, visceral fat, total body fat) in participants with type 2 diabetes (73). Finally, in a two-month randomized, double-blind, placebo-controlled study in 40 individuals with type 2 diabetic nephropathy (kidney disease), daily curcumin ingestion (66.3 mg) significantly reduced urinary concentrations of proteins and inflammation markers (TGF-β, IL-8), suggesting that curcumin might be helpful with slowing the progression of kidney damage and preventing kidney failure (74). Larger trials are needed to assess whether curcumin could be useful in the prevention or management of type 2 diabetes and vascular complications.

Disease Treatment


The ability of curcumin to regulate a variety of signaling pathways involved in cell growth, apoptosis, invasion, metastasis, and angiogenesis in preclinical studies elicited scientific interest in its potential as an anticancer agent in tumor therapy (75). To date, most of the controlled clinical trials of curcumin supplementation in cancer patients have been phase I trials, which are aimed at determining feasibility, tolerability, safety, and providing early evidence of efficacy (76). A phase I clinical trial in patients with advanced colorectal cancer found that doses up to 3.6 g/day for four months were well tolerated, although the systemic bioavailability of oral curcumin was low (77). When colorectal cancer patients with liver metastases took 3.6 g/day of curcumin orally for seven days, trace levels of curcumin metabolites were measured in liver tissue, but curcumin itself was not detected (11). In contrast, curcumin was measurable in normal and malignant colorectal tissue after patients with advanced colorectal cancer took 3.6 g/day of curcumin orally for seven days (10). In a pilot trial in patients awaiting gastrointestinal endoscopy or colorectal cancer resection, the administration of a mixture of three major curcuminoids (2.35 g/day for 14 days) resulted in detectable amounts of curcumin in colonic mucosa (mean concentration, 48.4 μg/g of tissue), demethoxycurcumin (7.1 μg/g), and bisdemethoxycurcumin (0.7 μg/g) (78).

While these findings suggested that oral curcumin may likely be more effective as a therapeutic agent in cancers of the gastrointestinal tract than of other tissues, some phase I/II trials have also examined whether supplemental curcumin may confer additional benefits to conventional drugs against different types of cancer. Combining curcumin with anticancer drugs like gemcitabine in pancreatic cancer (79, 80), docetaxel in breast cancer (81), and imatinib in chronic myeloid leukemia (82) may be safe and well tolerated. A recent single-arm, phase II trial combining three cycles of docetaxel/prednisone and curcumin (6 g/day) was carried out in 26 patients with castration-resistant prostate cancer (83). The level of prostate-specific antigen (PSA) was decreased in most patients and was normalized in 36% of them, and the co-administration of curcumin with drugs showed no toxicity beyond adverse effects already related to docetaxel monotherapy. Many registered phase I/II clinical trials designed to investigate the effectiveness of curcumin alone or with first-line treatment in patients with breast, prostate, pancreatic, lung, or colorectal cancer are under way (69).

Inflammatory diseases

Although curcumin has been demonstrated to have anti-inflammatory and antioxidant activities in cell culture and animal studies, few randomized controlled trials have examined the efficacy of curcumin in the treatment of inflammatory conditions. A placebo-controlled trial in 40 men who had surgery to repair an inguinal hernia or hydrocele found that oral curcumin supplementation (1.2 g/day) for five days was more effective than placebo in reducing post-surgical edema, tenderness and pain, and was comparable to phenylbutazone therapy (300 mg/day) (84).

Rheumatoid arthritis

A preliminary intervention trial that compared curcumin with a nonsteroidal anti-inflammatory drug (NSAID) in 18 patients with rheumatoid arthritis (RA) found that improvements in morning stiffness, walking time, and joint swelling after two weeks of curcumin supplementation (1.2 g/day) were comparable to those experienced after two weeks of phenylbutazone (NSAID) therapy (300 mg/day) (85). In a more recent randomized, open-label study in 45 RA patients, supplementation with a mixture of all three major curcuminoids (0.5 g/day for eight weeks) was found to be as effective as diclofenac (NSAID; 50 mg/day) in reducing measures of disease activity, tenderness, and swelling joints (86). Larger randomized controlled trials are needed to determine whether oral curcumin supplementation is effective in the treatment of RA.

Radiation dermatitis

Radiation-induced skin inflammation occurs in most patients receiving radiation therapy for sarcoma, lung, breast, or head and neck cancer. One randomized, double-blind, placebo-controlled trial in 30 women prescribed radiation therapy for breast carcinoma in situ reported a reduction of radiation-induced dermatitis severity and moist desquamation with a supplemental curcuminoid mixture (6 g/day for four to seven weeks). Curcumin failed to reduce skin redness and radiation-induced pain at the site of treatment (87).

Ulcerative colitis

Ulcerative colitis (UC) is a long-term condition characterized by diffuse and superficial inflammation of the colonic mucosa. Disease activity may fluctuate between periods of remission and periods of relapse. Preliminary evidence suggests that curcumin might be useful as an add-on therapy to control disease activity. One multicenter, randomized, double-blind, placebo-controlled study has examined the efficacy of curcumin enema (2 g/day) in the prevention of relapse in 82 patients with quiescent UC (88). Six-month treatment with curcumin significantly reduced measures of disease activity and severity and resulted in a lower relapse rate than with placebo in subjects on standard-of-care medication (sulfasalazine or mesalamine); yet, there was no difference in the proportion of patients who experienced relapse six months after curcumin was discontinued (88). In another randomized controlled trial in active UC patients treated with mesalamine, the percentage of patients in clinical remission was significantly higher after a one-month treatment with oral curcumin (3 g/day) than with placebo (89). Larger trials are needed to ensure that curcumin can be safely used with conventional UC treatments and to further support its potential therapeutic benefits for relapsing-remitting UC.

Oral health

Emerging evidence suggests that curcumin has anti-inflammatory and antimicrobial properties that could be beneficial in the treatment of certain diseases of the oral cavity. For example, the topical application of a curcumin gel was found to reduce gingival bleeding and periodontal bacteria after conventional periodontal therapy (scaling and root planing) (90-92). A mouthwash containing curcumin was also found to be as effective as chlorhexidine in reducing inflammation in individuals who underwent periodontal therapy for gingivitis (93).

Oral submucous fibrosis

Any part of the oral cavity may be affected by oral submucous fibrosis (OSMF), a currently incurable condition especially prevalent in Southeast Asia and India. OSMF is characterized by the formation of excess fibrous tissue (fibrosis) that leads to stiffness of the mucosa and restricted mouth opening. A few recent intervention studies showed that curcumin could improve some symptoms, such as burning sensations and reduced mouth opening (reviewed in 94). In an open-label intervention study in 40 OSMF patients randomized to receive either the conventional treatment (weekly intra-lesional injections of steroids) or daily oral administration of a Curcuma longa Linn extract (600 mg/day) for three months, the burning sensation significantly improved in the curcumin-treated group, while tongue protrusion was reduced with conventional therapy. No differences between the two treatment groups were seen with respect to mouth opening (95). A six-month follow-up of the effect of oral curcumin (2 g/day) in OSMF patients treated for three months found that curcumin outperformed steroid ointment in its ability to increase maximum mouth opening and to reduce self-reported burning sensation (96). Further studies should assess the appropriate dose of curcumin to achieve the greatest benefits and determine whether curcumin can enhance the effect of standard-of-care treatment in limiting OSMF disease progression.

Cognitive decline and Alzheimer’s disease

Alzheimer’s disease (AD) is a form of dementia characterized by extracellular deposition of β-amyloid plaques, intracellular formation of neurofibrillary tangles, and neuronal loss, eventually leading to brain atrophy and cognitive impairment in affected individuals (57). When injected into the carotid artery, curcumin was found to cross the blood-brain barrier in an animal model of AD (53), though it is not known whether curcumin taken orally can reach the blood-brain barrier at sufficient concentrations and impede cognitive decline in humans. As a result of promising findings in animal models (see Neuroprotective activity), a few recent clinical trials have examined the effect of oral curcumin supplementation on cognition in healthy older adults and AD patients (57). A randomized, double-blind, placebo-controlled trial in 60 healthy older adults (mean age, 68.5 years) investigated whether acute (80 mg) or chronic (80 mg/day for 4 weeks) oral intake of curcumin could improve their ability to cope with the mental stress and change in mood usually associated with undergoing a battery of cognitive tests (97). A significant reduction in mental fatigue and higher levels of calmness and contentedness following cognitive test sessions were observed in individuals who consumed curcumin (either acutely or chronically) compared to the placebo group. Additionally, the results of cognitive ability tests suggested that curcumin treatment had limited benefits on cognitive function, as shown by better scores in measures of sustained attention and working memory compared to placebo (97).

The results of a six-month trial in 27 patients with AD found that oral supplementation with up to 4 g/day of curcumin — containing all three major curcuminoids — was safe (6). Yet, measures of cognitive performance (using the Mini Mental State Examination [MMSE] scoring scale) and levels of F2-isoprostanes (oxidative stress markers) and antioxidants in blood were not found to be significantly different between curcumin- and placebo-treated subjects at the end of the intervention period. In another six-month, randomized, double-blind, placebo-controlled study of subjects with mild-to-moderate AD, curcumin failed to improve cognitive test scores and to reduce blood and cerebrospinal fluid (CSF) concentrations of β-amyloid peptide, CSF concentrations of total and phosphorylated Tau protein, and CSF concentrations of F2-isoprostanes (98).

Despite the lack of encouraging results from completed trials, several randomized controlled studies are under way to determine whether supplemental curcumin has the ability to reverse or prevent cognitive deficits in both healthy and cognitively impaired individuals (57).

Major depressive disorder

Major depressive disorder (MDD) is a neuropsychiatric disorder associated with abnormal neurotransmission; it is primarily treated with drugs that improve the bioavailability of neurotransmitters like serotonin, noradrenaline, and dopamine in the brain (99). Characteristics of MDD also include alterations in the hypothalamus-pituitary-adrenal axis, increased neuroinflammation, defective neurogenesis, and neuronal death.

A few clinical studies have examined the effect of curcumin alone or with conventional antidepressant drugs in MDD patients. A recent meta-analysis of six randomized controlled trials found that supplementation with curcumin significantly reduced depression symptoms (100). However, in one of the studies included in this meta-analysis — a double-blind, controlled study in 56 adults diagnosed with MDD — curcumin treatment (~880 mg/day of curcuminoids) for eight weeks was no more effective than placebo in reducing self-reported depression- and anxiety-related symptoms (101). Significant improvements in the severity and frequency of specific depression-related symptoms only occurred after four weeks of treatment, suggesting that a longer treatment period might be needed to uncover the antidepressant effects of curcumin (100, 101). In another randomized, placebo-controlled trial, supplemental curcumin (330 mg/day) for five weeks failed to relieve depressive symptoms in patients treated with conventional antidepressants (102). In contrast, in a six-week, randomized, single-blinded, placebo-controlled study in 60 MDD patients, supplemental curcumin (~880 mg/day of curcuminoids) alone yielded a similar response rate to the antidepressant, fluoxetine (a serotonin reuptake inhibitor [Prozac]; 20 mg/day) in terms of depressive symptoms; no additional effect was observed when both curcumin and fluoxetine treatments were combined (103). Moreover, in a randomized controlled study in 100 participants taking escitalopram (a serotonin reuptake inhibitor [Lexapro]; 5 to 15 mg/week), supplemental curcumin (1,000 mg/day) for six weeks increased the antidepressant effect of the medication (104). Curcumin also induced a reduction in plasma concentrations of inflammatory markers and an increase in plasma concentrations of brain-derived neurotrophic factor compared to placebo (antidepressant drug alone) (104).

Larger clinical trials are needed to address the long-term effect of curcumin in subjects with major depression.

Premenstrual syndrome

Premenstrual syndrome (PMS) refers to a range of emotional (e.g., irritability, anxiety), behavioral (e.g., fatigue, insomnia), and physical symptoms (e.g., breast tenderness, headache) occurring prior to the monthly menstrual period in up to 90% of premenopausal women. In a recent randomized, double-blind, placebo-controlled trial in 70 women with PMS, the daily supplementation with 0.2 g of curcumin for 10 days during three consecutive menstrual cycles significantly reduced overall PMS severity, as assessed by a composite measure of all emotional, behavioral, and physical symptoms (105). Additional trials are necessary to evaluate the efficacy of curcumin in the management of PMS.


Food sources

Turmeric is the dried ground rhizome of Curcuma longa Linn (106). It is used as a spice in Indian, Southeast Asian, and Middle Eastern cuisines. Curcuminoids comprise about 2%-9% of turmeric (107). Curcumin is the most abundant curcuminoid in turmeric, providing about 75% of the total curcuminoids, while demethoxycurcumin and bisdemethoxycurcumin generally represent 10%-20% and less than 5% of the total curcuminoids, respectively (108). Curry powder contains turmeric along with other spices, but the amount of curcumin in curry powders is variable and often relatively low (109). Curcumin extracts are also used as food-coloring agents (110).


Commercial curcumin is usually a mixture of curcumin, demethoxycurcumin, and bisdemethoxycurcumin (see Figure 1 above). Curcuminoid extracts are available as dietary supplements without a prescription in the US. The labels of a number of these extracts state that they are standardized to contain 95% curcuminoids, although such claims are not strictly regulated by the US Food and Drug Administration (FDA). Some curcumin preparations also contain piperine, which may increase the bioavailability of curcumin by inhibiting its metabolism (108). However, piperine may also affect the metabolism of drugs (see Drug interactions). Optimal doses of curcumin for cancer chemoprevention or therapeutic uses have not been established. It is unclear whether doses less than 3.6 g/day are biologically active in humans (see Metabolism and Bioavailability). Curcuminoid-containing supplements taken on an empty stomach may cause gastritis and peptic ulcer disease (108).


Adverse effects

In the United States, turmeric is generally recognized as safe (GRAS) by the FDA as a food additive (110). An increase in gallbladder contractions was observed in 12 healthy people supplemented with single doses of 20 to 40 mg of curcumin (111, 112). Yet, serious adverse effects have not been reported in humans taking high doses of curcumin. A dose escalation trial in 24 adults found that single oral dosages up to 12 g were safe, and adverse effects, including diarrhea, headache, rash, yellow stool, were not related to dose (7). In a phase I trial in Taiwan, curcumin supplementation up to 8 g/day for three months was reported to be well tolerated in patients with precancerous conditions or noninvasive cancer (8). Another clinical trial in the UK found that curcumin supplementation ranging from 0.45 to 3.6 g/day for four months was generally well tolerated by people with advanced colorectal cancer, although two participants experienced diarrhea and another reported nausea (9). Increases in serum alkaline phosphatase and lactate dehydrogenase were also observed in several participants, but it was not clear whether these increases were related to curcumin supplementation or cancer progression (3). In an open-label phase II trial, curcumin treatment (8 g/day) in combination with the anticancer drug gemcitabine was associated with severe abdominal pain in 7 out of 17 patients with advanced pancreatic cancer, leading to the treatment being discontinued in five patients while curcumin dosage was reduced to 4 g/day in two patients (79).

Pregnancy and lactation

Although there is no evidence that dietary consumption of turmeric as a spice adversely affects pregnancy or lactation, the safety of curcumin supplements in pregnancy and lactation has not been established.

Drug interactions

Curcumin has been found to inhibit platelet aggregation in vitro (113, 114), suggesting a potential for curcumin supplementation to increase the risk of bleeding in people taking anticoagulant or antiplatelet medications, such as aspirin, clopidogrel (Plavix), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, ticlopidine (Ticlid), and warfarin (Coumadin). In cultured breast cancer cells, curcumin inhibited apoptosis induced by the chemotherapeutic agents, camptothecin, mechlorethamine, and doxorubicin at concentrations of 1 to 10 μM (115). In an animal model of breast cancer, dietary curcumin inhibited cyclophosphamide-induced tumor regression. Yet, it is not known whether oral curcumin administration will result in breast tissue concentrations that are high enough to inhibit cancer chemotherapeutic agents in humans (11). Curcuminoids may interfere with the activity of efflux drug transporters of the ATP-binding cassette (ABC) family, including P-glycoprotein, multidrug resistance protein (MRP), and breast cancer-resistant protein (BCRP), which function as ATP-dependent efflux pumps that actively regulate the excretion of a number of drugs limiting their systemic bioavailability (116, 117). Curcumin was also found to affect the activity of phase I biotransformation enzymes like cytochrome P450 (CYP) 3A4 (CYP3A4) (118), which catalyzes the metabolism of about one-half of all marketed drugs in the US (119). In healthy Japanese volunteers, curcumin (2 g) was found to increase plasma sulfasalazine concentration following the administration of a therapeutic dose (2 g) of the anti-rheumatic drug sulfasalazine (Salazopyrin, Azulfidine) (120).

Some curcumin supplements also contain piperine to increase the bioavailability of curcumin. Piperine may also interfere with efflux drug transporters and phase I cytochrome P450 enzymes and increase the bioavailability and slow the elimination of a number of drugs, including phenytoin (Dilantin), propranolol (Inderal), theophylline, and carbamazepine (Tegretol) (121-123).

Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in February 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in March 2016 by:
Lynne Howells, Ph.D.
Research Fellow
Experimental Cancer Medicine Centre Lab Quality Manager
University of Leicester

Copyright 2005-2024  Linus Pauling Institute 


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  • Flavonoids are a large family of polyphenolic plant compounds. Six major subclasses of flavonoids, namely anthocyanidins, flavan-3-ols, flavonols, flavanones, flavones, and isoflavones, flavonols are the most widespread in the human diet. (More information)
  • Dietary flavonoids are naturally occurring in fruit, vegetables, chocolate, and beverages like wine and tea. There has been much interest in the potential health benefits of flavonoids associated with fruit- and vegetable-rich diets. (More information)
  • The physicochemical properties of flavonoids influence their metabolic fate, i.e., their digestion, absorption, and biotransformation. The bioavailability of these polyphenols in vivo is a major determinant in their ability to exert biological activities relevant to human health. (More information)
  • Many of the biological effects of flavonoids appear to be related to their ability to modulate a number of cell-signaling cascades. Flavonoids have been shown to exhibit antiinflammatory, antithrombogenic, antidiabetic, anticancer, and neuroprotective activities through different mechanisms of action in vitro and in animal models. (More information)
  • Accumulating evidence from randomized controlled trials suggests that consumption of flavan-3-ols and anthocyanidins can be beneficial for metabolic and cardiovascular health. (More information)
  • The results of small-scale randomized controlled trials suggest that consumption of flavonoid-rich food and beverages containing anthocyanins or flavan-3-ols may improve vascular endothelial function. As yet, it is not known whether these acute improvements result in long-term reductions in risk of cardiovascular disease. (More information)
  • Promising findings in randomized controlled studies indicate that supplementation with flavan-3-ols or anthocyanidins may improve glycemic control in subjects at-risk or diagnosed with type 2 diabetes mellitus. (More information)
  • Despite promising results in animal studies, only a limited number of observational studies have reported potential cancer preventive effects of flavonoids in humans. Higher intakes of soy isoflavones may be associated with reduced risks of breast cancer in postmenopausal women and prostate cancer in men. (More information)
  • Evidence suggesting that some flavonoids or flavonoid-rich foods may enhance cognitive function is currently limited, and it is not yet known whether their consumption could lower the risk of cognitive impairments and dementia in humans. (More information)
  • High intakes of dietary flavonoids are generally regarded as safe, especially because of their low bioavailability. However, flavonoid supplements may affect the action of anticoagulants and increase the toxicity of a wide range of drugs when taken concurrently. (More information)


Flavonoids are a large family of over 5,000 hydroxylated polyphenolic compounds that carry out important functions in plants, including attracting pollinating insects; combating environmental stresses, such as microbial infection; and regulating cell growth (1). Their bioavailability and biological activities in humans appear to be strongly influenced by their chemical nature. Since the 1990s, there has been a growing interest in dietary flavonoids due to their likely contribution to the health benefits of fruit- and vegetable-rich diets. This article reviews some of the scientific evidence regarding the role of dietary flavonoids in health promotion and disease prevention in humans; it is not meant to be a comprehensive review on every health topic studied.

Flavonoid Subclasses

Flavonoids are classified into 12 major subclasses based on chemical structures, six of which, namely  anthocyanidins, flavan-3-ols, flavonols, flavones, flavanones, and isoflavones (Table 1 and Figures 1-9) are of dietary significance. Glycosylated flavonols (bound to at least one sugar molecule) are the most widely distributed flavonoids in the diet (2, 3).

Table 1. Common Dietary Flavonoids
(Select the highlighted text to see chemical structures.)
Flavonoid Subclass Dietary Flavonoids (aglycones) Some Common Food Sources (see also Sources)
Anthocyanidins* Cyanidin, Delphinidin, Malvidin, Pelargonidin, Peonidin, Petunidin Red, blue, and purple berries; red and purple grapes; red wine



Monomers (Catechins):
(+)-Catechin, (-)-Epicatechin, (-)-Epigallocatechin, (+)-Gallocatechin; and their gallate derivatives

Teas (particularly white, green, and oolong), cocoa-based products, grapes, berries, apples

Dimers and Polymers:

Apples, berries, cocoa-based products, red grapes, red wine

Theaflavins, Thearubigins

Black tea

Flavonols Isorhamnetin, Kaempferol, Myricetin, Quercetin

Onions, scallions, kale, broccoli, apples, berries, teas

Flavones Apigenin, Luteolin, Baicalein, Chrysin

Parsley, thyme, celery, hot peppers

Flavanones Eriodictyol, Hesperetin, Naringenin

Citrus fruit and juices, e.g., oranges, grapefruits, lemons


Daidzein, Genistein, Glycitein, Biochanin A, Formononetin

Soybeans, soy foods, legumes

*Anthocyanidins with one or more sugar moieties (anthocyanidin glycosides) are called anthocyanins.
#Proanthocyanidin oligomers formed from (+)-catechin and (-)-epicatechin subunits are called procyanidins.

For more detailed information on the health effects of isoflavones, a subclass of flavonoids with estrogenic activity, see the article on Soy Isoflavones.

For more information on the health benefits of foods that are rich in flavonoids, see the articles on Fruit and Vegetables, Legumes, and Tea.  

Figure 1. Basic Structures of Flavonoid Subclasses 

Figure 2. Chemical Structures of Some Flavan-3-ol Monomers (Catechins) 

Figure 3. Chemical Structures of Theaflavins 

Figure 4. Chemical Structures of Anthocyanidins

Figure 5. Chemical Structures of Flavonols 

Figure 6. Chemical Structures of Flavones

Figure 7. Chemical Structures of Flavanones 

Figure 8. Chemical Structures of Isoflavones

Figure 9. Chemical Structures of Proanthocyanidin Dimers

Metabolism and Bioavailability

The amount of flavonoids present in ingested food has little importance unless dietary flavonoids are absorbed and become available to target tissues within the body. During and after intestinal absorption, flavonoids are rapidly and extensively metabolized in intestinal and liver cells such that they are likely to appear as metabolites (e.g., phase II metabolites) in the bloodstream and urine (4). Additionally, the biological activities of flavonoid metabolites are likely to be different from those of their parent compounds (5). Some of the factors influencing the metabolic fate and bioavailability of dietary flavonoids are mentioned below.

Chemical structure of flavonoids

Most flavonoids occur in edible plants and foods as β-glycosides, i.e., bound to one or more sugar molecules (6). Exceptions include flavan-3-ols (catechins and proanthocyanidins) and fermented soy-based products that are exposed to microbial β-glucosidases, which catalyze the release of sugar molecules from glycosylated isoflavones (7). Even after food processing and cooking, most flavonoid glycosides reach the small intestine intact. Only flavonoid aglycones (not bound to a sugar molecule) and a few flavonoid glucosides (bound to glucose) are easily absorbed in the small intestine (8). Glycosylated flavonoids might be able to penetrate the mucus layer of the intestine and be deglycosylated on the cell surface before absorption. Those that cannot be deglycosylated in the small intestine may be hydrolyzed by bacterial enzymes in the colon (7). Nevertheless, colonic bacteria might remove sugar moieties and rapidly degrade aglycone flavonoids, thus limiting their absorption in the colon (9).

In contrast to monomeric flavan-3-ols (catechins), the polymeric nature of proanthocyanidins likely prevents their intestinal absorption. Flavan-3-ol monomers and procyanidins are transformed by the intestinal microbiota to 5-(hydroxyphenyl)-γ-valerolactones which appear in the circulatory system and are excreted in urine as sulfate and glucuronide metabolites (Figure 10). Valerolactones may be further degraded by the colonic microbiota to smaller phenolic acids and aromatic compounds. The colonic microbiota also metabolize the gallate esters of flavonoids, generating gallate, which is further catabolized to pyrogallol. Microbe-derived flavonoid metabolites are readily absorbed into the circulatory system and excreted in both free forms and as phase II metabolites in urine (9).

Figure 10. Chemical Structures of Some Flavan-3-ol Metabolites

Interactions with food matrix

The presence of macronutrients in food influences the bioavailability of co-ingested flavonoids (reviewed in 8, 10, 11). The binding affinity and potential (non-) covalent interactions of flavonoids with food proteins, carbohydrates, and fats are directly associated with the physicochemical properties of flavonoids (reviewed in 8). Proteins in milk might reduce the absorption of polyphenols from cocoa or black tea. The presence of milk proteins bound to flavonoids was shown to weaken the flavonoid antioxidant capacity in vitro (12), and milk consumption has been shown to blunt the vascular benefits of tea flavonoids in healthy volunteers (13). Some carbohydrate-rich foods may increase the deglycosylation and absorption of flavonoids by stimulating gastrointestinal motility, mucosal blood flow, and colonic fermentation. Conversely, dietary flavonoids have been shown to interfere with carbohydrate digestion and absorption (see Biological Activities).

Composition of gut microbiota

In the large intestine, gut microbial enzymes transform flavonoids through deglycosylation, ring fission, dehydroxylation, demethylation, etc. into metabolites that can then be absorbed or excreted (9, 14). The diversity and activity of colonic bacteria, which are partly dependent on a person’s dietary habits, will determine which metabolites can be produced from ingested flavonoids (15, 16). The composition of the colonic microbiota can therefore affect the metabolic fate and bioavailability of dietary flavonoids (17).

The detoxification pathway

Flavonoids are recognized as xenobiotics by the body such that they undergo extensive modifications first in the intestinal mucosa and then in the liver.

Phase II enzymes

Depending on their structural characteristics, flavonoids can be rapidly transformed by phase II detoxification enzymes to form methylated, glucuronidated, and/or sulfated metabolites (2). This metabolic pathway increases the solubility of phenolic aglycones and facilitates their excretion in the bile and urine (11). Free (unconjugated) aglycones are generally absent from the bloodstream, with the possible exception of trace levels of catechins (17). Catechol-O-methyltransferase (COMT) is the detoxifying enzyme responsible for the methylation of the hydroxyl groups of flavonoids, producing O-methylated flavonoids. A single nucleotide polymorphism (SNP) in the gene for COMT — known as SNP rs4680 G>A — causes a valine-to-methionine substitution in the sequence of the enzyme. Individuals with the A/A genotype have a form of the enzyme that is three- to four-fold less active than the wild-type variant in G/G genotype carriers (18). It has been suggested that subjects who are less efficient at eliminating green tea flavonoids may be more likely to benefit from their consumption (19).

Efflux transporters

Flavonoid conjugates are excreted via the action of efflux transporters from the ATP-binding cassette (ABC) family, including P-glycoprotein, MRPs (multidrug resistance proteins), or BCRPs (breast cancer-resistant proteins). Depending on their physicochemical properties, some flavonoids may interfere with the activity of ABC transporters (20). This implies that flavonoids can affect their own bioavailability, as well as that of other substrates of these transporters (e.g., pharmacological drugs) (see Drug interactions).

Binding to plasma proteins

Flavonoid bioavailability may be inversely related to their binding affinity to plasma proteins (21). Greater binding affinity to plasma proteins (and thus, possibly, lower flavonoid bioavailability) has been linked to structural characteristics, such as methylation and galloylation. On the contrary, glycosylation reduced binding affinity to plasma proteins, suggesting that aglycones might have a limited bioavailability compared to glycosylated flavonoids. While glucuronidation is thought to facilitate the excretion of flavonoids from the body, glucuronides show little affinity to plasma proteins and might thus be able to diffuse to target tissues where deglucuronidation can take place (8)


In general, the bioavailability of flavonoids is low due to limited absorption, extensive metabolism, and rapid excretion. Isoflavones are thought to be the most bioavailable of all flavonoid subclasses, while anthocyanins and galloylated catechins are very poorly absorbed (8, 22). Yet, given the wide variability in structures within subclasses, it is difficult to generalize the absorbability and bioavailability of flavonoids based only on their structural classification. In addition, when evaluating the data from flavonoid research in cultured cells, it is important to consider whether the flavonoid concentrations and metabolites used are physiologically relevant (23). In humans, peak plasma concentrations of soy isoflavones and citrus flavanones have not been found to exceed 10 micromoles/liter (μM) after oral consumption. Peak plasma concentrations measured after the consumption of anthocyanins, flavan-3-ols, and flavonols (including those from tea) are generally lower than 1 μM (2). A recent quantitative analysis of 88 polyphenolic metabolites (not limited to flavonoids) identified in human blood and urine found median peak concentrations of 0.9 μM and 3.2 μM after food intake and oral supplementation, respectively (4).

Biological Activities

Direct antioxidant activity

Flavonoids are effective scavengers of free radicals in the test tube (in vitro) (24, 25). However, even with very high flavonoid intakes, plasma and intracellular flavonoid concentrations in humans are likely to be 100 to 1,000 times lower than concentrations of other antioxidants, such as ascorbate (vitamin C), uric acid, and glutathione. Moreover, most circulating flavonoids are actually flavonoid metabolites, some of which have lower antioxidant activity than the parent flavonoid (5). For these reasons, the relative contribution of dietary flavonoids to plasma and tissue antioxidant function in vivo is likely to be very small or negligible (26-28).

Metal chelation

Metal ions, such as iron and copper, can catalyze the production of free radicals. The ability of flavonoids to chelate (bind) metal ions appears to contribute to their antioxidant activity in vitro (29, 30). In living organisms, most iron and copper are bound to proteins, limiting their participation in reactions that produce free radicals. Although the metal-chelating activities of flavonoids may be beneficial in pathological conditions of iron or copper excess, it is not known whether flavonoids or their metabolites function as effective metal chelators in vivo (26).

Effects on cell-signaling pathways

Cells are capable of responding to a variety of different stresses or signals by increasing or decreasing the availability of specific proteins. The complex cascades of events that lead to changes in the expression of specific genes are known as cell-signaling pathways or signal transduction pathways. These pathways regulate numerous cell processes, such as proliferation, differentiation, inflammatory responses, apoptosis (programmed cell death), and survival. Although it was initially hypothesized that the biological effects of flavonoids would be related to their antioxidant activity, available evidence from cell culture experiments suggests that many of the effects of flavonoids, including antiinflammatory, antidiabetic, anticancer, and neuroprotective activities, are related to their ability to modulate cell-signaling pathways (27). Intracellular concentrations of flavonoids required to affect cellular signaling are considerably lower than those required to affect cellular antioxidant capacity. Flavonoid metabolites may retain their ability to interact with cell-signaling proteins even if their antioxidant activity is diminished (31, 32).

Effective signal transduction requires proteins known as kinases that catalyze the phosphorylation of target proteins, which become either activated or inhibited. Cascades involving specific phosphorylations or dephosphorylations of signal transduction proteins ultimately affect the activity of transcription factors — proteins that bind to specific response elements on DNA and promote or prevent the transcription of target genes. Results of numerous studies in cell culture suggest that flavonoids may affect chronic disease by selectively inhibiting kinases (27, 33). Cell growth and proliferation are also regulated by growth factors that initiate cell-signaling cascades by binding to specific receptors in cell membranes. Flavonoids may alter growth factor signaling by inhibiting receptor phosphorylation or blocking receptor binding by growth factors (34).

Each flavonoid subclass contains many types of chemicals with varying biological activities (and potential health benefits) such that the activity of a specific flavonoid cannot easily be generalized. Some examples of major biological activities of flavonoids are highlighted below.

Biological activities related to the prevention of cardiovascular disease

Flavonoids have been shown to (1) reduce inflammation by suppressing the expression of pro-inflammatory mediators (35-37); (2) down-regulate the expression of vascular cell adhesion molecules, which contribute to the recruitment of inflammatory white blood cells from the blood to the arterial wall (38, 39); (3) increase the production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS), thus improving vascular endothelial function (40); (4) inhibit angiotensin-converting enzyme, thus inducing vascular relaxation (41); (5) inhibit platelet aggregation (42); and (6) oppose smooth muscle cell proliferation and migration occurring during atherogenesis (43).

Biological activities related to the prevention of diabetes

Flavonoids have been found to interfere with the digestion, absorption, and metabolism of carbohydrates (reviewed in 44). Each subclass of flavonoids has also demonstrated anti-diabetic properties, including (1) improving insulin secretion and viability of pancreatic β-cells under glucotoxic or pro-inflammatory conditions, (2) increasing insulin-stimulated glucose uptake by target cells, (3) protecting muscle cells against fatty acid-induced insulin resistance, and (4) reducing hyperglycemia and improving glucose tolerance in animal models of obesity and/or type 2 diabetes mellitus (45).

Biological activities related to the prevention of cancer

Flavonoids have been found to (1) scavenge free radicals that can damage macromolecules, including DNA (46, 47); (2) interfere with biotransformation enzymes and efflux transporters, possibly preventing the activation of procarcinogenic chemicals and promoting their excretion from the body (48, 49); (3) regulate proliferation, DNA repair, or activation of pathways leading to apoptosis (programmed cell death) in case of irreversible DNA damage (50); and (4) inhibit tumor invasion and angiogenesis (51, 52).

Biological activities related to neuroprotection and cognitive function

Flavonoids are thought to (1) promote neurogenesis, synaptic growth, and neuron survival in the learning and memory-related brain regions (e.g., hippocampus) by stimulating the production of neurotrophins like BDNF; (2) protect hippocampal cells and striatal dopaminergic cells from cytotoxic molecules (pro-inflammatory mediators and ROS) released by abnormally activated microglia and hypertrophic astrocytes in neurodegenerative disorders; (3) reduce neuroinflammation by inhibiting the generation of pro-inflammatory cytokines, lipid mediators, and reactive oxygen species by astrocytes and microglial cells; (4) stimulate the production of nitric oxide (NO), which improves endothelial function, increases cerebral blood flow, and protects artery walls against the buildup of atherosclerotic plaques (reviewed in 53, 54).

Disease Prevention

Cardiovascular disease

Several prospective cohort studies conducted in the US and Europe have examined the relationship between some measure of dietary flavonoid intake and cardiovascular disease (CVD) or mortality. A recent meta-analysis of 14 prospective studies published between 1996 and 2012 reported that higher intakes in each flavonoid subclass were significantly associated with a reduced risk of cardiovascular events (55). Top versus bottom quantiles of intake for each of the flavonoid subclasses were associated with an approximate 10% reduction in the risk of CVD. Another meta-analysis of eight prospective studies found a 14% reduced risk of stroke with the highest versus lowest quintile of flavonol intakes (56). However, several serious limitations highlighted in a recent publication by Jacques et al. suggested caution when interpreting these results (57). In particular, most of the prospective studies in these meta-analyses did not include all flavonoid subclasses nor calculate intakes using the latest and more complete versions of the USDA databases for the flavonoid content of foods (58-60). Another major concern is the lack of adjustment regarding the overall quality of the diet. Consumers with higher flavonoid intakes are likely to have a greater consumption of fruit and vegetables and overall healthier diets than those with poor flavonoid intakes. Additionally, none of the studies excluded potential bias due to constituents of flavonoid-rich foods that are known to either lower (e.g., other phytochemicals, vitamins, dietary fiber) or increase (e.g., sodium, saturated fat) the risk of cardiovascular events (discussed in 57).

In the Framingham Offspring Cohort study that followed 2,880 adults for a mean of 14.9 years, consumption of all flavonoid subclasses except flavones and flavanones was inversely associated with CVD (57). Yet, adjusting for confounding factors, including fruit and vegetable intake and overall diet quality, attenuated these relationships such that they were no longer statistically significant. An analysis of a larger prospective study of the EPIC-Norfolk cohort (24,885 participants) that considered confounding by many dietary factors (vitamin C, dietary fiber, fat, saturated fat, potassium, sodium, and alcohol) found no significant association between flavan-3-ol intake and CVD-related or all-cause mortality (61).

A number of large prospective studies and small-scale, randomized controlled trials have investigated the effects of flavonoids on established biomarkers of CVD, including those involved in oxidative stress, inflammation, abnormal blood lipid profile, endothelial dysfunction, and hypertension; some of these studies are highlighted below.

Biochemical markers of cardiovascular disease

In a cross-sectional analysis of the Framingham Offspring Cohort study, the highest versus lowest intake of anthocyanins (≤3.5 mg/day versus ≥23.5 mg/day) was associated with lower concentrations of acute-phase reactant proteins (-100%), pro-inflammatory cytokines (-75%), and markers of oxidative stress (-52%), even after adjustment for confounding variables (62). Interestingly, a food-based analysis revealed that intakes of foods rich in anthocyanins, e.g., apples, red wine, and strawberries, were also inversely associated with an overall inflammation score based on 12 different biomarkers. Higher intakes of polymeric flavan-3-ols (i.e., theaflavins, thearubigins, and proanthocyanidins) were correlated with lower concentrations of pro-inflammatory cytokines and biomarkers of oxidative stress. Intake levels of total flavonoids and flavan-3-ol monomers (i.e., catechins) were inversely associated with concentrations of the biomarkers of oxidative stress. Although tea is a major source of flavan-3-ols, tea consumption was not correlated with the composite inflammation score or any components of this score in this study (62).

Cocoa is another source of flavan-3-ols, in particular (-)-epicatechin and procyanidins, that may provide cardiovascular benefits (63). Indeed, a recent randomized, double-blind, placebo-controlled study in 100 healthy adults (ages, 35-60 years) suggested that short-term benefits of cocoa flavan-3-ol consumption on cardiovascular health, including improvements in lipoprotein profile (i.e., higher HDL-cholesterol and lower total and LDL-cholesterol) and blood pressure, could be extrapolated to predict a 20%-30% reduced 10-year risk of CVD and CVD-related mortality (64).

An increasing number of trials in which participants were fed with berries (65-67) or juices (68) rich in anthocyanins or with purified anthocyanins (69) also reported reduced levels of inflammatory markers and/or improved antioxidant status, decreased LDL-cholesterol, improved insulin sensitivity, and lowered blood pressure (reviewed in 70). In a randomized, double-blind, placebo-controlled study in 150 individuals with hypercholesterolemia, supplementation with a purified anthocyanin mixture (320 mg/day) for 24 weeks reduced circulating markers of inflammation, including C-reactive protein (CRP), interleukin-1β (IL-1β), and soluble vascular adhesion molecule-1 (sVCAM-1) (71). Supplementation of dyslipidemic patients for 12 or 24 weeks with a mixture of 17 anthocyanins improved cholesterol clearance via the HDL-mediated reverse cholesterol transport from extra-hepatic tissues back to the liver and lowered LDL-cholesterol compared to a placebo in two randomized controlled trials (72, 73). However, a 12-week, randomized, double-blind, placebo-controlled study in 52 healthy postmenopausal women found that daily consumption of 500 mg of elderberry anthocyanins (as cyanidin-3-glucoside) had no effect on inflammation markers, markers of vascular health, lipid profile, and glycemia; all of these measures were in normal range of concentrations at baseline (74). Whether exposure to high-dose anthocyanins could lower the risk of CVD in subjects with established CVD risk factors and/or help maintain cardiovascular health in apparently healthy individuals remains to be confirmed.

Endothelial dysfunction

The vascular endothelial cells that line the inner surface of all blood vessels synthesize an enzyme, endothelial nitric oxide synthase (eNOS), whose function is essential to normal vascular physiology. Specifically, eNOS produces nitric oxide (NO), a compound that regulates vascular tone and blood flow by promoting the relaxation (vasodilation) of all types of blood vessels, including arteries (75). NO also regulates vascular homeostasis and protects the integrity of the endothelium by inhibiting vascular inflammation, leukocyte adhesion, platelet adhesion and aggregation, and proliferation of vascular smooth muscle cells (76). In the presence of cardiovascular risk factors (e.g., hypertension, hypercholesterolemia, hyperglycemia), early alterations in the structure and function of the vascular endothelium are associated with the loss of normal NO-mediated endothelium-dependent vasodilation. Endothelial dysfunction results in widespread vasoconstriction and coagulation abnormalities and is considered to be an early step in the development of atherosclerosis. Measures of brachial flow-mediated dilation (FMD), a surrogate marker of endothelial function, have been found to be inversely associated with risk of future cardiovascular events (77).

Preclinical studies have demonstrated the benefits of berry fruits, extracts, or purified anthocyanins on vascular function. Anthocyanin supplementation to diabetic mice was found to improve diabetes-induced vascular dysfunction by promoting NO-mediated endothelium-dependent vasodilation through the upregulation of adipocyte-derived adiponectin (78). Supplementation with purified anthocyanins (320 mg/day for 12 weeks) also increased serum adiponectin concentrations and improved FMD in 58 individuals with type 2 diabetes (78). In a randomized trial of 150 participants with hypercholesterolemia, supplemental anthocyanins increased FMD values by 28.4% compared to 2.2% in the placebo group (79).

Several small-scale, intervention studies have also examined the effect of flavan-3-ol-rich food and beverages, including tea, red wine, purple grape juice, cocoa, and chocolate, on endothelium-dependent vasodilation. A meta-analysis of nine intervention studies in a total of 213 participants estimated that the acute ingestion of 2 to 3 cups of tea (500 mL) — containing about 248 mg of flavonoids in green tea and 415 mg in black tea — significantly increased brachial FMD (see also the article on Tea) (80). Another meta-analysis of 18 randomized controlled studies found that acute (2 h post-ingestion) and chronic (≤18 months) consumption of flavan-3-ol-rich cocoa beverages and chocolate bars significantly increased FMD in participants (81). A small 15-day, cross-over intervention study in hypertensive individuals with endothelial dysfunction found that 100 g/day of flavan-3-ol-rich dark chocolate, but not 90 g/day of flavan-3-ol-free white chocolate, could restore FMD values almost to normal levels (82). Also, using a similar protocol, the authors showed that dark chocolate intake blunted acute endothelial dysfunction-induced by a glucose load challenge in 12 healthy volunteers (83). Other benefits of dark chocolate consumption included reductions in arterial stiffness (measured through pulse wave analysis) and serum concentrations of markers of oxidative stress and vasoconstriction (8-isoprostaglandin F2α and endothelin-1). A randomized controlled trial in overweight and obese participants also reported that the daily consumption of a high-flavan-3-ol cocoa drink (902 mg/day of flavan-3-ols), but not that of a cocoa drink low in flavan-3-ols (38 mg/day), resulted in a sustained increase in FMD during the 12-week study (84). A more recent four-week, randomized, double-blind, cross-over, controlled study in healthy overweight or obese adults found that the consumption of 22 g/day of natural cocoa (in the form of dark chocolate bar and cocoa drink; 814 mg/day of flavan-3-ols) increased arterial diameter and blood flow and lowered peripheral arterial stiffness, but there was no change in FMD (85). Another recent clinical trial found improvements in endothelium-dependent vasodilation in response to acute consumption of one bar (40 g) of dark chocolate (containing 10.8 mg of (+)-catechins and 36 mg of (-)-epicatechins) and daily consumption of two bars (80 g) for up to four weeks in 20 individuals with chronic heart failure (86). Oral administration of pure flavan-3-ol (-)-epicatechin to healthy volunteers showed NO-dependent vasodilatory effects similar to those observed following flavan-3-ol-rich cocoa ingestion (87). Administration of (-)-epicatechin also improved acetylcholine-induced endothelial-dependent vasodilation of thoracic aorta rings from rats with salt-induced hypertension (88).

Endothelial nitric oxide production also inhibits the adhesion and aggregation of platelets, one of the first steps in atherosclerosis and blood clot formation (76). A number of clinical trials that examined the potential for high flavonoid intakes to decrease various measures of platelet function outside of the body (ex vivo) have reported mixed results. A recent systematic review of these intervention studies suggested that consumption of flavan-3-ol-rich cocoa and grape seed extract was generally found to improve platelet function by inhibiting platelet adhesion, activation, and aggregation (89). Interestingly, in a cross-over, controlled study, the acute consumption of a flavan-3-ol-rich cocoa beverage (897 mg of total (-)-EC and procyanidins) exhibited additive anti-platelet effects to aspirin (81 mg) in healthy volunteers (90). In contrast, the results of interventions using apigenin-rich soup, quercetin-rich supplements or onion soups, isoflavone-rich soy protein isolates, black tea, wines, berries, or grape juices have given inconsistent results (reviewed in 89).


A meta-analysis of 20 short-term, randomized controlled trials, including a total of 856 mainly healthy participants, found that consumption of flavan-3-ol-rich dark chocolate and cocoa products significantly reduced systolic blood pressure by 2.77 mm Hg and diastolic blood pressure by 2.20 mm Hg. However, heterogeneity across studies was high, and risk of bias was significant (91). A greater blood pressure-reducing effect was observed in a subanalysis of studies using flavan-3-ol-free rather than flavan-3-ol-low control groups (91). Another meta-analysis of 22 trials (highly heterogeneous) found reductions in diastolic blood pressure (-1.60 mm Hg) and mean arterial pressure (-1.64 mm Hg) with chocolate or cocoa intake but no change in systolic blood pressure (81). Additionally, green tea flavan-3-ols have been shown to lower blood pressure especially in (pre-) hypertensive subjects. A pooled analysis of 13 randomized controlled trials in 1,040 subjects found a 2.05 mm Hg reduction in systolic blood pressure and a 1.71 mm Hg reduction in diastolic blood pressure with green tea consumption for at least three weeks (92). The inhibition of angiotensin-converting enzyme (ACE), a key regulator of arterial blood pressure, may partly explain how flavan-3-ol-rich food and beverages might exert blood pressure-lowering effects (93).

Some intervention trials have also examined the effect of the flavonol quercetin on blood pressure in human subjects. In a randomized, double-blind, cross-over, placebo-controlled trial in 96 participants diagnosed with metabolic disorders, supplementation with 150 mg/day of quercetin aglycone significantly reduced systolic blood pressure by 2.6 mm Hg without affecting diastolic blood pressure and other cardiometabolic markers (94). Similar results were found with 730 mg/day of quercetin in hypertensive individuals (95) and with 500 mg/day of quercetin in women with type 2 diabetes mellitus (96). In a recent six-week, cross-over, randomized, double-blind, placebo-controlled trial, daily ingestion of 162 mg of quercetin decreased 24 h-ambulatory blood pressure — but not systolic blood pressure in the resting state — in hypertensive but not in pre-hypertensive participants (97). There was no change in biomarkers of lipid metabolism, inflammation, oxidative stress, or endothelial function, including total, HDL-, LDL-cholesterol, serum CRP, soluble adhesion molecules, plasma oxidized LDL, urinary 8-isoprostaglandin F2α, serum endothelin-1, serum ACE, and plasma endogenous NOS inhibitor.

Additional trials may help establish whether the blood pressure-lowering effect of some flavonoids could be translated into long-term benefits for cardiovascular health.

Type 2 diabetes mellitus

The association between flavonoid consumption and risk for type 2 diabetes mellitus has been examined in a recent European, multicenter, nested case-control study — the "EPIC-InterAct" project — that included 16,835 diabetes-free participants and 12,043 diabetics. In this study, participants in the highest quintile of total flavonoid intake (>608.1 mg/day) had a 10% lower risk of diabetes than those in the lowest quintile (<178.2 mg/day) (98). Specifically, the risk of diabetes was inversely correlated with the intake of flavan-3-ols (monomers and dimers only) and flavonols (98, 99). Recent meta-analyses of randomized controlled trials have examined the possible health effects of green tea flavan-3-ol monomers (catechins) on glucose metabolism and have provided conflicting results. A meta-analysis of seven trials in pre-diabetic and diabetic patients found no effect of green tea or green tea extracts on fasting plasma glucose, fasting serum insulin, or measures of glycemic control (glycated hemoglobin, HbA1c) and insulin sensitivity (HOMA-IR) (100). Conversely, another meta-analysis of 17 trials in pre-diabetic, diabetic, or overweight/obese subjects found that administration of green tea extracts for 4 to 16 weeks improved fasting plasma glucose and HbA1c level (101). The effect on fasting glucose was observed only with high doses of catechins (≥457 mg/day) and when the confounding effect of caffeine was removed. Finally, a third meta-analysis of 25 trials found that ingestion of green tea extracts for at least two weeks could lower fasting blood glucose in both the presence or absence of caffeine (102).

Dark chocolate is another good source of flavan-3-ols such that the effects of cocoa flavan-3-ols have been examined in individuals at-risk or with established type 2 diabetes. In a 15-day, cross-over, randomized controlled study, the daily consumption of 100 g of dark chocolate bars containing 110.9 mg of (-)-EC and 36.1 mg of (+)-C significantly improved measures of pancreatic β-cell function and insulin sensitivity, along with cardiometabolic markers in glucose-intolerant and hypertensive subjects (103). Daily supplementation with flavonoid-enriched chocolate containing 850 mg of flavan-3-ols and 100 mg of isoflavones for one year significantly improved insulin sensitivity and reduced a predicted risk of coronary heart disease (CHD) at 10 years in 93 postmenopausal women treated for type 2 diabetes (104).

The EPIC-InterAct study did not find any association between dietary anthocyanin intake and risk of diabetes (98, 99). Yet, a 10-fold increase in anthocyanin consumption was correlated with a 15% lower risk of diabetes in the pooled analysis of three large US prospective cohorts (120,003 participants) (105). Of note, this pooled analysis also reported a moderately higher risk of diabetes (+6%) in individuals in the highest versus lowest quintiles of flavone and flavanone intakes. Moreover, the consumption of berries, rich in anthocyanins, has been shown to trigger favorable glycemic responses in type 2 diabetics (reviewed in 70). In recent intervention studies, anthocyanins demonstrated beneficial effects on metabolic abnormalities in patients at-risk or diagnosed with diabetes. In an eight-week, randomized, double-blind, placebo-controlled trial in 38 healthy overweight and obese subjects, the consumption of 2 g/day of grape polyphenols rich in proanthocyanidins and anthocyanins prevented increases in oxidative stress and insulin resistance induced by a six-day, high-fructose challenge (106). Another six-week randomized trial in individuals with diabetes showed that daily supplementation with Cornelian cherry (Cornus mas) extracts containing 600 mg of anthocyanins significantly lowered serum levels of HbA1c and triglycerides and increased serum insulin concentrations (107). The administration of 320 mg/day of anthocyanins for 24 weeks also improved serum lipid and lipoprotein profile, decreased markers of oxidative stress and inflammation, elevated antioxidant capacity, and reduced insulin resistance compared to a placebo in patients with diabetes (108). Further, supplemental anthocyanins up-regulated adiponectin expression and improved nitric oxide-mediated endothelium-dependent vasodilation within 12 weeks of treatment (see also Cardiovascular disease) (78).

These promising findings warrant additional randomized controlled trials to confirm preventive and/or therapeutic benefits of (cocoa) flavan-3-ols and anthocyanins in type 2 diabetes.


Although various flavonoids have been found to inhibit the development of chemically-induced cancers in animal models of lung (109), oral (110), esophageal (111), gastric (112), colon (113), skin (114), prostate (115, 116), and mammary cancer (117), observational studies do not provide convincing evidence that high intakes of dietary flavonoids are associated with substantial reductions in human cancer risk (reviewed in 118). A meta-analysis of 13 case-control and 10 prospective cohort studies found little-to-no evidence to support a preventive role of dietary flavonoid intake in gastric and colorectal cancer (119). In addition, a recently published analysis of two large prospective studies (the Health Professionals Follow-up Study [HPFS] and the Nurses’ Health Study [NHS]) — using the most up-to-date flavonoid food composition databases — found no association between the risk of colorectal cancer and intakes of each subclass of flavonoids or flavonoid-rich foods (tea, blueberries, oranges) (120). A meta-analysis of 19 case-control studies and 15 cohort studies found that total flavonoid intake and intakes of specific flavonoid subclasses (i.e., flavonols, flavones, flavanones) were inversely correlated with the risk of smoking-sensitive cancers of the aerodigestive tract (mouth, pharynx, larynx, esophagus, and stomach) in smokers but not in nonsmokers (121). The risk of lung cancer was not significantly associated with high flavonoid intakes (121), although an earlier meta-analysis of eight prospective studies (with substantial heterogeneity across them) suggested a protective role of flavonoids against lung cancer in smokers only (122). Further, a prospective analysis of over 45,000 postmenopausal women from the Multiethnic Cohort Study found a reduced risk of endometrial cancer with the highest intakes of total isoflavones, daidzein, and genistein (123). Additionally, limited evidence from observational studies suggests no relationship between total flavonoid intake and ovarian cancer (124-127). To date, there is little evidence that flavonoid-rich diets might protect against various cancers, but larger prospective cohort studies are needed to address the association.

Hormone-dependent cancers

Because isoflavones are phytoestrogens, it is thought that they may interfere with the synthesis and activity of endogenous hormones, eventually influencing hormone-dependent signaling pathways and protecting against breast and prostate cancers (128). A meta-analysis of 14 observational studies that examined breast cancer incidence in 369,934 women found an overall 11% reduced risk of breast cancer with the highest versus lowest intake of soy isoflavones (129). Subgroup analyses revealed a 24% lower risk of cancer in Asian but not in European or US women, and the risk was 22% lower in postmenopausal but not lower in premenopausal women. In addition to the ethnicity and menopausal status, polymorphisms for hormone receptors (130) and phase I biotransformation enzymes (131) have been found to modify the association between isoflavone intake and breast cancer. Another recent meta-analysis of 12 observational studies (six prospective cohort studies, one nested case-control study, and five case-control studies) investigated the chemopreventive effects of flavonoids (except isoflavones) (132). The results suggested that intakes of flavonols and flavones may also be inversely associated with the risk of breast cancer. Further, a pooled analysis of four case-control studies that stratified by menopausal status showed inverse associations between breast cancer and intakes of flavonols, flavones, or flavan-3-ols in postmenopausal women only. Finally, a meta-analysis of four prospective cohort studies found an overall 16% reduced risk of breast cancer recurrence in women with high versus low isoflavone intakes (129).

A meta-analysis of 13 observational studies also suggested an inverse relationship between prostate cancer risk and consumption of soy products, especially tofu (133). Yet, further analyses supported a protective role of soy food based only on case-control studies, which have inherent flaws such that associations may often be overestimated or underestimated. In a recent 12-month, multicenter, randomized, double-blind, placebo-controlled phase II clinical trial in 158 Japanese men (aged ≥50 years) with elevated risk of prostate cancer, oral isoflavone (60 mg/day) resulted in a significant decrease in prostate cancer incidence in participants aged 65 years and older (134). In this study, no changes were reported in sex hormone concentrations in blood, suggesting that isoflavones may reduce prostate cancer incidence without interfering with hormone-dependent pathways.

Additional investigations will be necessary to determine whether supplementation with specific flavonoids could benefit cancer prevention or treatment.

For more information on flavonoid-rich foods and cancer, see articles on Fruit and Vegetables, Legumes, and Tea.

Cognitive function

Inflammation, oxidative stress, and transition metal accumulation appear to play a role in the pathology of several neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease (135). Therefore, the various properties of flavonoids, including their role in protecting vascular health, could have beneficial effects on the brain, possibly in the protection against cerebrovascular disorders, cognitive impairments, and subsequent stroke and dementias. Dietary flavonoids and/or their metabolites have been shown to cross the blood-brain barrier (54) and exert preventive effects towards cognitive impairments in animal models of normal and pathological aging (53).

The cross-sectional data analysis of 2,031 participants (ages, 70-74 years) from the Hordaland Health Study in Norway indicated that, when compared to non-consumers, consumers of flavonoid-rich chocolate, tea, and wine had better global cognitive function, assessed by a battery of six cognitive tests (136). The risk of poor performance in all tests was estimated to be 60 to 74% lower in consumers of all three flavonoid-rich foods compared to non-consumers. An early prospective cohort study in 1,367 older French men and women (aged ≥65 years; free from dementia at baseline) found that those with the lowest flavonoid intakes (<11.5 mg/day) had a 50% higher risk of developing dementia over the next five years than those with higher intakes (137). In addition, those with higher dietary flavonoid intakes at baseline experienced significantly less age-related cognitive decline over a 10-year period than those with the lowest flavonoid intakes (138).

The effect of cocoa flavan-3-ols have been investigated in an eight-week, randomized, double-blind trial — the Cognitive, Cocoa, and Aging (CoCoA) study — in 90 individuals (ages, 64-82 years) with mild cognitive impairments (MCI); participants were given dairy-based cocoa drinks with either high (993 mg/day) or low (48 mg/day) levels of flavan-3-ols (139). The daily consumption of the cocoa drink high in flavan-3-ols improved some, but not all, measures of cognitive process speed and flexibility and verbal fluency compared to baseline test scores and scores following low flavan-3-ol drink consumption. A composite test score reflecting overall cognitive performance was found to be significantly greater in those given cocoa drinks high rather than low in flavan-3-ols. The study also reported reductions in cardiovascular risk markers (i.e., systolic and diastolic blood pressure, total and LDL-cholesterol, insulin resistance), and these changes were proposed to partly contribute to ameliorate cognitive performance in those who consumed the flavan-3-ol-rich cocoa drink (139). The data could be replicated in cognitively healthy older people (ages, 61-85 years), suggesting that cocoa flavan-3-ols might enhance some aspects of cognitive function during healthy aging (140). Interestingly, a two-week, randomized, double-blind, controlled study has reported an increase in blood flow velocity in the middle cerebral artery of 21 healthy subjects (mean age, 72 years) following the daily intake of a flavan-3-ol-rich cocoa drink (900 mg/day of flavan-3-ols) (141). Because cerebral blood flow is correlated with cognitive function in humans, these preliminary data suggest that cocoa flavan-3-ol consumption could exert a protective effect against dementia (54).

Yet, in other randomized controlled trials (142-144), the lack of an effect of cocoa flavan-3-ols on blood pressure, cerebral blood flow, mental fatigue, and cognitive performance in healthy young and old adults suggested that benefits may only be seen in very demanding cognitive exercises (145).

Some randomized controlled studies also reported improvements in measures of cognitive function in healthy and cognitively impaired subjects with other flavonoid subclasses, including anthocyanins (146), flavanones (147, 148), and isoflavones (149, 150). Although some flavonoids and flavonoid-rich foods may enhance cognitive function in the aging brain, it is not yet clear whether their consumption could lower the risk of cognitive impairments and dementia in humans.

For more detailed information on flavan-3-ol-rich tea and cognitive function, see the article on Tea.


Food sources

Recent data analyses of the National Health and Nutrition Examination Survey (NHANES) estimated flavonoid intakes in US adults (aged ≥19 years) average between 200 and 250 mg/day, with 80% being flavan-3-ols, 8% for flavonols, 6% for flavanones, 5% for anthocyanidins, and ≤1% for isoflavones and flavones (151, 152). The main dietary sources of flavonoids include tea, citrus fruit, citrus fruit juices, berries, red wine, apples, and legumes. Individual flavonoid intakes may vary considerably depending on whether tea, red wine, soy products, or fruit and vegetables are commonly consumed (reviewed in 2). Information on the flavonoid content of some flavonoid-rich foods is presented in Tables 2-8. These values should be considered approximate since a number of factors may affect the flavonoid content of foods, including agricultural practices, environmental conditions, ripening, storage, and food processing. For additional information about the flavonoid content of food, the USDA provides databases for the content of selected foods in flavonoids (60) and proanthocyanidins (58). For more information on the isoflavone content of soy foods, see the article on Soy Isoflavones or the USDA database for the isoflavone content of selected foods (59).

Table 2. Anthocyanidin Content of Anthocyanidin-rich Foods (mg/100 g or 100 mL*)
Food Anthocyanidins
Cyanidin Delphinidin Malvidin Pelargonidin Peonidin Petunidin
Blackberries, raw  100  0  0  <1  <1  0
Blood orange juice  5.5  <1  -  -  <1  -
Blueberries, raw  8.5  35.4  67.6  0  20.3  31.5
Currants, black, raw  62.5  89.6  -  1.2  <1  3.9
Elderberries, raw  485.3  0  -  <1  -  0
Grapes, red  1.2  2.3 39  <1  3.6  2
Onions, red, raw  3.2  4.3  -  <1  2.1 -
Plums, raw  5.6  0  0  0  <1  0
Radishes, raw  0  0  0 63.1  0  0
Raspberries, raw 45.8 1.3 <1 1 <1 <1
Red cabbage, raw 209.8 <1 - <1 - -
Strawberries, raw 1.7 <1 <1 24.9 <1 <1
Wine, red, Shiraz - 9.3 121.6 - 7.8 14.2
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
Table 3. Flavan-3-ol Content of Flavan-3-ol-rich Foods (mg/100 g or 100 mL*)
Food Flavon-3-ol Monomers# and Thearubigins
C GC EC ECG EGC EGCG Thearubigins
Apples, Red Delicious, raw, with skin 2  0 9.8  0 <1  <1  -
Apricots, raw 3.7 0 4.7 0 0 0 -
Chocolate, dark  24.2 -  84.4 - -  - -
Tea, black, brewed 1.5 1.2 2.1 5.9  8 9.4 81.3
Tea, green, brewed 4.5 1.5 8.3 17.9 29.2  70.2 1.1
Tea, oolong, brewed  <1 - 2.5  6.3 6.1 34.5 -
Tea, white, brewed  -  -  -  8.3  18.6  42.4 -
Wine, red, Shiraz  6.8 - 10 - - - -
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
#Catechins: C, (+)-catechin; GC, (-)-gallocatechin; EC (-)-epicatechin; ECG, (-)-epigallocatechin; ECG, (-)-epicatechin gallate; EGCG, (-)-epigallocatechin gallate.
Table 4. Proanthocyanidin Content of Flavan-3-ol-rich Foods (mg/100 g or 100 mL*)
Food Proanthocyanidins (Flavon-3-ol Polymers)
Monomers Dimers Trimers ≥4mers
Apples, Red Delicious, raw, with skin 8.3 15.1 10.1 94.2
Baking chocolate, unsweetened 198.5 206.5 130.9 1,100
Cocoa, dry powder, unsweetened 316.6 183.5 159.5 713.4
Cranberries, raw 7.3 25.9 18.9 385.6
Currants, black, raw <1 2.9 3 142.9
Grapes, red, raw 1.4 2.4 1 56.9
Nuts, pecan 17.2 42.1 26 408.6
Nuts, pistachio 10.9 13.3 10.5 202.6
Peaches, yellow, with peel, raw 4.5 12.2 4.4 50.6
Plums, with peel, raw 10.9 38.5 22.2 149.1
Spices, cinnamon, ground 23.9 256.3 1252.2 6,576
Strawberries, raw 3.7 5.3 4.9 127.8
Wine, table, red 16.6 20.5 1.8 22.7
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
Table 5. Flavonol Content of Flavonol-rich Foods (mg/100 g or 100 mL*)
Food Flavonols
Isorhamnetin Kaempferol Myricetin Quercetin
Blueberries, raw - 1.7 1.3 7.7
Broccoli, raw - 7.8 <1 3.3
Chili peppers, green, raw - 0 1.2 14.7
Cowpea, black seeds, raw - 1.9 2.7 17.2
Kale, raw 23.6 46.8 0 22.6
Onions, red, raw 4.6 <1 2.2 39.2
Parsley, fresh 0 1.5 14.8 <1
Rocket, wild, raw <1 1.8 - 66.2
Scallions, raw - 1.4 0 10.7
Spinach, raw - 6.4 <1 4
Tea, black, brewed - 1.4 <1 2.2
Tea, green, brewed - 1.3 1 2.5
Watercress, raw 0 23 <1 30
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
Table 6. Flavone Content of Flavone-rich Foods (mg/100 g or 100 mL*)
Food Flavones
Apigenin Luteolin
Celery hearts, green 19.1 3.5
Celery, raw 2.8 1
Chili peppers, green, raw 1.4 3.9
Oregano, fresh 2.6 1
Parsley, fresh 215.5 1.1
Peppermint, fresh 5.4 12.7
Thyme, fresh 2.5 45.2
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
Table 7. Flavanone Content of Flavanone-rich Foods (mg/100 g or 100 mL*)
Food Flavanones
Eriodictyol Hesperetin Naringenin
Grapefruit juice, white, fresh <1 2.3 18.2
Grapefruit, white, raw - <1 21.3
Lemon juice, fresh 4.9 14.5 1.4
Lemon, raw 21.4 27.9 <1
Orange juice, fresh <1 12 2.1
Orange, raw - 27.2 15.3
Pummelo juice, fresh 2.9 1.8 25.3
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.
Table 8. Isoflavone Content of Isoflavone-rich Foods (mg/100 g or 100 mL*)
Food Isoflavones
Diadzein Genistein Glycitein
Black bean sauce 6 4 <1
Natto 33.2 37.7 10.5
Soybeans, mature seeds, raw 62.1 81 15
Soymilk, low-fat 1 1.5 <1
Tofu, firm, cooked 10.3 10.9 1.3
*per 100 g (fresh weight) or 100 mL (liquids); 100 grams is equivalent to about 3.5 ounces; 100 mL is equivalent to about 3.5 fluid ounces.



Bilberry, elderberry, black currant, blueberry, red grape, and mixed berry extracts that are rich in anthocyanins are available as dietary supplements without a prescription in the US. The anthocyanin content of these products may vary considerably. Standardized extracts that list the amount of anthocyanins per dose are available.


Numerous tea extracts are available in the US as dietary supplements and may be labeled as tea catechins or tea polyphenols. Green tea extracts are the most commonly marketed, but black and oolong tea extracts are also available. Green tea extracts generally have higher levels of catechins (flavan-3-ol monomers), while black tea extracts are richer in theaflavins and thearubigins (tea flavan-3-ol dimers and polymers, respectively). Oolong tea extracts fall somewhere in between green and black tea extracts with respect to their flavan-3-ol content. Some tea extracts contain caffeine, while others are decaffeinated. Flavan-3-ol and caffeine content vary considerably among different products, so it is important to check the label or consult the manufacturer to determine the amounts of flavan-3-ols and caffeine that would be consumed daily with each supplement (for more information on tea flavan-3-ols, see the article on Tea).


Citrus bioflavonoid supplements may contain glycosides of hesperetin (hesperidin), naringenin (naringin), and eriodictyol (eriocitrin). Hesperidin is also available in hesperidin-complex supplements, with daily doses from 500 mg to 2 g (153).


The peels and tissues of citrus fruit (e.g., oranges, tangerines, and clementines) are rich in polymethoxylated flavones: tangeretin, nobiletin, and sinensetin (2). Although dietary intakes of these naturally occurring flavones are generally low, they are often present in citrus bioflavonoid complex supplements. Several dietary supplements may also contain various amounts of baicalein (aglycone) and/or baicalin (glycoside). Some tea preparations may also include baicalein-7-glucuronide (153).


The flavonol aglycone, quercetin, and its glycoside rutin are available as dietary supplements without a prescription in the US. Other names for rutin include rutoside, quercetin-3-rutinoside, and sophorin (153). Citrus bioflavonoid supplements may also contain quercetin or rutin.


A 50-mg soy isoflavone supplement usually includes glycosides of the isoflavones: genistein (genistin; 25 mg), daidzein (daidzin; 19 mg), and glycitein (glycitin; about 6 mg). Smaller amounts of daidzein, genistein, and formononetin are also found in biochanin A-containing supplements (derived from red clover) (153).


Adverse effects

No adverse effects have been associated with high dietary intakes of flavonoids from plant-based food. This lack of adverse effects may be explained by the relatively low bioavailability and rapid metabolism and elimination of most flavonoids.


Oral supplementation with quercetin glycosides at doses ranging between 3 mg/day-1,000 mg/day for up to three months has not resulted in significant adverse effects in clinical studies (reviewed in 154). A randomized, placebo-controlled study in 30 patients with chronic prostatitis reported one case of headache and another of tingling of the extremities associated with supplemental quercetin (1,000 mg/day for one month); both issues resolved after the study ended (155). In a phase I clinical trial in cancer patients unresponsive to standard treatments, administration of quercetin via intravenous infusion resulted in symptoms of nausea, vomiting, sweating, flushing, and dyspnea (difficulty breathing) at doses ≥10.5 mg/kg body weight (~756 mg of quercetin for a 70 kg individual) (156). Higher doses up to 51.3 mg/kg body weight (~3,591 mg of quercetin) were associated with renal (kidney) toxicity, yet without evidence of nephritis, infection, or obstructive uropathy (reviewed in 154).

Cocoa flavan-3-ols

In a recent randomized, double-blind, controlled study in healthy adults, the daily intake of 2 g of cocoa flavan-3-ols for 12 weeks was found to be well tolerated with no adverse side effects (157).

Tea extracts

In clinical trials employing caffeinated green tea extracts, cancer patients who took 6 g/day in three to six divided doses reported mild-to-moderate gastrointestinal side effects, including nausea, vomiting, abdominal pain, and diarrhea (158, 159). Central nervous system symptoms, including agitation, restlessness, insomnia, tremors, dizziness, and confusion, have also been reported. In one case, confusion was severe enough to require hospitalization (158). In a systematic review published in 2008, the US Pharmacopeia (USP) Dietary Supplement Information Expert Committee identified 34 adverse event reports implicating the use of green tea extract products (containing 25%-97% of polyphenols) as the likely cause of liver damage (hepatotoxicity) in humans (160). In a four-week clinical trial that assessed the safety of decaffeinated green tea extracts (800 mg/day of EGCG) in healthy individuals, a few of the participants reported mild nausea, stomach upset, dizziness, or muscle pain (161). In the Minnesota Green Tea Trial (MGTT), 1,075 postmenopausal women were randomized to receive green tea extracts (1,315±116 mg/day of catechins; the equivalent of four 8-ounce mugs of brewed decaffeinated green tea) or a placebo for one year. The total number of adverse events and the number of serious adverse events were not different between the treatment and placebo groups (162). However, the use of green tea extracts was directly associated with abnormally high liver enzyme levels in 7 out of the 12 women who experienced serious adverse events. Also, the incidence of nausea was twice as high in the green tea arm as in the placebo group (162).

Pregnancy and lactation

The safety of flavonoid supplements in pregnancy and lactation has not been established (153).

Drug interactions

Inhibition of ABC drug transporters

ATP-binding cassette (ABC) drug transporters, including P-glycoprotein, multidrug resistance protein (MRP), and breast cancer-resistant protein (BCRP), function as ATP-dependent efflux pumps that actively regulate the excretion of a number of drugs limiting their systemic bioavailability (8). ABC transporters are found throughout the body, yet they are especially important in organs with a barrier function like the intestines, the blood-brain barrier, blood-testis barrier, and the placenta, as well as in liver and kidneys (163). There is some evidence that the consumption of grapefruit juice inhibits the activity of P-glycoprotein (164). Genistein, biochanin A, quercetin, naringenin, hesperetin, green tea flavan-3-ol (-)-CG, (-)-ECG, and (-)-EGCG, and others have been found to inhibit the efflux activity of P-glycoprotein in cultured cells and in animal models (163). Thus, very high or supplemental intakes of these flavonoids could potentially increase the toxicity of drugs that are substrates of P-glycoprotein, e.g., digoxin, antihypertensive agents, antiarrhythmic agents, chemotherapeutic (anticancer) agents, antifungal agents, HIV protease inhibitors, immunosuppressive agents, H2 receptor antagonists, some antibiotics, and others (reviewed in 165).

Many anthocyanins and anthocyanidins, as well as some flavones (apigenin, chrysin), isoflavones (biochanin A, genistein), flavonols (kaempferol), and flavanones (naringenin), have been identified as inhibitors of BRCP-mediated transport, theoretically affecting drugs like anticancer agents (mitoxantrone, topotecan, thyrosine kinase inhibitors), antibiotics (fluoroquinolones), β-blockers (prazosin), and antiarthritics (sulfasalazine). Finally, flavonols (quercetin, kaempferol, myricetin), flavanones (naringenin), flavones (apigenin, robinetin), and isoflavones (genistein) have been reported to inhibit MRP, potentially affecting MRP-mediated transport of many anticancer drugs, e.g., vincristin, etoposide, cisplatin, irinotecan, methotrexate, camptothecin, anthracyclines, vinca alkaloids (reviewed in 163).

Anticoagulant and antiplatelet drugs

High intakes of flavonoids from purple grape juice (500 mL/day) and dark chocolate (235 mg/day of flavan-3-ols) have been found to inhibit platelet aggregation in ex vivo assays (166-169). Theoretically, high intakes of flavonoids (e.g., from supplements) could increase the risk of bleeding when taken with anticoagulant drugs, such as warfarin (Coumadin), heparin, dalteparin (Fragmin), enoxaparin (Lovenox), and antiplatelet drugs, such as clopidogrel (Plavix), dipyridamole (Persantine), non-steroidal anti-inflammatory drugs (NSAIDs: diclofenac, ibuprofen, naproxen), aspirin, and others (170).

Inhibition of CYP 3A4 by flavonoid-rich grapefruit

Cytochrome P450 (CYP) enzymes are phase I biotransformation enzymes involved in the metabolism of a broad range of compounds, from endogenous molecules to therapeutic agents. The most abundant CYP isoform in the liver and intestines is cytochrome P450 3A4 (CYP3A4); the CYP3A family catalyzes the metabolism of about one-half of all marketed drugs in the US and Canada (171). One grapefruit or as little as 200 mL (7 fluid ounces) of grapefruit juice have been found to irreversibly inhibit intestinal CYP3A4 (164). The most potent inhibitors of CYP3A4 in grapefruit are thought to be furanocoumarins, particularly dihydroxybergamottin, rather than flavonoids. All forms of the fruit — freshly squeezed juice, frozen concentrate, or whole fruit — can potentially affect the activity of CYP3A4. Some varieties of other citrus fruit (Seville oranges, limes, and pomelos) that contain furanocoumarins can also interfere with CYP3A4 activity.

Specifically, the inhibition of intestinal CYP3A4 by grapefruit consumption is known or predicted to increase the bioavailability and the risk of toxicity of more than 85 drugs. Because drugs with very low bioavailability are more likely to be toxic when CYP3A4 activity is inhibited, they are associated with a higher risk of overdose with grapefruit compared to drugs with high bioavailability. Some of the drugs with low bioavailability include, but are not limited to, anticancer drugs (everolimus); anti-infective agents halofantrine, maraviroc); statins (atorvastatin, lovastatin, and simvastatin); cardioactive drugs (amiodarone, clopidogrel, dronedarone, eplenorone, ticagrelor); HIV protease inhibitors (saquinavir), immunosuppressants (cyclosporine, sirolimus, tacrolimus, everolimus); antihistamines (terfenadine); gastrointestinal agents (domperidone); central nervous system agents (buspirone, dextromethorphan, oral ketamine, lurasidone, quetiapine, selective serotonin reuptake inhibitors [sertraline]); and urinary tract agents (darifenacin) (reviewed in 171). Because of the potential for adverse drug interactions, some clinicians recommend that people taking medications with low bioavailability (i.e., undergoing extensive metabolism by CYP3A4) avoid consuming grapefruit and grapefruit juice altogether during the treatment period (171).

Nutrient interactions


Flavonoids can bind nonheme iron, inhibiting its intestinal absorption (172, 173). Nonheme iron is the principal form of iron in plant foods, dairy products, and iron supplements. The consumption of one cup of tea or cocoa with a meal has been found to decrease the absorption of nonheme iron in that meal by about 70% (174, 175). Flavonoids can also inhibit intestinal heme iron absorption (176). Interestingly, ascorbic acid greatly enhances the absorption of iron (see the article on Iron) and is able to counteract the inhibitory effect of flavonoids on nonheme and heme iron absorption (173, 176, 177). To maximize iron absorption from a meal or iron supplements, flavonoid-rich food and beverages and flavonoid supplements should not be consumed at the same time.

Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in June 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in November 2015 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in February 2016 by:
Alan Crozier, Ph.D.
Professor, Department of Nutrition
University of California, Davis

Copyright 2005-2024  Linus Pauling Institute 


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  • Indole-3-carbinol (I3C) is derived from the breakdown of glucobrassicin, a compound found in cruciferous vegetables. (More information)
  • In the stomach, I3C molecules undergo acid-catalyzed condensation that generates a number of biologically active I3C oligomers, such as 3,3'-diindolylmethane (DIM) and 5,11-dihydroindolo-[3,2-b]carbazole (ICZ). (More information)
  • I3C and DIM have been found to modulate the expression and activity of biotransformation enzymes that are involved in the metabolism and elimination of many biologically active compounds, including steroid hormones, drugs, carcinogens, and toxins. (More information)
  • Preclinical studies suggested that anti-estrogenic activities of I3C and DIM might help reduce the risk of hormone-dependent cancers. Although supplementation with I3C and DIM could alter urinary estrogen metabolite profiles in women, the effects of I3C and DIM on breast cancer risk are not known. (More information)
  • Preclinical studies showed that I3C and I3C oligomers could affect multiple signaling pathways that are dysregulated in cancer cells, such as those controlling cell proliferation, apoptosis, migration, invasion, and angiogenesis. (More information)
  • Limited evidence from preliminary trials suggested that I3C supplementation may help treat conditions related to human papilloma virus (HPV) infection, such as cervical/vulvar intraepithelial neoplasias and recurrent respiratory papillomatosis. However, randomized controlled trials are needed to determine whether I3C supplementation is beneficial. (More information)
  • The timing of I3C exposure in animal models of chemically-induced cancers seems to determine whether I3C inhibits or promotes the development of tumors. Some experts have cautioned against the widespread use of I3C and DIM supplements for cancer prevention in humans until their potential risks and benefits are better understood(More information)


Some observational studies have reported significant associations between high intakes of cruciferous vegetables and lower risk of several types of cancer (1). Cruciferous vegetables differ from other classes of vegetables in that they are rich sources of sulfur-containing compounds known as glucosinolates (for detailed information, see the article on Cruciferous Vegetables) (2). The potential health benefits of consuming cruciferous vegetables are attributed to compounds derived from the enzymatic hydrolysis (breakdown) of glucosinolates. Among these compounds is indole-3-carbinol (I3C), a compound derived from the degradation of an indole glucosinolate commonly known as glucobrassicin (Figure 1).

Figure 1. Breakdown of Glucobrassicin. Glucobrassicin is metabolized by myrosinase to the unstable intermediate, thiohydroximate-O-sulfonate form, then in neutral pH to the unstable intermediate, 3-inolylmethyl-isothiocyanate, then eventually degrades to form indole-3-carbinol and a thiocyanate ion.

[Figure 1 - Click to Enlarge]

Metabolism and Bioavailability

A number of commonly consumed cruciferous vegetables, including broccoli, Brussels sprouts, and cabbage, are good sources of glucobrassicin — the glucosinolate precursor of I3C (see Food sources).

Myrosinase (β-thioglucosidase), an enzyme that catalyzes the hydrolysis of glucosinolates, is physically separated from glucosinolates in intact plant cells (3). When raw cruciferous vegetables are chopped or chewed, plant cells are damaged such that glucobrassicin is exposed to myrosinase. The hydrolysis of glucobrassicin initially produces a glucose molecule and the unstable aglycone, thiohydroximate-O-sulfonate. The spontaneous release of a sulfate ion results in the formation of another unstable intermediate form, 3-indolylmethylisothiocyanate (4). This compound easily splits into thiocyanate ion and I3C (Figure 1). In the acidic environment of the stomach, I3C molecules can combine with each other to form a complex mixture of polycyclic aromatic compounds, known collectively as acid condensation products (Figure 2) (5). Some of the most prominent acid condensation products include 3,3'-diindolylmethane (DIM), 5,11-dihydroindolo-[3,2-b]carbazole (ICZ), and a cyclic triindole (CT) (Figure 2). The biological activities of individual acid condensation products may differ from those of I3C (see Biological Activities).

When cruciferous vegetables are cooked, plant myrosinase is inactivated thus the hydrolysis of glucosinolates is prevented. Intact glucosinolates then transit to the colon and are metabolized by human intestinal bacteria. The generation of I3C from glucobrassicin may still occur to a lesser degree in the large intestine, due to the myrosinase activity of colonic bacteria (4). Thus, when cruciferous vegetables are cooked, I3C can still form in the colon, but I3C-derived acid condensation products are less likely to form in the more alkaline environment of the intestine.

No I3C could be detected in plasma following oral administration of single doses of I3C, ranging from 200 to 1,200 mg, to healthy women at high risk for breast cancer (6). However, DIM was detected and peaked in plasma around two hours after I3C ingestion, at concentrations from <100 nanograms per milliliter (ng/mL) with oral doses of 400 to 600 mg of I3C up to 500 ng/mL-600 ng/mL with oral doses of 1,000 to 1,200 mg of I3C. All DIM disappeared from the blood within 24 hours (6).

Formulation strategies, such as the encapsulation of I3C and DIM into nanoparticles or liposomes (7-9), are being developed with the aim of increasing the bioavailability and evaluating the safety and efficacy of these compounds in humans.

Figure 2. Condensation Derivatives of Indole-3-Carbinol: 3,3'-diindolylmethane (DIM), 5,6,11,12,17,18-hexahydrocyclononal [1,2-b:4,5-b':7,8-b"]triindole (CT), and 5,11-dihydroindolo-[3,2-b]carbazole (ICZ) 

[Figure 2 - Click to Enlarge]

Biological Activities

Effects on biotransformation enzymes

Biotransformation enzymes play major roles in the metabolism and elimination of many biologically active compounds, including physiologic regulators (e.g., estrogens), drugs, and environmental chemicals (xenobiotics; e.g., carcinogens, toxins). In general, phase I metabolizing enzymes, including the cytochrome P450 (CYP) family, catalyze reactions that increase the reactivity of hydrophobic (fat-soluble) compounds, which prepares them for reactions catalyzed by phase II detoxifying enzymes. Reactions catalyzed by phase II enzymes usually increase water solubility and promote the elimination of these compounds (10).

Aryl hydrocarbon receptor (AhR) pathway

I3C and some I3C condensation products can bind to a protein in the cytoplasm of cells called the aryl hydrocarbon receptor (AhR) (Figure 3) (11-13). In fact, ICZ is one of the most potent ligands for the AhR known with an affinity approaching that of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). I3C acid condensation products, as well as indoles and their acid condensation products formed from tryptophan metabolism, appear to be important endogenous ligands for the AhR (13). Binding allows AhR to enter the nucleus where it forms a complex with the AhR nuclear translocator (Arnt) protein. This AhR/Arnt complex binds to specific DNA sequences, known as xenobiotic response elements (XRE), in the regulatory regions (promoters) of target genes, especially those involved in xenobiotic metabolism (14). The promoters of genes coding for a number of CYP enzymes and several phase II enzymes contain XREs. Microarray gene expression profiling of I3C- or DIM-treated human prostate cancer cells showed that both compounds upregulated the phase I enzyme, CYP1A1, and the phase II enzymes, glutathione S-transferase theta-1 (GST q1) and aldo-keto reductase (15). Another study in human prostate cancer cells demonstrated that the removal of AhR abolished I3C- or DIM-induced CYP1A1 mRNA expression (16). The expression of CYP1A1 and CYP1A2 was also upregulated in human primary liver cells challenged with DIM (17). Further, I3C and DIM have been found to interfere with CYP activities involved in estrogen metabolism (see Anti-estrogenic activities).

Increasing the activity of biotransformation enzymes is generally considered a beneficial effect because the elimination of potential carcinogens or toxins is enhanced. However, there is a potential for adverse effects because some procarcinogens require biotransformation by phase I enzymes to become active carcinogens (18).

Figure 3. I3C and DIM Regulate Phase I Biotransformation Enzymes via AhR Signaling. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) regulate the expression of phase I metabolizing enzymes via the AhR signaling pathway.

[Figure 3 - Click to Enlarge]

Nuclear factor E2-related factor 2-dependent pathway

I3C and DIM have been shown to induce the expression of phase II detoxifying and antioxidant enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway.

Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol (Figure 4). Keap1 responds to oxidative stress signals or chemical inducers by freeing Nrf2. Upon release, Nrf2 translocates to the nucleus and binds to the antioxidant response element (ARE) located in the promoters of genes coding for antioxidant/detoxifying enzymes and scavengers. Nrf2/ARE-dependent genes code for numerous mediators of the antioxidant response, including glutathione S-transferases (GSTs), thioredoxin, NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) (19). DIM induced Nrf2/ARE-dependent upregulation of HO-1, and I3C stimulated NQO-1 and GST (µ2 isoform) expression in liver cancer cells (20). In addition, the transcription of Nrf2 coding gene, which was abnormally repressed through promoter DNA hypermethylation, was enhanced in mouse prostate cancer cells treated with DIM. DIM subsequently restored the expression of the Nrf2-target genes, NQO1 and GSTµ1 (21). DIM also reversed Nrf2 gene silencing in transgenic mouse prostate cancer tissues, inducing Nrf2 expression, and subsequently, NQO1 expression (Figure 4). This was accompanied by the suppression of proliferation and the induction of apoptosis in prostate cancer tissues (21). Similar observations have been reported with I3C (22).

Figure 4. I3C and DIM Regulate Phase II Biotransformation Enzymes via Nrf2 Signaling. Indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) increase the expression of phase II detoxifying/antioxidant enzymes via the nuclear factor E2-related factor 2 (Nrf2) signaling pathway. (A) I3C and DIM restore the transcription of Nrf2 gene by reversing promoter methylation, (B) I3C and DIM iinduce the nuclear translocation of Nrf2, and (C) I3C and DIM increase the expression of Nrf2 target genes coding for phase II enzymes and antioxidant enzymes. 

[Figure 4 - Click to Enlarge]

Anti-estrogenic activities

Endogenous estrogens are steroid hormones synthesized by humans and other mammals.

Inhibition of estrogen synthesis

In breast tissue, CYP19 (aromatase) catalyzes the final steps in the conversion of androgens (testosterone or androstenedione) to estrogens (17β-estradiol or estrone, respectively). Both I3C and DIM have been found to downregulate the expression of CYP19 in non-tumorigenic and tumorigenic estrogen-responsive (ER+) breast cells, whereas CYP19 expression was increased in I3C/DIM-treated tumorigenic estrogen-independent (ER-) breast cells (23).

Inhibition of estrogen metabolic activation

Prolonged exposure to estrogens is thought to play a role in cancer development through CYP-mediated generation of estrogen reactive metabolites that can damage DNA (24, 25).

Phase I metabolizing enzymes, CYP1A1, CYP1A2, and CYP1B1, have been involved in the oxidative metabolism of estrogens. 17β-estradiol can be converted to 2-hydroxyestradiol (2HE2) and 4-hydroxyestradiol (4HE2) by CYP1A1/2 and CYP1B1, respectively. 2HE2 and 4HE2 are further metabolized to 2- and 4-metoxymetabolites by the phase II enzyme, catechol-O-methyltransferase (COMT) (25). 2HE2 is a noncarcinogenic agent with weaker estrogenic potential than 17β-estradiol, while 4-HE2 can be converted to free radicals that can form DNA adducts and promote carcinogenesis (26, 27). In different breast cancer cell lines, I3C and DIM have been shown to upregulate the expression of CYP1A1, CYP1A2, and CYP1B1 at the transcript (mRNA) level but not at the protein level (28).

Additionally, the endogenous estrogens 17β-estradiol and estrone can be irreversibly metabolized to 16a-hydroxyestrone (16HE1) (29). In contrast to 2-hydroxyestrone (2HE1), 16HE1 is highly estrogenic and has been found to stimulate the proliferation of several estrogen-sensitive cancer cell lines (30, 31). It has been hypothesized that shifting the metabolism of 17β-estradiol toward 2HE1, and away from 16HE1, could decrease the risk of estrogen-sensitive cancers, such as breast cancer (32). In controlled clinical trials, oral supplementation with I3C or DIM has consistently increased urinary 2HE1 concentrations or urinary 2HE1:16HE1 ratios in women (33-39). However, large case-control and prospective cohort studies have failed to find significant associations between urinary 2HE1:16HE1 ratios and risk of breast and endometrial cancer (40-43).

Inhibition of estrogen signaling

Endogenous estrogens, including 17β-estradiol, exert their estrogenic effects by binding to specific nuclear receptors called estrogen receptors (ERs). Within the nucleus, estrogen-activated ERs can bind to specific DNA sequences, known as estrogen response elements (EREs), in the promoters of estrogen-responsive genes. ERE-bound estrogen-ER complexes act as transcription factors by recruiting coactivator proteins and chromatin remodeling factors to promoters, thereby triggering the transcription of target genes (44). There are two major ER subtypes, ERα and ERβ, coded by two separate genes ESR1 and ESR2, respectively. ERα is the main driver of the proliferative effect of estrogens, while the expression of ERβ has been inversely associated with mammary gland tumorigenesis (45). Elevated ERα levels promote cellular proliferation in the breast and uterus, possibly increasing the risk of developing estrogen-sensitive cancers (46).

Inhibition of estrogen-dependent cell proliferation

In estrogen-sensitive human breast cancer cells challenged with 17β-estradiol, I3C has been found to inhibit the transcription of estrogen-responsive genes without binding to either ERβ or ERα (47, 48). In fact, the binding of I3C to AhR was shown to trigger the proteasome-dependent degradation of ERα (49). I3C-induced loss of ERα resulted in the downregulation of ERα-responsive gene products like the transcription factor GATA3. Since GATA3 regulates the transcription of the ERα coding gene ESR1, I3C prevented the synthesis of new ERα transcripts and proteins, eventually abolishing the ERα signaling pathway. The disruption of the GATA3/ERα cross-regulatory loop by I3C ultimately halted ERα-dependent cell proliferation (49). Acid condensation products of I3C that bind and activate AhR may also inhibit the transcription of estrogen-responsive genes by competing for co-activators or increasing ERα degradation (14, 50). I3C treatment also affected the expression of other ERα-responsive genes, including those coding for insulin-like growth factor-1 receptor (IGFR1) and insulin receptor substrate-1 (IRS-1), involved in cell proliferation and deregulated in breast cancer (Figure 5) (51).

Figure 5. Overview of Anti-estrogenic Actions of I3C and DIM.  

[Figure 5 - Click to Enlarge]

Modulation of cell-signaling pathways

I3C and condensation derivatives have been found to affect multiple signaling pathways that are often deregulated in cancer cells. Below are some examples illustrating how I3C, DIM, or ICZ may influence cell proliferation, apoptosis, migration, invasion, angiogenesis, and immunity by targeting specific signaling pathways (23).

Induction of cell cycle arrest and apoptosis

Once a cell divides, it passes through a sequence of stages — collectively known as the cell cycle — before it divides again. Following DNA damage, the cell cycle can be transiently arrested at damage checkpoints, which allows for DNA repair or activation of pathways leading to cell death (apoptosis) if the damage is irreparable (52). Defective cell cycle regulation may result in the propagation of mutations that contribute to the development of cancer. In addition, unlike normal cells, cancerous cells lose their ability to respond to death signals that initiate apoptosis.

I3C-induced downregulation of the phosphatidylinositol 3-kinase (PI3K)/serine-threonine kinase (Akt) cell survival signaling pathway in mice with nasopharyngeal carcinoma resulted in inhibition of cell proliferation and induction of apoptosis (53). Inactivation of the Wnt/β-catenin signaling pathway in DIM-treated colon cancer cells decreased the expression of downstream targets, c-myc and cyclin D1, that promote cell proliferation and survival (54). In prostate cancer cells, I3C opposed the anti-apoptotic effect of epidermal growth factor (EGF) by limiting EGF receptor autophosphorylation (activation) and reducing EGF-induced activation of the PI3K/Akt signaling pathway and expression of the pro-survival target molecules, Bcl-x(L) and BAD (55). In another study, DIM caused apoptosis of prostate cancer cells by stimulating p38 mitogen-activated protein kinase (p38 MAPK)-induced upregulation of tumor suppressor p75NTR (56). The anti-proliferative effect of DIM in cancer cells has also been linked to the inhibition of histone deacetylase (HDAC) activity. Specifically, DIM was found to reverse HDAC-mediated epigenetic silencing of genes coding for key regulators of the cell cycle (57, 58). A recent genome-wide analysis of DNA methylation also showed that DIM could reverse aberrant promoter methylation in prostate cancer cells, at least partly through downregulating the expression of DNA methyltransferases (DNMTs) (59).

Inhibition of cell migration and invasion

The epithelial-to-mesenchymal transition (EMT) describes a process of epithelial cell transformation whereby cells lose their polarity and adhesion properties while gaining migratory and invasive properties through the expression of mesenchymal genes. Inhibition of EMT by I3C and ICZ in breast cancer cells has been associated with upregulation of an epithelial marker, E-cadherin, and downregulation of vimentin, focal adhesion kinase (FAK), and matrix metalloproteins (MMPs) — proteins and enzymes known to promote migration (60). DIM also inhibited migration and invasion of liver cancer cells in vitro and in vivo through inactivating the FAK signaling pathway (61). Moreover, DIM has been shown to reverse methylation-associated dysregulation of genes involved in cell adhesion, chemotaxis, and inflammation that contributes to cancer progression (59). DIM was able to inhibit lung metastasis in mice with liver (61) or mammary tumors (62).

Inhibition of angiogenesis

To fuel their rapid growth, invasive tumors must also develop new capillaries from preexisting blood vessels by a process known as angiogenesis. I3C inhibited lipopolysaccharide (LPS)-induced macrophage activation and secretion of proangiogenic molecules, such as nitric oxide (NO), vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), and MMP-9, and prevented the formation of capillary-like structures from co-cultured human umbilical endothelial cells (63). Similarly, I3C inhibited capillary-like tube formation from phorbol myristate acetate (PMA)-stimulated endothelial cells (64). DIM also blocked PMA-induced angiogenic activities in human umbilical endothelial cells (65).

Regulation of inflammation and cell-mediated immunity

Uncontrolled inflammation has been associated with several chronic diseases, including cancer. In the mouse ear edema model, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced upregulation of pro-inflammatory mediators, such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), has been found to be mitigated by DIM treatment (66). Nuclear factor-kappa B (NF-κB) is a major transcription factor regulating the expression of many pro-inflammatory genes like those coding for COX-2 and iNOS. Specifically, DIM inhibited TPA-induced activation of kinases (inhibitor of kappa B kinase [IκK] and extracellular signal-regulated kinase [ERK]) that control the transcriptional activity of NF-κB (66). In addition, recent animal studies showed that I3C and/or DIM could modulate cell-mediated immune response in experimental autoimmune encephalomyelitis (67), staphylococcal enterotoxin-induced lung inflammation (68), and delayed-type hypersensitivity (69). Specifically, I3C and/or DIM differentially regulated T-cell subpopulations via the activation or suppression of microRNA-dependent pathways controlling cell cycle progression and apoptosis.

Transplacental cancer prevention

The inclusion of I3C in the maternal diet was found to protect the offspring from lymphoma and lung tumors induced by dibenzo[a]pyrene, a polycyclic aromatic hydrocarbon (70, 71). Polycyclic aromatic hydrocarbons are chemical pollutants formed during incomplete combustion of organic substances, such as coal, oil, wood, and tobacco (72).

However, the physiological relevance of cell culture and animal studies to human health is unclear since little or no I3C is available to tissues after oral administration (see Metabolism and Bioavailability) (6).

Disease Prevention


Some observational studies provide some support for the hypothesis that higher intakes of cruciferous vegetables are associated with lower risk for some types of cancer (see the article on Cruciferous Vegetables) (1). Cruciferous vegetables are relatively good sources of nutrients that may have protective effects against cancer, including vitamin C, folate, selenium, carotenoids, and fiber. In addition, glucosinolates can be hydrolyzed to a variety of potentially protective isothiocyanates, in addition to indole-3-carbinol (see the article on Isothiocyanates). Consequently, evidence for an inverse association between cruciferous vegetable intake and cancer risk provides relatively little information about the specific effects of indole-3-carbinol on cancer risk.

At present, the effects of I3C or DIM supplementation on cancer risk in humans are not known.

Disease Treatment

Human papilloma virus infection-related diseases

Cervical intraepithelial neoplasia

Infection with certain strains of human papilloma virus (HPV) is an important risk factor for cervical cancer (73). Transgenic mice that express cancer-promoting HPV genes develop cervical cancer with chronic 17β-estradiol administration. In this model, feeding I3C markedly reduced the number of mice that developed cervical cancer (74). A small placebo-controlled trial in women examined the effect of oral I3C supplementation on the progression of precancerous cervical lesions classified as cervical intraepithelial neoplasia (CIN) 2 or CIN 3 (75). After 12 weeks, four out of the eight women who took 200 mg/day had complete regression of CIN, and four out of the nine who took 400 mg/day had complete regression; none of the 10 women who took a placebo had complete regression. HPV was present in 7 out of the 10 women in the placebo group, seven out of eight women in the 200 mg I3C group, and eight out of nine women in the 400 mg I3C group (75). However compared to placebo, oral supplementation with DIM (2 mg/kg/day) for 12 weeks in 64 women with CIN 2 or CIN 3 lesions failed to improve clinical parameters during a one-year follow-up period (76). In another six-month randomized, double-blind controlled trial, DIM supplementation (150 mg/day) failed to promote HPV clearance and prevent CIN progression in 551 women with low-grade cell abnormalities in cervical smears (77).

Although oral supplementation of I3C or DIM appears relatively safe and well tolerated, results obtained with I3C are only preliminary, and interventions with DIM failed to show preventative or therapeutic efficacy in women with precancerous lesions of the cervix. The intravaginal administration of DIM in the form of suppositories may prove to be a more effective approach to reverse CIN in women (78).

Vulvar intraepithelial neoplasia

HPV infection has also been associated with vulvar intraepithelial neoplasia (VIN), a precancerous condition that may progress to vulval cancer (79). A small randomized trial in 12 women with VIN found that supplementation with 200 mg/day or 400 mg/day of I3C for six months improved overall symptoms, as well as lesion size and appearance (80). Additional trials are necessary to determine whether I3C might be an effective treatment for VIN.

Recurrent respiratory papillomatosis

Recurrent respiratory papillomatosis (RRP) is a rare disease of children and adults, characterized by generally benign growths (papillomas) in the respiratory tract, which are caused by HPV infection (81). These papillomas occur most commonly on or around the vocal cords in the larynx (voice box), but they may also affect the trachea, bronchi, and lungs. The most common treatment for RRP is surgical removal of the papillomas. Since papillomas often recur, adjunct treatments may be used to help prevent or reduce recurrences (82). In immune-compromised mice transplanted with HPV-infected laryngeal tissue, only 25% of the mice fed I3C developed laryngeal papillomas compared to 100% of the control mice (83). In a small observational study of RRP patients, increased ratios of urinary 2HE1:16HE1 resulting from increased cruciferous vegetable consumption were associated with less severe RRP (84). In an uncontrolled pilot study, the effect of daily I3C supplementation (400 mg/day for adults and 10 mg/kg daily for children) on papilloma recurrence has been examined in RRP patients (85). Over a five-year follow-up period, 11 of the original 49 patients experienced no recurrence, 10 experienced a reduction in the rate of recurrence, 12 experienced no improvement, and 12 were lost to follow-up (86). I3C given for 6 months to 3 years to five children with an aggressive form of the disease halted the growth of the papillomas in three children after two years of treatment (87). In some patients, I3C may be an effective adjunct treatment to reduce the growth or recurrence of respiratory papillomas.

Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by chronic inflammation that may result in damage to the joints, skin, kidneys, heart, lungs, blood vessels, or brain (88). Estrogen is thought to play a role in the pathology of SLE because the disorder is much more common in women than men, and its onset is most common during the reproductive years when endogenous estrogen levels are highest (89). The potential for I3C supplementation to shift endogenous estrogen metabolism toward the less estrogenic metabolite 2HE1, and away from the highly estrogenic metabolite 16HE1 (see Anti-estrogenic activities), led to interest in its use in SLE (35). In an animal model of SLE, I3C feeding decreased the severity of kidney disease and prolonged survival (90). A small uncontrolled trial of I3C supplementation (375 mg/day) in female SLE patients found that I3C supplementation increased urinary 2HE1:16HE1 ratios, but the trial found no significant change in SLE symptoms after three months (90). Controlled clinical trials are needed to determine whether I3C supplementation could have beneficial effects in SLE patients.


Food sources

Glucobrassicin, the glucosinolate precursor of I3C, is found in a number of cruciferous vegetables, including broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, kale, kohlrabi, mustard greens, radish, rutabaga, and turnip (91, 92). Although glucosinolates are present in relatively high concentrations in cruciferous vegetables, glucobrassicin makes up only about 8%-12% of the total glucosinolates (93). Total glucosinolate contents of selected cruciferous vegetables are presented in Table 1. However, the amount of total glucosinolates and the amount of indole-3-carbinol formed from glucobrassicin in food is variable and depends, in part, on the processing and preparation of foods (for more detailed information, see the article on Cruciferous Vegetables).

Table 1. Glucosinolate Content of Selected Cruciferous Vegetables (94)
Food (raw) Serving Total Glucosinolates (mg)
Brussels sprouts ½ cup
Garden cress ½ cup
Mustard greens ½ cup, chopped
Kale 1 cup, chopped
Turnip ½ cup, cubes
Cabbage, savoy ½ cup, chopped
Watercress 1 cup, chopped
Kohlrabi ½ cup, chopped
Cabbage, red ½ cup, chopped
Broccoli ½ cup, chopped
Horseradish 1 tablespoon (15 g)
Cauliflower ½ cup, chopped
Bok choi (pak choi) ½ cup, chopped


Indole-3-Carbinol (I3C)

I3C is available without a prescription as a dietary supplement, alone or in combination products. Dosage ranges between 200 mg/day and 800 mg/day (95). I3C supplementation increased urinary 2HE1 concentrations in adults at doses of 300 to 400 mg/day (39). I3C doses of 200 mg/day or 400 mg/day improved the regression of cervical intraepithelial neoplasia (CIN) in a preliminary clinical trial (75). I3C in doses up to 400 mg/day has been used to treat recurrent respiratory papillomatosis (see Disease Treatment) (85, 86).

3,3'-Diindolylmethane (DIM)

DIM is available without a prescription as a dietary supplement, alone or in combination products. In a small clinical trial, DIM supplementation at a dose of 108 mg/day for 30 days increased urinary 2HE1 excretion in postmenopausal women with a history of breast cancer (34).


Adverse effects

Slight increases in the serum concentrations of the liver enzyme, alanine aminotransferase (ALT) were observed in two women who took unspecified doses of I3C supplements for four weeks (39). One person reported a skin rash while taking 375 mg/day of I3C (35). High doses of I3C (800 mg/day) have been associated with symptoms of disequilibrium and tremor, which resolved when the dose was decreased (85). In a phase I study in women at high risk for breast cancer, 5 out of 20 participants had gastrointestinal symptoms with single doses ≥600 mg, although others had no adverse effects with single doses up to 1,200 mg (6). No adverse effects were reported with daily consumption of 400 mg of I3C for four weeks (6).

In some animal models, I3C supplementation was found to enhance carcinogen-induced cancer development when given chronically after the carcinogen (96-99). When administered before or at the same time as the carcinogen, oral I3C inhibited tumorigenesis in animal models of cancers of the mammary gland (100, 101), uterus (102), stomach (103), colon (104, 105), lung (106), and liver (107, 108). Although the long-term effects of I3C supplementation on cancer risk in humans are not known, the contradictory results of animal studies have led several experts to caution against the widespread use of I3C and DIM supplements in humans until their potential risks and benefits are better understood (99, 109, 110).

Pregnancy and lactation

The safety of I3C or DIM supplements during pregnancy or lactation has not been established (95).

Drug interactions

No drug interactions with I3C or DIM supplementation in humans have been reported. However, preliminary evidence that I3C and DIM can increase the activity of CYP1A2 (111, 112) suggests the potential for I3C or DIM supplementation to decrease serum concentrations of medications metabolized by CYP1A2 (113). Both I3C and DIM modestly increase the activity of CYP3A4 in rats when administered chronically (114). This observation raises the potential for adverse drug interactions in humans since CYP3A4 is involved in the metabolism of approximately 60% of therapeutic drugs.

The acidic environment of the stomach allows I3C molecules to condense and generate a number of biologically active I3C oligomers (Figure 2). Drugs that block the production of stomach acids, like antacids, Histamine2 (H2) receptor antagonists, and proton-pump inhibitors, would likely prevent the generation of DIM and ICZ. However, it is not known whether these drugs limit the biological activities attributed to I3C and its derivatives (95).

Authors and Reviewers

Originally written in 2005 by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in December 2008 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Updated in January 2017 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in July 2017 by:
David E. Williams, Ph.D.
Principal Investigator, and Helen P. Rumbel Professor for Cancer Prevention
Linus Pauling Institute
Professor, Department of Environmental and Molecular Toxicology
Oregon State University

Copyright 2005-2024  Linus Pauling Institute


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  • Isothiocyanates are derived from the hydrolysis of glucosinolates — sulfur-containing compounds found in cruciferous vegetables. (More information)
  • Each glucosinolate forms a different isothiocyanate when hydrolyzed. For example, broccoli is a good source of glucoraphanin, the glucosinolate precursor of sulforaphane, and sinigrin, the glucosinolate precursor of allyl isothiocyanate. (More information)
  • Absorbed isothiocyanates are rapidly conjugated to glutathione in the liver, and then sequentially metabolized in the mercapturic acid pathway, before being excreted in the urine. (More information)
  • Isothiocyanates may modulate the expression and activity of biotransformation enzymes that are involved in the metabolism and elimination of xenobiotics (e.g., carcinogens) from the body. In cultured cells and animal models, isothiocyanates also exhibited antioxidant and anti-inflammatory activities and interfered with numerous cancer-related targets and pathways. (More information)
  • Although high intakes of cruciferous vegetables have been associated with a lower risk for cancer, there is insufficient evidence that exposure to isothiocyanates through cruciferous vegetable consumption decreases cancer risk. (More information)
  • Glucosinolates are present in relatively high concentrations in cruciferous vegetables, but the amounts of isothiocyanates formed from glucosinolates in foods are variable and depend partly on food processing and preparation. (More information)


Cruciferous vegetables, such as broccoli, cabbage, and kale, are rich sources of sulfur-containing compounds called glucosinolates (see the article on Cruciferous Vegetables). Isothiocyanates are biologically active hydrolysis (breakdown) products of glucosinolates. Cruciferous vegetables contain a variety of glucosinolates, each of which forms a different isothiocyanate when hydrolyzed (Figure 1) (1). For example, broccoli is a good source of glucoraphanin, the glucosinolate precursor of sulforaphane, and sinigrin, the glucosinolate precursor of allyl isothiocyanate (AITC) (see Food sources) (2). Watercress is a rich source of gluconasturtiin, the precursor of phenethyl isothiocyanate (PEITC), while garden cress is rich in glucotropaeolin, the precursor of benzyl isothiocyanate (BITC) (see Food sources). At present, scientists are interested in the cancer-preventive activities of vegetables that are rich in glucosinolates (see the article on Cruciferous Vegetables), as well as individual isothiocyanates (3).

Metabolism and Bioavailability


The hydrolysis of glucosinolates, which is catalyzed by a class of enzymes called myrosinases (β-thioglucosidases), leads to the formation of breakdown compounds, such as thiocyanates, isothiocyanates, indoles, oxazolidine-2-thiones (e.g., goitrin), epithionitrile, and nitrile (see the article on Cruciferous Vegetables). In intact plant cells, myrosinase is physically separated from glucosinolates. Yet, when plant cells are damaged, myrosinase is released and comes in contact with glucosinolates, catalyzing their conversion into highly reactive metabolites that impart a pungent aroma and spicy (some say bitter) taste. Likewise, when raw cruciferous vegetables are chopped during the food preparation process, glucosinolates are rapidly hydrolyzed by myrosinase, generating metabolites that are then absorbed in the proximal intestine. In contrast, cooking cruciferous vegetables before consumption inactivates myrosinase, thus preventing the breakdown of glucosinolates. However, lightly cooking (i.e., light steam for <5 minutes) will preserve some of the myrosinase and allow for isothiocyanate conversion. A small fraction of intact glucosinolates may be absorbed in the small intestine, but a large proportion reaches the colon (4). In the colon, myrosinase produced by the microbiota can catalyze the generation of a wide range of metabolites from glucosinolates, depending on the pH and the presence of cofactors (4, 5).

The hydrolysis of glucosinolates at neutral pH results in the formation of unique isothiocyanates (Figure 1). For example, sinigrin, glucoraphanin, glucotropaeolin, and gluconasturtiin are the glucosinolate precursors of AITC, sulforaphane, BITC, and PEITC, respectively (Figure 1). Once absorbed, glucosinolate-derived isothiocyanates (like sulforaphane) are promptly conjugated to glutathione by a class of phase II detoxification enzymes known as glutathione S-transferases (GSTs) in the liver, and then sequentially metabolized in the mercapturic acid pathway (Figure 2). This mechanism is meant to increase the solubility of isothiocyanates, thereby promoting a rapid excretion in the urine. Using sulforaphane as the model isothiocyanate, it has indeed been established that its metabolites — sulforaphane-glutathione, sulforaphane-cysteine-glycine, sulforaphane-cysteine, and sulforaphane N-acetylcysteine — collectively known as dithiocarbamates (Figure 2), are ultimately excreted in the urine (4).

Figure 1. Chemical Structures of Some Glucosinolates and their Isothiocyanate Derivatives. Chemical structures of the alpiphatic glucosinolates (sinigrin and glucoraphanin) and the aromatic glucosinolates (glucotropaeolin and gluconasturtiin). These are hydrolyzed to various isothiocyanates: allyl isothiocyanate, sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate.

[Figure 1 - Click to Enlarge]

Figure 2. Metabolism of Glucoraphanin via the Mercapturic Acid Pathway. Glucoraphanin is converted to sulforaphane (via myrosinase),  converted to sulforaphane-gluathione conjugate (via glutathione S-transferase), metabolized to sulforaphane-cysteine-glycine via gamma-glutamyltranspeptidase, then converted to sulforaphane-cysteine (via cysteinyl-glycinase), and then sulforaphane N-aceylcysteine (via N-acetyltransferase).

[Figure 2 - Click to Enlarge]


The composition and content of glucosinolates in cruciferous vegetables are relatively stable but depend on the genus and species and can vary with plant growing and post-harvest storage conditions and culinary processing (6, 7). Since most cruciferous vegetables are cooked prior to eating, bacterial myrosinase in the gut, rather than plant myrosinase, is responsible for the initial step in glucosinolate degradation (Figure 2). In a feeding study involving 45 healthy subjects, the mean conversion rate of glucosinolates (of which 85% was glucoraphanin) to dithiocarbamates over a 24-hour period was estimated to be around 12% with wide variations among participants (range, 1.1 to 40.7%) (6). In contrast, 70%-75% of ingested isothiocyanates were found to be metabolized to dithiocarbamates. Therefore, following the ingestion of cooked cruciferous vegetables, the conversion of glucosinolates into isothiocyanates by gut bacteria appears to be a limiting step in the generation of dithiocarbamates (6). However, differences in individuals’ capacity to metabolize glucosinolates have not been linked to differences in gut microbiota composition (8).

Biological Activities

Antioxidant activity

Many isothiocyanates, particularly sulforaphane, have been shown to induce the expression of antioxidant enzymes via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway (9, 10). Briefly, Nrf2 is a transcription factor that is bound to the protein Kelch-like ECH-associated protein 1 (Keap1) in the cytosol (Figure 3). Keap1 responds to oxidative stress signals or chemical inducers by freeing Nrf2. Isothiocyanates can react with sulfhydryl residues of Keap1, causing the release of Nrf2. Nrf2 can then translocate to the nucleus and bind to the antioxidant response element (ARE) located in the promoters of genes coding for antioxidant/detoxifying enzymes and scavengers. Nrf2/ARE-dependent genes code for several mediators of the antioxidant response, including glutathione S-transferases (GSTs), thioredoxin, NAD(P)H quinone oxidoreductase 1 (NQO-1), and heme oxygenase 1 (HO-1) (11).

In numerous animal models, sulforaphane (often administered ip, iv, or sc, rather than po) was shown to exert protective effects on many tissues and organs by activating the Nrf2/ARE-dependent pathway (12). For example, sulforaphane reduced contrast agent-induced kidney damage in rats by increasing Nrf2 nuclear translocation and upregulating the expression of HO-1 and NQO-1 (13). Upregulation of the Nrf2 pathway by sulforaphane also attenuated oxidative damage-induced vascular endothelial cell injury in a mouse model of type 2 diabetes mellitus (14). In a rat model of hepatic ischemia reperfusion injury — whereby cellular damage is caused by the restoration of oxygen delivery to a hypoxic liver — pre-treatment with sulforaphane limited the reduction in glutathione (GSH) and the antioxidant enzymes, superoxide dismutase (SOD) and GSH peroxidase (GPx). Sulforaphane also upregulated the expression of Nrf2, NQO-1, and HO-1, and decreased ischemic death and apoptosis of liver cells (15).

Human studies are limited. In a placebo-controlled study, oral sulforaphane (in the form of broccoli sprout homogenate) increased the expression of NQO-1 and HO-1 in the upper airway within two hours of ingestion (16). Yet, in a recent trial in patients with chronic obstructive pulmonary disease (COPD), oral administration of sulforaphane for four weeks failed to induce the expression of Nrf2, NQO-1, and HO-1 in alveolar macrophages, bronchial epithelial cells, or peripheral blood mononuclear cells (17).

Figure 3. Isothiocyanates Target Nrf2 and NF-kappaB Pathways. Isothiocyanates inhibit NF-kappaB-mediated inflammation and increase the expression of phase II detoxifying/antioxidant enzymes via the Nrf2 signaling pathway. [A] Isothiocyanates induce the nuclear translocation of Nrf2 and increase the expression of Nrf2 target genes coding for phase II enzymes and antioxidant enzymes. [B] Isothiocyanates may prevent (1) the phosphorylation of NF-kappaB inhibitor, IkappaB; (2) th nuclear translocation of NF-kappaB; and (3) the transcriptional activity of NF-kappa B.

[Figure 3 - Click to Enlarge]

Anti-inflammatory activity

The therapeutic potential of sulforaphane has also been linked to its capacity to target pro-inflammatory pathways. Sulforaphane was found to attenuate pancreatic injury in a mouse model of acute pancreatitis by stimulating Nrf2-induced antioxidant enzymes (18). Concomitantly, sulforaphane significantly reduced the nuclear translocation of the pro-inflammatory transcription factor nuclear factor (NF)-κB in pancreatic acinar cells, downregulating the expression of NF-κB target genes that code for pro-inflammatory mediators, such as tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and IL-6 (Figure 3) (18). Through inhibiting the NF-κB pathway, sulforaphane also targets other mediators of the inflammatory response, including the enzymes cyclooxygenase-2 (COX-2), prostaglandin E (PGE) synthase, and inducible nitric oxide synthase (iNOS). Sulforaphane exhibited anti-inflammatory effects in the lungs of mice with lipopolysaccharide (LPS)-induced acute respiratory distress syndrome (ARDS) by downregulating the expression of NF-κB, IL-6, TNF-α and COX-2, as well as decreasing production of nitric oxide (NO) and PGE2 (19). Other isothiocyanates have been shown to prevent the degradation of the NF-κB inhibitor, IκB, the nuclear translocation of NF-κB, and/or the transcriptional activity of NF-κB in vitro or in cultured cells (Figure 3) (20), which all can lead to a decrease in inflammatory responses.

The modulation of Nrf2 and NF-κB signaling pathways by isothiocyanates is especially relevant to the prevention of cancer because both oxidative stress and inflammation are significant contributors in the development and progression of cancer.

Anticancer activity

Biotransformation enzymes play important roles in the metabolism and elimination of a variety of chemicals, including drugs, toxins, and carcinogens. In general, phase I metabolizing enzymes catalyze reactions that increase the reactivity of hydrophobic (fat-soluble) compounds, preparing them for reactions catalyzed by phase II biotransformation enzymes. Reactions catalyzed by phase II enzymes generally increase water solubility and promote the elimination of the compound from the body (21).

Inhibition of phase I biotransformation enzymes

Isothiocyanates have been found to modulate the activity of phase I biotransformation enzymes, especially those of the cytochrome P450 (CYP) family. Using a primary rat hepatocyte-based model, both aliphatic (e.g., sulforaphane, AITC) and aromatic (e.g., BITC, PEITC) isothiocyanates (at 20-40 μM) have been found to downregulate CYP3A2 mRNA expression, as well as the activity of benzyloxyquinoline debenzylase, a marker of CYP3As (22). Aromatic isothiocyanates were also able to upregulate CYP1A1 and CYP1A2 mRNA expression and the activity of ethoxyresorufin-O-deethylase (EROD), a marker of CYP1A1/2 activities (22). In this model, sulforaphane inhibited EROD activity, yet failed to affect CYP1A1/2 mRNA expression (22). Using human liver microsomes, it was also recently reported that sulforaphane metabolites (0-200 μM) had little-to-no effect on the activities of CYP1A2, CYP2B6, CYP2D6, and CYP3A4 (23). The ability of PEITC to alter the expression and activity of CYP enzymes has been generally associated with a protective effect against (pro)carcinogen-induced tumor development in animal experiments (reviewed in 24). Increasing the activity of biotransformation enzymes may be beneficial if the elimination of potential carcinogens or toxins is enhanced. Yet, some procarcinogens require phase I enzymes in order to become active carcinogens capable of binding DNA and forming cancer-causing DNA adducts. Inhibition of specific CYP enzymes involved in carcinogen activation has been found to prevent the development of cancer in animal models (3).

Induction of phase II detoxifying enzymes

Many isothiocyanates are potent inducers of phase II detoxifying enzymes, including GSTs, UDP-glucuronosyl transferases (UGTs), NQO1, and glutamate cysteine ligase (GCL), that protect cells from DNA damage by carcinogens and reactive oxygen species (ROS) (25). The genes for these and other phase II enzymes contain AREs and are therefore under the control of Nrf2 (see Antioxidant activity). Limited data from clinical trials suggest that glucosinolate-rich foods can increase phase II enzyme activity in humans. When smokers consumed 170 g/day (6 oz/day) of watercress, urinary excretion of glucuronidated nicotine metabolites increased significantly, suggesting UGT activity increased (26). Brussels sprouts are rich in a number of glucosinolates, including precursors of AITC and sulforaphane. Consumption of 300 g/day (11 oz/day) of Brussels sprouts for one week significantly increased plasma and intestinal GST concentrations in nonsmoking men (27, 28).

Induction of cell cycle arrest and apoptosis

After a cell divides, it passes through a sequence of stages — collectively known as the cell cycle — before dividing again. Following DNA damage, the cell cycle can be transiently arrested to allow for DNA repair or activation of pathways leading to programmed cell death (apoptosis) when the damage cannot be repaired (29). Defective cell cycle regulation and pro-survival mechanisms may result in the propagation of mutations that contribute to the development of cancer. Isothiocyanates have been found to modulate the expression of the cell cycle regulators, cyclins and cyclin-dependent kinases (CDK), as well as trigger apoptosis in a number of cancer cell lines (20). In a mouse model of colorectal cancer, oral administration of PEITC reduced both the number and size of polyps; these changes were associated with activation of the CDK inhibitor, p21, inhibition of various cyclins (A, D1, and E), and induction of apoptosis (30). In a transgenic prostate adenocarcinoma mouse model, BITC limited the progress of prostatic intraepithelial neoplasia (PIN) to a well-differentiated carcinoma (31). This was related to a decreased expression of Ki67 (a marker of cell proliferation) and a downregulation of cyclin A, cyclin D1, and CDK2, which regulate cell cycle progression (31).

Inhibition of cell migration and invasion

The epithelial-to-mesenchymal transition (EMT) describes a process of epithelial cell transformation whereby cells lose their polarity and adhesion properties while gaining migratory and invasive properties through the expression of mesenchymal genes. Inhibition of the EMT by sulforaphane in thyroid cancer cells has been associated with upregulation of an epithelial marker, E-cadherin, and downregulation of a transcription factor (SNAI2), a filament protein (vimentin), and various enzymes (matrix metalloprotein [MMP]-2 and MMP-9) known to contribute to EMT and promote migration (32). In a xenograft mouse model of breast cancer, BITC inhibited high fat diet-driven promotion of breast tumor growth, as well as lung and liver metastasis (33). This study suggested that BITC might prevent the infiltration of macrophages in the tumor environment (33). In another model of breast tumor metastasis, PEITC inhibited the migration of tumor cells to the brain after injection into the heart of mice, limiting the growth of metastatic brain tumors (34).

Inhibition of angiogenesis

To fuel their rapid growth, invasive tumors must also develop new capillaries from preexisting blood vessels by a process known as angiogenesis. Isothiocyanates have been shown to prevent the formation of capillary-like structures from human umbilical endothelial cells (reviewed in 35). Isothiocyanates likely inhibit the expression and function of hypoxia inducible factors (HIFs) that control angiogenesis, as reported in endothelial cells and malignant cell lines (35).

Epigenetic regulation of gene expression

In the nucleus of a cell, DNA is coiled around proteins called histones, thereby forming the chromatin. The N-terminal tails of histones are targets for multiple modifications, including phosphorylation, methylation, acetylation, ubiquitination, poly ADP ribosylation, and sumoylation. Histone modification patterns have differential effects on chromatin structure, and, in synergy with DNA methylation, are implicated in the regulating expression of the genome (36). Within gene regulatory regions, the acetylation of lysine residues of histone tails has been correlated with activation of transcription. Conversely, the deacetylation of histones by histone deacetylases (HDAC) restricts access of transcription factors to the DNA and suppresses transcription. Because abnormal epigenetic marks disrupt the expression of specific tumor suppressor genes in cancer cells, compounds that re-induce their transcription, like those inhibiting HDACs, can potentially promote differentiation and apoptosis in transformed (precancerous) cells (37).

Isothiocyanates have been found to inhibit HDAC expression and/or activity in cultured cancer cells (38-43). Moreover, in vivo evidence for HDAC inhibition by sulforaphane came from a mouse model using prostate cancer xenografts (44). In humans, HDAC activity was reduced in blood cells following ingestion of 68 g (one cup) of sulforaphane-rich broccoli sprouts (44). Isothiocyanates may also affect microRNA-mediated gene silencing. In bladder cancer cells, E-cadherin induction by sulforaphane was partly due to the upregulation of miR-200c expression resulting in the miR-200c-dependent suppression of ZEB-1, a transcriptional repressor of E-cadherin (45). PEITC inhibited androgen receptor (AR) transcriptional activity in prostate cancer cells by repressing miR-141 expression and miR-141-mediated downregulation of small heterodimer partner (shp), a repressor of AR (46).

Antibacterial activity

Bacterial infection with Helicobacter pylori is associated with a marked increase in the risk of peptic ulcer disease and gastric cancer (47). In the test tube and in tissue culture, purified sulforaphane inhibited the growth and killed multiple strains of H. pylori, including antibiotic resistant strains (48). In an animal model of H. pylori infection, sulforaphane administration for five days eradicated H. pylori from 8 out of 11 xenografts of human gastric tissue implanted in immune-compromised mice (49). In another H. pylori-infected mouse model, a functional Nrf2 pathway was found to be required for the reduction of gastric inflammation and infection in mice fed broccoli sprouts (50). In a small clinical trial, consumption of up to 56 g/day (2 oz/day) of glucoraphanin-rich broccoli sprouts for one week was associated with H. pylori eradication in only three out of nine gastritis patients (51). In another trial, daily consumption of 70 g/day (~2-3 servings/day) of glucoraphanin-rich broccoli sprouts for two months significantly reduced markers of inflammation and infection in H. pylori–infected volunteers compared to those who consumed alfalfa sprouts (50). However, the extent to which glucoraphanin was converted to sulforaphane in broccoli sprout-fed participants was not measured.

Disease Prevention


Isothiocyanates are thought to play a prominent role in the potential anticancer and cardiovascular benefits associated with cruciferous vegetable consumption (52, 53). Genetic variations in the sequence of genes coding for GSTs may affect the activity of GSTs. Such variations have been identified in humans. Specifically, null variants of the GSTM1 and GSTT1 alleles contain large deletions, and individuals who inherit two copies of the GSTM1-null or GSTT1-null alleles cannot produce the corresponding GST enzymes (54). It has been proposed that a reduced GST activity in these individuals would slow the rate of excretion of isothiocyanates, thereby increasing tissue exposure to isothiocyanates after cruciferous vegetable consumption (55). In addition, GSTs are involved in "detoxifying" potentially harmful substances like carcinogens, suggesting that individuals with reduced GST activity might also be more susceptible to cancer (56-58). Further, induction of the expression and activity of GSTs and other phase II detoxification/antioxidant enzymes by isothiocyanates is an important defense mechanism against oxidative stress and damage associated with the development of diseases like cancer and cardiovascular disease (11). The ability of glucoraphanin-derived sulforaphane to reduce oxidative stress in different settings is linked to activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway (see Biological Activities). Yet, whether potential protection conferred by isothiocyanates via the Nrf2-dependent pathway is diminished in individuals carrying GST null variants is currently unknown. Some, but not all, observational studies have suggested that GST genotypes could influence the associations between cruciferous vegetable consumption and risk of disease (59).

Naturally occurring isothiocyanates and their metabolites have been found to inhibit the development of chemically-induced cancers of the lung, liver, esophagus, stomach, small intestine, colon, and breast in a variety of animal models (20). Although observational studies provide some evidence that higher intakes of cruciferous vegetables are associated with decreased cancer risk in humans (59), it is difficult to determine whether such protective effects are related to isothiocyanates or other factors associated with cruciferous vegetable consumption (see the article on Cruciferous Vegetables). Clinical evidence of a protective effect of isothiocyanates in humans is scarce. For example, in a recent randomized, cross-over intervention, administration of PEITC (40 mg/day for five days) caused a modest, yet significant, 7.7% reduction in the metabolic activation of the tobacco-specific lung carcinogen, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, in cigarette smokers (60). Another randomized c