Food and Beverages

Plant-based foods, including fruit, vegetables, legumes, whole grains, and nuts, are prominent features of healthy dietary patterns. In addition to providing energy and essential micronutrients, plant-based foods contribute thousands of biologically active phytochemicals (plant chemicals that may affect health) to the human diet. 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. Although scientists are very interested in the potential for specific phytochemicals to prevent or treat disease, current scientific evidence suggests that plant-based foods are the healthiest phytochemical delivery system.

 

 

Fruit and Vegetables

Summary

  • Dietary patterns characterized by high intakes of fruit and vegetables are consistently associated with significant reductions in cardiovascular disease risk. (More information)
  • Although prospective cohort studies provide weak support for an association between total fruit and vegetable consumption and cancer risk, they provide some evidence that high intakes of certain classes of fruit or vegetables are associated with reduced risk of individual cancers. (More information)
  • The results of epidemiological and controlled clinical trials suggest that diets rich in fruit and vegetables can help prevent bone loss. (More information)
  • The results of prospective cohort studies suggest that high intakes of vitamin C and carotenoid-rich fruit and vegetables may be associated with decreased risk of age-related eye diseases, such as macular degeneration or cataracts. (More information)
  • Many organizations, including the Centers for Disease Control and Prevention, recommend eating a variety of fruit and vegetables daily; the recommended serving number depends on total caloric intake, which is governed by age, gender, body composition, and physical activity level. (More information)

Introduction

Despite all of the controversy surrounding the optimal components of a healthy diet, there is little disagreement among scientists regarding the importance of fruit and vegetables. The results of numerous epidemiological studies and recent clinical trials provide consistent evidence that diets rich in fruit and vegetables can reduce the risk of chronic disease (1). On the other hand, evidence that very high doses of individual micronutrients or phytochemicals found in fruit and vegetables can do the same is inconsistent and relatively weak. Fruit and vegetables contain thousands of biologically active phytochemicals that are likely to interact in a number of ways to prevent disease and promote health (2). Fruit and vegetables are rich in antioxidants, which help protect the body from oxidative damage induced by pro-oxidants. The best way to take advantage of these complex interactions is to eat a variety of fruit and vegetables.

Disease Prevention

Cardiovascular disease

Dietary patterns characterized by relatively high intakes of fruit and vegetables are consistently associated with significant reductions in the risk of coronary heart disease (CHD) and stroke. A meta-analysis that combined the results of 11 prospective cohort studies found that people in the 90th percentile of fruit and vegetable intake (about 5 servings/day or more; for information about serving size, please see Examples of one serving of fruit or vegetables below) had a risk of myocardial infarction (MI) that was approximately 15% lower than those in the 10th percentile of intake (3). Among more than 126,000 men and women participating in the Health Professionals' Follow-up Study and the Nurses’ Health Study, those who consumed eight or more servings of fruit and vegetables daily had a risk of developing CHD over the next 8-14 years that was 20% lower than those who consumed less than three servings daily (4). In the same cohort, the risk of ischemic stroke (stroke caused by a reduction in blood flow to part of the brain) was 30% lower in those who consumed at least five servings of fruit and vegetables daily than in those who consumed less than three servings daily (5). Based on the results of Health Professionals' Follow-up Study and the Nurses’ Health Study, eating one extra serving of fruit or vegetables daily would decrease one’s risk of CHD by about 4% and decrease risk of ischemic stroke by 6%. In a meta-analysis designed to estimate the global burden of disease attributable to low fruit and vegetable consumption, epidemiologists concluded that increasing individual fruit and vegetable consumption (excluding potatoes) up to 600 g/day (about 7 servings/day) could decrease the risk of CHD by 31% and the risk of ischemic stroke by 19% (1). Three recent meta-analyses have examined fruit and vegetable consumption and risk of CHD or stroke. In a meta-analysis that included nine cohort studies, an additional daily serving of fruit and vegetables was associated with a 4% decreased risk for CHD (6). Another meta-analysis, which examined 12 separate studies, found that individuals who consumed more than five daily servings of fruit and vegetables experienced a 17% reduction in risk of CHD compared to those who consumed less than three servings daily (7). In a meta-analysis of eight studies examining fruit and vegetable intake, individuals who consumed three to five daily servings or more than five daily servings had an 11% or 26% reduction in risk of stroke, respectively, when compared to those who consumed less than three servings daily (8).

High blood pressure (hypertension) increases the risk of heart disease and stroke (9). Adding more fruit and vegetables to a sensible diet is one potential way to lower blood pressure. In the Dietary Approaches to Stop Hypertension (DASH) study, 459 people with and without high blood pressure were randomly assigned to one of three diets: (1) a typical American diet that provided about 3 servings/day of fruit and vegetables and 1 serving/day of a low-fat dairy product, (2) a fruit and vegetable diet that provided 8 servings/day of fruit and vegetables and 1 serving/day of a low-fat dairy product, or (3) a combination diet (now called the DASH diet) that provided 9 servings/day of fruit and vegetables and 3 servings/day of low-fat dairy products (10). After eight weeks, the blood pressures of those on the fruit and vegetable diet (8 servings/day) were significantly lower than those on the typical American diet, while blood pressures of those on the combination (DASH) diet (9 servings/day of fruit and vegetables) were lower still. For more information on the DASH eating plan, go to the National Heart, Lung, and Blood Institute website.

A number of compounds may contribute to the cardioprotective effects of fruit and vegetables, including vitamin C, folate, potassium, fiber, and various phytochemicals (11). However, supplementation of individual micronutrients or phytochemicals has not generally resulted in significantly decreased incidence of cardiovascular events in randomized controlled trials. Thus, in the case of fruit and vegetables, the benefit of the whole may be greater than the sum of its parts.

Type 2 diabetes mellitus

In addition to other complications, type 2 diabetes mellitus (DM) is associated with increased risk of cardiovascular disease—the leading cause of death in type 2 diabetics (12). Although the evidence for a beneficial effect of a diet rich in fruit and vegetables on diabetes is not as consistent as it is for heart disease, the results of a small number of studies suggest that higher intakes of fruit and vegetables are associated with improved blood glucose control and lower risk of developing type 2 DM. In a cohort of almost 10,000 adults in the United States, the risk of developing type 2 DM over the next 20 years was approximately 20% lower in those who reported consuming at least five daily servings of fruit and vegetables compared to those who reported consuming none (13). In another prospective cohort study that followed more than 40,000 US women for an average of nine years, fruit and vegetable intake was not associated with the risk of developing type 2 DM in the entire cohort, but higher intakes of green leafy and yellow vegetables were associated with significant reductions in the risk of type 2 DM in overweight women (14). Higher fruit and vegetable intakes were weakly associated with a reduced risk of diabetes in a cohort of more than 20,000 individuals followed for 12 years (15). In a cohort of 71,346 women participating in the Nurses' Health Study, total fruit and vegetable intake was not associated with risk for diabetes, although further analysis revealed that intake of fruit or green leafy vegetables was individually associated with a modest reduction in risk of diabetes (16). A systematic review and meta-analysis of five cohort studies found that fruit and vegetable intake was not associated with type 2 diabetes (17). However, in a cross-sectional study of more than 6,000 nondiabetic adults in the UK, those with higher fruit and vegetable intakes had significantly lower levels of glycated hemoglobin (HbA1c), a measure of long-term blood glucose control (18). Possible compounds in fruit and vegetables that may enhance glucose control include fiber and magnesium.

Cancer

The results of numerous case-control studies indicate that eating a diet rich in fruit and vegetables decreases the risk of developing a number of different types of cancer, particularly cancers of the digestive tract (oropharynx, esophagus, stomach, colon, and rectum) and lung (19-21). The results of some of these studies were the foundation for the National Cancer Institute’s “5 a Day” program, which was aimed at increasing the fruit and vegetable consumption of the American public to a minimum of five servings daily. The current US government campaign, Fruit & Veggies-More Matters™, has replaced the "5 a Day" program. In contrast to the results of case-control studies, many recent prospective cohort studies have found little or no association between total fruit and vegetable intake and the risk of various cancers (22-44). There are several possible explanations for this discrepancy. Case-control studies, in which the past diets of people diagnosed with a particular type of cancer are compared to the diets of people without cancer, are more susceptible to bias in the selection of participants and dietary recall than prospective cohort studies, which collect information on the diets of large cohorts of healthy people and follow the development of disease in the cohort over time (45). Although prospective cohort studies provide weak support for an association between total fruit and vegetable consumption and cancer risk, they provide some evidence that high intakes of certain classes of fruit or vegetables are associated with reduced risk of individual cancers. Higher intakes of fruit have been associated with modest but significant reductions in lung cancer risk in a pooled analysis of eight prospective cohort studies (28) and with reductions in risk of bladder cancer in some studies (46). In men, higher intakes of cruciferous vegetables have been associated with significant reductions in the risk of bladder cancer (47) as well as prostate cancer (48), and higher intakes of tomato products have been linked with significant reductions in risk of prostate cancer (49).

Osteoporosis

Several cross-sectional studies have reported that higher intakes of fruit and vegetables are associated with significantly higher bone mineral density (BMD) and lower levels of bone resorption (loss) in men and women (50-53). In a study that followed BMD over four years, higher fruit and vegetable intakes were associated with significantly less decline in BMD at the hip in elderly men but not elderly women (50). Fruit and vegetables are rich in precursors to bicarbonate ions, which serve to buffer acids in the body. When the quantity of bicarbonate ions is insufficient to maintain normal pH, the body is capable of mobilizing alkaline calcium salts from bone in order to neutralize acids consumed in the diet and generated by metabolism (54). Increased consumption of fruit and vegetables reduces the net acid content of the diet and may preserve calcium in bones, which might otherwise be mobilized to maintain normal pH. However, the results of a recent placebo-controlled trial in 276 postmenopausal women suggest that supplementing the diet with alkali, either through supplemental potassium citrate or an additional 300 g/day of fruit and vegetables, did not increase BMD or blunt the age-associated bone loss over a two-year period (55). Results from the DASH study support a beneficial link between fruit and vegetable intake and bone health. In addition to decreasing blood pressure, increasing fruit and vegetable intakes from about 3 to 9 servings daily decreased urinary calcium loss by almost 50 mg/day (10) and lowered biochemical markers of bone turnover, particularly bone resorption, including serum levels of C-terminal telopeptide of type 1 collagen (56). Taken together, the results of epidemiological studies and controlled clinical trials suggest that a diet rich in fruit and vegetables can help prevent bone loss, although the specific mechanisms are not known with certainty.

Age-related eye diseases

Cataracts

Cataracts are thought to be caused by oxidative damage of proteins in the eye’s lens induced by long-term exposure to UV light. The resulting cloudiness and discoloration of the lens leads to vision loss that becomes more severe with age. The results of several large prospective cohort studies suggest that diets rich in fruit and vegetables, especially carotenoid and vitamin C-rich fruit and vegetables, are associated with decreased incidence and severity of cataracts (57-60). In a study of male US health professionals, high intakes of both broccoli and spinach were associated with fewer cataract extractions (57).

Macular degeneration

Degeneration of the macula, the center of the retina, is the leading cause of blindness in people over the age of 65 in the United States (61). Lutein and zeaxanthin are carotenoids that are found in relatively high concentrations in the retina; these carotenoids may play a role in preventing damage to the retina caused by light or oxidants (62). In two case-control studies, high intakes of carotenoid-rich vegetables, especially those rich in lutein and zeaxanthin, such as dark green, leafy vegetables, were associated with a significantly lower risk of developing age-related macular degeneration (AMD) (63, 64). In a prospective cohort study of more than 118,000 men and women, those who consumed three or more servings of fruit daily had a risk of developing age-related macular degeneration over the next 12-18 years that was 36% lower than those who consumed less than 1.5 servings (65). Interestingly, vegetable intake was not associated with the risk of macular degeneration in this cohort. In a more recent study, combined lutein and zeaxanthin intake was not associated with prevalence of intermediate AMD in a cohort of women aged 50-79 years (66). However, further analysis of the data revealed that women younger than 75 years with stable intakes of lutein and zeaxanthin had a 43% lower risk of developing intermediate AMD (66).

Chronic Obstructive Pulmonary Disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a term that includes emphysema and chronic bronchitis, two chronic lung diseases that are characterized by airway obstruction. Although smoking is by far the most important risk factor for COPD, the results of several epidemiological studies suggest beneficial associations between vegetable and, more strongly, with fruit intakes and COPD risk (67). The results of several epidemiological studies in Europe indicate that higher fruit intakes, especially apple intakes, are associated with higher forced expiratory volume (FEV1) values, indicative of better lung function (68-70). In a study of 2,500 middle-aged Welsh men, those who ate at least five apples weekly had significantly slower declines in lung function than those who did not eat apples over a five-year period (69). In a study of 2,917 European men followed over 20 years, each 100 g (3.5 oz) increase in daily fruit consumption was associated with a 24% decrease in the risk of death from COPD (71). The reasons for the beneficial association between fruit intake and lung health are not yet known. Because oxidative stress is thought to play a role in the etiology of chronic obstructive lung disease, scientists are currently investigating the possibility that antioxidants found in fruit, such as vitamin C or flavonoids, could play a protective role. Higher fruit and vegetable intake was inversely associated with risk of COPD in a small case-control study of male cigarette smokers (72), providing support for the antioxidant hypothesis. Interestingly, when compared to a Western dietary pattern (refined grains, cured and red meats, French fries, and desserts), a prudent dietary pattern that emphasized fruit, vegetables, fish, and whole grains was associated with a 25%-50% reduction in COPD risk in large cohorts of men (73) and women (74).

Neurodegenerative diseases

Although it is not yet clear whether a diet rich in fruit and vegetables will decrease the risk of neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease in humans, recent studies in animal models of these diseases suggest that diets rich in fruit like blueberries (75) or tomatoes may be protective (76). Interestingly, a prospective study that followed 1,836 older Japanese Americans for an average of 6.3 years found that regular consumption of fruit and vegetable juices was associated with a decreased risk of developing Alzheimer's disease (77). More studies are needed to determine whether fruit and vegetable consumption is protective against neurodegenerative diseases.

Intake Recommendations

Many agencies within the US government, including the Centers for Disease Control and Prevention, recommend eating a variety of fruit and vegetables daily; the recommended serving number depends on age, sex, and activity level (78). Table 1 provides some examples of a single serving of fruit or vegetables. The 2005 Dietary Guidelines for Americans are similar with respect to fruit and vegetable intake recommendations, but they are tied to caloric intake and not to age or gender (79). Daily consumption of 2 cups (4 servings) of fruit and 2½ cups (5 servings) of vegetables are recommended for people who consume 2,000 kcal/d, while 1.5 cups of fruit and (3 servings) and 2 cups (4 servings) of vegetables are recommended for people who consume 1,600 kcal/d. In both cases, consumption of a variety of different fruit and vegetables is recommended, including dark green, red, orange, yellow, blue, and purple fruit and vegetables, as well as legumes (peas and beans), onions, and garlic. The Linus Pauling Institute's Rx for Health states that potatoes should not be included in the daily tally of fruit and vegetable intake. Moreover, certain groups of fruit and vegetables, such as cruciferous vegetables, may provide specific health benefits (see the article on Cruciferous Vegetables). Additionally, fiber-rich, whole fruit are recommended over high-sugar fruit juices.

Examples of one serving of fruit or vegetables

  • 6 fluid ounces of fruit or vegetable juice (¾ of a cup)
  • 1 medium sized apple or orange
  • 1 small banana
  • 1 cup of raw salad greens
  • ½ cup of cooked vegetables (about the size of a baseball)
  • ½ cup of chopped fruit or vegetables
  • ½ cup of cooked peas or beans
  • ¼ cup of dried fruit (about the size of a golf ball)

 

Table 1. Some Potentially Beneficial Compounds in Fruit and Vegetables
Vitamins Minerals Phytochemicals
Folate Magnesium Carotenoids
Vitamin A Potassium Chlorophylls
Vitamin C Selenium Fiber
Vitamin E   Flavonoids
Vitamin K   Indole-3-Carbinol
    Isoflavones
    Isothiocyanates
    Lignans
    Phytosterols

Authors and Reviewers

Originally written in 2003 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 May 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in May 2009 by:
Kaumudi Joshipura, Sc.D.
Professor of Epidemiology
Harvard School of Public Health
Associate Professor
Harvard School of Dental Medicine

Copyright 2003-2017  Linus Pauling Institute


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Cruciferous Vegetables

Summary

Introduction

Cruciferous or Brassica vegetables are so named because they come from plants in the family known to botanists and biologists as Cruciferae or alternately, Brassicaceae. The Brassicaceae family, which includes the model plant Arabidopsis thaliana, comprises approximately 375 genera and over 3,000 species (1). Many commonly consumed cruciferous vegetables come from the Brassica genus, including broccoli, Brussels sprouts, cabbage, cauliflower, collard greens, kale, kohlrabi, mustard, rutabaga, turnips, bok choy, and Chinese cabbage (2). Examples of edible crucifers from other genera within the Brassicaceae family include radish (Raphanus sativus), horseradish (Armoracia rusticana), watercress (Nasturtium officinale), wasabi (Wasabia japonica), and Swiss chard (Beta vulgaris flavescens) (2).

 

Cruciferous vegetables are unique in that they are a rich source of sulfur-containing compounds called glucosinolates (β-thioglucoside N-hydroxysulfates) that impart a pungent aroma and spicy (some say bitter) taste (Figure 1). Glucosinolates can be classified into three categories based on the chemical structure of their amino acid precursors: aliphatic glucosinolates (e.g., glucoraphanin), indole glucosinolates (e.g., glucobrassicin), and aromatic glucosinolates (e.g., gluconasturtiin) (Figure 1) (1). Around 130 glucosinolate structures have been described to date (3), but only a subset can be found in the human diet. In a cohort of 2,121 German participants in the European Prospective Investigation into Cancer and Nutrition (EPIC study), glucobrassicin, sinigrin, glucoraphasatin (dehydroerucin), glucoraphanin, and glucoiberin were found to contribute most to total glucosinolate intake (4).

Glucosinolates and their breakdown derivatives (metabolites), especially isothiocyanates and indole-3-carbinol, exert a variety of biological activities that may be relevant to health promotion and disease prevention in humans (see the MIC articles on Indole-3-Carbinol and Isothiocyanates).

Figure 1. Chemical Structures of Some Glucosinolates. Chemical structures of aliphatic glucosinolates, including sinigrin, glucoiberin, glucoraphasatin, glucoraphanin, and progoitrin. Chemical structures of two aromatic glucosinolates, glucotropaeolin and gluconasturtiin. Chemical structure of the indole glucosinolate, glucobrassicin. Plants synthesize glucosinolates from amino acids. Glucosinolates can be classified based on their amino acid precursors. Aliphatic glucosinolates are derived from alanine, leucine, isoleucine, valine, and methione. Aromatic glucosinolates are derived from phenylalanine or tyrosine, and tryptophan is the precursor of indole glucosinolates (ishida, 2014).

[Figure 1 - Click to Enlarge]

Metabolism and Bioavailability of Glucosinolates

Metabolism

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 (Figure 2). 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. In plants, thiocyanates, isothiocyanates, epithionitrile, and nitrile are defensive compounds against pathogens, insects, and herbivores (1). When raw cruciferous vegetables are chopped during the cooking process, glucosinolates are rapidly hydrolyzed by myrosinase, generating metabolites that are then absorbed in the proximal intestine. In contrast, boiling cruciferous vegetables before consumption inactivates myrosinase, thus preventing the breakdown of glucosinolates. A small fraction of intact glucosinolates may be absorbed in the small intestine, but a large proportion reaches the colon (5). Of note, boiling cruciferous vegetables has also been found to reduce their glucosinolate content to a much greater extent than steam cooking, microwaving, and stir-frying do (5). Nonetheless, when cruciferous vegetables are cooked, bacterial myrosinase-like activity in the colon is mainly responsible for glucosinolate degradation, generating a wide range of metabolites (5, 6).

A neutral pH may favor the formation of isothiocyanates from glucosinolates (Figure 2). Once absorbed, isothiocyanates, such as glucoraphanin-derived sulforaphane, are conjugated to glutathione in the liver, and then sequentially metabolized in the mercapturic acid pathway (Figure 3). Sulforaphane metabolites — sulforaphane-glutathione, sulforaphane-cysteine-glycine, sulforaphane-cysteine, and sulforaphane N-acetylcysteine (Figure 3) — collectively known as dithiocarbamates, are ultimately excreted in the urine (5).

Bioavailability

The composition and content of glucosinolates in cruciferous vegetables are relatively stable, yet depend on the genus and species and can vary with plant growing and post-harvest storage conditions and culinary processing (7, 8). Since most cruciferous vegetables are cooked prior to eating, bacterial myrosinase-like activity 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%) (7). 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 (7). However, differences in individuals’ capacity to metabolize glucosinolates have not been linked to differences in gut microbiota composition (9).

Figure 2. Breakdown of Glucosinolates. Glucosinolate is metabolized to glucosinolatethiohydroximate-O-sulfonate via myrosinase. In neutral pH, isothiocyanate can be formed, or oxazolidine-2-thione (via the unstable intermediate beta-OH-isothiocyanate), or indole-3-carbinol (via the unstable intermediate, indol-3-ylmethyl-isothiocyanate). In acidic pH, the compounds epithionitrile or nitrile can be formed. Figure adapted from Holst et al. (2004).

[Figure 2 - Click to Enlarge]

Figure 3. Metabolism of Glucoraphanin via the Mercapturic Acid Pathway. Glucoraphanin is metabolized by myrosinase to sulforaphane; sulforaphane is converted to sulforaphane-gluathione conjugate, then to sulforaphane-cysteine-glcine, then to sulforaphane-cysteine, then to sulforaphane N-acetylcysteine

[Figure 3 - Click to Enlarge]

Disease Prevention

Like most other vegetables, cruciferous vegetables are good sources of a variety of nutrients and phytochemicals that synergistically contribute to health promotion (see Bioactive compounds in cruciferous vegetables) (10). One challenge in studying the relationships between cruciferous vegetable intake and disease risk in humans is dissociating the benefits of whole diets that are generally rich in vegetables from those that are specifically rich in cruciferous vegetables (11). One characteristic that sets cruciferous vegetables apart from other vegetables is their high glucosinolate content (see Introduction). Glucosinolate hydrolysis products may play important roles in disease prevention by triggering antioxidant and anti-inflammatory response and contributing to the maintenance of cell homeostasis (see the MIC articles on Isothiocyanates and Indole-3-Carbinol).

Genetic influences

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) (Figure 3). This mechanism is meant to increase the solubility of isothiocyanates, thereby promoting a rapid excretion in the urine. Isothiocyanates are thought to play a prominent role in the potential anticancer and cardiovascular benefits associated with cruciferous vegetable consumption (12, 13). Genetic variations in the sequence of genes coding for GSTs may affect the activity of these enzymes. 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 (14). 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 (15). However, human interventional studies with watercress report there is no difference in the isothiocyanate excretion rate between positive (+/+) and null (-/-) genotypes (16). Similar studies with broccoli have shown that GSTM1-/- individuals excreted a greater proportion of ingested sulforaphane via mercapturic acid metabolism than GSTM1+/+ individuals (17, 18). 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 (19-21). Finally, 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 (22). The ability of sulforaphane (glucoraphanin-derived isothiocyanate) to reduce oxidative stress in different settings is linked to activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway. Yet, whether potential protection conferred by isothiocyanates via the Nrf2-dependent pathway is diminished in individuals carrying GST-/- variants is currently unknown.

Some, but not all, observational studies have found that GST genotypes could influence the associations between isothiocyanate intake from cruciferous vegetables and risk of disease (23).

Cardiovascular disease

High intakes of fruit and vegetables have been consistently associated with a reduced risk of cardiovascular disease (CVD) (24, 25). Yet, few observational studies have specifically examined the potential benefits of cruciferous vegetable consumption. In the Shanghai Women’s Health Study (mean follow-up, 10.2 years) and the Shanghai Men’s Health Study (mean follow-up, 4.6 years), which included a total of 134,796 Chinese adults, participants in the highest versus lowest quintile of cruciferous vegetable intakes had a 22% reduced risk of all cause-mortality and a 31% reduced risk of CVD-related mortality (26). In contrast, a pooled analysis of two large US prospective cohort studies, the Nurses’ Health Study (70,870 women) and the Health Professionals’ Follow-Up Study (38,918 men), found no significant association between cruciferous vegetable intake and combined risk of myocardial infarction (MI) and ischemic stroke (27). A case-control study conducted in 2,042 subjects (ages, <75 years) who survived a first acute myocardial infarction (MI), and matched healthy controls with no CVD history found that the individuals in the highest versus lowest tertile of cruciferous vegetable intakes (6 times/week versus <1 time/week) had 27% lower odds of MI (28). However, further analyses showed that the association between cruciferous vegetable intake and MI events was significant in individuals with two functional GSTT1 alleles but not in carriers of two alleles of the GSTT1 null variant (-/-) (28).

Analysis of data from two 12-week randomized controlled trials in 130 participants with mild or moderate CVD risk found that the consumption of 400 g/week of high-glucosinolate broccoli (containing 3 to 6 times more glucoraphanin and glucoiberin than standard broccoli) resulted in a significant reduction in low-density lipoprotein (LDL)-cholesterol concentration in plasma compared with standard broccoli (29). Whether the effect of glucosinolates on cholesterol metabolism might be beneficial in the prevention of CVD needs further investigation.

Cancer

A recent intervention study demonstrated that cruciferous vegetables could increase the detoxification of carcinogens and other xenobiotics in humans. In this 12-week randomized controlled trial in 391 healthy Chinese adults exposed to high levels of air pollution, daily consumption of a broccoli sprout-rich beverage (providing 600 µmol/day of glucoraphanin and 40 µmol/day of sulforaphane) significantly increased the urinary excretion of a known carcinogen, benzene, and a toxicant, acrolein, compared to placebo (20). The biological activities of glucosinolate derivatives, isothiocyanates and indole-3-carbinol, which include modulation of xenobiotic metabolism, but also antioxidant and anti-inflammatory properties, induction of cell cycle arrest and apoptosis, and inhibition of angiogenesis, likely contribute to the potential benefits of cruciferous vegetables in the prevention of cancer (see the MIC articles on Isothiocyanates and Indole-3-Carbinol) (23).

Evidence from observational studies

Numerous observational studies have examined the relationship between cruciferous vegetable intake and cancer risk. Results from recent published meta-analyses of observational studies are reported in Table 1 (adapted from 23). 

Table 1. Cruciferous Vegetables and Cancer Risk: Meta-analyses of Observational Studies
Type of Cancer Type of Observational Studies Relative Risk [RR] or Odds Ratio [OR] (95% Confidence Interval) Relative Risk [RR] in Subgroup Analyses (e.g., by food group or study type) References
Bladder cancer 5 prospective cohort and 5 case-control studies  RR: 0.80 (0.69-0.92) RR: 0.78 (0.67-0.89) with case-control studies only
RR: 0.86 (0.61-1.11) with cohort studies only 
Liu et al. (2013) (30)
12 prospective cohort and case-control studies RR: 0.84 (0.77-0.91)   Yao et al. (2014) (31)
7 prospective cohort and case-control studies RR: 0.85 (0.69-1.06)   Vieira et al. (2015) (32) 
8 prospective cohort studies RR: 0.97 (0.93-1.01)   Xu et al. (2015) (33)
Breast cancer 11 case-control studies RR: 0.85 (0.77-0.94)   Liu et al. (2013) (34)
Colorectal cancer 24 case-control and 11 prospective cohort studies RR: 0.82 (0.75-0.90) RR: 0.76 (0.60-0.97) for studies reporting on cabbage intake
RR: 0.82 (0.65-1.02) for studies reporting on broccoli intake
Wu et al. (2013) (35)
11 prospective cohort and 18 case-control studies OR: 0.92 (0.83-1.01) OR: 0.84 (0.72-0.98) for colon cancer
OR: 0.99 (0.67-1.46) for rectal cancer
OR: 1.09 (0.90-1.33) for colonic adenoma
OR: 0.80 (0.65-0.99) for studies reporting on broccoli intake
OR: 0.95 (0.80-1.14) for studies reporting on cabbage intake
OR: 1.0 (0.75-1.34) for studies reporting on Brussels sprouts
Tse et al. (2014) (36)
Endometrial cancer 1 prospective cohort study and 16 case-control studies OR: 0.79 (0.69-0.90) per 100 g/day   Bandera et al. (2007) (37)
Gastric cancer 6 prospective cohort and 16 case-control studies RR: 0.81 (0.75-0.88) RR: 0.78 (0.71-0.86) for case-control studies
RR: 0.89 (0.77-1.02) for cohort studies
RR: 0.68 (0.58-0.80) for studies reporting on cabbage intake
Wu et al. (2013) (38)
Lung cancer 6 prospective cohort and 13 case-control studies   RR: 0.77 (0.68-0.88) for case-control studies
RR: 0.83 (0.62-1.08) for cohort studies
Lam et al. (2009) (39)
5 prospective cohort and 6 case-control studies RR: 0.75 (0.63-0.89)   Wu et al. (2013) (40)
Ovarian cancer 5 prospective cohort and 6 case-control studies RR: 0.90 (0.82-0.98) RR: 0.84 (0.75-0.94) for case-control studies
RR: 1.0 (0.85-1.11) for cohort studies
Han et al. (2014) (41)
4 prospective cohort and 4 case-control studies RR: 0.89 (0.81-0.99)   Hu et al. (2015) (42)
Pancreatic cancer 4 prospective cohort and 5 case-control studies  OR: 0.79 (0.64-0.91)  OR: 0.72 (0.55-0.89) for case-control studies
OR: 0.87 (0.67-1.06) for cohort studies
OR: 0.78 (0.55-1.01) for high-quality studies
OR: 0.80 (0.66-0.94) for low-quality studies 
Li et al. (2015) (43)
Prostate cancer 7 prospective cohort and 6 case-control studies  RR: 0.90 (0.85-0.96) RR: 0.79 (0.69-0.89) for case-control studies
RR: 0.95 (0.89-1.02) for cohort studies 
Liu et al. (2012) (44)
Renal cell carcinoma 6 prospective cohort and 6 case-control studies  RR: 0.81 (0.72-0.91)  RR: 0.89 (0.82-0.98) for high-quality studies
RR: 0.72 (0.64-0.81) for case-control studies
RR: 0.92 (0.84-1.00) for cohort studies 
Zhao et al. (2013) (45)
3 prospective cohort and 7 case-control studies  RR: 0.73 (0.63-0.83) RR: 0.69 (0.60-0.78) for case-control studies
RR: 0.96 (0.71-1.21) for cohort studies 
Liu et al. (2013) (46)

Most meta-analyses found inverse associations between cruciferous vegetable intake and risk of bladder, breast, colorectal, endometrial, gastric, lung, ovarian, pancreatic, prostate, and renal cancer. Subgroup analyses showed that inverse associations remained significant in pooled analyses of case-control studies but not in pooled analyses of prospective cohort studies (see Table 1). Retrospective case-control studies are susceptible to bias in the selection of participants (cases and controls) and prone to dietary recall bias compared to prospective cohort studies, which collect dietary information from participants before they are diagnosed with cancer (47). The method of cooking cruciferous vegetables, which strongly affects the bioavailability and potential anticancer benefits of isothiocyanates (see Metabolism and Bioavailability of Glucosinolates) may be a source of bias and explain variation in the results of the studies (heterogeneity among studies). The lack of information regarding cooking methods prevented data adjustment to reduce bias.

In the past decades, some observational studies have examined the effect of individuals’ genetic variations on the relationship between cruciferous vegetable intake and the risk of different cancer types. For example, a pooled analysis of two prospective cohort studies and six case-control studies found an inverse association between cruciferous vegetable consumption and risk of colorectal neoplasm in carriers of the GSTT1 null variant but not in individuals with the GSTM1 null variant or those with both the GSTT1and GSTM1 null variants (-/-) (36). The results of a pooled analysis of five case-control studies also suggested a stronger association between cruciferous vegetable intake and lung cancer in carriers of both the GSTT1-/- and GSTM1-/- variants compared to carriers of wild-type alleles (+/+); however, it was not reported whether results from these two groups of individuals were significantly different (39). There is also a significant body of evidence suggesting that GSTM1+/+ individuals gain greater cancer protection from consumption total cruciferous vegetables or broccoli compared to GSTM1-/- variant carriers (25, 48, 49). Current evidence is scarce, and adequately powered, well-designed studies are required to assess and explain potential interactions between cruciferous vegetable intake and GST genotypes.

A few observational studies have looked at whether cruciferous vegetable intake could be associated with reduced risks of disease progression and mortality. The highest versus lowest intake of cruciferous vegetables (assessed before diagnosis) was associated with a better survival rate over 72 months after diagnosis in 547 women with lung cancer (50). A prospective study in 29,361 men who underwent a prostate-specific antigen (PSA) test found that intake of cruciferous vegetables was inversely associated with risk of metastatic prostate cancer — cancer that has spread beyond the prostate (i.e., late-stage prostate cancer) — during a mean follow-up of 4.2 years (51). Another prospective study in 1,560 men diagnosed with non-metastatic prostate cancer reported that higher post-diagnosis intake of cruciferous vegetables was associated with a 59% lower risk of prostate cancer progression during a two-year period after completion of the dietary assessment (52). In contrast, cruciferous vegetable consumption in a cohort of 11,390 women with stage I-III invasive breast cancer (from four US and Chinese prospective studies), assessed about two years after diagnosis, was not found to be associated with risk of cancer recurrence or total mortality (53)

Nutrient Interactions

Iodine and thyroid function

Very high intakes of cruciferous vegetables, such as cabbage and turnips, have been found to cause hypothyroidism (insufficient production of thyroid hormones) in animals (54). Two mechanisms can potentially explain this effect. The hydrolysis of progoitrin, found in cruciferous vegetables (see Figure 1), may yield a compound known as goitrin, which may interfere with thyroid hormone synthesis. The hydrolysis of another class of glucosinolates, known as indole glucosinolates, results in the release of thiocyanate ions (see Figure 2) that can compete with iodine for uptake by the thyroid gland (55). However, increased exposure to thiocyanate ions from cruciferous vegetable consumption or, more commonly, from cigarette smoking, does not appear to increase the risk of hypothyroidism unless accompanied by iodine deficiency. One study in humans found that the consumption of 150 g/day (5 oz/day) of cooked Brussels sprouts for four weeks had no adverse effects on thyroid function (56). Similarly, consumption of high amounts of cruciferous vegetables has been associated with increased thyroid cancer risk only in iodine-deficient areas (57).

Intake Recommendations

The 2015-2020 Dietary Guidelines for Americans recommend eating a variety of vegetables daily (2½ cup-equivalents/day for a 2,000 calorie diet) from all of the five vegetable subgroups (dark green, red and orange, legumes, starchy, and other; see 58). No separate recommendations have been established for cruciferous vegetables, yet the 2015-2020 Dietary Guidelines for Americans recommend that adults consume 1½-2½ cup-equivalents of dark-green vegetables (which include cruciferous vegetables) per week (58).

Bioactive compounds in cruciferous vegetables

Cruciferous vegetables are important sources of some vitamins and minerals, fiber, and various phytochemicals other than glucosinolates (Table 2). Many of these compounds likely contribute to the potential health-promoting benefits of cruciferous vegetables.

Table 2. Some Potentially Beneficial Compounds in Cruciferous (Brassica) Vegetables
Vitamins Minerals Phytochemicals
Folate Potassium Carotenoids
Vitamin C Selenium Chlorophyll
Vitamin K Calcium Fiber
    Flavonoids
    Indole-3-Carbinol
    Isothiocyanates
    Lignans
    Phytosterols
    Sulfur bioactives (other than glucosinolates) (59)

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 December 2016 by:
Barbara Delage, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in April 2017 by:
Maria Traka, Ph.D.
Senior Research Scientist
Chair of the Athena SWAN SAT
Food and Health Programme
Institute of Food Research
Norwich, United Kingdom

Copyright 2005-2017  Linus Pauling Institute


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17.  Gasper AV, Al-Janobi A, Smith JA, et al. Glutathione S-transferase M1 polymorphism and metabolism of sulforaphane from standard and high-glucosinolate broccoli. Am J Clin Nutr. 2005;82(6):1283-1291.  (PubMed)

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26.  Zhang X, Shu XO, Xiang YB, et al. Cruciferous vegetable consumption is associated with a reduced risk of total and cardiovascular disease mortality. Am J Clin Nutr. 2011;94(1):240-246.  (PubMed)

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29.  Armah CN, Derdemezis C, Traka MH, et al. Diet rich in high glucoraphanin broccoli reduces plasma LDL cholesterol: Evidence from randomised controlled trials. Mol Nutr Food Res. 2015;59(5):918-926.  (PubMed)

30.  Liu B, Mao Q, Lin Y, Zhou F, Xie L. The association of cruciferous vegetables intake and risk of bladder cancer: a meta-analysis. World J Urol. 2013;31(1):127-133.  (PubMed)

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Garlic

 

Garlic and Organosulfur Compounds

Summary

  • Garlic (Allium sativum L.) is a particularly rich source of organosulfur compounds, which are currently under investigation for their potential to prevent and treat disease. (More information)
  • The two main classes of organosulfur compounds found in whole garlic cloves are L-cysteine sulfoxides and γ-glutamyl-L-cysteine peptides. (More information)
  • Crushing or chopping garlic releases an enzyme called alliinase that catalyzes the formation of allicin from S-allyl-L-cysteine sulfoxide (Allin). Allicin rapidly breaks down to form a variety of organosulfur compounds. (More information)
  • In vivo studies indicate that allicin-derived organosulfur compounds may be poorly bioavailable, whereas water-soluble derivatives of γ-glutamyl-L-cysteine peptides have been detected in plasma, liver, and kidney following oral consumption. (More information)
  • Several different types of garlic supplements are available commercially, and each type provides a different profile of organosulfur compounds depending on how it was processed. (More information)
  • Numerous preclinical studies reported that organosulfur compounds from garlic could exert antioxidant, anti-inflammatory, antimicrobial, anticancer, and cardioprotective activities in various experimental settings. (More information)
  • The results of randomized controlled trials suggested that garlic supplementation modestly improves serum lipid profiles in individuals with elevated serum cholesterol and reduces blood pressure in hypertensive subjects, at least in the short term. It is not known whether garlic supplementation can help prevent cardiovascular disease(More information)
  • Current evidence from observational studies does not support an association between high intakes of garlic and prevention of cancer, including gastric and colorectal cancer. It is not known whether garlic-derived organosulfur compounds may be effective in preventing or treating human cancers. (More information)

Introduction

Garlic (Allium sativum L.) has been used for culinary and medicinal purposes in many cultures for centuries (1). Garlic is a particularly rich source of organosulfur compounds, which are thought to be responsible for its flavor and aroma, as well as its potential health benefits (2). Consumer interest in the health benefits of garlic is strong enough to place it among the best-selling herbal supplements in the United States (3). Scientists are interested in the potential for organosulfur compounds derived from garlic to prevent and treat chronic diseases, such as cancer and cardiovascular disease (4).

Organosulfur compounds from garlic

Two classes of organosulfur compounds are found in whole garlic cloves: L-cysteine sulfoxides and γ-glutamyl-L-cysteine peptides.

L-Cysteine sulfoxides

S-allyl-L-cysteine sulfoxide (alliin) accounts for approximately 80% of cysteine sulfoxides in garlic (Figure 1) (5). When raw garlic cloves are crushed, chopped, or chewed, an enzyme known as alliinase is released. Alliinase catalyzes the formation of sulfenic acids from L-cysteine sulfoxides (Figure 2). Sulfenic acids spontaneously react with each other to form unstable compounds called thiosulfinates. In the case of alliin, the resulting sulfenic acids react with each other to form a thiosulfinate known as allicin (half-life in crushed garlic at 23°C is 2.5 days). The formation of thiosulfinates is very rapid and has been found to be complete within 10 to 60 seconds of crushing garlic. Allicin breaks down in vitro to form a variety of fat-soluble organosulfur compounds (Figure 2), including diallyl trisulfide (DATS), diallyl disulfide (DADS), and diallyl sulfide (DAS), or in the presence of oil or organic solvents, ajoene and vinyldithiins (6). In vivo, allicin can react with glutathione and L-cysteine to produce S-allylmercaptoglutathione (SAMG) and S-allylmercaptocysteine (SAMC), respectively (Figure 2) (4).

γ-Glutamyl-L-cysteine peptides                                

Crushing garlic does not change its γ-glutamyl-L-cysteine peptide content. γ-Glutamyl-L-cysteine peptides include an array of water-soluble dipeptides, including γ-glutamyl-S-allyl-L-cysteine, γ-glutamylmethylcysteine, and γ-glutamylpropylcysteine (see Figure 1). Water-soluble organosulfur compounds, such as S-allylcysteine and SAMC (Figure 3), are formed from γ-glutamyl-S-allyl-L-cysteine during long-term incubation of crushed garlic in aqueous solutions, as in the manufacture of aged garlic extracts (see Sources). 

Non-sulfur garlic phytochemicals

Although little is known about their bioavailability and biological activities, non-sulfur garlic phytochemicals, including flavonoids, steroid saponins, organoselenium compounds, and allixin, likely work in synergy with organosulfur compounds (6).

Figure 1. Major Novolatile Sulfur-containing Compounds in Intact Garlic

[Figure 1 - Click to Enlarge]

 

Figure 2. Organosulfur Derivatives of Alliin in teh Process of Garlic Product Preparation

[Figure 2 - Click to Enlarge]

 

 Figure 3. Major Water-soluble Derivatives of gamma-Glutamyl-L-cysteine Peptides

[Figure 3 - Click to Enlarge]

Metabolism and Bioavailability

S-Allyl-L-cysteine sulfoxide (Alliin)

In studies conducted in rodents, orally administrated alliin was found to be absorbed intact and to reach plasma and liver without being converted to allicin. There are no thiosulfinates (like allicin) in intact garlic cloves, and none can be generated in the stomach because alliinase would be irreversibly inhibited under acidic conditions (6).

Allicin and derivatives

The absorption and metabolism of allicin and allicin-derived compounds (see Figure 2) are only partially understood (7). In humans, no allicin has been detected in the serum or urine up to 24 hours after the ingestion of 25 g of raw garlic containing a significant amount of allicin (8). Before ingestion in garlic preparations and after ingestion in the stomach, allicin likely breaks down to release a number of volatile compounds, including DAS and DADS. These organosulfur compounds are metabolized to allyl mercaptan, allyl methyl sulfide, and allyl methyl disulfide, which have been detected in human breath after garlic consumption (9-11). Although a number of biological activities have been attributed to various allicin-derived compounds, it is not yet clear which of these compounds or metabolites actually reaches target tissues (5). Allyl methyl sulfide — but not allyl mercaptan — has been detected in the urine within four hours of garlic ingestion, suggesting that this compound is absorbed into the circulation and rapidly excreted (11). Other allicin-derived compounds, including diallyl sulfides, ajoenes, and vinyldithiins, have not been detected in human blood, urine, or stool, even after the consumption of up to 25 g of fresh garlic or 60 mg of pure allicin (5). These findings suggest that, if they are absorbed, allicin and allicin-derived compounds are rapidly metabolized.

γ-Glutamyl-S-allyl-L-cysteine and derivatives

γ-Glutamyl-S-allyl-L-cysteine is thought to be absorbed intact and hydrolyzed to S-allyl-L-cysteine (SAC) and trans-S-1-propenyl-L-cysteine (see Figure 3), since metabolites of these compounds have been measured in human urine after garlic consumption (12, 13). The consumption of aged garlic extract, a commercial garlic preparation that contains SAC, has been found to increase plasma SAC concentrations in humans (14-16). SAC has been detected in plasma, liver, and kidney of SAC-fed animals (17). Water-soluble organosulfur compounds like SAC and its metabolite, N-acetyl-S-allyl-L-cysteine, may be used as reliable markers of compliance in clinical trials involving garlic intake (6, 18).

Biological Activities

Antioxidant activity

Glutathione

Low cellular concentrations of glutathione, a major intracellular antioxidant, and/or overproduction of reactive oxygen species (ROS) can lead to oxidative stress-induced damage to biological macromolecules and contribute to the development and progression of pathological conditions. In endothelial cells (that line the inner wall of blood vessels), garlic-derived allicin lowered ROS production and increased the concentration of glutathione (19). Oral administration of allicin to mice lowered ROS production and prevented ROS-induced cardiac hypertrophy by inhibiting pro-inflammatory pathways like mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/glycogen synthase kinase 3β (GSK3β) signaling pathways (20). It is thought that, upon crossing cell membranes, allicin interacts with glutathione and forms SAMG (see Figure 2), which could prolong the antioxidant activity of allicin (19).

Nrf2-dependent antioxidant pathway

Allicin was also found to upregulate the expression of glutamate-cysteine ligase (GCL), the rate-limiting enzyme in glutathione synthesis, and other Phase II detoxifying/antioxidant enzymes, likely via the activation of the nuclear factor E2-related factor 2 (Nrf2)-dependent pathway (19). 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) (21). Like allicin, oil-soluble organosulfides, DADS and DATS (see Figure 2), have been shown to stimulate Nrf2-dependent antioxidant pathway (4). For example, antioxidant and cytoprotective effects of DADS against acute ethanol-induced liver damage in mice were associated with the ability to trigger Nrf2-dependent HO-1 activation (22). DATS protected cardiac cells in vitro and in experimental diabetic rats from high glucose-induced oxidative stress and apoptosis by inducing PI3K/Akt-dependent Nrf2 antioxidant signaling (23).

Aged garlic extract have also been shown to increase expression of antioxidant enzymes via the Nrf2/ARE pathway (24). SAC, a major organosulfur compound in aged garlic extract, prevented renal damage caused by ROS in cisplatin-treated rats, by limiting cisplatin-induced reduction of glutathione level, Nrf2 expression, and activity of several antioxidant enzymes (catalase, glutathione reductase, glutathione peroxidase) (25). SAC also protected neurons from oxidative damage and apoptosis in wild-type mice but not in mice without a functional Nrf2 signaling pathway (26).

Nitric oxide (NO) signaling cascade

The generation of nitric oxide (NO) catalyzed by endothelial nitric oxide synthase (eNOS) plays a critical role in protecting the vascular endothelium from oxidative and inflammatory insults (27). ROS-induced NO inactivation can impair vascular endothelial function, contributing to various pathologies like atherosclerosis, hypertension, cardiovascular disease, and central nervous system disorders (27, 28). Interestingly, ingestion of 2 g of fresh garlic was found to increase NO plasma concentrations within two to four hours in healthy volunteers (29). DADS and DATS protected eNOS activity and NO bioavailability in cultured endothelial cells challenged with oxidized low-density lipoprotein (LDL) (30). In a model of traumatic brain injury in rats, allicin attenuated brain edema, neurological deficits, and apoptotic neuronal death, and exhibited antioxidant and anti-inflammatory effects, partly by increasing Akt-mediated eNOS activation (31). Aged garlic extract and SAC were also found to stimulate NO production in different experimental settings (32). In a model of erectile dysfunction in diabetic rats, SAC restored electrically-induced penile erection by stimulating eNOS activity and inhibiting the expression of NADPH oxidase (Nox) responsible for ROS overproduction (33).

Anti-inflammatory activity

Garlic-derived organosulfur compounds have been found to inhibit mediators of the inflammatory response, including cytokines, chemokines, adhesion molecules, and enzymes like cyclooxygenase (COX), lipoxygenase (LOX), and inducible nitric oxide synthase (iNOS) (34-36). 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, as well as genes involved in cell proliferation, adhesion, survival, and differentiation. The anti-inflammatory effects of organosulfur compounds result from their ability to counteract the activation of pro-inflammatory pathways — like NF-κB-, MAPK-, and PI3K/Akt-dependent signaling pathways — by pro-inflammatory stimuli (4). DATS inhibited bacterial lipopolysaccharide (LPS)-induced macrophage activation by limiting LPS binding to toll-like receptor 4 (TLR4) and blocking the upregulation of TLR4 and TLR4-associated molecule MyoD88 expression (37). DATS also inhibited LPS-induced NF-κB-dependent expression of COX-2, iNOS, tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) (37). In a mouse model of inflammation, the decrease of LPS-induced paw edema by DATS was associated with reduced serum concentrations of the pro-inflammatory cytokines, TNF-α, IL-6, and monocyte chemotactic protein-1 (MCP-1) (36).

Protection of the cardiovascular system

Inhibition of cholesterol synthesis

Garlic and garlic-derived organosulfur compounds have been found to decrease the synthesis of cholesterol by hepatocytes (38). Several garlic-derived organosulfur compounds, including S-allylcysteine and ajoene, have been found to inhibit 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA reductase), a critical enzyme in the cholesterol biosynthesis pathway (39, 40). Garlic-derived compounds may also inhibit other enzymes in this pathway, including sterol 4α-methyl oxidase (41).

Inhibition of platelet aggregation

An increase in the ability of platelets to aggregate has been linked to the narrowing of blood vessels and the occurrence of acute thrombotic events. A variety of garlic-derived organosulfur compounds have been found to inhibit platelet aggregation in the test tube (42-44). Aged garlic extract was found to inhibit chemically stimulated platelet aggregation by downregulating the fibrinogen binding activity of glycoprotein IIb/IIIa fibrinogen receptor found on platelets (45, 46) and/or by preventing intraplatelet calcium mobilization (42).

Inhibition of vascular smooth muscle cell (VSMC) proliferation

The proliferation and migration of normally quiescent VSMCs are central features of vascular diseases, including atherosclerosis and coronary restenosis (when treated arteries become blocked again) (47). Although the significance of these findings for human cardiovascular disease is not yet clear, limited cell culture research suggested that organosulfur compounds from garlic could inhibit the proliferation and migration of VSMCs (39, 48, 49).

Inhibition of vascular cell adhesion molecules

An elevation of oxidized low-density lipoprotein (LDL) concentration in plasma has been involved in the pathogenesis of atherosclerosis. Oxidized LDL may stimulate the recruitment of inflammatory white blood cells from the blood to the arterial wall by inducing the expression of vascular cell adhesion molecules. DADS and DATS inhibited the expression of adhesion molecules, E-selectin and vascular cell adhesion molecule-1 (VCAM-1), on endothelial cell surface by reversing oxidized LDL-induced inhibition of PI3K/Akt and cAMP responsive element binding protein (CREB) signaling pathways (50).

Hydrogen sulfide-mediated vasodilatory activity

The preservation of normal arterial function plays an important role in cardiovascular disease prevention. Hydrogen sulfide (H2S), a gaseous signaling molecule produced by some cells within the body, acts as a vasodilator (relaxes blood vessels) and thus may have cardioprotective properties (51, 52). H2S production may be involved in vascular smooth muscle cell relaxation through regulating the opening/closing of potassium channels and/or enhancing NO-dependent signaling pathway (reviewed in 53). A study found that garlic-derived compounds are converted to hydrogen sulfide by red blood cells in vitro (54). However, human consumption of a high dose of raw garlic does not increase breath hydrogen sulfide levels, suggesting that significant metabolism of garlic compounds to hydrogen sulfide does not occur in vivo (11).

Note that the potential benefits of garlic consumption/supplementation on cardiovascular health may also be attributed to antioxidant and anti-inflammatory activities described above.

Anticancer activity

Effects on carcinogen metabolism

Inhibition of metabolic activation of carcinogens: Some chemical carcinogens do not become active carcinogens until they have been metabolized by Phase I biotransformation enzymes, such as those belonging to the cytochrome P450 (CYP) family. Inhibition of specific CYP enzymes involved in carcinogen activation inhibits the development of cancer in some animal models (55). In particular, DAS and its metabolites have been found to inhibit CYP2E1 activity in vitro (56, 57) and when administered orally at high doses to animals (58, 59). Oral administration of garlic oil and DAS to humans has also resulted in evidence of decreased CYP2E1 activity (60-62).

Induction of Phase II detoxifying enzymes: Reactions catalyzed by phase II detoxifying enzymes generally promote the elimination of drugs, toxins, and carcinogens from the body. Consequently, increasing the activity of phase II enzymes, such as glutathione S-transferases (GSTs) and NQO-1, may help prevent cancer by enhancing the elimination of potential carcinogens (see the Nrf2-dependent antioxidant pathway) (63). In animal studies, oral administration of garlic preparations and organosulfur compounds was found to increase the expression and activity of phase II enzymes in a variety of tissues (64-66). For example, DADS protected rodent liver against carbon tetrachloride (CCl4; an environmental pollutant)-induced lipid peroxidation and cell necrosis by blocking CYP2E1-mediated CCL4 metabolic activation and by upregulating Nrf2 downstream genes for NQO-1, HO-1, GCL, GST, and superoxide dismutase (SOD1) (67, 68).

Induction of cell cycle arrest

In normal cells, the cell cycle is tightly regulated to ensure faithful DNA replication and chromosomal segregation prior to cell division. When defects occur during DNA replication or chromosomal segregation and in case of DNA damage, the cell cycle can be transiently arrested at check points to allow for repair. Apoptosis is triggered when repair fails. Defective check points and evasion of apoptosis allow the unregulated division of cancer cells (69). Organosulfur compounds, including allicin, DAS, DADS, DATS, ajoene, and SAMC, have been found to induce cell cycle arrest when added to cancer cells in cell culture experiments (reviewed in 4, 70). DATS reduced the incidence of poorly differentiated prostate tumors and limited the number of metastatic lesions in the lungs of mice genetically modified to develop prostate adenocarcinomas (71). DATS was shown to inhibit cancer cell proliferation, as well as neuroendocrine differentiation — a hallmark of prostate cancer malignancy — but had no effect on apoptosis and markers of invasion (71). In a rat model of chemically induced colon cancer, inhibition of cell proliferation by aged garlic extract was associated with a reduction in the incidence of precancerous lesions and dysplastic adenomas, but not of adenocarcinomas (72).

Induction of apoptosis

Apoptosis is a physiological process of programmed death of cells that are genetically damaged or no longer necessary. Precancerous and cancerous cells are resistant to signals that induce apoptosis (73). Garlic-derived organosulfur compounds, including allicin, ajoene, DAS, DADS, DATS, and SAMC, have been found to induce apoptosis when added to various cancer cell lines grown in culture (reviewed in 4, 70). Oral administration of aqueous garlic extract and S-allylcysteine has been reported to enhance apoptosis in an animal model of oral cancer (74, 75). Garlic oil reduced the incidence of N-nitrosodiethylamine-induced liver nodules by preventing oxidative damage to lipids and DNA and by promoting apoptosis (76). Garlic oil upregulated the activity of various antioxidant enzymes and expression of pro-apoptotic effectors like Bax and Caspase-3 and downregulated the expression of the anti-apoptotic genes β-arrestin-2, Bcl-2, and Bcl-X (76).

Inhibition of angiogenesis

To fuel their rapid growth, invasive tumors must develop new blood vessels by a process known as angiogenesis. Anti-angiogenic properties of several organosulfur compounds, including alliin, DATS, and ajoene, have been observed in in vitro or ex vivo experiments (70). In human breast cancer cells, DADS inhibited TNF-α-induced release of MCP-1, a chemokine that promotes tissue remodeling, angiogenesis, and metastasis (77). Aged garlic extract was also found to suppress in vitro angiogenesis by inhibiting endothelial cell proliferation, loss of adhesion, motility, and tube formation (78).

Antimicrobial activity

Garlic extracts have been found to have antibacterial and antifungal properties (79, 80). Thiosulfinates, particularly allicin, are thought to play an important role in the antimicrobial activity of garlic (80-82). Allicin-derived compounds, including DATS and ajoene, also have some antimicrobial activity in vitro (5). To date, randomized controlled trials using oral garlic preparations have not provided strong evidence for such activity in humans (83-85). A small randomized controlled trial found that application of 1% ajoene cream to the skin twice daily was as effective in treating tinea pedis (fungal skin infection known as athlete’s foot) as 1% terbinafine (Lamisil) cream (86). In another preliminary randomized controlled trial, circulating immune innate cells (γδT-lymphocytes and natural killer (NK) cells), isolated from healthy adults supplemented with aged garlic extract, proliferated better in ex vivo culture than those from volunteers who consumed a placebo, suggesting a greater pathogen-fighting ability. The number of self-reported illnesses was similar between groups after 90 days of aged garlic extract or placebo supplementation, but aged garlic extract significantly reduced the severity of self-reported cold or flu symptoms (87).

Disease Prevention

Cardiovascular disease

Interest in garlic and its potential to prevent cardiovascular disease began with observations that people living near the Mediterranean basin had lower mortality from cardiovascular disease (88). Garlic is a common ingredient in Mediterranean cuisine, but a number of characteristics of the "Mediterranean diet" have been proposed to explain its cardioprotective effects (89). Although few observational studies have examined associations between garlic consumption and cardiovascular disease risk, numerous intervention trials have explored the effects of garlic supplementation on cardiovascular disease risk factors.

Platelet aggregation

Platelet aggregation is one of the first steps in the formation of blood clots that can occlude coronary or cerebral arteries, leading to myocardial infarction or ischemic stroke, respectively. Evidence that garlic inhibits platelet aggregation is based mainly on in vitro experiments and a small number of ex vivo assays. Of 10 randomized controlled trials that tested the antithrombotic effect of garlic preparation, four reported a modest but significant decrease in ex vivo platelet aggregation with garlic supplementation compared to placebo (reviewed in 90). Because garlic oil extract in particular may have antithrombotic activity, a small randomized controlled trial in 12 healthy adults was conducted to test the acute effect of one large dose of garlic oil (extracted from 9.9 g of fresh garlic) on ex vivo platelet aggregation (91). The garlic oil extract had a mild effect on adrenaline-induced platelet aggregation (12% reduction) but had no effect on adenosine diphosphate (ADP)- or collagen-induced aggregation measured four hours post-consumption. Another study in 14 healthy volunteers showed that aged garlic extract dose-dependently inhibited ADP-stimulated platelet aggregation by downregulating the fibrinogen binding activity of glycoprotein IIb/IIIa fibrinogen receptor found on platelets (46).

Serum lipid profiles

A recent systematic review of randomized controlled trials examining the effect of supplementation with various garlic preparations on serum lipid profiles in individuals with elevated and normal serum cholesterol levels reported mixed results (92). The most recent and comprehensive meta-analysis compared the results from 39 randomized controlled trials published between 1955 and 2011 that tested the effect of garlic preparations on serum lipid concentrations (93). These 39 trials studied 2,298 adult participants (mean age, 49.5 years), administered garlic-only preparations, used a true placebo, and lasted for at least two weeks. The majority of included trials recruited subjects with elevated total cholesterol at baseline (>200 mg/dL [>5.2 mmol/L], 29 trials) and lasted more than eight weeks (30 trials). The authors found that garlic preparations significantly lowered total cholesterol and low-density lipoprotein (LDL)-cholesterol compared to placebo. High-density lipoprotein (HDL)-cholesterol concentrations were mildly increased and triglyceride concentrations were not affected by garlic supplementation. All administered garlic preparations (garlic powder, aged garlic extract, garlic oil, and fresh garlic) were well tolerated and associated with only minor side effects (garlic odor and mild gastrointestinal discomfort) (93).

Although garlic supplementation for a minimum of two months may lower total- and LDL-cholesterol concentrations in individuals with elevated total cholesterol, the benefits may not last beyond the short term (90, 92). Whether garlic possesses long-lasting lipid-lowering effects remain questionable and future investigations may focus on ways to maximize potential benefits of garlic preparations on serum lipids. 

Atherosclerosis

Very few studies have attempted to assess the effect of garlic supplementation on the progression of atherosclerosis in humans. One early study in Germany used ultrasound imaging to assess the effect of 900 mg/day of dehydrated garlic on the progression of atherosclerotic plaque in the carotid and femoral arteries (94). After four years, the increase in plaque volume was significantly greater in women taking the placebo (+53.1%) than in women taking the garlic supplement (-4.6%), while no significant difference in plaque volume was found between garlic (+1.1%) and placebo (+5.5%) in men (94, 95). In a smaller pilot study, investigators measured coronary artery calcium using electron-beam computed tomography to assess the effect of supplementation with aged garlic extract on the progression of atherosclerosis in 19 adults already taking HMG-CoA reductase inhibitors (lipid-lowering drugs also known as statins) (18). After one year, increases in coronary artery calcium score were significantly lower in those taking aged garlic extract than in those taking a placebo. Nevertheless, although coronary calcium scores may have a predictive value regarding future cardiac events in asymptomatic subjects, it may not be a reliable marker of plaque burden in symptomatic patients (96, 97). In a recent double-blind, controlled study, the extent of coronary atherosclerosis was assessed with cardiac computed tomography angiography in 72 individuals (55 at study completion) at high risk of coronary heart disease randomized to receive either 2,400 mg of aged garlic extract or placebo for 52 weeks (98). The result suggested a significant decrease in the extent of coronary plaques with low-attenuation area (a type of vulnerable plaques prone to rupture) (99, 100) with aged garlic extract compared to placebo, but no differences in total plaque volume and proportions of non-calcified plaques and dense calcium were found between treatment and placebo groups (98).

Hypertension

Most systematic reviews and/or meta-analyses of randomized controlled trials to date have provided mixed results regarding the potential blood pressure-lowering effect of garlic, possibly because most of these trials enrolled both normotensive and hypertensive subjects (90, 101-105).

A systematic review and meta-analysis by Xiong et al. (106) included seven randomized, placebo-controlled trials that exclusively enrolled individuals with high blood pressure, i.e., with systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg. Five out of seven trials identified in this systematic review reported statistically significant reductions in SBP and DBP with several garlic preparations (dried garlic homogenate, garlic powder, and aged garlic extract) (106). Another recent meta-analysis included nine randomized controlled trials in 482 hypertensive individuals who were given garlic powder (six studies), garlic homogenate (one study), aged garlic extract (two studies), or placebo for 8 to 26 weeks (107). Garlic preparations were found to significantly reduce SBP by a mean of 9.1 mm Hg and DBP by a mean of 3.8 mm Hg compared to placebo. The most recent meta-analysis found that garlic preparations reduced SBP by a mean 8.7 mm Hg (10 trials, 440 subjects) and DBP by 6.1 mm Hg (8 trials, 257 subjects) (102). Such reductions in blood pressure seem comparable to those reported with currently used classes of blood pressure-lowering medications (average reduction, -9.1 mm Hg for SBP and -5.5 mm Hg for DBP) (108). The effect of blood pressure reduction from such medications at standard dose has been estimated to lower the risk of coronary heart disease events by about one-quarter and the risk of stroke by about one-third (108). Nonetheless, evidence showing that garlic supplements may reduce the risk of cardiovascular morbidity and mortality is still lacking (109).

In a recent 12-week, randomized, placebo-controlled trial in untreated hypertensive subjects, daily intake of aged garlic extract (1.2 g of which contained 1.2 mg of S-allyl-L-cysteine [SAC]) was shown to significantly lower SBP by 11 mm Hg and DBP by 6 mm Hg on average in 50%-60% of participants, but reductions in blood pressure were not reported in 40%-50% of participants compared to placebo (110). Whether interindividual differences in nutritional status and genetic polymorphisms can explain differences in blood pressure response to garlic treatment need to be explored in future studies (53, 110).

Overall, short-term garlic supplementation appears to effectively reduce blood pressure with minimal side effects in hypertensive patients.

Summary

The results of randomized controlled trials have suggested that garlic supplementation modestly improves serum lipid profiles in individuals with elevated serum cholesterol and reduces blood pressure in hypertensive subjects. It is not yet clear whether garlic supplementation can reduce atherosclerosis or prevent cardiovascular events, such as myocardial infarction or stroke.

Cancer

Gastric cancer

A recent meta-analysis of 17 studies (mostly case-control studies) reported an inverse association between high versus low garlic consumption and the risk of gastric cancer (111). Nevertheless, this conclusion is hindered by a number of limitations, especially related to the retrospective design of most studies included in the analysis, as well as great variations in the amount and duration of garlic intakes. In a 2009 review of the literature, Kim et al. (112) identified 20 human studies that examined garlic intake in relation to gastric cancer risk: three intervention studies, one case-cohort study, 13 case-control studies, and three cross-sectional/ecologic studies. Using the Food and Drug Administration (FDA)’s evidence-based criteria for the scientific evaluation of health claims (113), the authors excluded 16 studies for methodological flaws; only four studies (two case-control (114, 115), one case-cohort (116), and one intervention (85)) received moderate-to-high quality ratings (112). Among these four studies, garlic intake during adolescence or 20 years prior to the interview was not found to be associated with the risk of gastric cancer in one of the case-control studies in Sweden (338 gastric cancer patients and 669 control subjects) (114). Another case-control study in Korea failed to show an association between past garlic consumption and gastric cancer in 136 people diagnosed with gastric cancer and 136 cancer-free subjects (115). In addition, a prospective case-cohort study in the Netherlands found no association between the use of garlic supplements (unknown composition) and gastric cancer risk (116). Finally, a randomized, double-blind, placebo-controlled intervention study in 3,365 subjects from the Shandong province of China found that supplementation with aged garlic extract and steam-distilled garlic oil for 7.3 years did not reduce the prevalence of precancerous gastric lesions or the incidence of gastric cancer (85). An updated analysis of the data collected 7.3 years after garlic supplementation ended provided further confirmation for a lack of significant reduction in gastric cancer incidence or mortality with supplemental garlic (117).

Helicobacter pylori (H. pylori) infection and gastric cancer: Infection with some strains of H. pylori bacteria markedly increases the risk of gastric cancer. Although garlic preparations and organosulfur compounds could inhibit the growth of H. pylori in the laboratory (118, 119), there is little evidence to suggest that high garlic intakes or garlic supplementation may help prevent or eradicate H. pylori infection in humans (120). Higher intakes of garlic were not associated with a significantly lower prevalence of H. pylori infection in China or Turkey (121, 122). Moreover, clinical trials using garlic cloves (123), aged garlic extract (84), steam-distilled garlic oil (84, 124), garlic oil macerate (125), or garlic powder (126) have not found garlic supplementation to be effective in eradicating H. pylori infection in humans.

Colorectal cancer

A 2014 meta-analysis of prospective cohort studies in 335,923 subjects (including 4,610 colorectal cancer [CRC] cases) found no association of consuming raw or cooked garlic (three studies, four cohorts) or supplemental garlic (four studies, five cohorts) with CRC (127). Another recent systematic review and meta-analysis that combined data from seven cohort and seven case-control studies also failed to find a statistically significant reduction in CRC risk with garlic intake (128). Yet, these results are in contrast with previous pooled analyses of data from case-control studies (129) or from both case-control and prospective studies (130) that reported an approximate 30% lower CRC risk in individuals with the highest garlic intakes compared to those with the lowest intakes. Inclusion of case-control studies, which are more susceptible to bias, may explain these discrepancies among meta-analyses (128). For information regarding different types of epidemiological studies, see the Spring/Summer 2016 LPI Research Newsletter.

A small preliminary intervention trial in 37 patients with colorectal adenomas examined whether supplementation with aged garlic extract for 12 months affected adenoma size and recurrence. Both the number and size of adenomas were significantly reduced in patients given a high dose of aged garlic extract compared to those given a much lower dose (0.16 mL/day) (131, 132). Larger randomized controlled trials are needed to determine whether garlic or garlic extracts can substantially reduce adenoma progression to advanced cancer and recurrence.

Other types of cancer

In a small, placebo-controlled intervention study in 50 patients with cancer (42 with liver cancer, seven with pancreatic cancer, and one with colon cancer), supplementation with 500 mg/day of aged garlic extract for six months failed to prevent quality of life deterioration caused by disease progression and chemotherapy-associated adverse effects (133). Yet, the active treatment limited the decline in natural killer cell count and activity that accompanies digestive cancer progression and reduces patient survival (133).

At present, evidence from trials is limited and results from observational studies do not suggest a role of high intakes of garlic in the prevention of cancer in humans (112).

Sources

Food sources

Allium vegetables, including garlic and onions, are the richest sources of organosulfur compounds in the human diet (134). To date, the majority of scientific research relating to the health effects of organosulfur compounds has focused on those derived from garlic. Fresh garlic cloves contain about 2 to 6 mg/g of γ-glutamyl-S-allyl-L-cysteine (0.2%-0.6% fresh weight) and 6 to 14 mg/g of alliin (0.6%-1.4% fresh weight). Garlic cloves yield about 2.5 to 4.5 mg of allicin per gram of fresh weight when crushed. One fresh garlic clove weighs 2 to 4 g (5).

Effects of cooking

The enzyme alliinase can be inactivated by heat. In one study, microwave cooking of unpeeled, uncrushed garlic totally destroyed alliinase enzyme activity (135). An in vitro study found that prolonged oven heating or boiling (i.e., six minutes or longer) suppressed the inhibitory effect of uncrushed and crushed garlic on platelet aggregation, but crushed garlic retained more anti-aggregatory activity compared to uncrushed garlic (136). Administering raw garlic to rats significantly decreased the amount of DNA damage caused by a chemical carcinogen, but heating uncrushed garlic cloves for 60 seconds in a microwave oven or 45 minutes in a convection oven prior to administration blocked the protective effect of garlic (137). The protective effect of garlic against DNA damage can be partially conserved by crushing garlic and allowing it to stand for 10 minutes prior to microwave heating for 60 seconds or by cutting the tops off garlic cloves and allowing them to stand for 10 minutes before heating in a convection oven. Because organosulfur compounds derived from alliinase-catalyzed reactions may play a role in some of the biological effects of garlic, some scientists recommend that crushed or chopped garlic be allowed to "stand" for at least 10 minutes prior to cooking (135).

Supplements

Several different types of garlic preparations are available commercially, and each type provides a different profile of organosulfur compounds depending on how it was processed (see Table 1). Not all garlic preparations are standardized, and even standardized brands may vary with respect to the amount and the bioavailability of the organosulfur compounds they provide (5).

Powdered (dehydrated) garlic

Powdered or dehydrated garlic is made from garlic cloves that are usually sliced and dried at a low temperature to prevent alliinase inactivation (138). The dried garlic is pulverized and often made into tablets. To meet United States Pharmacopeial Convention (USP) standards, powdered garlic supplements must contain no less than 0.1% γ-glutamyl-S-allyl-L-cysteine and no less than 0.3% alliin (dry weight) (139). Although powdered garlic supplements do not actually contain allicin, the manufacturer may provide a value for the "allicin potential" or "allicin yield" of a supplement on the label. These values represent the maximum achievable allicin yield of a supplement (140). It is determined by dissolving powdered garlic in water at room temperature and measuring the allicin content after 30 minutes (139). Because alliinase is inactivated by the acidic pH of the stomach, most powdered garlic tablets are enteric-coated to keep them from dissolving before they reach the neutral pH of the small intestine. It has been argued that it is more appropriate to measure "allicin release" using a USP method for assessing drug release from enteric-coated tablets under conditions that mimic those of the stomach and intestine (139). Allicin release by this method has been shown to parallel true bioavailability (140). Most tablet brands have been found to produce little allicin under these conditions, due mainly to low alliinase activity and prolonged disintegration times (140, 141). Many manufacturers provide information on the "allicin potential" of their powdered garlic supplements, but few provide information on the "allicin release." A number of controlled clinical trials have examined the effect of powdered or dehydrated garlic supplements on cardiovascular risk factors (see Cardiovascular disease). The most commonly used doses ranged from of 600 to 900 mg/day and provided 3.6 to 5.4 mg/day of potential allicin (90).

Garlic fluid extracts (aged garlic extract™)

When garlic cloves are incubated in a solution of ethanol and water for up to 20 months, allicin is mainly converted to allyl sulfides, which are lost by evaporation or converted to other compounds (138). The resulting extract contains primarily water-soluble organosulfur compounds, such as SAC and SAMC (see Figure 3) (142). Garlic fluid extracts, including aged garlic extracts, are standardized to their S-allyl-L-cysteine content. In controlled clinical trials, daily intakes of aged garlic extract at doses between 1.2 g-2.4 g (containing 1.2 to 2.4 mg of S-allyl-L-cysteine) consistently resulted in reductions in SBP by 9 mm Hg-10 mm Hg and reductions in DBP by 4 mm Hg-8 mm Hg in a majority of patients with uncontrolled hypertension (110, 143). Additionally, aged garlic extract at doses of 2.4 to 7.2 g/day resulted in short-term reductions in ex vivo platelet aggregation (144) and reductions in serum cholesterol concentrations up to 12 weeks (16).

Steam-distilled garlic oil

Steam distillation of crushed garlic cloves results in a product that contains mainly allyl sulfides, including DATS, DADS, and DAS (see Figure 2) (138). These fat-soluble steam distillation products are usually dissolved in vegetable oil.

Garlic oil macerates

Incubation of crushed garlic cloves in oil at room temperature results in the formation of vinyldithiins and ajoene from allicin, in addition to allyl sulfides, such as DADS and DATS (see Figure 2) (5). Ether extracts are similar in composition to garlic oil macerates but more concentrated (145).

Table 1. Principal Organosulfur Compounds in Commercial Garlic Preparations (4, 6)
Product Principal Organosulfur Compounds Delivers Allicin-derived Compounds?
Fresh garlic cloves

Cysteine sulfoxides (Alliin)
γ-Glutamyl-L-cysteine peptides

Yes, when chopped, crushed, or chewed raw.
Minimal, when garlic cloves are cooked before crushing or chopping.
Garlic powder (tablets) Cysteine sulfoxides (Alliin)
γ-Glutamyl-L-cysteine peptides
Varies greatly among commercial products.
Enteric-coated tablets that pass the USP allicin release test are likely to provide the most.
Steam-distilled garlic oil (capsules) Diallyl disulfide (DADS)
Diallyl trisulfide (DATS)
Allyl methyl trisulfide
Yes, but there is only 1% of oil-soluble sulfur compounds in 99% of vegetable oil.
Garlic oil macerate (capsules) Vinyldithiins
(E/Z)-ajoene
Diallyl trisulfide
Yes
Aged garlic extract™
(tablets or capsules)
S-Allyl-L-cysteine (SAC)
S-Allylmercaptocysteine (SAMC)
trans-S-1-Propenyl-L-cysteine
Minimal

Safety

Adverse effects

The most commonly reported adverse effects of oral ingestion of garlic and garlic supplements are breath and body odor (90, 146). Gastrointestinal symptoms have also been reported, including heartburn, abdominal pain, belching, nausea, vomiting, flatulence, constipation, and diarrhea (106). The most serious adverse effects associated with oral garlic supplementation are related to uncontrolled bleeding. Several cases of serious postoperative or spontaneous bleeding associated with garlic supplementation have been reported in the medical literature (147-150). Garlic may also trigger allergic responses in some individuals, including asthma in people with occupational exposure to garlic powder or dust (151). Exposure of the skin to garlic has been reported to cause contact dermatitis in some individuals (146, 152). More serious skin lesions, including blisters and burns, have also been reported with topical exposure to garlic for six or more hours.

The safety characteristics of the various garlic preparations likely depend on their specific chemical composition (see Table 1). Aged garlic extract — the only water-based garlic supplement — showed a safe profile in toxicity studies and exhibited no undesirable side effects when combined with anticoagulants (warfarin), antiplatelets (aspirin), cholesterol-lowering (statins) drugs, or anticancer drugs (doxorubicin, 5-fluorouracil, methotrexate) in clinical settings (reviewed in 6). Safety and toxicity data are lacking for lipophilic (hydrophobic) garlic preparations, but some of their constituents have been shown to interfere with drug-metabolizing enzymes and transporters (see Drug interactions).

Pregnancy and lactation

No adverse effects on pregnancy outcomes have been reported when garlic is consumed in the diet. Although no adverse pregnancy outcomes were reported in a study of Iranian women who took dehydrated garlic tablets (800 mg/day) for two months during the third trimester of pregnancy (153), the safety of garlic supplements in pregnancy has not been established. There is some evidence that garlic consumption alters the odor and possibly the flavor of breast milk. In a controlled cross-over trial, oral consumption of 1.5 g of garlic extract by lactating women increased the perceived intensity of breast milk odor (154). Infants spent more time breast-feeding after their mothers consumed the garlic extract compared to a placebo, but the amount of milk consumed and number of feedings were not significantly different. Additionally, it is not known if topical use of garlic is safe during pregnancy or lactation.

Drug interactions

Anticoagulant medications

Garlic may enhance the anticoagulant effects of warfarin (Coumadin). There have been two case reports in which prothrombin time (INR) increased in patients who started taking garlic tablets or garlic oil without changing their warfarin dose or other habits (155). However, a more recent study in closely monitored patients on warfarin therapy found that garlic fluid extracts (aged garlic extract) did not increase hemorrhagic risk (156). Since garlic supplements have been found to inhibit platelet aggregation (90), there is a potential for additive effects when garlic supplements are taken together with other medications or supplements that inhibit platelet aggregation, such as high-dose fish oil or vitamin E (157). More research is needed to determine whether garlic supplements are safe for people on anticoagulatory therapy.

HIV protease inhibitors

Supplementation of healthy volunteers with garlic caplets twice daily (allicin yield, 7.2 mg/day) for three weeks resulted in a 50% decrease in the bioavailability of the protease inhibitor, saquinavir (Fortovase) (158). Although saquinavir undergoes significant metabolism by CYP3A4, supplementation with garlic extract for two weeks did not significantly alter a measure of CYP3A4 activity in healthy volunteers (159). Garlic extract supplementation (10 mg/day) for four days did not significantly alter single-dose pharmacokinetics of the protease inhibitor, ritonavir (Norvir), but further research is needed to determine steady-state interactions between well-characterized garlic supplements and ritonavir (160). In vitro hepatic models suggested that flavonoids and sulfur-containing compounds in garlic supplements might 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-resistance protein (BCRP), which function as ATP-dependent efflux pumps that actively regulate the excretion of a number of drugs limiting their systemic bioavailability. They may also affect the activity of phase I biotransformation enzymes like cytochrome P450 (CYP) 3A4 (CYP3A4) (161, 162). Modifications of efflux transporter and CYP3A4 activities may explain how supplementation with garlic phytochemicals might hinder the therapeutic efficacy of medications like antiretroviral drugs (162).


Authors and Reviewers

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

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

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

Reviewed in December 2016 by:
Karin Ried, Ph.D., MSc.
Research Director
National Institute of Integrative Medicine

Copyright 2005-2017  Linus Pauling Institute 


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Legumes

Summary

  • Foods from the legume family include beans, peas, lentils, peanuts, and soybeans. (More information)
  • Legumes are excellent sources of protein, low-glycemic index carbohydrates, essential micronutrients, and fiber.
  • Substituting legumes for foods that are high in saturated fats or refined carbohydrates is likely to lower the risk of cardiovascular disease and type 2 diabetes mellitus. (More information)
  • Although legumes are rich in a number of compounds that could potentially reduce the risk of certain cancers, the results of epidemiological studies are too inconsistent to draw any firm conclusions regarding legume intake and cancer risk in general. (More information)
  • The 2005 Dietary Guidelines for Americans recommend a weekly intake of six servings (3 cups) of legumes for people who consume 2,000 kcal/day. (More information)

Introduction

Legumes are plants with seed pods that split into two halves. Edible seeds from plants in the legume family include beans, peas, lentils, soybeans, and peanuts. Since peanuts are nutritionally similar to tree nuts, information on the health benefits of peanuts is presented in the article on nuts. Although legumes are an important part of traditional diets around the world, they are often neglected in typical Western diets. Legumes are inexpensive, nutrient-dense sources of protein that can be substituted for dietary animal protein (1). While sources of animal protein are often rich in saturated fats, the small quantities of fats in legumes are mostly unsaturated fats. Not only are legumes excellent sources of essential minerals, but they are also rich in dietary fiber and other phytochemicals that may affect health. Soybeans have attracted the most scientific interest, mainly because they are a unique source of phytoestrogens known as isoflavones (2). Although most other legumes lack isoflavones, they also represent unique packages of nutrients and phytochemicals that may work synergistically to reduce risk of chronic diseases.

Note: Research on the health effects of diets rich in legumes and soyfoods is summarized below. For a discussion of the potential health benefits and risks of soy isoflavones, see the article on Soy Isoflavones.

Disease Prevention

Type 2 diabetes mellitus

The glycemic index is a measure of the potential for carbohydrates in different foods to raise blood glucose levels. In general, consuming foods with high-glycemic index values causes blood glucose levels to rise more rapidly, which results in greater insulin secretion by the pancreas, than after consuming foods with low-glycemic index values. Chronically elevated blood glucose levels and excessive insulin secretion are thought to play important roles in the development of type 2 diabetes mellitus (DM) (3). Because legumes generally have low-glycemic index values, substituting legumes for high-glycemic index foods like white rice or potatoes lowers the glycemic load of one’s diet. Low-glycemic load diets have been associated with reduced risk of developing type 2 DM in several large prospective studies (4-7). Obesity is another important risk factor for type 2 DM. Numerous clinical trials have shown that the consumption of low-glycemic index foods delays the return of hunger, decreases subsequent food intake, and increases the sensation of fullness compared to high-glycemic index foods (8, 9). The results of several small, short-term trials (1-6 months) suggest that low-glycemic load diets result in significantly more weight or fat loss than high-glycemic load diets (10-13). Thus, diets rich in legumes may decrease the risk of type 2 diabetes by improving blood glucose control, decreasing insulin secretion, and delaying the return of hunger after a meal. For more information on glycemic index values and glycemic load, see the article on Glycemic Index and Glycemic Load. One study in elderly men and women reported that consumption of legumes was protective against the development of glucose intolerance (14). More recently, a prospective cohort study in 64,227 middle-aged Chinese women found that total legume consumption, which included soybeans, peanuts, and other legumes, was associated with a 38% lower risk of developing type 2 DM (15). Moreover, a prospective study that followed 10,449 diabetics for nine years found that legume intake was inversely associated with cardiovascular-related mortality and all-cause mortality, but not with cancer-related mortality (16).

Cardiovascular disease

Beans, peas, and lentils

One prospective cohort study that examined the effect of legume intake on cardiovascular disease risk followed men and women for 19 years and found those who ate dry beans, peas, or peanuts at least four times weekly had a risk of coronary heart disease (CHD) that was 21% lower than those who ate them less than once weekly (17). When compared to a typical Western diet, legume intake as part of a healthy dietary pattern that included higher intakes of vegetables, fruit, whole grains, fish, and poultry was associated with a risk of CHD that was 30% lower in men (18) and 24% lower in women (19). The results of controlled clinical trials suggest that increasing bean consumption improves serum lipid and lipoprotein profiles. A meta-analysis that combined the results of 11 clinical trials found that increasing the consumption of dry beans resulted in modest (6-7%) decreases in total cholesterol and LDL-cholesterol (20). Several characteristics of beans may contribute to their cardioprotective effects. Beans are rich in soluble fiber, which is known to have a cholesterol-lowering effect. Elevated plasma homocysteine levels are associated with increased cardiovascular disease risk, and beans are good sources of folate, which helps to lower homocysteine levels. Beans are also good sources of magnesium and potassium, which may decrease cardiovascular disease risk by helping to lower blood pressure (20). The low-glycemic index values of beans means that they are less likely to raise blood glucose and insulin levels, which may also decrease cardiovascular disease risk. For more information on glycemic index values, see the article on Glycemic Index and Glycemic Load.

Soy

In 1999, the US Food and Drug Administration (FDA) approved the following health claim: “Diets low in saturated fat and cholesterol that include 25 grams of soy protein a day may reduce the risk of heart disease” (21). Most of the evidence to support this health claim was included in the Anderson et al. meta-analysis of 38 controlled clinical trials that was published in 1995. This meta-analysis found that an average intake of 47 g/day of soy protein decreased serum total cholesterol levels by an average of 9% and LDL cholesterol levels by an average of 13% (22). Hypocholesterolemic effects were primarily noted in individuals with high baseline cholesterol levels (22). A more recent meta-analysis of 33 studies published since 1995 confirmed the hypocholesterolemic effect of soy protein reported in the Anderson et al. publication (23). Another recent meta-analysis of 30 studies in individuals with normal or mildly elevated cholesterol levels concluded that about 25 g/day of soy protein significantly lowers LDL cholesterol concentrations by about 6% (24). Yet, a recent science advisory from the Nutrition Committee of the American Heart Association concluded that earlier research indicating soy protein consumption results in clinically important reductions in LDL cholesterol compared to other proteins has not been confirmed (25). The consumption of isolated soy isoflavones (as supplements or extracts) does not appear to have favorable effects on serum lipid profiles (26-29). In addition to possibly lowering cholesterol, many soy products may be beneficial for overall cardiovascular health due to their relatively high content of polyunsaturated fat, fiber, and phytosterols compared to animal products (30).

Cancer

Beans, peas, and lentils

Although beans are rich in a number of compounds that could potentially reduce the risk of certain cancers, the results of epidemiological studies are too inconsistent to draw any firm conclusions regarding bean intake and cancer risk in general (31, 32).

Prostate cancer: There is limited evidence from observational studies that legume intake is inversely related to the risk of prostate cancer. In a six-year prospective study of more than 14,000 Seventh Day Adventist men living in the United States, those with the highest intakes of legumes (beans, lentils, or split peas) had a significantly lower risk of prostate cancer (33). More recently, a prospective study of more than 58,000 men in the Netherlands found that those with the highest intakes of legumes had a risk of prostate cancer that was 29% lower than those with the lowest intakes (34). Similarly, in a case-control study of 1,619 North American men diagnosed with prostate cancer and 1,618 healthy men matched for age and ethnicity, those with the highest legume intakes had a risk of prostate cancer that was 38% lower than those with the lowest intakes (35). Excluding the intake of soy foods from the analysis did not weaken the inverse association between legume intake and prostate cancer, suggesting that soy was not the only legume that conferred protection against prostate cancer. A recent prospective study in a multi-ethnic cohort of 82,483 men examined the risk of prostate cancer in men who consumed legumes excluding soy products. In this study, men who consumed the highest amount of non-soy legumes had a 10% lower risk of total prostate cancer and a 28% lower risk of nonlocalized or high-grade prostate cancer compared to those who consumed the least amount of non-soy legumes (36).

Soy

Prostate cancer: Although there is considerable scientific interest in the potential for soy products to prevent prostate cancer, evidence that higher intakes of soy foods can reduce the risk of prostate cancer in humans is limited. Only two out of six case-control studies found that higher intakes of soy products were associated with a significantly lower risk of prostate cancer. In the largest case-control study, North American men who consumed an average of at least 1.4 oz of soy foods daily were 38% less likely to have prostate cancer than men who did not consume soy foods (35). A much smaller case-control study of Chinese men found that men who consumed at least 4 oz of soy foods daily were only half as likely to have prostate cancer as those who consumed less than 1 oz daily (37). However, case-control studies conducted among North American (38, 39), Japanese (40), and Taiwanese men (41) did not find that higher soy intakes were associated with significantly lower prostate cancer risk. A six-year prospective cohort study of more than 12,000 Seventh Day Adventist men in the US found that those who drank soy milk more than once daily had a risk of prostate cancer that was 70% lower than those who never drank soy milk (42), but a 23-year study of more than 5,000 Japanese American men found no association between tofu consumption and prostate cancer risk (43). More recently, a prospective study in a cohort of 43,509 Japanese men found that consumption of soy foods was associated with a decreased risk of localized prostate cancer in men older than 60 years (44). Clinical trials are needed to determine whether consumption of soy foods affects risk of prostate cancer.

Breast cancer: More than 25 epidemiological studies have assessed the relationship between soy food intake and the risk of breast cancer. A recent meta-analysis of prospective cohort studies and case-control studies reported differential effects based on the typical level of soy consumption (45). In Asian populations, where soy intake is high, the authors found an inverse association between soy food intake and breast cancer; however, no association was observed in studies completed in Western populations, where soy food intake is much lower (45). Age at exposure to soy foods may affect subsequent risk of developing breast cancer. For instance, two case-control studies have found higher soy intake during adolescence may lower risk of developing breast cancer later in life (46, 47). Soy intake later in life may not have as strong as an effect on breast cancer as exposure during adolescence (45).

Intake Recommendations

Substituting beans, peas, and lentils for foods that are high in saturated fat or refined carbohydrates is likely to help lower the risk of type 2 DM and cardiovascular disease. Soybeans and foods made from soybeans (soy foods) are excellent sources of protein. In fact, soy protein is complete protein, meaning it provides all of the essential amino acids in adequate amounts for human health (2). Like beans, peas, and lentils, soy foods are also excellent substitutes for protein sources that are high in saturated fat like red meat or cheese. Although a number of health-related organizations recommend daily consumption of five to nine servings (2½-4½ cups) of fruit and vegetables daily (see the article on  Fruit and Vegetables), few make specific recommendations for legumes. In the 2005 Dietary Guidelines for Americans, an intake of 3 cups (6 servings) of legumes weekly is recommended for people who consume about 2,000 kcal/day. A serving of legumes is equal to ½ cup of cooked beans, peas, lentils, or tofu (48). Table 1 lists some potentially beneficial compounds in legumes.

Table 1. Some Potentially Beneficial Compounds in Legumes
Macronutrients Vitamins Minerals Phytochemicals
Essential Fatty Acids Folate Magnesium Fiber
    Potassium Flavonoids
      Soy Isoflavones
      Lignans
      Phytosterols

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

Reviewed in April 2009 by:
James W. Anderson, M.D.
Professor of Medicine and Clinical Nutrition
University of Kentucky School of Medicine

Copyright 2004-2017  Linus Pauling Institute


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Nuts

Summary

  • Nuts are good sources of fiber, phytosterols, and unsaturated fat. (More information)
  • The results of most prospective cohort studies suggest that regular nut consumption (equivalent to 1 oz at least five times weekly) is associated with a significantly lower risk of cardiovascular disease. (More information)
  • One prospective cohort study has found that regular nut consumption is associated with significantly lower risk of developing type 2 diabetes. (More information)
  • Most prospective studies have shown that people who consume nuts regularly weigh less than those who rarely consume nuts. Nonetheless, since an ounce of most nuts provides about 160 kcal of energy, substituting nuts for other less healthy snacks is a good strategy for avoiding weight gain when increasing nut intake. (More information)

Introduction

In the not too distant past, nuts were considered unhealthy because of their relatively high fat content. In contrast, recent research suggests that regular nut consumption is an important part of a healthful diet (1). Although the fat content of nuts is relatively high (14-19 grams/ounce), most of the fats in nuts are the healthier, monounsaturated and polyunsaturated fats (see Table 1(2). The term “nuts” includes almonds, Brazil nuts, cashews, hazelnuts, macadamia nuts, pecans, pistachios, walnuts, and peanuts. Despite their name, peanuts are actually legumes like peas and beans. However, they are nutritionally similar to tree nuts and have some of the same beneficial properties.

Disease Prevention

Cardiovascular disease

Coronary heart disease

In large prospective cohort studies, regular nut consumption has been consistently associated with significant reductions in the risk of coronary heart disease (CHD) (3). One of the first studies to observe a protective effect of nut consumption was the Adventist Health Study, which followed more than 30,000 Seventh Day Adventists over 12 years (4). In general, the dietary and lifestyle habits of Seventh Day Adventists are closer to those recommended for cardiovascular disease prevention than those of average Americans. Few of those who participated in the Adventist Health Study smoked, and most consumed a diet lower in saturated fat than the average American. In this healthy group, those who consumed nuts at least five times weekly had a 48% lower risk of death from CHD and a 51% lower risk of a nonfatal myocardial infarction (MI) compared to those who consumed nuts less than once weekly (4). In Seventh Day Adventists who were older than 83 years of age, those who ate nuts at least five times weekly had a risk of death from CHD that was 39% lower than those who consumed nuts less than once weekly (5). A smaller prospective study of more than 3,000 Black men and women reported similar results (6). Those who consumed nuts at least five times weekly had a risk of death from CHD that was 44% lower than those who consumed nuts less than once weekly (6).

The cardioprotective effects of nuts are not limited to Seventh Day Adventists. In a 14-year study of more than 86,000 women participating in the Nurses’ Health Study, those who consumed more than 5 oz of nuts weekly had a risk of CHD that was 35% lower than those who ate less than 1 oz of nuts monthly (7). Similar decreases were observed for the risk of nonfatal MI and death from CHD. More recently, a 17-year study of more than 21,000 male physicians found that those who consumed nuts at least twice weekly had a risk of sudden cardiac death that was 53% lower than those who rarely or never consumed nuts, although there was no significant decrease in the risk of nonfatal MI or nonsudden CHD death (8). A follow-up analysis in this cohort of male physicians found that nut consumption was not associated with incident heart failure (9). The Iowa Women’s Health Study, which followed more than 30,000 postmenopausal women for 12 years, is the only published prospective study that did not observe a significant inverse association between nut consumption and CHD mortality, although a slight but significant decrease in all-cause mortality was observed in those who consumed nuts twice weekly (10). Overall, the results of most prospective cohort studies suggest that regular nut consumption is associated with a substantial decrease in the risk of death related to CHD. In fact, a recent pooled analysis of four of the US epidemiological studies mentioned above found those with the highest intake of nuts (about 5 times per week) had a 35% lower risk of CHD (11).

Results of controlled clinical trials indicate that at least part of the cardioprotective effect of nuts is derived from beneficial effects on serum total and LDL cholesterol concentrations (3). At least 18 controlled clinical trials have found that adding nuts to a diet that is low in saturated fat results in significantly reductions in serum total cholesterol and LDL cholesterol concentrations in people with normal or elevated serum cholesterol. These effects have been observed for almonds (12-15), hazelnuts (16), macadamia nuts (17-19), peanuts (20, 21), pecans (22), pistachio nuts (23, 24) and walnuts (25-30). More recently, a cross-sectional study found that frequent nut and seed consumption was associated with lower serum levels of inflammatory biomarkers in a multi-ethnic population (31). Although the evidence is circumstantial, these findings suggest that compounds in nuts may lower the risk of cardiovascular disease by decreasing inflammation.

Cardioprotective compounds in nuts

Substituting dietary saturated fats with polyunsaturated and monounsaturated fats like those found in nuts can decrease serum total and LDL cholesterol concentrations (3). However, in some clinical trials, the cholesterol-lowering effect of nut consumption was greater than would be predicted from the polyunsaturated and monounsaturated fat content of the nuts, suggesting there may be other protective factors in nuts (32). Other bioactive compounds in nuts that may contribute to their cholesterol-lowering effects include fiber and phytosterols (33). See  Table 1 for the unsaturated fat, fiber, and phytosterol content of selected nuts. Walnuts are especially rich in alpha-linolenic acid, an omega-3 fatty acid with a number of cardioprotective effects, including the prevention of cardiac arrhythmias that may lead to sudden cardiac death. Other nutrients that may contribute to the cardioprotective effects of nuts include folate, vitamin E, and potassium (3, 33-35). The US Food and Drug Administration (FDA) has acknowledged the emerging evidence for a relationship between nut consumption and cardiovascular disease risk by approving the following qualified health claim for nuts (36): “Scientific evidence suggests but does not prove that eating 1.5 ounces per day of most nuts as part of a diet low in saturated fat and cholesterol may reduce the risk of heart disease.” For more information on the nutrient content of nuts, search the USDA National Nutrient Database.

Table 1. Energy, Fat, Phytosterols and Fiber in a 1-oz Serving of Selected Nuts
Nut
(1 ounce)
Energy (kcal) Total Fat (g) MUFA* (g) PUFA* (g) Phytosterols (mg) Fiber (g)
Almonds
163
14.0
8.8
3.4
39
3.5
Brazil nuts
186
18.8
7.0
5.8
N/A
2.1
Cashews
163
13.1
7.7
2.2
45
0.9
Hazelnuts
178
17.2
12.9
2.2
27
2.7
Macadamia nuts
204
21.5
16.7
0.4
33
2.4
Peanuts (legume)
161
14.0
6.9
4.4
62
2.4
Peanut butter, smooth (2 Tbsp)
188
16.1
7.6
4.4
33
1.9
Pecans
196
20.4
11.6
6.1
29
2.7
Pine nuts (pignoli)
191
19.4
5.3
9.7
40
1.0
Pistachio nuts
158
12.6
6.6
3.8
61
2.9
Walnuts, Black
175
16.7
4.3
9.9
31
1.9
*MUFA, Monounsaturated Fatty Acids; PUFA, Polyunsaturated Fatty Acids

Type 2 diabetes mellitus

Recent results from the Nurses’ Health Study suggest that nut and peanut butter consumption may be inversely associated with the risk of type 2 diabetes mellitus (DM) in women (37). In this cohort of more than 86,000 women followed over 16 years, those who consumed an ounce of nuts at least five times weekly had a risk of developing type 2 DM that was 27% lower than those who rarely or never consumed nuts. Similarly those who consumed peanut butter at least five times weekly had a risk of developing type 2 DM that was 21% lower than those who rarely or never consumed peanut butter. While these findings require confirmation in other studies, they provide additional evidence that nuts can be a component of a healthful diet. Compounds in nuts that could contribute to the observed decrease in type 2 DM include unsaturated fats, fiber, and magnesium.

Overweight and obesity

A major concern is that increased consumption of nuts may cause weight gain and obesity. However, several cross-sectional analyses of large cohort studies, including the Adventist Health Study (5) and the Nurses' Health Study (7), have shown that individuals who consume nuts regularly tend to weigh less than those who rarely consume them. Recently, a 28-month prospective study conducted in Spain found that participants who consumed higher amount of nuts had lower risk of weight gain than those who rarely ate nuts (38). A similar association was observed in the Nurses' Health Study II (39). These epidemiological data indicate that in free-living subjects, higher nut consumption does not cause greater weight gain; rather, incorporating nuts into diets may be beneficial for weight control. It is possible that higher amounts of protein and fiber in nuts enhance satiety and suppress hunger.

Safety

Nut allergies

Allergies to peanuts and tree nuts (almonds, cashews, hazelnuts, pecans, pistachios, and walnuts) are among the most common food allergies, affecting at least 1% of the US population (40). Although all food allergies have the potential to induce severe reactions, peanuts and tree nuts are among the foods most commonly associated with anaphylaxis, a life-threatening allergic reaction (41). People with severe peanut or tree nut allergies need to take special precautions to avoid inadvertently consuming peanuts or tree nuts by checking labels and avoiding unlabeled snacks, candies, and desserts. See the Food Allergy and Anaphylaxis Network website for additional tips to avoiding unintentional peanut or tree nut exposure.

Adverse effects

Brazil nuts grown in areas of Brazil with selenium-rich soil may provide more than 100 μg of selenium in one nut, while those grown in selenium-poor soil may provide ten times less (42). For information regarding toxicity of selenium, see the article on Selenium.

Intake Recommendations

Regular nut consumption, equivalent to an ounce of nuts five times weekly, has been consistently associated with significant reductions in coronary heart disease (CHD) risk in epidemiological studies. Consuming 1-2 oz of nuts daily as part of a diet that is low in saturated fat has been found to lower serum total and LDL cholesterol in a number of controlled clinical trials. Since an ounce of most nuts provides at least 160 calories (kcal), simply adding an ounce of nuts daily to one’s habitual diet without eliminating other foods may result in weight gain. Substituting unsalted nuts for other less healthy snacks or for meat in main dishes are two ways to make nuts part of a healthful diet. Table 2 lists some potentially beneficial compounds in nuts.

Table 2. Some Potentially Beneficial Compounds in Nuts
Macronutrients Vitamins Minerals Phytochemicals
Unsaturated Fats Folate Magnesium Fiber
  Vitamin E Potassium Phytosterols

Authors and Reviewers

Originally written in 2003 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

Reviewed in June 2009 by:
Frank B. Hu, M.D., Ph.D.
Professor of Nutrition and Epidemiology
Harvard School of Public Health

Copyright 2003-2017  Linus Pauling Institute 


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16.  Durak I, Koksal I, Kacmaz M, Buyukkocak S, Cimen BM, Ozturk HS. Hazelnut supplementation enhances plasma antioxidant potential and lowers plasma cholesterol levels. Clin Chim Acta. 1999;284(1):113-115.

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22.  Morgan WA, Clayshulte BJ. Pecans lower low-density lipoprotein cholesterol in people with normal lipid levels. J Am Diet Assoc. 2000;100(3):312-318.  (PubMed)

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Whole Grains

Summary

    • Grains are the edible seeds of specific grasses of the Poaceae family and include wheat, rice, maize (corn), barley, oats, rye, triticale, millet, bulgur, and sorghum. Quinoa, amaranth, and buckwheat are pseudo-grains that are nutritionally similar to true grains. (More information)
  • Whole grains are defined as intact or cracked, crushed, and flaked grain seeds in which all the components of the kernel, i.e., the bran, the endosperm, and the germ, are retained in the same relative proportions as in the intact grain. (More information)
  • Bran and germ, which are lost during the refining (milling) process, are rich in minerals, vitamins, phytochemicals, and dietary fiber that play important roles in the health benefits associated with whole-grain consumption. (More information)
  • There is no consensus as to what constitutes a whole-grain food. Products that bear the FDA health claims for whole grains contain at least 51% of whole-grain ingredients by weight. (More information)
  • Observational studies have found that diets rich in whole grains are associated with reduced risks of type 2 diabetes mellitus and cardiovascular disease compared to diets high in refined grains. (More information)
  • Although the protective effects of whole grains against cancer are not as well established as those against cardiovascular disease and type 2 diabetes mellitus, some prospective cohort studies have found whole-grain intake to be associated with a decreased risk of esophageal and colorectal cancers. (More information)
  • Results from large prospective cohort studies showed that whole-grain consumption was inversely correlated with all-cause mortality and mortality from several conditions, including cardiovascular disease, cancer, type 2 diabetes mellitus, respiratory disease, and infections. (More information)
  • Diets rich in whole grains and fiber may help prevent constipation in healthy people and the formation of pouches (diverticula) in the wall of the colon. In a recent prospective cohort study, higher intakes of dietary fiber, especially from cereal and fruit, was associated with a significantly lower risk of diverticular disease. (More information)
  • The 2015-2020 Dietary Guidelines for Americans recommend consuming a minimum of three servings (about 90 g) of whole-grain products daily. (More information)

Introduction

Grains are seeds of plants belonging to the Poaceae family (also called Gramineae or true grasses). Some examples of edible grains include wheat, rice, maize (corn), barley, oats, rye, triticale (wheat-rye hybrid), millet, bulgur, and sorghum (1). Although they are not members of the Poaceae family, whole-grain ingredients also include pseudo-grains like quinoa, amaranth, and buckwheat. A whole grain has an outer layer of bran, a carbohydrate-rich middle layer called the endosperm, and an inner germ layer (Figure 1). Whole-grain foods contain entire grain seeds either intact, cracked, crushed, or flaked, as long as the bran, endosperm, and germ are retained in the same proportions as they exist in the intact kernel (1). Whole grains are rich in potentially beneficial compounds, including vitamins, minerals, fiber, and phytochemicals, such as lignans and phytosterols (2). Most of these compounds are located in the bran or the germ of the grain, both of which are lost during the refining (milling) process, leaving only the starchy endosperm (1). Compared to diets high in refined grains, diets rich in whole grains are associated with reduced risks of several chronic diseases. The health benefits of whole grains are not entirely explained by the individual contributions of the nutrients and phytochemicals they contain. Whole grains represent a unique package of energy, micronutrients, and phytochemicals that work synergistically to promote health and prevent disease (3).

Figure 1. Anatomy of a Whole Grain, including bran, endosperm, and germ.

Disease Prevention

Because there is no globally accepted definition as to what constitutes a whole-grain food, it is difficult to compare studies that examined the effects of whole-grain consumption on markers of health and disease outcomes. The US Food and Drug Administration (FDA) approved health claims for whole grains (see Finding whole grain foods) to foods containing ≥51% of whole-grain ingredients by weight or ≥8 g of whole grains per one ounce (~30 g)-serving size (4). An international multidisciplinary expert group recently proposed to label "whole grain" a food with a whole-grain content of ≥8 g per ounce (5). Yet, to date, most epidemiological studies that examined the health impact of consuming whole-grain foods have included foods containing ≥25% of whole grains and added brans by weight (6).

Type 2 diabetes mellitus

A recent meta-analysis of eight large prospective cohort studies, including 385,868 participants, have found that high versus low intakes of total grains and whole grains were associated with a significant reduction in the risk of developing type 2 diabetes mellitus (7). On the other hand, no relationship was found between refined-grain intake and diabetes in a meta-analysis of six prospective studies of 258,078 subjects (7). Specifically, the consumption of three daily servings of whole-grain foods was associated with a 32% lower risk of diabetes (see below for Examples of one serving of whole grains). Further analyses showed a significantly lower risk of diabetes with high versus low consumption of whole grains as a single food (i.e., brown rice, wheat bran) or as an ingredient in food (i.e., whole-grain bread, whole-grain breakfast cereal) but not with refined grains like white rice and wheat germ (7). In addition, a pooled analysis of three large prospective cohorts — the Health Professionals Follow-up Study [HPFS] and the Nurses’ Health Studies [NHS I and II] — reported a 17% increased risk of type 2 diabetes in participants in the highest (≥5 servings/week) versus lowest (<1 serving/month) quintile of white rice intake, while brown rice consumption (≥2 servings/week versus <1 serving/month) was associated with an 11% reduction in risk (8). Interestingly, substituting 50 g/day (⅔ serving/day) of brown rice or other whole grains for the same amount of white rice could be associated with a predicted diabetes risk reduction of 16% or more (8).

Whole grains and glucose control

Whole grains have been hypothesized to reduce the risk of type 2 diabetes mellitus by improving postprandial glycemia. Immediately after a meal, blood glucose and lipid concentrations are increased, and secretion of insulin by the pancreas stimulates glucose and lipid storage into tissues. Prolonged postprandial hyperglycemia and hyperlipidemia have been associated with oxidative stress, inflammation, insulin resistance, and endothelial dysfunction, all contributing to the development of chronic diseases like type 2 diabetes mellitus (9). The refining process that removes bran and germ facilitates the digestion of the carbohydrate-rich endosperm such that carbohydrates from refined grains were thought to elicit a higher and more rapid elevation in blood glucose, as well as a greater demand for insulin, than whole grains (10). However, compared with foods made from refined grains, whole-grain products do not necessarily have a lower glucose-raising potential, i.e., a lower glycemic index (GI) (11). The GI concept is based on the idea that foods containing carbohydrates that are easily digested, absorbed, and metabolized have a high GI (GI ≥70 on the glucose scale); in contrast, foods containing slowly digestible carbohydrates that elicit a reduced postprandial glucose response are considered to have a low GI (GI ≤55 on the glucose scale) (see also the article on Glycemic Index and Glycemic Load) (12). Bread, breakfast cereal, rice, and snack products have been attributed either a low or high GI, whether or not they include whole grains (11), suggesting that the type of food rather than its whole-grain content affects postprandial blood glucose concentrations.

In some observational studies, higher whole-grain intakes have been associated with decreased insulin resistance (13) and increased insulin sensitivity (14) in healthy individuals. In a controlled cross-over trial in 11 overweight or obese adults, consumption of a diet rich in whole grains for six weeks lowered several clinical measures of insulin resistance compared with a diet high in refined grains (15). However, in a recent randomized controlled study of 61 adults with metabolic syndrome, the consumption of a diet based on several whole-grain cereal products for 12 weeks had no effect on fasting plasma concentrations of glucose, insulin, lipids, or on insulin resistance compared with a refined grain-based diet. Yet, postprandial plasma insulin and triglycerides — but not postprandial plasma glucose — were significantly reduced with the whole grain-based diet (16). A decreased postprandial insulin response may be associated with an increase in tissue sensitivity to insulin (3). In another intervention trial in 20 healthy volunteers, three-day consumption of whole barley-based bread induced a lower insulin peak value following a standard breakfast than the same course with refined wheat bread. Whole barley-based bread consumption was also associated with an increase in circulating concentrations of gut-related hormones (e.g., peptide YY, glucagon-like peptide) and a higher gut fermentation activity. This suggested improvements in hormonal control of digestion and in colonic fermentation of resistant starch (indigestible fiber) (17), possibly promoting the feeling of satiety (18) and increasing insulin sensitivity (19).

Whole-grain consumption might be improving insulin sensitivity rather than blunting postprandial hyperglycemia; however, well-designed, large randomized controlled trials are necessary to provide further insight into how whole-grain consumption may protect against type 2 diabetes.

Cardiovascular disease

A meta-analysis of 10 large prospective cohort studies published between 1998 and 2010 found that the highest intake of whole grains (about three servings daily) was associated with an overall 21% reduced risk of cardiovascular disease (CVD), including coronary heart disease (CHD), ischemic heart disease, heart failure, and ischemic stroke, when compared to the lowest intake of whole grains and after adjustment for several CVD risk factors (20). Further, although evidence is currently limited, whole-grain intake may be associated with a reduced risk of hypertension, a risk factor for cardiovascular disease (21, 22).

Compared to refined grains, whole grains are rich in nutrients associated with cardiovascular risk reduction. In the Health Professionals Follow-up Study (HPFS) in 42,850 men, the top versus bottom quintile (49.6 g/day vs. 3.3 g/day) of whole-grain intake was associated with a 16% reduced risk of CHD after multiple adjustments for age, gender, and CHD risk factors (23). Further adjustments for whole-grain constituents, such as fiber, folate, magnesium, manganese, vitamin B6 and vitamin E, attenuated the association such that it was no longer statistically significant, suggesting that the micronutrient and fiber content may explain the cardiovascular benefits of consuming whole grains. Protective cardiovascular effects associated with higher intakes of whole grains and lower intakes of refined grains have included improvements in blood lipid profiles and reductions in markers of subclinical inflammation.

Whole grains and cardiometabolic markers

A meta-analysis of 21 randomized controlled trials indicated that whole-grain interventions for 4 to 16 weeks could improve an individual’s blood concentrations of fasting glucose, insulin, total and LDL-cholesterol, as well as reduce diastolic and systolic blood pressure (20).  Consistent with this, a recently updated meta-analysis of 23 randomized controlled trials published between 1988 and 2015 indicated that consumption of whole grains (28 g/day-213 g/day for 2 to 16 weeks), especially whole-grain oats in cereal and other products, for a couple of weeks resulted in significant reductions in blood concentrations of triglycerides and total and LDL-cholesterol when compared to control diets with refined grain (24). Interventions that included mixed whole-grain products (bread, muesli, ready-to-eat cereal, pasta, rice, crisps, muffins, cookies) also improved blood HDL-cholesterol concentrations (24). In addition, although wheat fiber has not been found to lower serum cholesterol concentrations, numerous clinical studies have demonstrated that increasing intakes of oat fiber and soluble fiber from barley resulted in modest reductions in total and LDL-cholesterol (25-27). In light of such findings, the US Food and Drug Administration (FDA) approved claims regarding whole grains and reduction in risk of CHD that apply to diets low in saturated fat and cholesterol providing at least 3 g/day of β-glucan soluble fiber from oats (oat bran, rolled oats [oatmeal], whole oat flour) or whole-grain barley (28). Whole grains are also sources of phytosterols — compounds that can decrease serum cholesterol by interfering with its intestinal absorption (2).

Whole grains and inflammation markers

Evidence from observational studies suggested an inverse association between whole-grain intake and chronic low-grade inflammation that characterizes cardiovascular and metabolic diseases (29). However, intervention studies have provided mixed results. In a recent cross-over trial in healthy low whole-grain consumers, the effect of increased consumption of mixed whole grains (mean intake, 168 g/day) for six weeks was compared to whole-grain consumption of less than 16 g/day. Increasing whole-grain intake had no effect on absolute counts of immune cells in blood (leukocytes, lymphocytes, natural killer cells), on ex vivo phagocytic activities of these cells, or on markers of inflammation (e.g., IL-10, TNF-α, C-reactive protein [CRP]) in blood (30). Previous randomized controlled studies in healthy normal weight, overweight, or obese subjects have also failed to demonstrate any benefits of whole-grain intake on markers of inflammation (31-35). One eight-week dietary intervention study in 80 overweight or obese subjects found that replacement of refined products in the habitual diet by whole-grain wheat products resulted in a significant reduction in pro-inflammatory cytokine TNF-α, a transient increase in anti-inflammatory IL-10, and no change in CRP compared to intake of refined wheat (36). In another randomized cross-over intervention study, overweight/obese children (ages, 8-15 years) were provided with a list of whole-grain products and asked to either obtain half of their grain servings from whole-grain foods every day for six weeks (whole-grain group) or abstain from consuming any of these foods (control group). Mean daily consumption of 98 g of whole-grain products (compared to 11 g/day) resulted in reductions in serum concentrations of CRP, sICAM-1 (soluble intercellular adhesion molecule-1), acute phase protein SAA (serum amyloid A), and leptin (37). An increased whole-grain intake to about five daily servings (compared to <1 serving/day) also reduced blood concentrations of CRP but had no effect on IL-10 and TNF-α concentrations in obese adults with metabolic syndrome following a hypocaloric diet (38). Inconsistency among studies may be attributed to differences in the health status of participants, the duration of interventions, and/or the types of whole grains selected. In particular, if foods with a low glycemic index (GI) can lower cardiometabolic and inflammation markers (39), substituting refined grain products by whole grains with high GI may not demonstrate any benefits regarding the risk of heart disease.

Cancer

Although the protective effects of whole grains against various types of cancer are not as well established as those against type 2 diabetes mellitus and cardiovascular disease, numerous case-control studies have found inverse associations between whole-grain intake and cancer risk (40-42). An early meta-analysis of 40 case-control studies examining 20 different types of cancer found that people with higher whole-grain intakes had an overall risk of cancer that was 34% lower than those with lesser whole-grain intakes (40). Higher intakes of whole grains were most consistently associated with decreased risk of gastrointestinal tract cancers, including cancers of the mouth, throat, esophagus, stomach, colon, and rectum. A prospective cohort study that followed more than 61,000 Swedish women for 15 years found that those who consumed more than 4.5 servings of whole grains daily had a 35% lower risk of colon cancer than those who consumed less than 1.5 servings of whole grains daily (43). In the large National Institutes of Health (NIH)-AARP Diet and Health prospective study in 291,988 men and 197,623 women, mean whole-grain intakes — much lower than in the above-mentioned Swedish cohort — were also inversely associated with risk of colorectal cancer, especially rectal cancer (44). Specifically, the highest versus lowest quintile of whole-grain intake (2.6 servings/day vs. 0.4 servings/day) was associated with a 36% lower risk of developing rectal cancer (44). In a nested case-control study, including participants of the multicenter European Prospective Investigation into Cancer and Nutrition (EPIC), the top versus bottom quartile of plasma alkylresorcinol concentrations, used as a surrogate marker of whole-grain wheat and rye intakes, was found to be associated with a 52% lower incidence of distal colon cancer. No correlations were reported with the incidence of rectal cancer, colon cancer, and proximal colon cancer, or with the overall incidence of colorectal cancers (45). Not all cohort studies have suggested that whole grains might protect against intestinal cancers (46, 47). However, a dose-response analysis based on the results of six cohort studies found a 17% reduction in colorectal cancer risk with an increment of three servings (three oz-eq or 90 g) of whole grains daily (48). Of note, a recent analysis of three Scandinavian cohorts that are also part of the EPIC study and include over 110,000 participants showed an inverse correlation between total whole-grain intake and esophageal cancer risk. Each 10 g-increase in whole-grain wheat intake was found to be associated with a 50% lower risk of esophageal cancer. Such an association was not observed with whole-grain rye or with whole-grain oats (49).

In contrast to refined-grain products, whole grains are rich in numerous compounds that may be protective against cancer, particularly cancers of the gastrointestinal tract (50). Whole grains are a major source of fiber, and high-fiber intakes are thought to speed up the passage of stool through the colon, allowing less time for potentially carcinogenic compounds to stay in contact with cells that line the inner surface of the colon (51). Dietary fiber can also exert chemopreventive effects via short-chain fatty acids that are generated when fiber is fermented by the colonic microbiota (52). Whole grains also contain compounds such as phenolic acids, lignans, phytoestrogens, flavonoids, and vitamin E, that may modify signal transduction pathways that promote the development of cancer or bind potentially damaging free metal ions in the gastrointestinal tract (53, 54).

Mortality

Recent large prospective cohort studies have investigated the relationship between whole-grain consumption and the risk of all-cause and cause-specific mortality. Higher versus lower intakes of whole grains (1.20 oz-eq/day versus 0.13 oz-eq/day) have been associated with a 17% lower risk of all-cause mortality in the NIH-AARP Diet and Health Study of 367,442 older adults (55). Higher whole-grain intakes were significantly associated with a decreased risk of mortality from cardiovascular disease (-17%), cancer (-15%), type 2 diabetes mellitus (-48%), respiratory disease (-11%), and infections (-23%). These associations were largely attenuated after adjustments for cereal fiber intakes, suggesting a major role for fiber in the protective effects of whole grains on mortality (55). Another recent analysis of two US prospective cohort studies, the Nurses’ Health Study (NHS) in 74,341 women and the Health Professionals Follow-up Study (HPFS) in 43,744 men, reported a 9% lower risk of all-cause mortality in individuals in the highest versus lowest quintile of whole-grain intake (56). Higher whole-grain consumption was associated with a 15% lower risk of cardiovascular disease-related mortality, but no correlation was found with cancer-related mortality. Finally, the association of whole-grain intake with mortality was also examined in over 110,000 participants of the Scandinavian HELGA cohort (57). In this cohort, a doubling of the consumption of whole-grain products or that of specific whole-grain wheat, rye, or oats was associated with a reduced risk of all-cause and cause-specific mortality.

These results from cohort studies in the US and northern Europe consistently suggested a role of whole-grain consumption in the prevention of early death.

Intestinal health

Diets rich in whole grains and fiber may help prevent or improve constipation symptoms by softening and adding bulk to stool and by speeding its passage through the colon (58, 59). Such diets are also associated with decreased risk of diverticulosis, a condition characterized by the formation of small pouches (diverticula) in the colon. Although most people with diverticulosis experience no symptoms, about 10%-25% may develop pain or inflammation, known as diverticulitis (58). Diverticulitis was virtually unheard of before the practice of milling (refining) flour began in industrialized countries, and the role of a low-fiber diet in the development of diverticular disease is well established (60). If high-fiber diets reduce the risk of diverticular disease (61, 62), then the source of fiber (e.g., from cereal, fruit, vegetables) may be important. Interestingly, a 5 g-increase in intake of fiber from cereal was found to be associated with a 14% reduced risk of diverticular disease in a UK-based cohort of 690,075 women (mean age, 60 years) followed for up to six years; the risk of diverticular disease was decreased by 15% and 5% with a 5 g-increase in the consumption of fruit fiber and vegetable fiber, respectively (62). High-fiber diets are also recommended for people with diverticulosis in order to prevent the formation of additional diverticula rather than to resolve formed diverticula (58). People with diverticulosis are sometimes advised to avoid eating small seeds and husks to prevent them from becoming lodged in diverticula and causing diverticulitis, especially if they do not consume a high-fiber diet (58). However, it should be noted that no study has ever shown that avoiding seeds or popcorn reduces the risk of diverticulitis in an individual with diverticulosis (60).

Body weight management

Prospective cohort studies have consistently suggested that whole-grain consumption is associated with lower body mass index (BMI) and lower risks of weight gain and obesity (6, 20). However, a recent meta-analysis of randomized controlled trials published between 1988 and 2012 reported no significant effects of whole-grain intakes (from 18.2 g/day-150 g/day for 2 to 16 weeks) on body weight (26 trials), body fat (7 studies), and waist circumference (9 studies) in up to 2,060 normal-weight or overweight/obese adults without chronic health conditions (63). In a recent randomized, open-label, controlled trial in 60 overweight/obese individuals with metabolic syndrome, the consumption of whole grains (about 6-12 servings/day) was compared to that of refined grains during a 12-week intervention period that included a weight-maintenance diet for the first six weeks followed by six weeks of a hypocaloric diet (64). Increased whole-grain intake failed to lower body weight, BMI, percentage of body fat, or waist circumference beyond reductions also observed with consumption of refined grains. Of note, individuals who consumed whole grains showed an improved fasting glycemia compared to those fed refined grains, but other cardiometabolic variables remained unchanged (64). These results contrast with other energy-restricted dietary interventions showing a more favorable effect of whole grains on percentage of body fat compared to refined grains (38, 65). Further investigation is warranted to clarify whether whole-grain consumption could play a role in body weight regulation.

Intake Recommendations

Whole-grain intakes approaching three servings daily are associated with significant reductions in chronic disease risk in populations with relatively low whole-grain intakes. The 2015-2020 Dietary Guidelines for Americans — issued jointly by the US Department of Health and Human Services and US Department of Agriculture — recommend that at least half of all grains consumed be whole grains and to increase whole-grain intake by replacing refined grains with whole grains (66). In the 2015-2020 Dietary Guidelines for Americans, the unit of measure of a whole-grain serving size is the ounce-equivalent (oz-eq). A whole-grain serving size corresponds to (1) one ounce (~30 g) of a 100% whole-grain food in its ready-to-eat form, (2) two ounces of partly whole-grain products, or (3) the amount of food containing 16 g of whole-grain ingredients (67). Table 1 summarizes the 2015-2020 US Dietary Guidelines for whole-grain intakes.

Table 1. 2015-2020 US Dietary Guideline Recommendations1,2 for Whole-grain Intakes (according to 66)
Life Stage Age Daily Intake (oz-eq/day)3 Daily Intake (g/day)4
Children  2-3 years  1.5-2.5 24-40
Children 4-8 years  2-3 32-48
Children  9-13 years  2.5-4.5 40-72
Adolescents  14-18 years  3-5 48-80
Adults  19 years and older 3-5 48-80

1Dietary guidelines apply when no quantitative Dietary Reference Intake (DRI) value is available.
2The recommendations are based on estimated energy needs that vary with age and gender. Recommended daily intakes of whole grains at all calorie requirement levels can be found in the '2015-2020 Dietary Guidelines for Americans' report (see Appendix 3: Healthy US-style eating pattern) (66). For example, for 2,000 calories per day, the daily recommendation for whole-grain consumption is at least three ounce-equivalents or more per day (≥3 oz-eq).
3For example, one ounce-equivalent of whole grains can correspond to one ounce (~30 g) of a 100% whole-grain food or two ounces of partly whole-grain products.
4Daily intake of whole grains based on 100% whole-grain foods containing 16 grams of whole grains per ounce-equivalent (16 g/oz-eq).

The US National Health and Nutrition Examination Survey (NHANES) 2009-2010 reported mean whole-grain intakes of 0.57 oz-eq/day in children and adolescents and 0.82 oz-eq/day in adults (68). Approximately 40% of Americans consume no whole grains, and only 2.9% of children/adolescents and 7.7% of adults consume ≥3 oz-eq/day of whole grains (68). In view of the potential health benefits of increasing whole-grain intake, three daily servings of whole-grain foods should be seen as a minimum amount, and whole-grain foods should be substituted for refined carbohydrates whenever possible.

Examples of one serving of whole grains

  • 1 slice of whole-grain bread
  • ½ whole-grain English muffin, bagel, or bun
  • 1 ounce of ready to eat whole-grain cereal
  • ½ cup of oatmeal, brown rice, or whole-wheat pasta (cooked)
  • 5-6 whole-grain crackers
  • 1 tortilla (6" diameter)
  • 1 pancake (5" diameter)

Increasing whole-grain intake

Finding whole-grain foods

Whole-grain foods may contain amaranth, whole-grain barley, brown and wild rice, buckwheat (kasha), millet, oats, popcorn, quinoa, whole rye, triticale, whole wheat (wheat berries) with various wheat species (including common wheat, emmer, spelt, and khorasan) (69). Unfortunately, it is not always clear from the label whether a product is made mostly from whole grains or refined grains. Some strategies to use when shopping for whole-grain foods include:

  • Look for products that list whole grain(s) as the first ingredient(s).
  • Look for whole-grain products that contain at least 2 grams of fiber per serving, since whole-grain foods are usually rich in fiber.
  • Look for products that display the following health claim: "Diets rich in whole grain foods and other plant foods and low in total fat, saturated fat, and cholesterol may help reduce the risk of heart disease and certain cancers." Products displaying this health claim must contain at least 51% whole grain by weight or at least 8 grams of whole grains per ounce-equivalent (4).
  • Look for whole-wheat pasta that lists whole-wheat flour as the first ingredient. Most pasta is made from refined semolina or durum wheat flour.
  • Be aware that foods labeled with words like "multi-grain," "stone-ground," "100% wheat," "seven-grain," "cracked wheat," or "bran" are usually not 100% whole-grain products or can even be completely devoid of any whole grains (1).
Some strategies for increasing whole-grain intake
  • Eat whole-grain breakfast cereal, such as wheat flakes, shredded wheat, muesli (rolled oats), and oatmeal. Bran cereal is not actually whole-grain cereal, but the high-fiber content makes it a good breakfast choice.
  • Substitute whole-grain bread, rolls, tortillas, and crackers for those made from refined grains.
  • Substitute whole-wheat pasta or pasta made from 50% whole wheat and 50% white flour for conventional pastas.
  • Substitute brown rice for white rice.
  • Add whole-grain barley to soups and stews.
  • When baking, substitute whole-wheat flour (100% whole-wheat flour, white whole-wheat flour, or whole-wheat pastry flour) for white or unbleached flour.

Bioactive Components in Whole Grains

Whole grains are a source of numerous biologically active components; some are listed in Table 2.

Table 2. Some Potentially Beneficial Compounds in Whole Grains
Macronutrients Vitamins Minerals Phytochemicals
Unsaturated Fats Folate Magnesium Fiber
  Vitamin E Potassium Flavonoids
    Selenium Lignans
      Phytosterols

 


Authors and Reviewers

Originally written in 2003 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 May 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

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

Reviewed in January 2016 by:
Simin Liu, M.D., M.S., M.P.H., Sc.D.
Professor of Epidemiology, Professor of Medicine
Brown University

Copyright 2003-2017  Linus Pauling Institute 


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Glycemic Index and Glycemic Load

Summary

  • The glycemic index (GI) is a measure of the blood glucose-raising potential of the carbohydrate content of a food compared to a reference food (generally pure glucose). Carbohydrate-containing foods can be classified as high- (≥70), moderate- (56-69), or low-GI (≤55) relative to pure glucose (GI=100). (More information)
  • Consumption of high-GI foods causes a sharp increase in postprandial blood glucose concentration that declines rapidly, whereas consumption of low-GI foods results in a lower blood glucose concentration that declines gradually. (More information)
  • The glycemic load (GL) is obtained by multiplying the quality of carbohydrate in a given food (GI) by the amount of carbohydrate in a serving of that food. (More information)
  • Prospective cohort studies found high-GI or -GL diets to be associated with a higher risk of adverse health outcomes, including type 2 diabetes mellitus and cardiovascular disease. (More information)
  • Meta-analyses of observational studies have found little-to-no evidence of an association between high dietary GI and GL and risk of cancer. (More information)
  • Lowering the GL of the diet may be an effective method to improve glycemic control in individuals with type 2 diabetes mellitus. This approach is not currently included in the overall strategy of diabetes management in the US. (More information)
  • Several dietary intervention studies found that low-GI/GL diets were as effective as conventional, low-fat diets in reducing body weight. Both types of diets resulted in beneficial effects on metabolic markers associated with the risk of type 2 diabetes mellitus and cardiovascular disease. (More information)
  • Lowering dietary GL can be achieved by increasing the consumption of whole grains, nuts, legumes, fruit, and non-starchy vegetables, and decreasing intakes of moderate- and high-GI foods like potatoes, white rice, white bread, and sugary foods. (More information)

Glycemic Index

Glycemic index of individual foods

In the past, carbohydrates were classified as simple or complex based on the number of simple sugars in the molecule. Carbohydrates composed of one or two simple sugars like fructose or sucrose (table sugar; a disaccharide composed of one molecule of glucose and one molecule of fructose) were labeled simple, while starchy foods were labeled complex because starch is composed of long chains of the simple sugar, glucose. Advice to eat less simple and more complex carbohydrates (i.e., polysaccharides) was based on the assumption that consuming starchy foods would lead to smaller increases in blood glucose than sugary foods (1). This assumption turned out to be too simplistic since the blood glucose (glycemic) response to complex carbohydrates has been found to vary considerably. The concept of glycemic index (GI) has thus been developed in order to rank dietary carbohydrates based on their overall effect on postprandial blood glucose concentration relative to a referent carbohydrate, generally pure glucose (2). The GI is meant to represent the relative quality of a carbohydrate-containing food. Foods containing carbohydrates that are easily digested, absorbed, and metabolized have a high GI (GI≥70 on the glucose scale), while low-GI foods (GI≤55 on the glucose scale) have slowly digestible carbohydrates that elicit a reduced postprandial glucose response. Intermediate-GI foods have a GI between 56 and 69 (3). The GI of selected carbohydrate-containing foods can be found in Table 1.

Measuring the glycemic index of foods

To determine the glycemic index (GI) of a food, healthy volunteers are typically given a test food that provides 50 grams (g) of carbohydrate and a control food (white, wheat bread or pure glucose) that provides the same amount of carbohydrate, on different days (4). Blood samples for the determination of glucose concentrations are taken prior to eating, and at regular intervals for a few hours after eating. The changes in blood glucose concentration over time are plotted as a curve. The GI is calculated as the incremental area under the glucose curve (iAUC) after the test food is eaten, divided by the corresponding iAUC after the control food (pure glucose) is eaten. The value is multiplied by 100 to represent a percentage of the control food (5):

GI =  (iAUCtest food/iAUCglucose) x 100

For example, a boiled white potato has an average GI of 82 relative to glucose and 116 relative to white bread, which means that the blood glucose response to the carbohydrate in a baked potato is 82% of the blood glucose response to the same amount of carbohydrate in pure glucose and 116% of the blood glucose response to the same amount of carbohydrate in white bread. In contrast, cooked brown rice has an average GI of 50 relative to glucose and 69 relative to white bread. In the traditional system of classifying carbohydrates, both brown rice and potato would be classified as complex carbohydrates despite the difference in their effects on blood glucose concentrations.

While the GI should preferably be expressed relative to glucose, other reference foods (e.g., white bread) can be used for practical reasons as long as their preparation has been standardized and they have been calibrated against glucose (2). Additional recommendations have been suggested to improve the reliability of GI values for research, public health, and commercial application purposes (2, 6).

Physiological responses to high- versus low-glycemic index foods

By definition, the consumption of high-GI foods results in higher and more rapid increases in blood glucose concentrations than the consumption of low-GI foods. Rapid increases in blood glucose (resulting in hyperglycemia) are potent signals to the β-cells of the pancreas to increase insulin secretion (7). Over the next few hours, the increase in blood insulin concentration (hyperinsulinemia) induced by the consumption of high-GI foods may cause a sharp decrease in the concentration of glucose in blood (resulting in hypoglycemia). In contrast, the consumption of low-GI foods results in lower but more sustained increases in blood glucose and lower insulin demands on pancreatic β-cells (8).

Glycemic index of a mixed meal or diet

Many observational studies have examined the association between GI and risk of chronic disease, relying on published GI values of individual foods and using the following formula to calculate meal (or diet) GI (9):

Meal GI = [(GI x amount of available carbohydrate)Food A + (GI x amount of available carbohydrate)Food B +…]/ total amount of available carbohydrate

Yet, the use of published GI values of individual foods to estimate the average GI value of a meal or diet may be inappropriate because factors such as food variety, ripeness, processing, and cooking are known to modify GI values. In a study by Dodd et al., the estimation of meal GIs using published GI values of individual foods was overestimated by 22 to 50% compared to direct measures of meal GIs (9).

Besides the GI of individual foods, various food factors are known to influence the postprandial glucose and insulin responses to a carbohydrate-containing mixed diet. A recent cross-over, randomized trial in 14 subjects with type 2 diabetes mellitus examined the acute effects of four types of breakfasts with high- or low-GI and high- or low-fiber content on postprandial glucose concentrations. Plasma glucose was found to be significantly higher following consumption of a high-GI and low-fiber breakfast than following a low-GI and high-fiber breakfast. However, there was no significant difference in postprandial glycemic responses between high-GI and low-GI breakfasts of similar fiber content (10). In this study, meal GI values (derived from published data) failed to correctly predict postprandial glucose response, which appeared to be essentially influenced by the fiber content of meals. Since the amounts and types of carbohydrate, fat, protein, and other dietary factors in a mixed meal modify the glycemic impact of carbohydrate GI values, the GI of a mixed meal calculated using the above-mentioned formula is unlikely to accurately predict the postprandial glucose response to this meal (3). Moreover, the GI is a property of a given food carbohydrate such that it does not take into account individuals’ characteristics like ethnicity, metabolic status, or eating habits (e.g., the degree to which we masticate) which might, to a limited extent, also influence the glycemic response to a given carbohydrate-containing meal (11-14).

Using direct measures of meal GIs in future trials — rather than estimates derived from GI tables — would increase the accuracy and predictive value of the GI method (2, 6). In addition, in a recent meta-analysis of 28 studies examining the effect of low- versus high-GI diets on serum lipids, Goff et al. indicated that the mean GI of low-GI diets varied from 21 to 57 across studies, while the mean GI of high-GI diets ranged from 51 to 75 (15). Therefore, a stricter use of GI cutoff values may also be warranted to provide more reliable information about carbohydrate-containing foods.

Glycemic Load

The glycemic index (GI) compares the potential of foods containing the same amount of carbohydrate to raise blood glucose. However, the amount of carbohydrate contained in a food serving also affects blood glucose concentrations and insulin responses. For example, the mean GI of watermelon is 76, which is as high as the GI of a doughnut (see Table 1). Yet, one serving of watermelon provides 11 g of available carbohydrate, while a medium doughnut provides 23 g of available carbohydrate.

The concept of glycemic load (GL) was developed by scientists to simultaneously describe the quality (GI) and quantity of carbohydrate in a food serving, meal, or diet. The GL of a single food is calculated by multiplying the GI by the amount of carbohydrate in grams (g) provided by a food serving and then dividing the total by 100 (4):

GLFood = (GIFood x amount (g) of available carbohydrateFood per serving)/100

For a typical serving of a food, GL would be considered high with GL≥20, intermediate with GL of 11-19, and low with GL≤10. Using the above-mentioned example, despite similar GIs, one serving of watermelon has a GL of 8, while a medium-sized doughnut has a GL of 17. Dietary GL is the sum of the GLs for all foods consumed in the diet.

It should be noted that while healthy food choices generally include low-GI foods, this is not always the case. For example, intermediate-to-high-GI foods like parsnip, watermelon, banana, and pineapple, have low-to-intermediate GLs (see Table 1).

Disease Prevention

Type 2 diabetes mellitus

The consumption of high-GI and -GL diets for several years might result in higher postprandial blood glucose concentration and excessive insulin secretion. This might contribute to the loss of insulin-secreting function pancreatic β-cells and lead to irreversible type 2 diabetes mellitus (16).

A US ecologic study of national data from 1909 to 1997 found that the increased consumption of refined carbohydrates in the form of corn syrup, coupled with the declining intake of dietary fiber, has paralleled the increased prevalence of type 2 diabetes (17). In addition, high-GI and -GL diets have been associated with an increased risk of type 2 diabetes in several large prospective cohort studies. A recent updated analysis of three large US cohorts indicated consumption of foods with the highest versus lowest GI was associated with a risk of developing type 2 diabetes that was increased by 44% in the Nurses’ Health Study (NHS) I, 20% in the NHS II, and 30% in the Health Professionals Follow-up Study (HPFS). High-GL diets were associated with an increased risk of type 2 diabetes (+18%) only in the NHS I and in the pooled analysis of the three studies (+10%) (18). Additionally, the consumption of high-GI foods that are low in cereal fiber was associated with a 59% increase in diabetes risk compared to low-GI and high-cereal-fiber foods. High-GL and low-cereal-fiber diets were associated with a 47% increase in risk compared to low-GL and high-cereal-fiber diets. Moreover, obese participants who consumed foods with high-GI or -GL values had a risk of developing type 2 diabetes that was more than 10-fold greater than lean subjects consuming low-GI or -GL diets (18).

However, a number of prospective cohort studies have reported a lack of association between GI or GL and type 2 diabetes (19-24). The use of GI food classification tables based predominantly on Australian and American food products might be a source of GI value misassignment and partly explain null associations reported in many prospective studies of European and Asian cohorts.

Nevertheless, conclusions from several recent meta-analyses of prospective studies (including the above-mentioned studies) suggest that low-GI and -GL diets might have a modest but significant effect in the prevention of type 2 diabetes (18, 25, 26). Organizations like Diabetes UK (27) and the European Association for the Study of Diabetes (28) have included the use of diets of low GI/GL and high in dietary fiber and whole grains in their recommendations for diabetes prevention in high-risk individuals. The use of GI and GL is currently not implemented in US dietary guidelines (29).

Cardiovascular disease

Observational studies

Numerous observational studies have examined the relationship between dietary GI/GL and the incidence of cardiovascular events, especially coronary heart disease (CHD) and stroke. A meta-analysis of 14 prospective cohort studies (229,213 participants; mean follow-up of 11.5 years) found a 13% and 23% increased risk of cardiovascular disease (CVD) with high versus low dietary GI and GL, respectively (30). Three independent meta-analyses of prospective studies also reported that higher GI or GL was associated with increased risk of CHD in women but not in men (31-33). A recent analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) study in 20,275 Greek participants, followed for a median of 10.4 years, showed a significant increase in CHD incidence and mortality with high dietary GL specifically in those with high BMI (≥28 kg/m2) (34). This is in line with earlier findings in the Nurses’ Health Study (NHS) showing that a high dietary GL was associated with a doubling of the risk of CHD over 10 years in women with higher (≥23 kg/m2) vs. lower BMI (35). A similar finding was reported in a cohort of middle-aged Dutch women followed for nine years (36).

Additionally, high dietary GL (but not GI) was associated with a 19% increased risk of stroke in pooled analyses of prospective cohort studies (32, 37). A meta-analysis of seven prospective studies (242,132 participants; 3,255 stroke cases) found that dietary GL was associated with an overall 23% increase in risk of stroke and a specific 35% increase in risk of ischemic stroke; GL was not found to be related to hemorrhagic stroke (38).

Overall, observational studies have found that higher glycemic load diets are associated with increased risk of cardiovascular disease, especially in women and in those with higher BMIs.

GI/GL and cardiometabolic markers

The GI/GL of carbohydrate foods may modify cardiometabolic markers associated with CVD risk. A meta-analysis of 27 randomized controlled trials (published between 1991 and 2008) examining the effect of low-GI diets on serum lipid profile reported a significant reduction in total and LDL-cholesterol independent of weight loss (15). Yet, further analysis suggested significant reductions in serum lipids only with the consumption of low-GI diets with high fiber content. In a three-month, randomized controlled study, an increase in the values of flow-mediated dilation (FMD) of the brachial artery, a surrogate marker of vascular health, was observed following the consumption of a low- versus high-GI hypocaloric diet in obese subjects (39).

High dietary GLs have been associated with increased concentrations of markers of systemic inflammation, such as C-reactive protein (CRP), interleukin-6, and tumor necrosis factor-α (TNF-α) (40, 41). In a small 12-week dietary intervention study, the consumption of a Mediterranean-style, low-GL diet (without caloric restriction) significantly reduced waist circumference, insulin resistance, systolic blood pressure, as well as plasma fasting insulin, triglycerides, LDL-cholesterol, and TNF-α in women with metabolic syndrome. A reduction in the expression of the gene coding for 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, in blood cells further confirmed an effect for the low-GI diet on cholesterol homeostasis (42). Well-controlled, long-term intervention studies are needed to confirm the potential cardiometabolic benefits of low GI/GL diets in people at risk for CVD. 

Cancer

Evidence that high-GI or -GL diets are related to cancer is inconsistent. A recent meta-analysis of 32 case-control studies and 20 prospective cohort studies found modest and nonsignificant increased risks of hormone-related cancers (breast, prostate, ovarian, and endometrial cancers) and digestive tract cancers (esophageal, gastric, pancreas, and liver cancers) with high versus low dietary GI and GL (43). A significant positive association was found only between a high dietary GI and colorectal cancer (43). Yet, earlier meta-analyses of prospective cohort studies failed to find a link between high-GI or -GL diets and colorectal cancer (44-46). Another recent meta-analysis of prospective studies suggested a borderline increase in breast cancer risk with high dietary GI and GL. Adjustment for confounding factors across studies found no modification of menopausal status or BMI on the association (47). Further investigations are needed to verify whether GI and GL are associated with various cancers.

Gallbladder disease

Results of two studies indicate GI and GL may be related to gallbladder disease: a higher dietary GI and GL were associated with significantly increased risks of developing gallstones in a cohort of men participating in the Health Professionals Follow-up Study (48) and in a cohort of women participating in the Nurses’ Health Study (49). However, more epidemiological research is needed to determine an association between dietary glycemic index/load and gallbladder disease.

Disease Treatment

Diabetes mellitus

Whether low-GI foods could improve overall blood glucose control in people with type 1 or type 2 diabetes mellitus has been investigated in a number of intervention studies. A meta-analysis of 19 randomized controlled trials that included 840 diabetic patients (191 with type 1 diabetes and 649 with type 2 diabetes) found that consumption of low-GI foods improved short-term and long-term control of blood glucose concentrations, reflected by significant decreases in fructosamine and glycated hemoglobin (HbA1c) levels (50). However, these results need to be cautiously interpreted because of significant heterogeneity among the included studies. The American Diabetes Association has rated poorly the current evidence supporting the substitution of low-GL foods for high-GL foods to improve glycemic control in adults with type 1 or type 2 diabetes (51, 52). Well-controlled studies are needed to further assess whether the use of low-GI/GL diets could significantly improve long-term glycemic control and the quality of life of subjects with diabetes.

A randomized controlled study in 92 pregnant women (20-32 weeks) diagnosed with gestational diabetes found no significant effects of a low-GI diet on maternal metabolic profile (e.g., blood concentrations of glucose, insulin, fructosamine, HbA1c; insulin resistance) and pregnancy outcomes (i.e., maternal weight gain and neonatal anthropometric measures) compared to a conventional high-fiber, moderate-GI diet (53). The low-GI diet consumed during the pregnancy also failed to improve maternal glucose tolerance, insulin sensitivity, and other cardiovascular risk factors, or maternal and infant anthropometric data in a three-month postpartum follow-up study of 55 of the mother-infant pairs (54). In addition, another trial in 139 pregnant women (12-20 weeks’ gestation) at high risk for gestational diabetes showed no statistical differences regarding the diagnosis of gestational diabetes during the second and third trimester of pregnancy, the requirement for insulin therapy, and pregnancy outcomes and neonatal anthropometry whether women followed a low-GI diet or a high-fiber, moderate-GI diet (55). At present, there is no evidence that a low-GI diet provides benefits beyond those of a healthy, moderate-GI diet in women at high risk or affected by gestational diabetes.

Obesity

Obesity is often associated with metabolic disorders, such as hyperglycemia, insulin resistance, dyslipidemia, and hypertension, which place individuals at increased risk for type 2 diabetes mellitus, cardiovascular disease, and early death (56, 57). Traditionally, weight-loss strategies have included energy-restricted, low-fat, high-carbohydrate diets with >50% of calories from carbohydrates, ≤30% from fat, and the remainder from protein. However, a recent meta-analysis of randomized controlled intervention studies (≥6 months’ duration) has reported that low- or moderate-carbohydrate diets (4%-45% carbohydrate) and low-fat diets (10%-30% fat) were equally effective at reducing body weight and waist circumference in overweight or obese subjects (58).

Low-GI/GL diet versus moderate-GI/GL, low-fat diet

Several dietary intervention studies have examined how low-GI/GL diets compared with conventional low-fat diets to promote weight loss. Lowering the GI of conventional energy-restricted, low-fat diets was proven to be more effective to reduce postpartum body weight and waist and hip circumferences and prevent type 2 diabetes mellitus in women with prior gestational diabetes mellitus (59). In a six-month dietary intervention study in 73 obese adults, no differences in weight loss were reported in subjects following either a low-GL diet (40% carbohydrate and 35% fat) or a low-fat diet (55% carbohydrate and 20% fat). Yet, the consumption of a low-GL diet increased HDL-cholesterol and decreased triglyceride concentrations significantly more than the low-fat diet, but LDL-cholesterol concentration was significantly more reduced with the low-fat than low-GI diet (60).

A one-year randomized controlled study of 202 individuals with a body mass index (BMI) ≥28 and at least another metabolic disorder compared the effect of two dietary counseling-based interventions advocating either for a low-GL diet (30%-35% of calories from low-GI carbohydrates) or a low-fat diet (<30% of calories from fat) (61). Weight loss with each diet was equivalent (~4 kg). Both interventions similarly reduced triglycerides, C-reactive protein (CRP), and fasting insulin, and increased HDL-cholesterol. Yet, the reduction in waist and hip circumferences was greater with the low-fat diet, while blood pressure was significantly more reduced with the low-GL diet (61). In the GLYNDIET study, a six-month randomized dietary intervention trial, the comparison of two moderate-carbohydrate diets (42% of calories from carbohydrates) with different GIs (GI of 34 or GI of 62) and a low-fat diet (30% of calories from fat; GI of 65) on weight loss indicated that the low-GI diet reduced body weight more effectively than the low-fat diet. Additionally, the low-GI diet improved fasting insulin concentration, β-cell function, and insulin resistance better than the low-fat diet. None of the diets modulated hunger or satiety or affected biomarkers of endothelial function or inflammation. Finally, no significant differences were observed in low- compared to high-GL diets regarding weight loss and insulin metabolism (62).

Low-GI/GL diet versus high-GI/GL diet

In a meta-analysis of 14 randomized controlled trials published between 2005 and 2011, neither high- nor low-GI/GL dietary interventions conducted for 6 to 17 months had any significant effect on body weight and waist circumference in a total of 2,344 overweight and obese subjects (63). Low-GI/GL diets were found to significantly reduce C-reactive protein and fasting insulin but had no effect on blood lipid profile, fasting glucose concentration, or HbA1c concentration compared to high-GI/GL diets.

It has been suggested that the consumption of low-GI foods delayed the return of hunger, decreased subsequent food intake, and increased satiety when compared to high-GI foods (64). The effect of isocaloric low- and high-GI test meals on the activity of brain regions controlling appetite and eating behavior was evaluated in a small randomized, blinded, cross-over study in 12 overweight or obese men (65). During the postprandial period, blood glucose and insulin rose higher after the high-GI meal than after the low-GI meal. In addition, in response to the excess insulin secretion, blood glucose dropped below fasting concentrations three to five hours after high-GI meal consumption. Cerebral blood flow was significantly higher four hours after ingestion of the high-GI meal (compared to a low-GI meal) in a specific region of the striatum (right nucleus accumbens) associated with food intake reward and craving. If the data suggested that consuming low- rather than high-GI foods may help restrain overeating and protect against weight gain, this has not yet been confirmed in long-term randomized controlled trials. In the recent multicenter, randomized controlled Diet, Obesity, and Genes (DiOGenes) study in 256 overweight and obese individuals who lost ≥8% of body weight following an eight-week calorie-restricted diet, consumption of ad libitum diets with different protein and GI content for 12 months showed that only high-protein diets — regardless of their GI — could mitigate weight regain (66). However, the dietary interventions only achieved a modest difference in GI (~5 units) between high- and low-GI diets such that the effect of GI in weight maintenance remained unknown.

Lifestyle modification programs do not currently include the reduction of calories from carbohydrate as an alternative to standard prescription of low-fat diets, nor do they suggest the use of GI/GL as a guide to healthier dietary choices (67).

Lowering Dietary Glycemic Load

Some strategies for lowering dietary GL include:

• Increasing the consumption of whole grains, nuts, legumes, fruit, and nonstarchy vegetables
• Decreasing the consumption of starchy, moderate- and high-GI foods like potatoes, white rice, and white bread
• Decreasing the consumption of sugary foods like cookies, cakes, candy, and soft drinks

Table 1 includes GI and GL values of selected foods relative to pure glucose (68). Foods are ranked in descending order of their GI values, with high-GI foods (GI≥70) at the top and foods with low-GI values (≤55) at the bottom of the table. To look up the GI values for other foods, visit the University of Sydney’s GI website.

Table 1. GI and GL Values for Selected Foods
Food GI
(Glucose=100)
Serving Size Carbohydrate* per Serving (g) GL per Serving
Russet potato, baked
111
1 medium
30
33
Potato, white, boiled (average)
82
1 medium
30
25
Puffed rice cakes
82
3 cakes
21
17
Cornflakes
79
1 cup
26
20
Jelly beans
78
1 oz
28
22
Doughnut
76
1 medium
23
17
Watermelon
76
1 cup
11
8
Soda crackers
74
4 crackers
17
12
Bread, white-wheat flour
71
1 large slice
14
10
Pancake
67
6" diameter
58
39
Rice, white, boiled
66
1 cup
53
35
Table sugar (sucrose)
63
2 tsp
10
6
Dates, dried
62
2 oz
40
25
Spaghetti, white, boiled (20 min)
58
1 cup
44
25
Honey, pure
58
1 Tbsp
17
10
Pineapple, raw
58
½ cup
19
11
Banana, raw
55
1 cup
24
13
Maple syrup, Canadian
54
1 Tbsp
14
7
Parsnips, peeled, boiled
52
½ cup
10
5
Rice, brown, boiled
50
1 cup
42
20
Spaghetti, white, boiled (average)
46
1 cup
44
20
Whole-grain pumpernickel bread
46
1 large slice
12
5
All-Bran™ cereal
45
1 cup
21
10
Spaghetti, whole-meal, boiled
32
1 cup
37
14
Orange, raw
42
1 medium
11
5
Apple, raw
39
1 medium
15
6
Pear, raw
38
1 medium
11
4
Skim milk
33
8 fl oz
13
4
Carrots, boiled
33
½ cup
4
1
Lentils, dried, boiled
29
1 cup
24
7
Kidney beans, dried, boiled
28
1 cup
29
8
Pearled barley, boiled
28
1 cup
38
11
Cashews
25
1 oz
9
2
Peanuts
18
1 oz
6
1
*Amount of available carbohydrates in a food serving that excludes indigestible carbohydrates, i.e., dietary fiber.

Authors and Reviewers

Originally written in 2003 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 February 2009 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

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

Reviewed in March 2016 by:
Simin Liu, M.D., M.S., M.P.H., Sc.D.
Professor of Epidemiology, Professor of Medicine
Brown University

Copyright 2003-2017  Linus Pauling Institute 


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43.  Turati F, Galeone C, Gandini S, et al. High glycemic index and glycemic load are associated with moderately increased cancer risk. Mol Nutr Food Res. 2015;59(7):1384-1394.  (PubMed)

44.  Aune D, Chan DS, Lau R, et al. Carbohydrates, glycemic index, glycemic load, and colorectal cancer risk: a systematic review and meta-analysis of cohort studies. Cancer Causes Control. 2012;23(4):521-535.  (PubMed)

45.  Choi Y, Giovannucci E, Lee JE. Glycaemic index and glycaemic load in relation to risk of diabetes-related cancers: a meta-analysis. Br J Nutr. 2012;108(11):1934-1947.  (PubMed)

46.  Mulholland HG, Murray LJ, Cardwell CR, Cantwell MM. Glycemic index, glycemic load, and risk of digestive tract neoplasms: a systematic review and meta-analysis. Am J Clin Nutr. 2009;89(2):568-576.  (PubMed)

47.  Mullie P, Koechlin A, Boniol M, Autier P, Boyle P. Relation between breast cancer and high glycemic index or glycemic load: a meta-analysis of prospective cohort studies. Crit Rev Food Sci Nutr. 2016;56(1):152-159.  (PubMed)

48.  Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Dietary carbohydrates and glycaemic load and the incidence of symptomatic gall stone disease in men. Gut. 2005;54(6):823-828.  (PubMed)

49.  Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Glycemic load, glycemic index, and carbohydrate intake in relation to risk of cholecystectomy in women. Gastroenterology. 2005;129(1):105-112.  (PubMed)

50.  Wang Q, Xia W, Zhao Z, Zhang H. Effects comparison between low glycemic index diets and high glycemic index diets on HbA1c and fructosamine for patients with diabetes: A systematic review and meta-analysis. Prim Care Diabetes. 2015;9(5):362-369.  (PubMed)

51.  Evert AB, Boucher JL. New diabetes nutrition therapy recommendations: what you need to know. Diabetes Spectr. 2014;27(2):121-130.  (PubMed)

52.  Evert AB, Boucher JL, Cypress M, et al. Nutrition therapy recommendations for the management of adults with diabetes. Diabetes Care. 2014;37 Suppl 1:S120-143.  (PubMed)

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54.  Louie JC, Markovic TP, Ross GP, Foote D, Brand-Miller JC. Effect of a low glycaemic index diet in gestational diabetes mellitus on post-natal outcomes after 3 months of birth: a pilot follow-up study. Matern Child Nutr. 2015;11(3):409-414.  (PubMed)

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Coffee

Summary

  • Coffee is a complex mixture of chemicals that provides significant amounts of chlorogenic acid and caffeine. (More information)
  • Unfiltered coffee is a significant source of diterpenes (mainly cafestol and kahweol) that appear to raise serum total and LDL-cholesterol concentrations in humans. (More information)
  • The results of observational studies suggest that coffee consumption is associated with lower risks of type 2 diabetes mellitus, Parkinson’s disease, liver disease, and mortality. However, it is premature to recommend coffee consumption for disease prevention based on this evidence. (More information)
  • Coffee consumption has been associated with lower risks of cirrhosis, cirrhosis-related mortality, and liver cancer. Coffee consumption was also found to be inversely associated with the risk of oral/pharyngeal cancer, colon cancer, prostate cancer, endometrial cancer, and melanoma. Evidence also suggests that coffee consumption is not a risk factor for lung cancer. (More information)
  • Despite evidence from clinical trials that caffeine in coffee can increase blood pressure, most prospective cohort studies have not found moderate coffee consumption to be associated with increased risk of cardiovascular disease. (More information)
  • Caffeine intake comparable to the amount in 2-3 cups of coffee may raise blood pressure, especially in people with borderline or high blood pressure. However, regular coffee consumption in hypertensive subjects has not been associated with an increased risk of cardiovascular disease. (More information)
  • Current evidence from dose-response meta-analyses of observational studies does not exclude that moderate maternal coffee consumption could adversely affect fetal growth during pregnancy. Limiting intakes of caffeinated coffee to ≤1 cup/day during pregnancy and 2-3 cups/day during breast-feeding is recommended. (More information)
  • Ensuring adequate calcium and vitamin D intakes and limiting coffee consumption to 3 cups/day (~300 mg/day of caffeine) are unlikely to cause any adverse effects on calcium absorption and bone health. (More information)
  • Overall, there is little evidence of health risks and some evidence of health benefits for adults consuming moderate amounts of filtered coffee (3-4 cups/day providing ~300-400 mg/day of caffeine). (More information)

Introduction

Coffee, an infusion of ground, roasted coffee beans, is among the most widely consumed beverages in the world. The main types of coffee consumed are (1) boiled unfiltered coffee, (2) filtered coffee, and (3) decaffeinated coffee (1). Although caffeine has received the most attention from scientists, coffee is a complex mixture of many chemicals, including carbohydrates, lipids (fats), amino acids, vitamins, minerals, alkaloids, and phenolic compounds (2). The composition of coffee varies with the source of coffee beans (Coffea arabica or Coffea canephora var. robusta) (3), as well as with the method of preparation (i.e., filtration methods, boiling, steeping, or brewing under pressure) (1, 4).

Some Bioactive Compounds in Coffee

Chlorogenic acids

Chlorogenic acids are a family of esters formed between quinic acid and phenolic compounds known as cinnamic acids (mostly caffeic acid and ferulic acid) (1). The most abundant chlorogenic acid in coffee is 5-O-caffeoylquinic acid, an ester formed between quinic acid and caffeic acid (Figure 1). Coffee represents one of the richest dietary sources of chlorogenic acids. The chlorogenic acid content of a 200 mL (7-oz) cup of coffee has been reported to range from 70 to 350 mg, which would provide about 35 to 175 mg of caffeic acid. Although chlorogenic and caffeic acids have demonstrated antioxidant activities in vitro (5), it is unclear how much antioxidant activity they contribute in vivo because they are extensively metabolized, and the metabolites often have lower antioxidant activity than the parent compounds (6, 7). Additionally, the antioxidant capacity of coffee is attenuated by the decaffeination process, which decreases total polyphenol content (8). Other phenolic compounds in coffee, though less abundant than chlorogenic acids, include tannins, lignans, and anthocyanine (1).

Figure 1. Chemical Structure of a Chlorogenic Acid.

[Figure 1 - Click to Enlarge]

Caffeine

Caffeine (1,3,7-trimethylxanthine) is a purine alkaloid that occurs naturally in coffee beans (Figure 2). At intake levels associated with coffee consumption, caffeine appears to exert most of its biological effects through antagonism of the A1 and A2A subtypes of the adenosine receptor (1). Adenosine is an endogenous compound that modulates the response of neurons to neurotransmitters. Adenosine has mostly inhibitory effects in the central nervous system, so the effects of adenosine antagonism by caffeine are generally stimulatory. Caffeine is rapidly and almost completely absorbed in the stomach and small intestine and then distributed to all tissues, including the brain. Caffeine concentrations in coffee beverages can be quite variable. A standard cup of coffee is often assumed to provide 100 mg of caffeine, but an analysis of 14 different specialty coffees purchased at coffee shops in the US found that the amount of caffeine in 8 oz (~240 mL) of brewed coffee ranged from 72 to 130 mg (9). Caffeine in espresso coffees ranged from 58 to 76 mg in a single shot (~35 to 50 mL). In countries other than the US, coffee is often stronger, but the volume per cup is smaller, making 100 mg of caffeine/cup a reasonable estimate.

Figure 2. Chemical Structures of Caffeine and Adenosine. 

[Figure 2 - Click to Enlarge]

Diterpenes

Cafestol and kahweol are fat-soluble compounds known as diterpenes (Figure 3), which have been found to raise serum total and LDL-cholesterol concentrations in humans (10). Some cafestol and kahweol are extracted from ground coffee during brewing, but are largely removed from coffee by paper filters. Scandinavian boiled coffee, Turkish coffee, and French press (cafetiere) coffee contain relatively high levels of cafestol and kahweol (6 to 12 mg/cup), while filtered coffee, percolated coffee, and instant coffee contain low levels of cafestol and kahweol (0.2 to 0.6 mg/cup) (11). Although diterpene concentrations are relatively high in espresso coffee, the small serving size makes it an intermediate source of cafestol and kahweol (4 mg/cup). Since coffee beans are high in cafestol and kahweol, ingestion of coffee beans or grounds on a regular basis may also raise serum total and LDL-cholesterol.

 Figure 3. Chemical Structures of Two Diterpenes, Cafestol and Kahweol.

[Figure 3 - Click to Enlarge]

 

Trigonelline

Trigonelline (N-methylnicotinic acid) is a plant alkaloid derived from niacin (vitamin B3) (Figure 4). Trigonelline is largely broken down to nicotinic acid during the roasting process, although some intact molecules remain in roasted beans. Trigonelline has been found to exert antioxidant, hypoglycemic, and hypolipidemic activities (reviewed in 1).

Figure 4. Chemical Structure of Trigonelline.

[Figure 4 - Click to Enlarge]

Disease Prevention

Type 2 diabetes mellitus

Observational studies

The three largest prospective cohort studies in the US to examine the relationship between caffeinated coffee consumption and type 2 diabetes mellitus were the Health Professionals Follow-up Study ([HPFS]; 41,934 men), the Nurses’ Health Study ([NHS I]; 84,276 women), and the NHS II (88,259 women). Men who drank at least six cups of coffee daily had a 54% lower risk of developing type 2 diabetes than men who did not drink coffee. In the NHS I cohort, women who drank at least six cups of coffee daily had a 29% lower risk of type 2 diabetes than women who did not drink coffee (12). In the NHS II cohort, women who consumed ≥4 cups of coffee daily had a 39% lower risk of developing type 2 diabetes; similar results were found in women who drank 2 to 3 cups/day of coffee (13). In a pooled analysis of all three cohorts, an increase in caffeinated coffee intake by >1 cup/day over a four-year period was associated with a 13% decreased risk of type 2 diabetes in the subsequent four years; those who decreased their intake of caffeinated coffee by >1 cup/day had a 20% increased risk of type 2 diabetes over the four-year period (14).

Several other cohort studies have found higher coffee intakes to be associated with significant reductions in the risk of type 2 diabetes. A systematic review and meta-analysis of 18 prospective cohort studies (published between 1966 and 2009), including more than 450,000 men and women, found that the risk of developing type 2 diabetes was 24% lower in those consuming 3 to 4 cups/day of coffee compared to those consuming ≤2 cups/day or none (15). Two additional meta-analyses that included data from more recent prospective cohort studies were published concomitantly and found similar results (16, 17). The data analysis of 28 prospective studies in over 1 million participants with 45,335 incident cases of diabetes reported a 30% decreased risk of type 2 diabetes with coffee intake of 5 cups/day versus 0 cups/day (16). In addition, a 9% reduction in the incidence of type 2 diabetes was estimated for every one cup per day increase in total coffee intake. Likewise, a dose-response analysis of 11 studies found a 6% reduction in type 2 diabetes incidence for every one cup per day increase in decaffeinated coffee intake. Every 140 mg/day (~1 cup/day of coffee) increment in caffeine intake was also associated with an 8% reduction in the risk of type 2 diabetes (16). Although decaffeinated coffee consumption is associated with a more modest decrease in the risk of type 2 diabetes, it is likely that compounds other than caffeine contribute to the reduction in diabetes risk.

Intervention studies

The mechanisms that might contribute to the association between coffee consumption and lower risk of type 2 diabetes in prospective cohort studies are unclear. Bioactive compounds other than caffeine appear to show temporary hypoglycemic effects. For example, the acute ingestion of chlorogenic acid (1 g) and trigonelline (0.5 g) transiently lowered blood glucose concentration shortly after the administration of 75 g of glucose in an oral glucose tolerance test (18). Conversely, short-term clinical trials have found that acute administration of caffeine (3 to 6 mg/kg) impaired glucose tolerance and decreased insulin sensitivity in healthy participants (19). In addition, incremental doses of decaffeinated coffee (1, 2, and 4 servings) failed to lower postprandial blood glucose in the presence of 100 mg of caffeine (20). However, despite the deleterious effect of caffeine on glucose homeostasis, caffeinated coffee consumption may favorably affect other metabolic pathways. In a single-blinded clinical trial, subjects at risk for type 2 diabetes abstained from drinking caffeinated coffee for one month, then consumed 4 cups/day of coffee for another month, and finally consumed 8 cups/day for a third month. Compared to one month of coffee abstinence, the consumption of 8 cups/day of coffee for one month appeared to increase antioxidant capacity and reduce subclinical inflammation, as indicated by changes in plasma markers of oxidative stress and inflammation (21).

Until the relationship between long-term coffee consumption and type 2 diabetes risk is better understood, it is premature to recommend coffee consumption as a means of preventing type 2 diabetes (12, 22).

Parkinson’s disease

Studies in animal models of Parkinson’s disease suggest that caffeine may protect dopaminergic neurons by acting as an adenosine A2A-receptor antagonist in the brain (23). Several large prospective cohort studies have examined coffee and/or caffeine intakes in association with Parkinson’s disease risk. A meta-analysis of nine prospective cohort studies found higher caffeine intake to be associated with significant reductions in Parkinson’s disease risk in both men (-39%) and women (-29%) (24). In another meta-analysis of six case-control studies and seven prospective studies, including 901,764 participants and 3,954 cases, an inverse association between coffee intake and Parkinson’s disease risk — only significant in men — was found to be nonlinear, with no further risk reduction beyond 3 to 4 cups/day of coffee. This meta-analysis also reported significant reductions in Parkinson’s disease risk in men (-43%) and women (-36%) with the highest (700 mg/day) versus lowest (100 mg/day) intake of caffeine (25).

However, while prospective studies have consistently found a lower risk of developing Parkinson’s disease with higher coffee and caffeine intakes in men, such an association has not always been observed in women (26-28). It is hypothesized that estrogen replacement therapy may modify the interaction between caffeine and risk of Parkinson’s disease in postmenopausal women. Indeed, because estrogen and caffeine are metabolized by hepatic cytochrome P450 (CYP) 1A2 in the body, estrogen might compete for CYP1A2 activity and hinder the metabolism of caffeine in estrogen users (29). An analysis of data from more than 77,000 female nurses, followed for 18 years in NHS I, revealed that coffee consumption was inversely associated with Parkinson’s disease risk in women who had never used postmenopausal estrogen (30). However, drinking ≥6 cups of coffee was associated with an increased risk or Parkinson’s disease in women who had used postmenopausal estrogen (30). In a prospective cohort study that included more than 238,000 women, a significant inverse association between coffee consumption and Parkinson’s disease mortality was also observed in women who had never used postmenopausal estrogen, but not in those who had used postmenopausal estrogen (31). Yet, in a recent analysis of the National Institutes of Health (NIH)-AARP Diet and Health Study, which included 303,880 participants and 1,100 cases, the highest versus lowest intake of caffeine was associated with a reduced risk of Parkinson’s disease in postmenopausal women who ever used hormones but not among never users (24)

At present, it remains unclear whether caffeine consumption can prevent Parkinson’s disease, particularly in women taking estrogen. Of note, whether caffeine could help reduce some common symptoms associated with Parkinson’s disease (e.g., sleepiness, freezing of gait) is under investigation (32, 33).

Cognitive decline and dementia

Results from observational studies regarding a possible link between coffee consumption and cognitive disorders are inconclusive. A recent meta-analysis of nine prospective cohort studies in 34,282 older adults reported an 18% reduced risk of cognitive disorders with 1 to 2 cups/day of coffee compared to <1 cup/day (34). Yet, there was no difference in risk of cognitive disorders between daily coffee intakes >3 cups and <1 cup (34). Two other meta-analyses of prospective studies failed to find an association between high versus low intakes of coffee and risk of cognitive disorders (35, 36). No dose-response relationship was reported between coffee intake and risk of cognitive disorders (36).

Whether moderate coffee intake may reduce the risk of cognitive decline and dementia later in life is still not known.

Cirrhosis and liver cancer

Chronic inflammation-inducing liver injury may result in cirrhosis. In cirrhosis, the formation of fibrotic scar tissue leads to the progressive deterioration of liver function and other complications, including liver cancer (primarily hepatocellular carcinoma [HCC]) (37). The most common causes of cirrhosis in developed countries are alcohol abuse and chronic infections with hepatitis B and C viruses. Often associated with metabolic disorders, nonalcoholic fatty liver disease (NAFLD) is a liver condition that can progress to nonalcoholic steatohepatitis (NASH) in about one-third of NAFLD patients, thereby increasing the risk of cirrhosis and HCC (38).

A cross-sectional study in 177 subjects with chronic liver disease (especially chronic hepatitis B or C and NASH) found an association between daily caffeine intake >308 mg — equivalent to >2 cups/day of coffee — and a lower risk of having advanced liver fibrosis (39). Of note, no association was reported with non-coffee sources of caffeine like caffeinated soda or green and black tea (39). Recent cross-sectional studies also suggested a protective association of coffee intake against fibrosis development in patients with hepatitis C (40, 41). Additional studies have suggested that consumption of coffee, but not of caffeine, was inversely associated with the risk of advanced liver fibrosis in patients with NAFLD or NASH (42-44).

A recent meta-analysis of four case-control and three prospective cohort studies reported an inverse association between coffee consumption and risk of cirrhosis (45). In addition, a few large prospective cohort studies found that coffee drinking was associated with reduced mortality from alcoholic cirrhosis (46-49). A 17-year study of more than 51,000 men and women in Norway found that those who consumed ≥2 cups/day of coffee had a risk of cirrhosis-related death that was 40% lower than those who never consumed coffee (49). A 22-year prospective cohort study in 125,580 US adults found that coffee drinking was protective against alcoholic cirrhosis but not nonalcoholic cirrhosis (48). Specifically, the risk of developing alcoholic cirrhosis was 40% lower in those who drank 1 to 3 cups/day of coffee and 80% lower in those who drank ≥4 cups/day (48). Recent data from 63,275 Chinese participants of the Singapore Chinese Health Study showed that consumption of ≥2 cups/day of coffee was associated with a 66% lower risk of death from non-viral hepatitis-related cirrhosis — no such association was found with mortality from cirrhosis due to viral hepatitis (46).

Several case-control and prospective cohort studies have found significant inverse associations between coffee consumption and the risk of HCC (reviewed in 50). In a recent 18-year prospective cohort study of 162,022 US adults — comprising Japanese Americans, Caucasians, Mexican Americans, African Americans, and Native Hawaiians — consumption of coffee, but not decaffeinated coffee, was inversely associated with risk of developing HCC (51). Specifically, drinking 2 to 3 cups/day of coffee was associated with a 38% reduced risk of HCC compared to no coffee drinking (51). In addition, the risk of chronic liver disease-related mortality was 71% lower in individuals consuming ≥4 cups/day of regular coffee and 46% lower in those consuming ≥2 cups/day of decaffeinated coffee compared to non-consumers (51). A pooled analysis of this study with 10 other prospective cohort studies found an overall 46% lower risk of liver cancer with coffee consumption (see also Cancer) (52).

Cancer

Numerous observational studies have examined the relationship between coffee consumption and cancer risk (53, 54). Results from recently published meta-analyses of observational studies are reported in Table 1. In addition, a recent meta-analysis of prospective cohort studies by Wang et al. (54) investigated the relationships between the highest versus lowest categories of coffee intake and the risk of most cancer types. Coffee consumption was found to be associated with reduced risks of oral/pharyngeal cancer (6 studies; -31%), colon cancer (10 studies; -13%), liver cancer (9 studies; -54%), prostate cancer (14 studies; -11%), endometrial cancer (12 studies; -27%), and melanoma (6 studies; -11%) (54). Overall, these results are in agreement with those from other pooled analyses of prospective studies presented in Table 1. However, unlike the results reported by Wang et al. (54), coffee consumption has been inversely associated with the risk of colon cancer in case-control studies, but not in prospective cohort studies (see Table 1). Also, in the case of prostate cancer, several meta-analyses suggested a reduced risk with increased coffee intake in prospective but not case-control studies (54-56). However, whether this association exists only in certain study populations or at specific cancer stages remains unclear (57, 58). There seems to be little evidence of associations between coffee consumption and breast cancer, esophageal cancer, glioma, laryngeal cancer, pancreatic cancer, rectal cancer, stomach cancer, and thyroid cancer (Table 1) (54).

 

Table 1. Coffee and Cancer Risk: Meta-Analyses of Observational Studies
Type of Cancer
Type of Observational Studies Relative Risk [RR] or Odds Ratio [OR]# (95% Confidence Interval) Relative Risk [RR] or Odds Ratio [OR] in Subgroup Analyses (e.g., by study types) References
Breast cancer 10 case-control and 16 prospective cohort studies

RR: 0.96 (0.93-1.00)

RR: 0.93 (0.86-1.00) for case-control studies
RR: 0.98 (0.93-1.02) for cohort studies
RR: 0.81 (0.67-0.97) for ER-negative cancer 
RR: 1.01 (0.93-1.09) for ER-positive cancer
Li et al. (2013; 59)
20 case-control and 17 prospective cohort studies RR: 0.97 (0.93-1.00)

RR: 0.94 (0.89-1.00) for case-control studies
RR: 0.98 (0.95-1.02) for cohort studies
RR: 0.99 (0.94-1.04) for caffeine
RR: 0.98 (0.92-1.05) for decaffeinated coffee
RR: 0.69 (0.53-0.89) among BRCA1 mutation carriers

Jiang et al. (2013; 60)
Colorectal cancer
   
25 case-control studies OR: 0.85 (0.75-0.97) OR: 0.68 (0.57-0.81) for colon cancer
OR: 0.95 (0.79-1.15) for rectal cancer 
Li et al. (2013; 61)
16 prospective cohort studies RR: 0.94 (0.88-1.01) RR: 0.93 (0.86-1.01) for colon cancer
RR: 0.98 (0.88-1.09) for rectal cancer 
Li et al. (2013; 61)
7 case-control and 5 prospective cohort studies  - RR: 0.78 (0.65-0.95) for case-control studies
RR: 0.82 (0.65-1.02) for cohort studies 
 Akter et al. (2016; 62)
19 prospective cohort studies RR: 0.98 (0.90-1.06) RR: 0.92 (0.83-1.02) for colon cancer
RR: 1.06 (0.95-1.19) for rectal cancer 
Gan et al. (2017; 63)
Endometrial cancer
 
10 case-control and 6 prospective cohort studies RR: 0.71 (0.62-0.81) RR: 0.69 (0.55-0.87) for case-control studies
RR: 0.70 (0.61-0.80) for cohort studies
 Je et al. (2012; 64)
13 prospective cohort studies RR: 0.80 (0.74-0.86) RR: 0.66 (0.52-0.84) for caffeinated coffee
RR: 0.77 (0.63-0.94) for decaffeinated coffee
Zhou et al. (2015; 65)
Esophageal cancer 10 case-control and 4 prospective cohort studies RR: 0.88 (0.76-1.01)   Zheng et al. (2013; 66)
Glioma 2 case-control and 4 prospective cohort studies RR: 1.01 (0.83-1.22)    Malerba et al. (2013; 67)
Laryngeal cancer   5 case-control studies and 1 prospective cohort study RR: 1.47 (1.03-2.11)   Chen et al. (2014; 68)
 7 case-control studies and 1 prospective cohort study RR: 1.22 (0.92-1.62)    Ouyang et al. (2014; 69)
Liver cancer 10 prospective cohort studies RR: 0.55 (0.44-0.67) RR: 0.57 (0.42-0.79) for women
RR: 0.58 (0.40-0.83) for men
Yu et al. (2016; 52)
Lung cancer 12 case-control and 5 prospective cohort studies OR: 1.31 (1.11-1.55) OR: 1.36 (1.10-1.69) for hospital-based case-control studies
OR: 0.99 (0.77-1.28) for community-based case-control studies
OR: 1.59 (1.26-2.00) for cohort studies
OR: 1.41 (1.21-1.63) for men
OR:1.16 (0.86-1.56) for women
OR: 1.24 (1.00-1.54) for smokers
OR: 0.85 (0.64-1.11) for non-smokers
Xie et al. (2016; 70)
Melanoma 4 case-control and 8 prospective cohort studies RR: 0.80 (0.69-0.93) RR: 0.85 (0.71-1.01) for caffeinated coffee
RR: 0.92 (0.81-1.05) for decaffeinated coffee
Wang et al. (2016; 71)
Oral cancer 9 case-control and 3 prospective cohort studies RR: 0.69 (0.54-0.89) RR: 0.65 (0.46-0.92) for case-control studies
RR: 0.81 (0.62-1.05) for cohort studies
RR: 0.81 (0.58-1.13) for studies in the US
RR: 0.57 (0.38-0.86) for studies in Europe
Zhang et al. (2015; 72)
Pancreatic cancer
  
22 case-control and 15 prospective cohort studies RR: 1.08 (0.94-1.25) RR: 1.10 (0.92-1.31) for case-control studies
RR: 1.04 (0.80-1.36) for cohort studies
Turati et al. (2012; 73)
20 prospective cohort studies  RR: 0.88 (0.64-1.12)   Ran et al. (2016; 74)
21 prospective cohort studies RR: 0.99 (0.81-1.21)    Nie et al. (2016; 75)
Prostate cancer   12 case-control and 12 prospective cohort studies RR: 0.94 (0.85-1.05) RR: 1.36 (1.06-1.75) for studies in the US
RR: 1.08 (0.80-1.45) for studies in Europe
RR: 0.92 (0.66-1.28) for studies in Asia RR: 0.61 (0.42-0.90) for fatal cancer
RR: 0.70 (0.52-0.94) for high-grade tumors
RR: 1.07 (0.89-1.29) for low-grade tumors
 Zhong et al. (2014; 58)
 12 case-control and 9 prospective cohort studies RR: 0.91 (0.86-0.97) RR: 0.91 (0.95-1.26) for case-control studies
RR: 0.89 (0.84-0.95) for cohort studies
Lu et al. (2014; 56)
13 prospective cohort studies RR: 0.90 (0.85-0.95) RR: 0.93 (0.87-1.00) for studies in the US
RR: 0.83 (0.75-0.92) for studies in Europe
RR: 0.82 (0.51-1.31) for studies in Asia RR: 0.76 (0.55-1.06) for fatal cancer
RR: 0.82 (0.61-1.10) for advanced tumors
RR: 0.89 (0.83-0.96) for non-advanced tumors
Liu et al. (2015; 57)
Stomach cancer
 
 
9 prospective cohort studies RR: 1.18 (0.90-1.55)   Zeng et al. (2015; 76)
13 prospective cohort studies RR: 1.13 (0.94-1.35)   RR: 1.36 (1.06-1.75) for studies in the US
RR: 1.08 (0.80-1.45) for studies in Europe
RR: 0.92 (0.66-1.28) for studies in Asia
Li et al. (2015; 77)
13 case-control and 9 prospective cohort studies RR: 0.96 (0.82-1.12) RR: 0.85 (0.77-0.95) for case-control studies
RR: 1.12 (0.94-1.33) for cohort studies
Xie et al. (2016; 78)
 Thyroid cancer 5 case-control and 2 prospective cohort studies  OR: 0.88 (0.71-1.07)   Han et al. (2017; 79)
#Odds ratio or relative risk of cancer for the highest vs. lowest categories of coffee intake.

Finally, there is some evidence suggesting a potential increase in the risk of lung cancer with the highest versus lowest levels of coffee intakes. Yet, cigarette smoking has a major confounding effect on this association (see Health risks associated with coffee consumption) (54, 70).

Mortality

Three large US prospective cohort studies, namely NHS I (74,890 women), NHS II (93,054 women), and HPFS (40,557 men), examined whether coffee drinking was associated with all-cause, cardiovascular disease-related, or cancer-related mortality (80). Compared to no coffee consumption, the consumption of coffee, whether caffeinated or decaffeinated, up to 5 cups/day, was inversely associated with all-cause mortality. There was no difference in risk of death between non-consumers and consumers of >5 cups/day of coffee. Coffee consumption was also found to be inversely associated with mortality related to cardiovascular disease, neurological disease, and suicide (80). Other large cohort studies have reported habitual consumption of any coffee being inversely associated with all-cause and cardiovascular disease-related mortality, but generally not with cancer-related mortality (81-86). Moreover, the associations have not always been consistent among women and men, especially regarding cancer-related mortality (85, 86). A dose-response meta-analysis of 21 prospective studies found a nonlinear inverse association between coffee consumption and all-cause and cardiovascular disease-related mortality (87). Consumption of only 1 cup/day of coffee was significantly associated with lower risk of all-cause (-8%) and cardiovascular disease-related mortality (-11%). The largest risk reductions for all-cause (-16%) and cardiovascular disease-related mortality (-21%) were found to be associated with the consumption of 4 cups/day and 3 cups/day of coffee, respectively (87).

Safety

Adverse effects

Most adverse effects attributed to coffee consumption are related to caffeine. In healthy adults, daily caffeine consumption ≤400 mg — corresponding to 6.5 mg/kg body weight/day for a 70-kg person — is usually not associated with adverse effects (88). Caffeine intakes of less than 300 mg/day in women of childbearing age (equivalent to 4.3 mg/kg body weight/day for a 70-kg woman) and less than 2.5 mg/kg body weight/day in children are unlikely to cause adverse effects (88).

Adverse reactions to caffeine may include tachycardia (rapid heart rate), palpitations, insomnia, restlessness, nervousness, tremor, headache, abdominal pain, nausea, vomiting, diarrhea, and diuresis (increased urination) (89). Very high caffeine intakes, not usually from coffee, may induce hypokalemia (abnormally low serum potassium) (90). Sudden cessation of caffeine consumption after long-term use may result in caffeine withdrawal symptoms (91). Gradual withdrawal from caffeine appears less likely to result in withdrawal symptoms than abrupt withdrawal (92). Commonly reported caffeine withdrawal symptoms include headache, fatigue, drowsiness, irritability, difficulty concentrating, and depressed mood.

Potential health risks associated with regular coffee consumption

Cardiovascular disease

Serum lipids: An early meta-analysis of nine randomized controlled trials found that the consumption of unfiltered, boiled coffee dose-dependently increased serum total and LDL-cholesterol concentrations, while the consumption of filtered coffee resulted in very little change (93). A more recent meta-analysis of 12 randomized controlled trials reported that the consumption of coffee increased serum total cholesterol by 8.1 mg/dL, LDL-cholesterol by 5.1 mg/dL, and triglycerides by 12.6 mg/dL (94). The consumption of filtered coffee raised total cholesterol by only 3.6 mg/dL compared to an increase of 12.9 mg/dL with unfiltered coffee consumption. Unlike filtered coffee, consumption of unfiltered coffee significantly increased LDL-cholesterol and triglycerides by 11.9 mg/dL and 18.8 mg/dL, respectively (94). The cholesterol-raising factors in unfiltered coffee have been identified as cafestol and kahweol, two diterpenes that are largely removed from coffee by paper filters (see Diterpenes) (10).

Homocysteine: An elevated plasma total homocysteine concentration has been associated with increased risk of cardiovascular disease, including coronary heart disease, stroke, and peripheral vascular disease, but the relationship may not be causal (95). Higher coffee intakes have been associated with increased plasma homocysteine concentrations in cross-sectional studies conducted in Europe, Scandinavia, and the US (96-100). Controlled clinical trials have confirmed the homocysteine-raising effect of coffee at intakes of about 4 cups/day (101-103).

Hypertension: Hypertension is a well-recognized risk factor for cardiovascular disease. Two meta-analyses of randomized controlled trials showed that high intakes of coffee (3 to 5 cups/day) for <85 days significantly increased systolic/diastolic blood pressure by 1.2/0.5 mm Hg (104) or 2.4/1.2 mm Hg (105). Although the increases in blood pressure seem modest by individual standards, it has been estimated that an average systolic blood pressure reduction of 2 mm Hg in a population may result in 10% lower mortality from stroke and 7% lower mortality from coronary heart disease (106). However, a more recent pooled analysis excluding the trials that used decaffeinated coffee in control groups — and thus assessed the effect of caffeine rather than that of coffee — found no significant changes in systolic blood pressure and diastolic blood pressure with high coffee intakes (107). Additionally, two meta-analyses combined the data from observational studies that examined prospectively the association between habitual coffee consumption and risk of hypertension (107, 108). One meta-analysis of six prospective cohort studies included 172,567 non-hypertensive participants (one study enrolled pre-hypertensive subjects) of which 37,135 cases of incident hypertension were reported over follow-up periods spanning from 6.4 years to 33 years (108). Compared to coffee intakes of <1 cup/day, intakes of 1 to 3 cups/day were found to be associated with a 9% increased risk of hypertension. However, no such association could be observed for coffee intakes >3 cups/day (108). Another meta-analysis of four prospective cohort studies found no association between coffee consumption and risk of hypertension (107). Also, a recent analysis of data from 29,985 postmenopausal women followed for nearly four years in the Women’s Health Initiative Observational Study found no increased risk of hypertension with intakes of caffeinated coffee, decaffeinated coffee, or caffeine (109).

While there is little evidence of an association between long-term coffee consumption and risk of hypertension, the available evidence from trials suggests that consumption of caffeine modestly raises systolic blood pressure. Whether this may result in increased risk of stroke and coronary heart disease in the population, particularly in those with hypertension, is still uncertain. Yet, to date, regular coffee consumption in hypertensive subjects has not been associated with an increased risk of cardiovascular disease (110).

Coronary heart disease: A meta-analysis of 20 prospective cohort studies, including 407,806 participants and 15,599 incident coronary heart disease (CHD) cases, found no significant association between coffee consumption and CHD risk (111). Yet, a more recent meta-analysis of 22 prospective cohort studies reported a modest reduction in CHD risk with moderate (3-5 cups/day) — but not high (≥6 cups/day) — coffee intakes compared to low intakes (<1 cup/day) (112).

In addition, cross-sectional studies have provided little evidence that the formation of atherosclerotic plaques, an early event in the development of CHD, is more prevalent in regular coffee drinkers than in non-drinkers (113-116). Coffee consumption has not been linked to the development of atherosclerosis in two prospective cohort studies. In the Coronary Artery Risk Development in Young Adults (CARDIA) study that followed approximately 4,000 young US adults for 15 to 20 years, there was no evidence of an association between regular coffee intake and progression of coronary artery calcification, a measure of subclinical atherosclerosis (117). Moreover, in the Multi-Ethnic Study of Atherosclerosis (MESA) that followed about 6,500 US adults over a median period of 11.1 years, occasional but not regular drinking of coffee was associated with a 28% increased risk of cardiovascular disease compared with no drinking (114). This study found no association between coffee intake and progression of coronary artery calcification (114).

Cardiac arrhythmias: Early clinical trials found coffee or caffeine intake equivalent to 5 to 6 cups/day did not increas the frequency or severity of cardiac arrhythmias in healthy people or in people with coronary heart disease (118, 119). A meta-analysis of six prospective cohort studies in 214,316 participants found no association between coffee consumption and risk of atrial fibrillation, the most common type of cardiac arrhythmias. In addition, a recent meta-analysis of 11 short-term intervention studies (single dose to two-week trials) found that caffeine consumption did not increase the occurrence of ventricular arrhythmias (120). Finally, two meta-analyses of observational studies found no evidence to suggest that caffeine consumption was associated with an increased risk of atrial fibrillation and even reported a modest reduction in risk with moderate intakes (121, 122).

Thus, consumption of coffee or caffeine at usual intakes does not appear to increase the risk of cardiac arrhythmias. The current evidence does not support clinical recommendations that discourage moderate consumption of coffee in patients at risk or with suspicions of cardiac arrhythmia (120, 123).

Stroke: A 2011 meta-analysis that included eight prospective cohort studies — all following participants who were free of cardiovascular disease and diabetes mellitus at baseline — found that consumption of 3 to 4 cups/day of coffee was associated with an 18% lower risk of stroke compared with no consumption and that higher intakes were not associated with an increased risk (124). Since this meta-analysis, a few large prospective studies have reported mixed results on the association between coffee consumption and stroke incidence or stroke-related mortality. Results from 42,659 participants in the German cohort of the European Prospective Investigation in Cancer and Nutrition (EPIC-Germany) reported no association between coffee consumption and stroke incidence over an 8.9 year-period (125). Compared to no intake, consumption of ≥3-6 cups/week of coffee was associated with a reduced risk of stroke in a prospective study of 82,369 Japanese participants (126). Also, the consumption of 4 to 5 cups/day of coffee was associated with a reduced risk of stroke-related mortality among men, but not women, followed in the large prospective NIH-AARP Diet and Health Study (81).

Lung cancer

Several observational studies have examined the relationship between coffee intake and lung cancer risk in humans. A recent meta-analysis of 12 case-control and 5 prospective cohort studies, including a total of 12,276 cases and 102,516 controls, found an overall 31% increased risk of lung cancer with the highest versus lowest levels of coffee intake (see Table 1). Subgroup analyses outlined a significant increase in lung cancer risk with coffee intake in hospital-based case-control (+36%) and prospective cohort studies (+59%), in studies conducted in American (+34%) and Asian (+49%) populations, in men (+41%), and in smokers (+24%); conversely, no significant association between coffee intake and lung cancer risk was found in community-based case-control studies, in studies conducted in European populations, in women, and in non-smokers (70). Another meta-analysis of 13 case-control and 8 prospective cohort studies, including 19,892 cases and 623,645 controls, found a 9% increased risk of lung cancer in coffee drinkers compared to non-drinkers (127). However, a pooled analysis restricted to the 16 (out of 21) studies that adjusted for smoking found no significant association between coffee intake and risk of lung cancer [RR: 1.03 (0.95-1.12)].

Cigarette smoking is a major confounding factor in the association between coffee consumption and lung cancer risk, and the evidence suggests that coffee intake is unlikely to be a risk factor for lung cancer. Of note, residual confounding by smoking remains a concern when a slight increase in lung cancer risk is still observed in studies even after adjustment for tobacco smoking (127).

Adverse pregnancy outcomes

It has been suggested that in utero exposure to caffeine through maternal coffee consumption might have adverse effects on the embryo/fetus during pregnancy and the offspring.

Miscarriage: The results of observational studies that have examined the relationship between maternal coffee or caffeine intake and the risk of miscarriage (spontaneous abortion) have been conflicting. While some prospective cohort studies have observed significant associations between high caffeine intakes, particularly from coffee, and the risk of spontaneous abortion (128-132), other studies have not (133-136). The most recent meta-analysis of 14 prospective cohort studies in 130,456 pregnant women and 3,429 cases of miscarriage found risk of miscarriage increased by 40% and 72% with maternal caffeine intakes of 350 to 699 mg/day and ≥700 mg/day during pregnancy, respectively (137). No significant associations were found for daily doses of caffeine less than 350 mg. A dose-response analysis found a 7% increase in the risk of miscarriage per 100 mg/day-increment in caffeine intake during pregnancy (137). Of note, one prospective cohort study that assessed caffeine intake by measuring serum concentrations of paraxanthine, a caffeine metabolite, found that the risk of spontaneous abortion was only elevated in women with paraxanthine concentrations that suggested caffeine intakes of ≥600 mg/day (138).

It has been proposed that an association between caffeine consumption and the risk of spontaneous abortion could be explained by the relationship between nausea and fetal viability (139). Nausea is more common in women with viable pregnancies than nonviable pregnancies, such that women with viable pregnancies may be more likely avoid or limit caffeine consumption due to nausea (140). However, at least one study found that the significant increase in risk of spontaneous abortion observed in women with caffeine intakes >300 mg/day was independent of nausea in pregnancy (141). Additionally, two other studies found that caffeine consumption was associated with an increased risk of spontaneous abortion in women who experienced nausea or aversion to coffee during pregnancy (131, 142). Nonetheless, this does not exclude the possibility of reverse causality, when the loss of fetal viability results in reduction of pregnancy symptoms, like nausea and aversion to coffee, and may be followed by an increase in coffee intake (137).

Of note, consumption of <400 mg/day of caffeine or <4 cups/day of caffeinated coffee by women prior to pregnancy has not been linked to the risk of miscarriage in an analysis of a large prospective study (NHS I) that followed 11,072 women and a total of 15,590 pregnancies (143).

Although the topic remains unsettled, the American College of Obstetricians and Gynecologists recommends that women limit their daily caffeine intake to <200 mg during pregnancy (144).

Intrauterine growth restriction and low birth weightObservational studies examining the effects of maternal caffeine and coffee consumption on fetal growth have assessed intrauterine growth restriction (IUGR; also known as small-for-gestational age; defined as fetal weight <10th percentile for gestational age), and/or incidence of low birth weight (defined as weight at birth <2,500 g [5.5 pounds]).

A recent meta-analysis of eight prospective cohort and four case-control studies reported a 38% increased risk of low birth weight with the highest versus lowest intakes of caffeine during pregnancy (145). This risk appeared to increase linearly with incremental doses of caffeine (145, 146). A dose-response meta-analysis of six prospective cohort and five case-control studies found a 7% increased risk of low-birth-weight infants per 100 mg of caffeine consumed daily during pregnancy (146). Likewise, a 100 mg-increment in maternal caffeine intakes has been associated with a 10% increased risk of small-for-gestational age infants in the dose-response analysis of 10 prospective cohort and 5 case-control studies (146).

At present, only one study has examined the impact of limiting caffeine intake during pregnancy on birth weight. In a double-blind, intervention trial that randomized 1,197 regular coffee drinkers (≥3 cups/day of coffee) to drink decaffeinated (median caffeine intake of 117 mg/day) or caffeinated coffee (median caffeine intake of 317 mg/day) throughout the second half of their pregnancy, no differences in length of gestation or infant birth weight were found between the two groups (147).

Although the relationship between maternal caffeine consumption and fetal growth requires further clarification, it appears that even moderate caffeine intakes might adversely affect fetal growth in non-smoking women (145, 146, 148). Limiting caffeine intake to ≤100 mg/day (≤1 cup/day of coffee) during pregnancy may be recommended to avoid any adverse effect, assuming that the associations of caffeine intake with the risk of IUGR and low birth weight are causal (145, 146).

Birth defects: Potential relationships between coffee consumption during pregnancy and congenital birth defects have been investigated in the US population-based National Birth Defects Prevention Study (NBDPS), an ongoing multi-site case-control study. In an analysis that included mothers of 1,531 infants with cleft lips (with or without cleft palates), 813 infants with cleft palates only, and 5,711 control infants, no association was found between the highest versus lowest intakes of coffee and caffeine and the risk of orofacial clefts (149). Another analysis, including mothers of 3,346 cases and 6,642 control infants, suggested an increased risk of anotia/microtia and craniosynostosis with the consumption of coffee or caffeine. However, no dose-response could be detected (150). Further, an analysis of the NBDPS in mothers of 844 infants with limb deficiencies and 8,069 control infants found no increased risk associated with coffee and/or caffeine intake during pregnancy (151). There was no association between maternal coffee or caffeine intake during pregnancy and risk of congenital talipes equinovarus (known as "clubfoot") in another US population-based case-control study of mothers of 646 infants with isolated clubfoot and 2,037 control infants (152). Finally, a recent meta-analysis that combined data from one prospective cohort study and six case-control studies found no association between maternal coffee consumption during pregnancy and risk of neural tube defects (153).

At present, there is no convincing evidence that maternal consumption of 3 cups/day of coffee or 300 mg/day of caffeine during pregnancy increases the risk of congenital malformations in humans.

Childhood acute leukemia: The etiology of acute lymphoblastic leukemia (ALL) and acute myeloblastic leukemia (AML), which primarily affect children, is unclear. It has been suggested that exposure to caffeine during pregnancy might have long-lasting adverse effects on the health of the offspring. A meta-analysis of seven case-control studies that examined maternal coffee consumption during pregnancy in relation to the incidence of childhood acute leukemia found coffee consumption was associated with increased risks of overall acute leukemia (+72%), ALL (+65%), and AML (+58%) (154). Another meta-analysis of eight case-control studies found an increased risk of ALL (+43%), but not AML, with the highest versus lowest intakes of coffee during pregnancy (155). High versus low consumption of other sources of caffeine during pregnancy (tea, cola beverages) and childhood (cola beverages) were not found to be associated with childhood acute leukemia (155).

The evidence of a positive association between maternal coffee intake and childhood acute leukemia is currently limited to case-control studies. Case-control studies usually include more cancer cases than prospective cohort studies, but they are subject to recall bias with respect to coffee consumption and selection bias with respect to the control group (156). Further studies with a prospective design are needed to confirm the possible link between coffee intake during pregnancy and childhood acute leukemia.

Lactation

The American Academy of Pediatrics categorizes caffeine as a maternal medication that is usually compatible with breast-feeding (157). Although high maternal caffeine intakes have been reported to cause irritability and poor sleeping patterns in infants, no adverse effects have been reported with moderate maternal intake of caffeinated beverages equivalent to 2 to 3 cups of coffee daily.

Nutrient interactions

Calcium, osteoporosis, and risk of fracture

Osteoporosis is a multifactorial bone disorder that compromises bone mass and strength and increases the risk of fracture. The results of early controlled studies in humans indicated that coffee and caffeine consumption decreased the efficiency of calcium absorption resulting in a loss of about 4 to 6 mg of calcium per cup of coffee (158, 159). However, there is little evidence to suggest detrimental effects of coffee on bone health in populations with adequate calcium intakes (160). To date, results from observational studies that examined associations between coffee intakes and measures of bone mineral density (BMD) loss — generally used to diagnose osteoporosis — have been mixed (161-164). Further, two meta-analyses of observational studies reported no significant associations between coffee intake and risk of hip fracture (165, 166). A third meta-analysis of six case-control and nine prospective cohort studies found no overall association between coffee intake and total fracture (167). Yet, a gender subgroup analysis of eight studies showed a 14% increased risk of fracture in women — but not in men — with the highest versus lowest intakes of coffee. Another subgroup analysis of six studies found a 35% increased risk of osteoporotic fracture in participants with the highest versus lowest intakes of coffee (167).

Current evidence is scarce to suggest that coffee consumption could increase the risk of bone loss and fracture. Limiting coffee consumption to ≤3 cups/day while ensuring adequate calcium and vitamin D intakes should prevent any potential adverse effects on calcium absorption and bone health.

Nonheme iron

Phenolic compounds in coffee can bind nonheme iron and inhibit its intestinal absorption (168). Drinking 150 to 250 mL of coffee with a test meal has been found to inhibit iron absorption by 24%-73% (169, 170). To maximize iron absorption from a meal or supplements, people with poor iron status should not consume coffee at the same time.

Drug interactions

Habitual caffeine consumption increases hepatic cytochrome P450 (CYP) 1A2 activity, which has implications for the metabolism for a number of medications (171). Conversely, drugs that inhibit the activity of CYP1A2 interfere with the metabolism and elimination of caffeine, thereby increasing the risk of adverse effects (172).

Drugs that alter caffeine metabolism

The following medications may impair the hepatic metabolism of caffeine, delaying its excretion and potentially increasing the risk of caffeine-related side effects: cimetidine (Tagamet), disulfiram (Antabuse), estrogens, fluconazole (Diflucan), fluvoxamine (Luvox), mexiletine (Mexitil), quinolone class antibiotics (Cipro, Avelox), riluzole (Rilutek), terbinafine (Lamisil), and Verapamil (Calan) (173). Concomitant use of ephedrine and caffeine can lead to life-threatening adverse effects, including heart attack, stroke, seizures, and death (173). Use of the drug phenytoin (Dilantin) or cigarette smoking increases the hepatic metabolism of caffeine, resulting in increased elimination and decreased plasma caffeine concentrations (89).

Caffeine effects on other drugs

Caffeine and other methylxanthines may enhance the effects and side effects of β-adrenergic stimulating agents, such as epinephrine and albuterol (89, 171). Caffeine doses of 400 to 1,000 mg may inhibit the hepatic metabolism of the antipsychotic medication, clozapine (Clozaril), potentially elevating serum clozapine concentration and increasing the risk of toxicity. Those taking levothyroxine are advised to avoid drinking coffee at the same time they take their medication because coffee may reduce the absorption of levothyroxine in some patients. Caffeine consumption can decrease the elimination of theophylline, potentially increasing serum theophylline levels. Caffeine has been also found to decrease the systemic elimination of acetaminophen (i.e., paracetamol) and to increase the bioavailability of aspirin, which may partially explain its efficacy in enhancing their analgesic effects. This is important because many pain-relievers on the market today combine caffeine with aspirin and/or acetaminophen. Further, caffeine may decrease the bioavailability of lithium and alendronate (Fosamax) by enhancing their elimination (173).


Authors and Reviewers

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

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

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

Reviewed in June 2017 by:
Rob van Dam, Ph.D.
Adjunct Associate Professor of Nutrition and Epidemiology
Harvard T.H. Chan School of Public Health

Copyright 2005-2017  Linus Pauling Institute 


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Tea

Summary

  • Tea is an infusion of the leaves of the Camellia sinensis plant, which is not to be confused with herbal teas. (More information)
  • All the tea types, including white, green, oolong, black, and Pu-erh tea, are produced from the leaves of the Camellia sinensis plant. Different processing methods yield the various types of tea. (More information)
  • Biologically active chemicals in tea include flavonoids, caffeine, fluoride, and theanine. Green teas are especially rich in a group of flavonoids called flavan-3-ol monomers or catechins. Black teas contain more complex chemicals — theaflavins and thearubigins — derived from catechins. (More information)
  • Observational studies in humans suggest that daily consumption of tea may be associated with a reduced risk of cardiovascular disease (CVD). Intervention studies showed that tea exhibited cholesterol-lowering, anti-inflammatory, antioxidant, and anti-hypertensive properties, which might be beneficial in the prevention of CVD. (More information)
  • Tea consumption has been associated with reduced risk of developing type 2 diabetes mellitus in large prospective cohort studies. Yet, the mechanisms behind this association are complex, possibly involving a role for tea bioactive compounds in the regulation of energy balance, lipid and glucose metabolism, insulin sensitivity, body composition, and/or body temperature. (More information)
  • Despite promising results from animal studies, current evidence does not support a role for tea consumption in the prevention of most cancers in humans. (More information)
  • It is still unclear whether tea consumption is associated with increased bone mineral density and/or reduced risk of osteoporotic fractures. (More information)
  • Limited research suggests an inverse association between tea consumption and risk of tooth cavities. The incorporation of green tea extract in mouthwashes and/or toothpastes may also help reduce dental plaque and gum inflammation in patients. (More information)
  • The pooled analysis of three large US prospective cohort studies found an 11% lower risk of kidney stones with the highest versus lowest level of tea intake. More research is needed to assess whether the oxalate content in tea may affect subjects with a history of kidney stones. (More information)
  • The mounting evidence for a role of tea consumption in the prevention of cognitive decline comes from observational studies. Clinical studies would be needed to establish whether tea or its bioactive constituents could limit cognitive decline and/or improve cognitive dysfunction in older individuals. (More information)
  • The use of green tea extracts in clinical trials was found to cause gastrointestinal disorders and liver toxicity. Tea consumption may also potentially interfere with certain medications, including the anticoagulant, warfarin, and some cardiovascular drugs. (More information)

Introduction

Tea is an infusion of the leaves of the Camellia sinensis plant and, aside from water, is the most widely consumed beverage in the world (1). Different processing methods of tea leaves involve variable degrees of oxidation yielding different types of tea (green, oolong, or black tea). In 2014, Americans consumed 3.6 billion gallons of tea, of which 84% was black tea, 15% was green tea, and the remaining was white, oolong, and dark tea (2). Herbal teas are infusions of herbs or plants other than Camellia sinensis and will not be discussed in this article. Although tea contains a number of bioactive chemicals, including caffeine and fluoride, most research has focused on the potential health benefits of a class of compounds in tea known as flavonoids. In many cultures, tea is an important source of dietary flavonoids.

Definitions

Types of tea

All teas are derived from the leaves of the tea plant Camellia sinensis, but different processing methods produce different types of tea. Fresh tea leaves are rich in polyphenolic compounds known as flavonoids (see the article on Flavonoids). Flavonoids are divided in six subclasses: flavan-3-ols, anthocyanidins, flavanones, flavonols, flavones, and isoflavones (Figure 1). Tea leaves contain a polyphenol oxidase (PPO) enzyme in separate compartments from flavan-3-ol monomers or catechins (Figure 2) (3). When tea leaves are intentionally broken or rolled during processing, cell compartmentalization is disrupted and PPO comes into contact with catechins. This causes catechins to condense (join together) forming dimers and polymers known as theaflavins (Figure 3) and thearubigins, respectively (4). This oxidation process is often described as "fermentation" in the tea industry. Steaming, firing, or baking tea leaves inactivates PPO and stops the oxidation process (5).

The two prominent varieties of Camellia sinensis used in tea cultivation are Camellia sinensis var. sinensis and Camellia sinensis var. assamica. The former is native of China and usually used to make white and green tea. The latter originates from the Assam region of India, as well as regions of Southeast Asia, and is often used to make black teas, including pu-erh tea in the Yunnan province of China.

Although there are thousands of tea cultivars derived from the principal Camellia sinensis tea varieties, teas are usually divided into five types based on the extent of oxidation they undergo during processing. The withering method (the process of allowing the fresh leaves to dry) and the process of deactivating PPO may also differ among tea preparations (1).

Figure 1. Basic Structures of Flavonoid Subclasses: flavan-3-ols, anthocyanidins, flavonols, flavones, flavanones, and isoflavones.

Figure 2. Chemical Structures of Principal Flavan-3-ols (Catechins): (+)-catechin, (-)-epicatechin, (-)-epigallocatechin, (-)-epicatechin gallate, and (-)-epigallocatechin gallate

Figure 3. Chemical Structures of Some Theaflavins in Tea: theaflavin, theaflavin 3-gallate, theaflavin 3'-gallate, theaflavin 3,3'-digallate

White tea

White tea is made from unopened buds and immature leaves, which are steamed or fired to inactivate polyphenol oxidase, and then dried. Thus, due to minimal oxidation, white tea retains the high concentrations of catechins present in fresh tea leaves (see Flavonoids below).

Green tea

Green tea is made from more mature tea leaves than white tea, and tea leaves may be withered prior to steaming or firing, and then rolled and dried. Like white teas, green teas are high in catechins, but the total content and composition of catechins may vary depending on the cultivar and the commercial source (6). Of note, green teas and white teas may sometimes contain similar amounts of catechins but still exhibit different antioxidant capacities; this is due to the presence of other non-catechin antioxidants in teas (6).

Oolong (Wulong) tea

Tea leaves destined to become oolong teas are "bruised" to allow the release of some of the polyphenol oxidase present in the leaves. Oolong teas are allowed to oxidize to a greater extent than for white or green teas, but for less time than black teas, before they are heated and dried. Consequently, the catechin, theaflavin, and thearubigin levels in oolong teas are generally between those of unfermented green and white teas and completely oxidized black teas (1).

Black tea

Tea leaves destined to become black tea are fully rolled or broken to maximize the interaction between catechins and polyphenol oxidase. Because they are allowed to oxidize completely before drying, most black teas are relatively low in monomeric flavan-3-ols, like (-)-epigallocatechin gallate (EGCG), and rich in theaflavins (2%-6% of extracted solids) and thearubigins (>20% of extracted solids) (see Table 1 below). Some theaflavins have shown greater antioxidant activities than EGCG (7).

Pu-erh tea (also pu’erh tea, pu’er tea, or Chinese black tea)

Most pu-erh tea is produced in the Yunnan province of China from the larger leaves of the assamica variety of Camellia sinensis. The making process may include both enzymatic oxidation and fungus-led fermentation. In the case of "raw (aged) pu-erh tea," the initial preparation resembles that used to make green tea. The leaves are heated, dried, and then dampened before being pan-fired and compressed; the preparation is then carefully stored in a controlled environment and left to age for decades. A faster aging process, combining oxidation and fermentation by the fungus Aspergillus niger for several months, can also be used to produce "ripened pu-erh tea."

Cup sizes

The definition of a cup of tea varies in different countries or regions. In Japan, a typical cup of green tea may contain only 100 mL (3.5 ounces). A traditional European teacup holds approximately 125 to 150 mL (5 ounces), while a mug of tea may contain about 240 mL (8 ounces).

Bioactive Compounds in Tea

Tea contains over 2,000 components, including polyphenols (flavonoids), pigments (carotenoids and chlorophyll), alkaloids (caffeine, theophylline, theobromine), lignans, carbohydrates, lipids, proteins, amino acids (including L-theanine), vitamins (vitamin C, vitamin E, riboflavin), and various minerals and trace elements (8). Only some of them are described below.

Flavonoids

Dietary flavonoids are divided in six subclasses: flavan-3-ols, anthocyanidins, flavanones, flavonols, flavones, and isoflavones (see the article on Flavonoids). Total flavonoid content in green tea and black tea is of about 138 mg and 118 mg per 100 mL, respectively (9). A major subclass of flavonoids in tea is that of flavan-3-ols. Flavan-3-ol monomers, also known as catechins, constitute 30%-42% of the solid weight of brewed green tea. The principal catechins found in tea are (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG) (see Figure 2). When catechins are enzymatically oxidized by polyphenol oxidase during the oxidation process that yields black tea, they form low molecular weight dimers known as theaflavins (see Figure 3) and complex polymers (of mostly unknown structures) called thearubigins. Non-oxidized teas are rich in catechins, while fully oxidized teas are rich in theaflavins and thearubigins (Table 1) (5).

Table 1. Flavan-3-ol Monomers and Thearubigins Content of Tea (mg/100 mL) (10)
Type of Tea1 EC ECG EGC EGCG Thearubigins
Tea, white, brewed -2 8.3 18.6 42.4 -
Tea, green, brewed 8.3 17.9 29.2 70.2 1.1
Tea, oolong, brewed 2.5 6.3 6.1 34.5 -
Tea, black, brewed 2.1 5.9 8.0 9.4 81.3
11 g of tea leaves infused in 100 mL of boiling water (1% weight/volume)
2The lack of a value for a particular flavonoid in a food in the database does not imply a zero value, but only that data were unavailable.

Tea is also a good source of another class of flavonoids called flavonols. Flavonols found in tea include kaempferol, quercetin, and myricetin. The flavonol content of tea is minimally affected by processing, and flavonols are present in comparable quantities in oxidized and non-oxidized teas. Unlike flavan-3-ols, flavonols are usually present in tea as glycosides, i.e., bound to a sugar molecule (Figure 4). Despite their poor bioavailability, flavonoids are thought to contribute substantially to the health benefits associated with daily tea consumption (10). For more detailed information, see the article on Flavonoids.

Figure 4. Chemical Structures of Some Flavonols in Tea: kaempferol glycoside, quercetin glycoside, and myricetin glycoside.

Caffeine

All teas contain caffeine, unless they are deliberately decaffeinated during processing. The caffeine content of different varieties of tea may vary considerably and is influenced by factors like brewing time, the amount of tea and water used for brewing, and whether the tea is loose or in teabags. In general, a mug of tea contains about half as much caffeine as a mug of coffee (11). The caffeine contents of more than 20 green and black teas prepared according to package directions are presented in Table 2 (12). The caffeine content of oolong teas is comparable to green teas (13). There is little information on the caffeine content of white teas, since they are often grouped together with green teas (14). Buds and young tea leaves have been found to contain higher levels of caffeine than older leaves (15), suggesting that the caffeine content of some white teas may be slightly higher than that of green teas (16).

Table 2. Caffeine Content of Teas and Coffee (12, 14, 17)
Type of Tea Caffeine (mg/L) Caffeine (mg/8 ounces)
Green 40-234 9-63
Black 177-333 42-79
Coffee, brewed 306-553 72-130

Caffeine is a known stimulant of the central nervous system, thought to protect dopaminergic neurons by antagonizing adenosine A2A receptors (Figure 5) (18). Because adenosine has mostly inhibitory effects in the central nervous system, the effects of adenosine antagonism by caffeine are generally stimulatory.

Figure 5. Chemical Structures of Caffeine and Adenosine

Fluoride

Tea plants accumulate fluoride in their leaves. In general, the oldest tea leaves contain the most fluoride (19). Most high-quality teas are made from the bud or the first two to four leaves — the youngest leaves on the plant. Fluoride levels in green, oolong, and black teas are generally comparable to those recommended for the prevention of dental caries (cavities). Thus, daily consumption of up to one liter of green, oolong, black, or pu-erh tea would be unlikely to result in fluoride intakes higher than those recommended for dental health (20, 21). The fluoride content of white tea is likely to be less than other teas, since white teas are made from the buds and youngest leaves of the tea plant. A comparative study of green, oolong, and black teas from six provinces of China found that fluoride content was inversely correlated with the quality level of tea sensory attributes (i.e., appearance, taste, flavor) (22). The fluoride content of 17 brands of green, oolong, and black teas is presented in Table 3 (20). These values do not include the fluoride content of the water used to make the tea. For more information, see the article on Fluoride.

Table 3. Fluoride Content of Teas (21)
Type of Tea Fluoride (mg/liter)1 Fluoride (mg/8 ounces)
Green 1.2-1.7 0.3-0.4
Oolong 0.6-1.0 0.1-0.2
Black 1.0-1.9 0.2-0.5
Pu-erh tea 0.9-1.6 0.2-0.4
1Fluoride in 1% weight/volume tea prepared by continuous infusion from 5 minutes (number before hyphen) to 360 minutes (number after hyphen).

L-theanine

L-theanine (also L-g-glutamylethylamide) is a non-protein amino acid that constitutes about 1%-2% (w/w) of Camellia sinensis dry leaves (23). L-theanine is rapidly absorbed in the small intestine and has a bioavailability close to 100% (24). L-theanine can cross the blood-brain barrier and exert neuroprotective effects (25). Because its chemical structure resembles that of glutamate, a neurotransmitter critically involved in memory, theanine may compete with glutamate for binding to glutamate receptors (Figure 6). This glutamate antagonism has been associated with the prevention of neuronal death by theanine after brain ischemia (reviewed in 25).

Figure 6. Chemical Structures of Theanine and Glutamate

Disease Prevention

Cardiovascular disease

Many epidemiological studies have considered the relationship between tea consumption and manifestations of cardiovascular disease (CVD), including coronary heart disease (CHD) and stroke (reviewed in 26). A recent meta-analysis by Zhang et al. included the results of prospective observational studies (cohort or nested case-control studies) that examined the association between tea consumption and cardiovascular morbidity and mortality (27). The results showed that a three-cup (125 mL/cup) increase in daily tea intake was associated with a 27% lower risk of CHD (seven studies), an 18% lower risk of total stroke (eight studies), a 16% lower risk of ischemic stroke (four studies), a 21% lower risk of intracerebral hemorrhage (a type of hemorrhagic stroke), a 26% lower risk of cardiac deaths (12 studies), and a 24% lower risk of total deaths (seven studies). No associations were found between tea consumption and stroke mortality (five studies) or risk of subarachnoid hemorrhage (a subtype of stroke; two studies). Further subgroup analyses indicated that green tea consumption was specifically linked to a reduced risk of stroke, cardiac mortality, and all-cause mortality, while a lower CHD risk was associated with black tea consumption (27). Another recent meta-analysis of prospective cohort studies found that the highest versus lowest level of green tea consumption was associated with a 33% lower risk of cardiovascular mortality (five studies) and a 20% lower risk of all-cause mortality (five studies) (28). Black tea consumption was linked to a 10% reduced risk of all-cause mortality, but not specifically to cardiovascular-related mortality (28).

Tea is a major source of flavonoids in US and European diets (29, 30). The results of several epidemiological studies suggest that dietary flavonoids might influence cardiovascular health. A recent meta-analysis of 14 prospective cohort studies reported that highest versus lowest quantiles of flavonol, flavan-3-ol, flavanone, flavone, anthocyanidin, and proanthocyanidin intake were associated with modest reductions (~10%) in cardiovascular risk (31). A dose-response analysis based on the results of 13 studies in nearly 350,000 individuals and 12,445 CVD cases found a 5% risk reduction with an average 10 mg-incremental increase in daily flavonol intakes (31). It is not clear whether the antioxidant, anti-inflammatory, and/or vasodilatory properties of flavonoids are responsible for some of the cardiovascular benefits associated with tea consumption (see also the article on Flavonoids).

Intervention studies

A number of intervention trials have investigated the effects of tea consumption on markers of cardiovascular health, including biological parameters related to lipid and glucose metabolism, inflammation, blood coagulation, endothelial health, and body composition. 

Metabolic markers of cardiovascular disease: Clinical trials examining the effects of green and/or black tea beverages or extracts have been relatively heterogeneous, especially regarding concentrations of active substances, duration of interventions, and included populations. Pooled analyses of mostly short-term interventions (<3 months) have suggested a reduction in total and LDL cholesterol concentrations with green tea catechin consumption, but the data regarding a potential lipid-lowering effect of black tea are inconsistent (32-34).The studies mentioned below investigated the effect of tea/tea extracts given for at least three months.

Black tea: The Tea’s Effect on Atherosclerosis (TEA) pilot study in 28 older adults at increased risk for cardiovascular disease (CVD) did not find any effect of a six-month black tea consumption intervention (three glasses per day equivalent to 318 mg/day of black tea catechins) on specific biomarkers, including circulating lipoproteins, inflammation markers, homocysteine concentration, adhesion molecules, and hemostatic factors (35). Yet, in a randomized, placebo-controlled study in 47 individuals with borderline-to-moderate hypercholesterolemia, the daily consumption of 1 g of pu-erh tea (Chinese black tea) extract for three months reduced the blood concentrations of total cholesterol, LDL-cholesterol, and triglycerides (36). A three-month, placebo-controlled trial in 77 healthy subjects who drank 9 g of black tea infused in 600 mL of boiling water per day (about 740 mg/day of black tea polyphenols) had improvements in lipoprotein and triglyceride profiles, fasting serum glucose concentrations, and measures of antioxidant activities in the plasma (37). The same protocol was found to also reduce markers of oxidative stress and inflammation in the plasma of individuals at risk for CVD (38). In contrast, a recent randomized, double-blind, placebo-controlled trial in 77 regular tea drinkers (35 to 75 years old) found that the daily consumption of 429 mg of black tea polyphenols for six months had no effect on fasting blood glucose and serum lipids (39).

Green tea: Daily supplementation with a capsule containing 150 mg of green tea catechins, 75 mg of black tea theaflavins, and 150 mg of other polyphenols, for six months significantly lowered plasma LDL-cholesterol concentrations and the ratio total cholesterol:HDL in a randomized, double-blind, placebo-controlled study in 220 individuals with mild-to-moderate hypercholesterolemia (40). In a pilot study in 74 overweight/obese breast cancer survivors, the daily consumption of green tea (containing 26.7 mg of caffeine and 235.6 mg of catechins with 128.8 mg as EGCG) for six months increased HDL concentration compared to a citrus-based herbal placebo but had no effect on LDL concentration and markers of glycemic control (41). Another placebo-controlled study conducted in obese subjects with controlled hypertension found that the daily ingestion of one capsule of green tea extract (379 mg/capsule containing 208 mg of EGCG) for three months significantly lowered systolic and diastolic blood pressure and improved blood lipid profile, antioxidant status, and measures of glycemic control and inflammation (42).

Endothelial dysfunction: The vascular endothelial cells that line the inner surface of all blood vessels synthesize an enzyme, endothelial nitric oxide synthase (eNOS), which plays a critical role in maintaining cardiovascular health. Specifically, eNOS utilizes L-arginine to produce 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 (26). 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 (43). 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. The measurement of brachial flow-mediated dilation (FMD) is often used as a surrogate marker of endothelial function; FMD values are inversely correlated with the risk of future cardiovascular events (44).

Black tea: Two small controlled clinical trials found that daily consumption of 900 to 1,250 mL of black tea for four weeks significantly improved endothelium-dependent FMD in patients with coronary heart disease (45) and in patients with mildly elevated serum cholesterol concentrations (46). Improvements were noted in comparison to an equivalent amount of hot water. Incremental doses of black tea flavonoids (0, 100, 200, 400, and 800 mg/day; each dose being given for one week) have been associated with dose-dependent increases in brachial FMD in 19 healthy volunteers. Specifically, FMD values went from 7.8% at baseline (no flavonoids) to 10.3% with 800 mg/day of flavonoids (47). Of note, in this study, the ingestion of black tea flavonoids significantly lowered systolic and diastolic blood pressure in a non dose-dependent manner, while other variables, including markers of arterial stiffness, glucose metabolism, inflammation, endothelial activation, and lipid profile, remain largely unchanged (47). In a recent randomized trial, seven days of black tea consumption (450 mL/day) followed by the ingestion of two cups (300 mL) 20 minutes before an experimental ischemia-reperfusion (IR) injury procedure on healthy participants failed to prevent IR injury-associated FMD reduction. Even if tea flavonoids were able to limit the impact of IR injury on FMD — for example by counteracting the production of reactive oxygen species — the presence of caffeine in black tea (and the lack of control for it) could have confounded this effect (48).

Green tea: In a small study conducted in 14 healthy young adults (50% smokers), a significant increase in brachial FMD was reported 30 to 120 minutes after the consumption of 450 mL of green tea (6 g of green tea, including 125 mg of caffeine) compared to caffeine alone or hot water (49). Another study that compared the acute effect of black and green tea on brachial FMD in 21 postmenopausal women found a similar increase in FMD two hours after the ingestion of either tea preparation (50). Both black and green teas have been found to be equally able to increase eNOS activity and NO production in cultured endothelial cells (50, 51). Specifically, the prominent green tea catechin, EGCG, and black tea polyphenols, theaflavins and thearubigins, are thought to contribute to the protective effect of drinking tea by promoting antioxidant activity and endothelium-dependent vasodilation (51). Other flavonoids, like (-)-epicatechin and quercetin glucoside have recently failed to show an effect on FMD (and blood pressure) in hypertensive adults (52). For more information, see the article on Flavonoids.

A meta-analysis of nine human intervention studies estimated that the acute and/or short-term (up to four weeks), daily ingestion of 500 mL of tea — containing about 248 mg of flavonoids in green tea and 415 mg in black tea — significantly increased brachial FMD (53). Yet, the clinical relevance of these FMD improvements is unclear. It is also not clear whether the chronic consumption of tea might benefit vascular endothelial function and eventually lower the risk of cardiovascular disease.

Hypertension: Hypertension (high blood pressure) is a risk factor for CVD morbidity and mortality.

Black tea: A recent meta-analysis of 11 small randomized controlled trials in either healthy or at-risk individuals found a significant reduction of 2 mm Hg in systolic and 1 mm Hg in diastolic blood pressure with the daily consumption of at least 400 mL (13 oz) of black tea for one week to six months, providing a minimum of 240 mg/day of flavonoids (54). Two recent trials also reported that black tea lowered the rate of circadian variations in blood pressure at nighttime and variations after a dietary fat challenge. A six-month intervention in 76 participants from the general population (most with moderate hypertension) showed that the consumption of three cups per day of black tea, supplying a daily total of 1.29 g of polyphenols and 288 mg of caffeine, lowered the rate of nighttime blood pressure variations compared to a polyphenol-free caffeine-matched placebo (55). Two cups of black tea per day, equivalent to 300 mg of polyphenols, also limited blood pressure variations after a fat-rich meal in 19 patients with primary (idiopathic) hypertension (56). Mechanisms underlying the blood pressure-lowering properties of black tea may involve the inhibition of angiotensin-II synthesis by flavonoids (see below).

Green tea: Several recent meta-analyses of randomized controlled trials indicated that the consumption of green tea or green tea extracts could significantly lower blood pressure (57-60). In one of them, the pooled analysis of 13 trials in 1,367 subjects found a 2.0 mm Hg reduction in systolic blood pressure and a 1.9 mm Hg reduction in diastolic blood pressure with green tea polyphenols (208 mg/day-1,207 mg/day) for a median period of 12 weeks (60). Subgroup analyses suggested greater blood pressure lowering effect with polyphenol intake levels lower than 582.8 mg/day and with adjustment for the confounding effect of caffeine. Another meta-analysis included randomized controlled trials that specifically explored the effect of green tea or green tea extracts on blood pressure in overweight or obese subjects. The pooled analysis of 14 trials showed significant reductions of 1.4 mm Hg in systolic blood pressure and 1.3 mm Hg in diastolic blood pressure (58). The anti-hypertensive effect of green tea may be mediated by a number of mechanisms. For example, pharmacological concentrations of several catechins have been shown to inhibit the activity of a key regulator of arterial blood pressure, angiotensin-converting enzyme (ACE), in vitro (61). ACE catalyzes the conversion of angiotensin-I into angiotensin-II, a potent inducer of vasoconstriction. In addition, studies in rats showed that chronic treatment with epicatechin prevented salt-induced hypertension, partly through inhibition of endothelin-1 expression and NADPH oxidase (NOX) activity (62). Other potential benefits of green tea consumption, including improvements in blood lipid profile, insulin sensitivity, and endothelial function, may also contribute to its blood pressure-lowering effects.

Type 2 diabetes mellitus

Impaired glucose tolerance in patients with prediabetes is often associated with loss of insulin sensitivity, impaired lipid metabolism, low-grade inflammation, and endothelial dysfunction (63). Without changes in lifestyle behavior (especially regarding dietary habits and physical activity), individuals with prediabetes will eventually progress to develop overt type 2 diabetes mellitus (64).

In this context, the association between tea consumption and risk of type 2 diabetes 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 individuals with diabetes (65). The results showed that tea consumption was inversely associated with diabetes incidence. The consumption of four cups per day rather than none was found to be associated with a 16% lower risk of diabetes (65). Of note, in a meta-analysis of 15 prospective cohort studies, including the EPIC-InterAct study, an incremental increase of two cups per day in tea consumption was found to be associated with an estimated 4.6% risk reduction (66). The EPIC-InterAct study also found that participants in the highest quintile (>608.1 mg/day) of total flavonoid intake had a 10% lower risk of diabetes than those in the lowest quintile (<178.2 mg/day) (67). Specifically, the risk of diabetes was inversely correlated with the consumption of flavan-3-ols (catechins, proanthocyanidins, and theaflavins) and flavonols (67, 68). The intakes of other flavonoid subclasses that are less abundant in tea, namely anthocyanidins, flavanones, flavones, and isoflavones, were not associated with a reduced risk of diabetes (67).

Recent meta-analyses of randomized controlled trials that examined the possible health benefits of green tea catechins on glucose metabolism have provided conflicting results. A meta-analysis of seven trials in prediabetic 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 (HbA1c) and insulin sensitivity (HOMA-IR) (69). Conversely, another meta-analysis of 17 trials in prediabetic, diabetic, or overweight/obese subjects found that administration of green tea extracts for 4 to 16 weeks improved fasting plasma glucose and HbA1c levels (70). 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. However, 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 (71).

Overweight and obesity

A recent meta-analysis of five small, randomized controlled trials (<100 participants per study) found that regular consumption of green or pu-erh tea extracts reduced body weight and body mass index (BMI) in overweight/obese participants with metabolic syndrome (72). The influence of green tea on body composition may be attributed to the regulation of appetite, fat absorption, fatty acid oxidation, and thermogenesis by catechins and caffeine (73). Yet, studies in overweight/obese people who are otherwise healthy have provided mixed results (reviewed in 74). Intervention studies in Caucasian populations have shown a less favorable effect of green tea catechins on body weight and energy expenditure compared to those conducted in Asian subjects. These discrepancies suggested that differences in genetic background, body composition, and dietary habits (including caffeine consumption) might interfere with the possible anti-obesity effect of green tea consumption. Large-scale, intervention trials that control for energy intake and physical activity are needed to determine if tea or tea extracts promote weight loss or improve weight maintenance in different populations with obesity and/or metabolic syndrome (74).

Cancer

Tea and tea constituents have been found to have cancer preventive activities in a variety of animal models of cancer, such as cancer of lung, mouth, esophagus, stomach, colon, and prostate (75). However, the results of epidemiological studies in humans have been mostly inconclusive.

Breast cancer

An early meta-analysis of prospective cohort studies had reported that black tea intake (five cohorts) — but not green tea (three cohorts) — was associated with a 15% higher risk of breast cancer (76). The relationship between tea consumption and breast cancer has been recently examined in the Swedish Women’s Lifestyle and Health prospective cohort Study (WLHS), which followed 42,099 women for 20 years and documented 1,395 breast cancer cases (77). The results indicated a 14% higher risk of breast cancer with each cup (200 mL) of tea consumed daily. The risk was specifically increased in postmenopausal women rather than in premenopausal women. Similarly, in a recent case-control study in Chinese women in Hong Kong, regular tea consumption was inversely correlated with breast cancer risk in premenopausal women but associated with an increased risk in postmenopausal women (78). The risk associated with consuming tea was also significantly higher for estrogen- and progesterone-receptor-positive (ER+/PR+) breast cancer type in the Swedish cohort, while the highest risk was found in women with ER-negative tumors in the Chinese study (77, 78). Yet, in the European Prospective Investigation into Nutrition and Cancer Study (EPIC) in 335,060 women followed for 11 years (10,198 incidental breast cancer cases), tea intake was not associated with breast cancer overall or when the data were analyzed for menopausal status or breast cancer type (79). The most recent meta-analysis of prospective cohort studies found no association between consumption of green or black tea and breast cancer (80). Thus, current epidemiological evidence does not suggest a benefit of tea in breast cancer prevention despite promising data from cultured cells and rodent models (81).

However, some observational studies found that consumption of certain subclasses of flavonoids might have the potential to reduce the incidence of breast cancer in postmenopausal women (82). Recently, the effects of decaffeinated green tea extracts on biomarkers of breast cancer risk were examined in the Minnesota Green Tea Trial (MGTT) in 1,075 high-risk postmenopausal women randomized to receive the equivalent of four 8-ounce mugs/day (960 mL/day) in green tea extracts (1,315±116 mg/day of catechins) or a placebo for one year (83). The results have yet to be published.

Mouth, throat, and esophageal cancers

In the large, prospective NIH-AARP Diet and Health study (1995-2006) in 481,563 US adults, 1,305 cases of oral (392), pharyngeal (178), laryngeal (307), and esophageal (428) cancers have been identified during the follow-up period (84). The highest versus lowest level of tea intake (≥1 cup/day vs. non-consumption) was correlated with a 63% lower risk of pharyngeal cancer but with no other above-cited cancer types (84). Observational studies do not currently provide clear evidence for an association between tea consumption and laryngeal (85) or esophageal (86) cancers. In the case of esophageal cancer, the consumption of high-temperature beverages (including very hot tea) might even damage the epithelium and increase the risk of cancer (87). High temperature may act as a confounding factor that complicates the interaction between tea consumption and esophageal cancer (88). In 2009, a phase II, randomized, double-blind trial was conducted in 41 patients with high-risk oral premalignant lesions (OPLs). Participants were randomly assigned to orally receive 0.5, 0.75, or 1 g of green tea extract per m2 (body surface area) or a placebo, thrice a day for three months. While the results suggested that OPLs might be clinically responsive to green tea extract treatment, larger trial populations are needed to confirm these preliminary data (89).

Gastric cancer

Several prospective cohort studies reported no association between tea consumption and risk of gastric cancer (90-92), including the US NIH-AARP Diet and Health study (84). Tea consumption also failed to predict gastric cancer cases in the EPIC study, which followed 477,312 participants and identified 683 cases during a median 11.6 years of follow-up (93). Yet, a decreased risk of intestinal type gastric cancer was observed in women in the highest versus lowest quartile of tea consumption (≥475 mL/day vs. ≤21 mL/day). Interestingly, women (but not men) in the highest versus lowest quartile of flavonol, flavanol, theaflavin, or total flavonoid intakes had a significantly reduced risk of developing gastric cancer (94). A pooled analysis of six Japanese cohort studies, including 219,080 total participants and 3,577 cases, found an inverse association between green tea consumption and gastric cancer in women but not in men: daily consumption of at least five cups of tea was associated with a 21% lower risk of gastric cancer in women compared to low intakes (<1 cup/day) (95).

Gynecologic cancers

Meta-analyses of case-control studies have found a significant 34% reduction in risk of ovarian cancer for highest versus lowest intake of green tea (four studies) (96), but no association was observed for black tea (six studies) (97). Yet, a meta-analysis of six prospective studies showed an inverse relationship between black tea consumption and ovarian cancer (98). A recent analysis of the Nurses’ Health Studies (NHS I and II) showed a 31% lower risk of ovarian cancer in women consuming at least 1 cup/day compared to rare/non-black tea drinkers (99). In a prospective study in 244 women diagnosed with ovarian cancer and followed for over three years, green tea consumption was associated with a mean survival time greater for consumers (5.39 years) than for non-consumers (4.19 years) (100). However, in a single-arm, phase II trial in 16 women in complete remission from advanced stage ovarian cancer, the daily intake of 500 mL of green tea (containing 319.8 mg of EGCG) failed to effectively prevent cancer recurrence within the 18-month follow-up period (101). Further, a recent systematic review and meta-analysis of observational studies suggested a possible benefit of green tea — but not black tea — for endometrial cancer (102).

Additional studies have examined the association between tea consumption and risk of lung, prostate, liver, or colorectal cancer in humans, providing mixed results (reviewed in 103).

Bone health and osteoporosis

The etiology of osteoporosis is complex, involving factors such as aging, decreased sex hormones, inadequate nutrition, physical inactivity, genetic predisposition, as well as socioeconomic determinants. Tea bioactive components, including flavonoids, caffeine, and fluoride, have the potential to influence health and the risk of osteoporosis and fracture (104, 105). A small prospective study in 164 elderly women found that consumption of tea limited the age-related loss in total hip bone mineral density (BMD) over a four-year follow-up period (106). Also, in a six-month randomized, placebo-controlled trial in 171 postmenopausal women with osteopenia, the daily consumption of green tea catechins (500 mg) alone or combined with Tai Chi exercise (3 hours/week) improved bone turnover by stimulating bone formation (107).

Hip fracture is one of the most serious consequences of osteoporosis. A recent prospective study in 1,188 elderly women (mean age, 80 years) followed for 10 years found that participants in the highest versus lowest tertile of tea consumption (≥3 cups/day vs. ≤1 cup/week) had a 30% lower risk of any osteoporotic fracture. However, no interaction was found when the analysis was conducted on major fractures (hip, spine, humerus, and wrist) or hip fractures only (108). Yet, a meta-analysis based on 147,488 individuals from 11 observational studies published between 1990 and 2010 suggested that the consumption of 1-4 cups/day was associated with a significantly lower risk of hip fracture (109). The results of another recent meta-analysis of mostly case-control studies did not suggest any interaction between tea consumption and risk of any fracture or hip fracture (110). Additional studies are required to determine whether tea consumption affects the development of osteoporosis or the risk of osteoporotic fracture in a meaningful way.

Dental health

The cross-sectional analysis of the Ohsaki prospective cohort study that included data from 25,078 Japanese participants found an inverse association between the daily consumption of at least one cup of tea and the risk of tooth loss (111). Specifically, the risk of tooth loss was 11% lower in women and 23% lower in men who consumed at least five cups per day of tea compared to those drinking less than one cup per day. An earlier cross-sectional study of more than 6,000 14-year old children in the UK found that those who drank tea had significantly fewer dental caries than coffee drinkers; results were independent of the amount of beverage consumed or whether sugar was added (112). Although tea is a good source of fluoride — a recognized anticaries agent — both flavonoids and tannins in tea have been shown to have antimicrobial properties (reviewed in 113). Oral bacteria like Streptococcus mutans and Porphyromonas gingivalis have been associated with plaque formation, dental caries, and periodontal (gum) diseases. Untreated caries and gum inflammation can lead to severe pain, local infection, tooth loss or extraction, nutritional problems, and serious systemic infections in susceptible individuals. A pilot study in 25 adults suggested that mouthwash with a 2% green tea solution could lower acidity level and Streptococcus mutans count in saliva and plaque and improve measures of gum bleeding after exposure to sugar (114). A small, randomized study in 66 young volunteers (12-18 years old) also reported a significant antibacterial effect of a mouth rinse made with pulverized tea leaves compared to a placebo solution (115). Recent randomized, double-blind, controlled studies demonstrated further that tea extract-containing mouthwashes could benefit dental health and offer a possible alternative to current chlorhexidine- and fluoride-containing rinsing solutions (116-118). Finally, the incorporation of tea extract in toothpastes was found to be as effective — if not better — than regular pastes (containing fluoride and triclosan) to reduce dental plaque and gum inflammation in patients with mild to moderate periodontitis (119).

For more information on dental caries, see the article on Fluoride.

Kidney stones

The formation of kidney stones, usually composed of calcium oxalate or calcium phosphate, is a common condition that affects 7% of US women and 11% of US men during their lifetime (120). A pooled analysis of three ongoing prospective cohort studies — the Health Professionals Follow-up Study and the Nurses’ Health Studies I and II, including a total of 194,095 participants — found that the risk of developing symptomatic kidney stones was 11% lower in individuals consuming at least one 8-ounce mug of tea per day compared to those consuming less than one cup per week (121). High fluid intake, including tea intake, is generally considered the most effective and economical means of preventing kidney stones (122). However, the finding that black tea may contain high amounts of oxalate (48 to 92 mg/100 mL) suggested that black tea consumption may increase urinary oxalate concentrations, a risk factor for calcium oxalate stone formation (123). The Academy of Nutrition and Dietetics recommends that kidney stone patients restrict oxalate intake to 40 mg/day-50 mg/day, and some experts advise those with a history of calcium oxalate stones to limit the consumption of oxalate-rich food, including black (but not green) tea (123, 124). Yet, recent studies have reported amounts of oxalate in different samples of green teas (0.8 to 14 mg/100 mL) (125) and black teas (1 to 2.6 mg/100 mL) (126, 127) much lower than previously published, suggesting that tea consumption would not increase kidney stone incidence or recurrence.

Mood

The term "mood" refers to an emotional state of mind that includes aspects like contentedness, relaxation, alertness, energy, and relief from depression, anxiety, and feelings of guilt and failure (128). Clinical depression is described as a mood disorder. An analysis of the NIH-AARP Diet and Health Study (1995-2006) in 263,923 participants — of which 11,311 self-reported depression — found that consumption of decaffeinated (but not caffeinated) hot tea was associated with an increased risk for depression (129). However, smaller cohort studies had previously recorded significantly less depressive symptoms in participants with higher versus lower intakes of tea (130, 131).

Tea consumption may have short-term effects on mood. In a recent cross-sectional study in 95 university staff members, consumption of tea recorded during 10 working days was associated with self reports of feeling less tired and performing better at work (132). Tea was also found to increase the positive valence of mood immediately after consumption in a small randomized controlled study in 150 participants (133).

Cognitive function

Cognitive function includes the domains of attention, memory, processing speed, and executive function, which decline gradually with increasing age.

Cognitive performance

A few studies investigated whether tea consumption was associated with cognitive benefits, especially in the domain of attention (reviewed in 134). Two cross-over, randomized, double-blind, placebo-controlled studies evaluated the effects of two servings of black tea over the course of 60 min (study 1; 26 volunteers) or three servings of black tea over the course of 90 min (study 2; 32 volunteers) on measures of attention and alertness (135). Both studies reported improved performance on objective attention tests and self-reported alertness with black tea compared to placebo. In a small open-label study, 19 participants were asked to consume either black tea (with/without caffeine), coffee (with caffeine), or water (with/without caffeine) before undergoing a battery of psychometric tests (136). Most of the improvements in cognitive function (measured with the Critical Flicker Fusion Threshold [CFFT] task) and subjective alertness were attributed to caffeine in the beverages. In addition, CFFT task scores were greater after consumption of caffeinated tea compared to caffeinated water (136). In a follow-up study, caffeinated tea outperformed caffeinated coffee in the CFFT test, suggesting that tea ingredients other than caffeine might have acute effects on cognitive function (137). A recent meta-analysis of small, randomized controlled trials (<50 participants/trial) that measured the acute effect of L-theanine (36 mg-250 mg) with or without caffeine (40 mg-250 mg) suggested an increase in alertness and attention-switching accuracy but no change regarding other parameters, such as calmness, contentedness, or anxiety (138).

Cognitive decline

The cross-sectional data analysis of 2,501 participants (≥55 years old) in the Singapore Longitudinal Ageing Study (SLAS) indicated that higher intakes of tea correlated with better global cognitive function, as assessed by Mini-Mental State Examination (MMSE) scores (139). Conversely, lower levels of tea consumption were associated with a higher prevalence of cognitive impairments, defined as MMSE scores ≤23. Similar observations have been reported in several other cross-sectional studies (140-143). In the SLAS study, the follow-up of 1,438 cognitively healthy people for one to two years showed that the risk of cognitive decline (defined as a drop of ≥1 point in the MMSE score) was up to 43% lower in tea drinkers compared to non-drinkers (139). Further research in 716 SLAS participants (mean age, 64.5 years) with normal cognitive function confirmed that those consuming tea scored higher in the MMSE global cognition test than non-consumers. Tea consumption was also correlated with higher cognitive test scores regarding memory, executive function, and information-processing speed (144). Tea consumption was also modestly associated with a reduced risk of cognitive decline in 2,722 women (but not in men) followed for a median 7.9 years in the US population-based Cardiovascular Health Study, despite a much lower frequency of tea consumption (up to 5 cups/week) than that observed in the SLAS (over 10 cups/day) (145). In a prospective cohort study in Japanese older people (>60 years old) followed for nearly five years, daily green tea consumers were shown to have lower risks of mild cognitive impairments (MCI) and dementia compared to non-consumers (146). In a recent pilot trial, the consumption of green tea extracts (2 g/day, of which 227 mg of catechins and 42 mg of theanine) for three months resulted in higher MMSE scores (compared to baseline) due to improved short-term memory scores in 12 elderly nursing home residents (ages, 70 to 98 years) with symptoms from MCI to severe dementia (147).

Long-term, large randomized controlled trials are needed to establish whether tea or its bioactive components could limit cognitive decline and/or improve cognitive dysfunction in older individuals.

Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disease characterized by the selective death of dopaminergic brain cells in the substantia nigra. PD is estimated to affect 0.5%-4% of older people (≥65 years old) worldwide (148). A retrospective study in 279 subjects with PD suggested that the onset of motor symptoms in those drinking more than 3 cups/day of tea was delayed by several years compared to nondrinkers (149); yet, after disease onset, a similar rate of disease progression was observed among tea drinkers and non-drinkers (150). A meta-analysis of eight case-control studies, including 4,250 controls and 1,418 PD cases, found a 15% reduced risk of PD with higher versus lower intake of tea (151). Another meta-analysis of four case-control studies and four prospective cohort studies published between 1999 and 2012 indicated that individuals in the highest category of tea consumption had a 37% lower risk of PD compared to those in the lowest category (152). The authors estimated that each 2 cups/day-increase in tea consumption was associated with a 26% lower risk of developing PD (152). If a protective effect of tea consumption can be further demonstrated, several bioactive compounds, especially caffeine (153) and flavonoids (154), could be responsible for the tea benefits in PD prevention.

Safety

Adverse effects

Tea

Tea is generally considered to be safe, even in large amounts. However, two cases of hypokalemia (abnormally low serum potassium concentrations) in the elderly have been attributed to excessive consumption of black and oolong tea (3 L/day-14 L/day) (155, 156). Hypokalemia is a potentially life-threatening condition that has been associated with caffeine toxicity (157, 158). Case reports of stomach cramps (159), kidney stones (160), and skeletal fluorosis (161-163) due to excessive tea consumption have also been published.

Tea extracts

In clinical trials employing caffeinated green tea extracts, cancer patients who took 6 g/day, in three to six divided doses, experienced mild-to-moderate gastrointestinal side effects, including nausea, vomiting, abdominal pain, and diarrhea (164, 165). 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 (164). 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 (166). Nineteen additional cases of hepatotoxicity associated with the consumption of herbal products containing green tea have been reported for the period 2008-2015 (167). 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 (168). 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 (169). 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 (169).

Pregnancy and lactation

The safety of tea extracts or supplements for pregnant or breast-feeding women has not been established. Some organizations, like the American College of Obstetricians and Gynecologists, suggest to limit caffeine consumption during pregnancy to less than 200 mg/day (170), because higher caffeine intakes have been associated with increased risk of miscarriage and low birth weight in some epidemiological studies (171, 172).

Drug interactions

Green tea

Excessive green tea consumption may decrease the therapeutic effects of the anticoagulant, warfarin (Coumadin, Jantoven). Such an effect was documented in only one patient who began drinking one-half gallon to one gallon of green tea daily (173). It is probably not necessary for people on warfarin therapy to avoid green tea entirely; however, large quantities of green tea may increase the risk of bleeding in warfarin-treated patients (174). Green tea extracts may also reduce the efficacy or increase the toxicity of at least two other cardiovascular drugs, namely simvastatin (Zocor) and nadolol (Corgard) (175). Preclinical studies suggested that green tea extracts may interfere with drug metabolism by affecting the activity of cytochrome P450 3A4 (CYP3A4), which catalyzes the metabolism of about one-half of all marketed drugs in the US and Canada (176). Additional information on drug interactions is available in the article on Flavonoids.

Caffeine

A number of drugs can impair the metabolism of caffeine, increasing the potential for adverse effects from caffeine (177). Such drugs include cimetidine (Tagamet), disulfiram (Antabuse), estrogens, fluoroquinolone antibiotics (e.g., ciprofloxacin, enoxacin, norfloxacin), fluconazole (Diflucan), fluvoxamine (Luvox), mexiletine (Mexitil), riluzole (Rilutek), terbinafine (Lamisil), and verapamil (Calan). High caffeine intakes may increase the risk of toxicity of some drugs, including albuterol (Ventolin), metaproterenol (Alupent), clozapine (Clozaril), ephedrine, stimulant drugs (e.g., epinephrine), monoamine oxidase inhibitors, phenylpropanolamine, and theophylline. High caffeine intakes may also reduce the bioavailability and/or the efficacy of drugs like carbamazepine, valproate, dipyridamole (Persantine), pentobarbital (Nembutal), and phenobarbital (Luminal). Abrupt caffeine withdrawal has been found to increase serum lithium levels in people taking lithium, potentially increasing the risk of lithium toxicity.

Nutrient interactions

Iron

Flavonoids in tea can bind nonheme iron, inhibiting its intestinal absorption (178, 179). Nonheme iron is the principal form of iron in plant foods, dairy products, and iron supplements. The consumption of one cup of tea with a meal has been found to decrease the absorption of nonheme iron in that meal by about 70% (180, 181). Flavonoids can also inhibit intestinal heme iron absorption (182). Interestingly, ascorbic acid (vitamin C) greatly enhances the absorption of iron and is able to counteract the inhibitory effect of flavonoids on nonheme and heme iron absorption (179, 182, 183). To maximize iron absorption from a meal or iron supplements, subjects with poor iron status should not consumed tea at the same time (184). In addition, healthy individuals at no risk of iron deficiency do not need to restrict their consumption of tea (184, 185).


Authors and Reviewers

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

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

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

Reviewed in January 2016 by:
Richard Draijer, Ph.D.
Lead Scientist, Unilever R&D
Vlaardingen, The Netherlands

Reviewed in January 2016 by:
Guus Duchateau, Ph.D.
Science Leader, Unilever R&D
Vlaardingen, The Netherlands

Reviewed in January 2016 by:
Suzanne Einöther
Scientist, Unilever R&D
Vlaardingen, The Netherlands

Copyright 2002-2017  Linus Pauling Institute


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178.  Kim EY, Ham SK, Shigenaga MK, Han O. Bioactive dietary polyphenolic compounds reduce nonheme iron transport across human intestinal cell monolayers. J Nutr. 2008;138(9):1647-1651.  (PubMed)

179.  Thankachan P, Walczyk T, Muthayya S, Kurpad AV, Hurrell RF. Iron absorption in young Indian women: the interaction of iron status with the influence of tea and ascorbic acid. Am J Clin Nutr. 2008;87(4):881-886.  (PubMed)

180.  Hurrell RF, Reddy M, Cook JD. Inhibition of non-haem iron absorption in man by polyphenolic-containing beverages. Br J Nutr. 1999;81(4):289-295.  (PubMed)

181.  Zijp IM, Korver O, Tijburg LB. Effect of tea and other dietary factors on iron absorption. Crit Rev Food Sci Nutr. 2000;40(5):371-398.  (PubMed)

182.  Ma Q, Kim EY, Lindsay EA, Han O. Bioactive dietary polyphenols inhibit heme iron absorption in a dose-dependent manner in human intestinal Caco-2 cells. J Food Sci. 2011;76(5):H143-150.  (PubMed)

183.  Kim EY, Ham SK, Bradke D, Ma Q, Han O. Ascorbic acid offsets the inhibitory effect of bioactive dietary polyphenolic compounds on transepithelial iron transport in Caco-2 intestinal cells. J Nutr. 2011;141(5):828-834.  (PubMed)

184.  Nelson M, Poulter J. Impact of tea drinking on iron status in the UK: a review. J Hum Nutr Diet. 2004;17(1):43-54.  (PubMed)

185.  Mennen L, Hirvonen T, Arnault N, Bertrais S, Galan P, Hercberg S. Consumption of black, green and herbal tea and iron status in French adults. Eur J Clin Nutr. 2007;61(10):1174-1179.  (PubMed)

Alcoholic Beverages

Summary

      • Those who consume more than minimal amounts of alcohol should make sure they also consume adequate folate by taking a daily multivitamin that provides 400 μg of folic acid. (More information)
      • There is consensus that the health risks of moderate alcohol consumption outweigh the health benefits for some people. People who should abstain from alcohol include (1, 2): children and adolescents; pregnant women and women who may become pregnant; anyone who has trouble limiting his or her alcohol consumption to moderate levels, particularly recovering alcoholics and those with a family history of alcoholism or alcohol problems; and anyone with chronic liver disease or alcohol-related disease or organ damage. 
      • Anyone planning to drive, operate heavy machinery, or perform other potentially hazardous activities requiring coordination and skill should not consume alcohol.
      • People who would benefit from individualized advice regarding potential health risks and benefits of moderate alcohol consumption include: anyone taking medications (over-the-counter or prescription) with the potential for adverse interactions with alcohol; and anyone with a personal or family history (e.g., parent or sibling) of breast cancer, coronary heart disease, or other conditions related positively or inversely to moderate drinking.

Introduction

While excessive alcohol consumption has been linked to a number of serious health and social problems, observational studies have associated moderate alcohol consumption with some important health benefits. The relationship between alcohol consumption and mortality is often described as J-shaped, meaning that when graphed from alcohol abstinence on the left to heavy drinking on the right, light-to-moderate alcohol consumption (≤2 drinks/day) is associated with lower rates of mortality — mostly from cardiovascular disease — than abstention, while heavy alcohol consumption (>3-4 drinks/day) is associated with higher rates of mortality from a number of causes (3-5). Because the consumption of alcohol can be viewed as a “double-edged sword,” individual decisions regarding alcohol use should take into consideration scientific evidence regarding potential health benefits and risks, as well as personal and family histories of health problems and addictions.

It is important to note the data on alcohol-disease relationships come from only observational studies, not randomized controlled trials, and observational data cannot establish causation. In observational research, potential confounding variables should be adequately adjusted for using statistical techniques. For instance, nondrinkers have been shown to differ from those who consume alcohol in ways that might affect the disease outcome of interest (6). Even when controlling for many potential confounders, residual confounding may still occur.

Definitions (7)

Standard alcoholic drink (8)

A standard alcoholic drink contains approximately 14 grams of alcohol, which is equivalent to 12 ounces of beer (~5% alcohol), 8.5 ounces of malt liquor (~9% alcohol), 5 ounces of wine (~12% alcohol), 3.5 ounces of fortified wine (e.g., sherry or port), or 1.5 ounces of liquor (distilled spirits; ~40% alcohol).

Moderate alcohol consumption

  • Men: No more than two standard alcoholic drinks/day (9)
  • Women: No more than one standard alcoholic drink/day* (9)
  • There is consensus that distributing total weekly alcohol intake evenly to most days is the healthiest drinking pattern. 

Heavy alcohol consumption (8)

  • Men: More than 14 standard alcoholic drinks/week or more than 4 standard alcoholic drinks in a day
  • Women: More than 7 standard alcoholic drinks/week or more than 3 standard alcoholic drinks in a day*

*In addition to weighing less, on average, women absorb and metabolize alcohol differently than men. In general, women have less body water than men of similar body weight, so women achieve higher blood alcohol concentrations after drinking equivalent amounts of alcohol (10). Women also appear to be more vulnerable to adverse health effects of heavy drinking than men. Thus, most definitions of “moderate” or “heavy” drinking offer a lower threshold for women.

Potential Health Benefits of Moderate Alcohol Consumption

Mortality

Data from observational studies have shown that light-to-moderate alcohol consumption (≤1 drink/day for women and ≤2 drinks/day for men) is protective against all-cause mortality (4, 11-15). As mentioned above, a J-shaped relationship is apparent when all-cause mortality is plotted against alcohol consumption (alcohol abstinence on the left and heavy drinking on the right of the x-axis) (4, 16). In other words, those who drink moderately have the lowest risk of total mortality when compared to nondrinkers and heavy drinkers, and heavy drinkers have the highest risk of mortality.

The association of reduced mortality with moderate alcohol consumption is largely attributed to a decrease in cardiovascular mortality (14, 16-18), especially from coronary heart disease (see Cardiovascular disease below). However, concern has been raised that some earlier observational studies have misclassified former drinkers in the lifetime abstention group (i.e., the referent group), but most recent studies have not supported such a ‘misclassification hypothesis’ (15, 16, 19).

Cardiovascular disease

Coronary heart disease

Over the past four decades, the most consistent evidence of a health benefit associated with moderate alcohol consumption has been a significant reduction in the risk of coronary heart disease (CHD) — a finding confirmed by a large number of epidemiological studies. When the results of 28 prospective cohort studies were combined in a meta-analysis, adults who consumed an average of 25 grams/day of alcohol (the amount in two standard alcoholic drinks) had a risk of CHD that was 20% lower than adults who did not consume alcohol (20). More recent data from two large prospective cohort studies conducted in the US suggest that the magnitude of CHD risk reduction associated with moderate alcohol consumption may be closer to 30%. In a 12-year study of more than 38,000 male health professionals, those who consumed alcohol at least 3-4 times weekly had a risk of myocardial infarction (heart attack) that was 32% lower than men who drank alcohol less than once weekly (21). Similarly, in a 20-year study of more than 120,000 men and women, those who reported consuming 1-2 alcoholic drinks daily had a risk of death from CHD that was 30% lower than those who did not drink alcohol (22). A 2011 systematic review and meta-analysis of 29 studies found that alcohol consumption was associated with a 29% reduced risk of CHD compared to abstention; intakes of 2.5 to 60.0 grams/day of alcohol were associated with a lower risk of CHD (16).

How does alcohol consumption reduce CHD risk? The development of CHD is characterized by the formation of cholesterol-laden plaque in the arteries (atherosclerosis), vascular inflammation, and clot formation (23). Numerous small, randomized trials have examined the effect of daily alcohol consumption on markers of CHD risk, consistently finding that moderate alcohol consumption significantly increases concentrations of high-density lipoprotein (HDL)-cholesterol — the ‘good cholesterol’ (24, 25). HDLs transport cholesterol from tissues, including arterial walls, back to the liver for elimination or recycling. In addition to increasing HDL levels, moderate alcohol consumption has been shown to increase apolipoprotein A1, a major component of circulating HDL (25). Higher levels of high-density lipoprotein (HDL)-cholesterol have been associated with reductions in CHD risk (26).

Alcohol may also have anti-thrombotic properties. Clot formation is the result of complex interactions between factors that promote coagulation and factors that inhibit coagulation or promote the dissolution of clots. Several randomized trials have found that moderate alcohol consumption decreases serum levels of fibrinogen, a protein that promotes clot formation (25) and increases serum levels of an enzyme that helps dissolve clots (tissue type plasminogen activator) (24).

Further, moderate alcohol consumption may have an anti-inflammatory effect since serum levels of C-reactive protein (CRP), a marker of systemic inflammation and sensitive predictor of CHD risk, are lower in people who drink moderately than those who abstain from alcohol (27-32). Moderate alcohol consumption has also been associated with improvements in adiponectin levels (25), insulin sensitivity (see Type 2 diabetes mellitus below), abdominal obesity (33), and endothelial function (34)

Does the type of alcohol consumed (wine, beer, or liquor) affect CHD risk? Significant reductions in CHD risk have been associated with moderate consumption of wine, beer, and liquor. However, the “French Paradox” — the observation that mortality from CHD is relatively low in France despite relatively high levels of dietary saturated fat and cigarette smoking — led to the idea that regular consumption of red wine might provide additional protection from CHD (35, 36). Red wine contains the phenolic compound resveratrol — although usually at variable and low concentrations (see the article on Resveratrol) — as well as flavonoids like procyanidins; these compounds could provide additional cardiovascular benefits beyond those associated with ethanol. Beer also contains polyphenolic compounds that might confer some cardioprotection (37).

Some large prospective cohort studies have found wine drinkers to be at lower risk of CHD than beer or liquor drinkers (22, 38-40), but others have found no difference (21, 41, 42). Moreover, some studies have observed a decreased risk of myocardial infarction or CHD in predominantly beer-drinking populations in the Czech Republic (43), in Germany (44), and in Japanese men residing in Hawaii (45). A 2011 meta-analysis of prospective cohort and case-control studies found that moderate consumption of wine or beer was associated with a decreased risk of non-fatal vascular events (46). This analysis did not associate drinking liquor with cardiovascular benefit, although the authors noted that binge drinking — which is known to increase CHD risk — was apparent in several of the included studies (46).

Socioeconomic status and lifestyle characteristics (e.g., tobacco use, exercise habits) may differ among people who prefer wine, beer, or liquor, and this may in part explain any additional benefit of one beverage type observed in some studies. For example, several early studies found that people who prefer wine tend to have higher incomes, have more formal education, smoke less, and eat more fruit and vegetables and less saturated fat than people who prefer other alcoholic beverages (47-49). These potential confounders should be controlled or adjusted for in the analysis of observational data.

Thus, although moderate alcohol consumption has been consistently associated with 20%-30% reductions in CHD risk, it is not yet clear whether drinking a specific type of alcoholic beverage might confer additional cardiovascular benefit.

Stroke

Ischemic strokes, which represent 87% of all strokes, are the result of insufficient blood flow to an area of the brain, which may occur when an artery supplying the brain becomes blocked by a blood clot (50). Hemorrhagic strokes occur when a blood vessel ruptures and bleeds into the brain. Although they are less prevalent than ischemic strokes, hemorrhagic strokes are generally more severe and contribute disproportionately to overall stroke mortality (51). Light or moderate alcohol consumption has been associated with a reduced risk of ischemic stroke, but not hemorrhagic stroke, in a number of observational studies (52-58). When the results of 19 prospective cohort and 16 case-control studies of alcohol consumption and the risk of stroke were combined in a meta-analysis, moderate alcohol consumption was associated with a significant reduction in the risk of ischemic stroke (59). Overall, those who consumed one or two drinks daily had a 28% lower risk of ischemic stroke than those who did not consume alcohol. Another meta-analysis of more recent studies (1980-2009) confirmed that moderate alcohol consumption was protective against only ischemic stroke in both men and women (60). A more recent meta-analysis of 27 prospective cohort studies found that light-to-moderate alcohol consumption (<15 grams/day) in women was associated with a reduced risk of ischemic (RR, 0.72) but not hemorrhagic stroke; moderate alcohol consumption (15-30 grams/day) was not linked to either type of stroke in men in this analysis (61).

Thus, light-to-moderate alcohol consumption appears to decrease risk of ischemic stroke, but not hemorrhagic stroke, likely due to the anti-thrombotic effect of alcohol.

Peripheral arterial disease

Just as atherosclerosis of the arteries supplying the heart muscle leads to coronary heart disease, atherosclerosis of the arteries of the extremities leads to peripheral arterial disease (PAD). When atherosclerosis is severe enough to diminish blood flow to the legs, even walking may result in leg or hip pain known as intermittent claudication (62). Impaired vascular endothelial function is also characteristic of the disease and may contribute to the clinical symptoms (63).

Although much less consistent than the evidence for heart disease and stroke, there is limited evidence that moderate alcohol consumption is associated with decreased risk of PAD. Four prospective cohort studies have found moderate alcohol consumption to be associated with significant decreases in several different indicators of PAD (64-67). One of these studies found that the inverse association between alcohol intake and PAD risk was significant in nonsmokers but not smokers, suggesting that the adverse effects of cigarette smoking on PAD risk may outweigh any protective effects of alcohol consumption (64).

Heart failure

Coronary heart disease is a major cause of heart failure. A prospective study in a cohort of 21,601 men and another in a cohort of 126,236 men and women found that moderate alcohol intake was inversely associated with heart failure, especially heart disease related to CHD (68, 69). More recently, in a cohort of 4,490 older adults (65 years or older at baseline) followed for more than 20 years (1,380 cases of heart failure), drinking one or more alcoholic drink per week was associated with a 26% lower risk of heart failure compared to abstainers (70).

Sudden cardiac death

While several studies have found that heavy alcohol consumption increases risk of sudden cardiac death (SCD; see below), the association of light-to-moderate alcohol consumption and SCD is less clear. Studies on this association have reported mixed results, but the two largest prospective cohort studies to date have found a lower risk of SCD with light-to-moderate alcohol consumption (71, 72).

Type 2 diabetes mellitus

Three meta-analyses have found a U-shaped relationship between alcohol consumption and incidence of type 2 diabetes mellitus, with greater protection being observed for women (73-75). The most recent meta-analysis included 20 prospective cohort studies and associated moderate alcohol consumption (22-25 grams of alcohol daily or 1.6-1.8 drinks/day) with a 40% risk reduction for women and a 13% risk reduction for men compared to lifetime alcohol abstainers (74). Heavy alcohol consumption (62 grams/day or 4.4. drinks/day for men and 51 grams/day or 3.6 drinks/day for women) was associated with an increased risk for type 2 diabetes (74).

Increased insulin secretion by the pancreas and decreased insulin sensitivity are important factors leading to the development of type 2 diabetes. Research suggests that moderate alcohol intake may decrease serum insulin levels, increase adiponectin (an adipocyte hormone inversely associated with type 2 diabetes) levels (25), and improve insulin sensitivity (76-79). On the other hand, heavy alcohol consumption may increase the risk of type 2 diabetes by contributing to obesity, especially abdominal obesity, disturbing carbohydrate metabolism, and/or impairing pancreatic or liver function (80).

Osteoporosis

Osteoporosis, a condition common among the elderly, results from progressive loss of bone mineral density (BMD). Several observational studies have associated light or moderate alcohol consumption with higher BMD in older adults compared to abstainers (81-91). Some studies have found stronger protective relationships among wine (89) or beer drinkers (89, 90) in comparison to those who consume liquor, suggesting that non-alcohol components (e.g., silicon in beer) might help explain the association. The effects of alcohol on bone health may also be dependent on age, gender, and hormonal status (reviewed in 92).

It is important to note that the available data come from observational studies, and the observed associations may be confounded, e.g., individuals who consume alcohol in moderation may have an overall healthier lifestyle than those who drink heavily or abstain. However, a recent study in perimenopausal women found that moderate alcohol intake was associated with improved BMD independent of various lifestyle factors, including smoking status, fruit and vegetable intake, and physical activity level (90).

Cognitive decline, dementia, and Alzheimer’s disease

Although alcoholism and heavy alcohol consumption (>3-4 drinks/day) is known to increase the risk of cognitive impairment and dementia (93-95), recent meta-analyses and reviews have reported that light-to-moderate alcohol consumption in older adults is associated with a decreased risk of dementia and Alzheimer’s disease when compared to abstention (93, 96, 97). Some meta-analyses have not found a significant reduced risk for vascular type dementia (96, 98) or for cognitive decline (93, 96, 98, 99). A few studies have suggested that consumption of wine may be especially protective against dementia, although inconsistent findings have been observed, and many studies have not distinguished among the various types of alcohol.

At least three epidemiological studies have used magnetic resonance imaging (MRI) to examine relationships between alcohol intake and subclinical abnormalities in the brains of healthy middle-aged or older adults. Two studies found that infarctions (areas of dead tissue) were less frequent in the brains of those reporting light or moderate alcohol intake compared to those who abstained from alcohol (100, 101). However, another study found no relationship between alcohol intake and the presence of infarction (102). Two of the studies measuring brain atrophy, a characteristic of Alzheimer’s disease and alcoholic dementia, found brain atrophy to be lower in those who abstained from alcohol compared to alcohol consumers (100, 102). The other study found less brain atrophy with light-to-moderate alcohol consumption but only in carriers of the apolipoprotein E (APOE) ε4 allele, who are at increased risk for Alzheimer’s disease (101). Because of the complex nature of alcohol’s effects on the brain, further research is needed to determine the risks and benefits of alcohol consumption with respect to cognitive function and dementia.

Gallstones

The majority of prospective cohort studies (103-107) and case-control studies (108, 109) have found that men and women with moderate alcohol intakes have lower risks of gallstones or gallbladder surgery (cholecystectomy) than those who do not consume alcohol. Although the reasons for the consistent inverse association between moderate alcohol consumption and gallstone incidence are not entirely clear, regular alcohol intake may result in bile that is less likely to crystallize into gallstones or stimulate gallbladder emptying (106).

Health Risks of Moderate Alcohol Consumption

Pregnancy

Fetal alcohol spectrum disorders (FASD) is a continuum of developmental abnormalities resulting from gestational alcohol exposure; FASD may affect as many as 1%-2% of US children (110, 111). Fetal alcohol syndrome (FAS) — a severe FASD — is a cluster of physical and mental birth defects associated with heavy alcohol consumption during pregnancy. Some characteristics of FAS include facial abnormalities, mental retardation, and growth impairment. More moderate alcohol consumption during pregnancy (7-14 drinks/week) has been associated with more subtle effects on cognitive and behavioral development (112, 113). Children of mothers who drank moderately during pregnancy have been found to have problems with memory, attention and learning, and behavior (114). Overall, studies on the association of low-to-moderate drinking during pregnancy and mental health of offspring have reported mixed results (reviewed in 115). However, it is important to note that these studies are observational in nature and may have not adequately controlled for potential confounding factors (e.g., lifestyle differences [in women who drank alcohol during pregnancy versus those who abstained] that influence mental development) (115).

Since no safe level of alcohol consumption has been established at any stage of pregnancy, pregnant women and women who are planning a pregnancy should abstain from alcohol (116, 117).

Breast cancer

More than 100 observational studies have been completed on the association between alcohol consumption and female breast cancer, with most finding an increased risk (118-121). Even though the available data come from observational studies, many consider the association to be causal. Regular alcohol consumption as low as one or two drinks per day has been associated with modest but significant increases in breast cancer risk. A threshold for harm, however, is difficult to define due to potential underreporting of alcohol intake by heavy drinkers, which could result in heavy drinkers being misclassified as ‘moderate alcohol consumers’ (122).

A linear dose-dependent relationship between alcohol consumption and breast cancer risk has been observed for premenopausal and postmenopausal breast cancer regardless of the type of alcoholic beverage consumed. Pooled and meta-analyses have found that each 10-gram increase in daily alcohol consumption (slightly less than one drink) is associated with a 7%-10% increased risk of breast cancer in women (123-125). Studies of alcohol consumption and breast cancer-specific mortality have reported mixed results, with a recent meta-analysis of 25 prospective cohort studies finding an increased risk only with alcohol consumption in excess of 20 grams (1.4 drinks)/day (126). Moderate alcohol consumption has been consistently associated with reduced risk of all-cause mortality (see Mortality above).  

Although the mechanisms for the consistent association between alcohol intake and breast cancer incidence have not been clearly identified, proposed mechanisms include acetaldehyde formation, induction of CYP2E1 metabolism and increased oxidative stress, increased circulating estrogen or androgen levels, and enhanced invasiveness of breast cancer cells (119, 127). Current estimates are that about one in eight women (12.4%) in the US will develop breast cancer at some point in her lifetime (128). Although there are many risk factors for breast cancer, alcohol consumption is one of only a few modifiable risk factors. 

Folate and breast cancer

Alcohol interferes with the absorption, transport, and metabolism of folate, which is required for DNA methylation and DNA repair (see the article on Folate). Alterations in these processes may result in mutations or altered gene expression, which increase the risk of cancer (118). Several (129-134), but not all (135-139), studies have found that sufficient folate intake may modify the association between alcohol intake and breast cancer risk. Although the interactions between folate, alcohol, and breast cancer risk remain to be clarified, it makes sense for women who drink alcohol to take a daily multivitamin containing 400 μg of folic acid.

Progression to heavy or hazardous drinking

Some people, such as recovering alcoholics and those with family histories of alcohol abuse or alcoholism, may not be able to maintain moderate drinking habits. Susceptibility to alcoholism is affected by genetic, psychosocial, and environmental factors. Children of an alcoholic parent have been found to be at significantly higher risk of developing alcoholism than those without an alcoholic parent (140). This increase in risk is likely related to interactions between genetic factors and factors related to the family environment. The National Institute on Alcohol Abuse and Alcoholism recommends that people with a family history of alcoholism, especially in a parent, approach moderate drinking carefully (141).

Medication interactions

In the liver, alcohol is metabolized by the same enzymes as many medications. Therefore, alcohol consumption can affect the activation or breakdown of a number of medications. The consumption of alcohol may also increase sedation, drowsiness, and hypotensive effects caused by numerous prescription and over-the-counter medications. Although serious interactions between alcohol and medications are more common in the presence of heavy alcohol consumption, even moderate alcohol consumption may hypothetically increase the risk of some adverse reactions in susceptible people (142). Women and older adults are particularly at risk for interactions between alcohol and medications (143, 144).

Many different classes of prescription medication may interact adversely with alcohol, including antibiotics, anticonvulsants, anticoagulants (e.g., Coumadin), antidepressants, antidiabetic agents, antihypertensive agents, vasodilators (e.g., nitrates and calcium channel blockers), barbiturates, benzodiazepines (sedatives), histamine H2-receptor blockers, muscle relaxants, and narcotic and non-narcotic pain relievers. Over-the-counter medications and herbal preparations may also interact with alcohol, including pain medications like aspirin, acetaminophen (Tylenol), ibuprofen (Advil, Motrin), and naproxen sodium (Aleve); cold and allergy medications like diphenhydramine (Benadryl) and chlorpheniramine; heartburn medications like cimetidine (Tagamet) and ranitidine (Zantac); and herbal preparations like chamomile, valerian, and kava.

To help avoid potentially serious interactions between alcohol and medications, make sure your health care provider is aware of your alcohol intake. Before taking prescription or over-the-counter medications, read the product warning labels or consult a pharmacist or health care provider to determine whether alcohol consumption increases the risk of adverse effects. It may, in general, be advisable to separate taking any medication and drinking alcohol by two to three hours. For more information on potentially serious interactions between alcohol and medications, see the National Institute on Alcohol Abuse and Alcoholism website.

Health Benefits of Heavy Alcohol Consumption

None

Health Risks of Heavy Alcohol Consumption

Pregnancy

Heavy consumption of alcohol during pregnancy causes fetal alcohol syndrome (FAS). See above.

Cardiovascular disease

Hypertension

Heavy alcohol consumption has been consistently associated with an increased risk of high blood pressure (hypertension) in prospective cohort and case-control studies (145-147). A 2009 systematic review and meta-analysis of 12 prospective cohort studies found consuming 50 grams (3.6 drinks)/day of alcohol was associated with a 1.6-fold and 1.8-fold higher risk of hypertension in men and women, respectively; alcohol intake at twice that level (100 grams (~7 drinks)/day) was associated with a relative risk of 2.5 for men and 2.8 for women (148).

The results of numerous clinical trials indicate that reducing alcohol intake lowers blood pressure in hypertensive and normotensive individuals. A meta-analysis that combined the results of 15 randomized controlled trials found that reducing alcohol consumption resulted in significant decreases in both systolic and diastolic blood pressure (149).

Stroke

Ischemic strokes are the result of insufficient blood flow to an area of the brain, which may occur when an artery supplying the brain becomes blocked by a blood clot. Hemorrhagic strokes occur when a blood vessel ruptures and bleeds into the brain. Although regular, moderate alcohol consumption has been associated with decreased risk of ischemic stroke in some studies, heavy alcohol consumption has been associated with increased risk of both ischemic stroke and hemorrhagic stroke. A meta-analysis that combined the results of 19 prospective cohort and 16 case-control studies found that heavy drinking more than doubled the risk of hemorrhagic stroke and increased the risk of ischemic stroke by 70% (59). A meta-analysis of recent studies (1980-2009) confirmed that heavy drinking is associated with increased risks of ischemic and hemorrhagic stroke in both men and women (60). Heavy alcohol consumption may increase the risk of stroke by contributing to hypertension, cardiomyopathy (heart muscle damage), cardiac rhythm disturbances, and coagulation (clotting) disorders and impaired hemostasis.

Cardiac arrhythmias and sudden cardiac death

The long-recognized association between bouts of heavy alcohol consumption and cardiac rhythm disturbances (arrhythmias) was called “holiday heart syndrome” because it was first described in people who were admitted to hospitals after holidays or weekends (150). Atrial fibrillation is the cardiac arrhythmia most commonly associated with heavy alcohol use (151, 152). A 2010 systematic review and meta-analysis found a dose-dependent association between daily alcohol consumption and risk of this type of cardiac arrhythmia, with an increased risk being found with consumption greater than 24 grams/day (1.7 drinks/day) for women and 36 grams/day (2.6 drinks/day) for men (153). A 2014 meta-analysis of seven prospective studies found that consumption of more than two drinks per day was associated with increased risk of atrial fibrillation in men and women, and the risk increased by 8% with each additional daily drink (154, 155). Additionally, several studies have found that heavy alcohol consumption (>5 drinks per day) increases risk of sudden cardiac death (SCD) (156, 157).

The ways by which alcohol may trigger arrhythmias and SCD are not fully known. Alcohol may interfere with the contractility of heart muscle cells, change the shape and structure of heart muscle cells, contribute to electrolyte imbalance, and/or induce oxidative stress (158).

Alcoholic cardiomyopathy

Alcoholic cardiomyopathy is a heart muscle disease caused by long-term, heavy alcohol consumption (159); this disease likely occurs in only a small proportion (<10%) of heavy drinkers (160). Alcoholic cardiomyopathy occurs in two stages: (1) an early asymptomatic stage, when the damage to the heart muscle has no obvious symptoms; and (2) a symptomatic stage, when the heart muscle is too weak to pump effectively. Although the level of alcohol consumption resulting in alcoholic cardiomyopathy has not been clearly established, people consuming at least seven alcoholic drinks daily for more than five years are thought to be at risk of developing asymptomatic alcoholic cardiomyopathy. Those who continue to drink heavily ultimately develop heart failure. Research suggests that women may be more susceptible to alcohol’s toxic effects on the heart muscle than men (161, 162).

Alcoholic liver disease

Chronic excessive alcohol use is a major cause of illness and death from liver disease (163). Alcoholic liver disease is characterized by a spectrum of liver injury, including steatosis (fatty liver), hepatitis (a potentially fatal inflammation of the liver), fibrosis, and cirrhosis — the most advanced form of alcoholic liver disease. In cirrhosis, the formation of fibrotic scar tissue results in progressive deterioration of liver function. Complications of advanced liver disease include severe bleeding from distended veins in the esophagus (esophageal varices), brain damage (hepatic encephalopathy), fluid accumulation in the abdomen (ascites), and kidney failure.

A 2004 meta-analysis of nine studies found a dose-responsive increase in risk for liver cirrhosis with increasing amounts of alcohol consumed: relative risks (RR) of 2.9 for 25 grams (1.8 drinks)/day, 7.1 for 50 grams (3.6 drinks)/day, 26.5 for 100 grams (7.1 drinks)/day (164). Another meta-analysis found a higher RR for liver cirrhosis with increasing doses but also suggested a threshold response for morbidity from liver cirrhosis (higher risk in women with consumption >24 g (1.7 drinks)/day of alcohol, and higher risk in men with consumption >36 g (2.6 drinks)/day of alcohol) (165). Risk of mortality from liver cirrhosis was increased with any alcohol consumption in women and with consumption of >12 g (0.9 drinks)/day in men; a stronger relationship between alcohol consumption and mortality from liver cirrhosis versus morbidity might be expected because alcohol consumption is known to exacerbate any existing liver disease (165).

Serious liver disease has been found to develop in approximately 10% of those who consume more than 60 grams per day of alcohol (4.3 drinks/day). Women are more susceptible to serious alcoholic liver disease than men (165, 166), and individuals with hepatitis C infection have an increased risk of alcoholic liver disease (167).

Cancer

Heavy alcohol consumption has been found to increase the risk of cancer at a number of sites (168). Heavy alcohol consumption is consistently and dose-dependently associated with increases in risk of cancers of the mouth, pharynx, larynx, esophagus, liver, colon, rectum, and breast (165). Moreover, the combination of smoking and alcohol results in even more dramatic increases in cancer risks (169). Increased risk of liver cancer with long-term heavy alcohol consumption may be related to alcoholic cirrhosis of the liver or increased susceptibility to cancer caused by viral hepatitis.

Alcohol-related brain disorders

Chronic heavy alcohol use and alcohol dependence are associated with detrimental effects on the brain and its function, especially memory and executive functions (170). Alcoholics have been observed to suffer from cerebral atrophy (shrinkage of brain tissue), which likely contributes to alcohol-associated dementia and cognitive impairment (94). In contrast to the progressive cerebral atrophy observed in Alzheimer’s disease, alcohol-related cerebral atrophy may decrease after a period of abstinence. Alcohol-related brain disorders may be associated with nutritional deficiencies like thiamin (171) or niacin (172)

Pancreatitis

Pancreatitis is a painful inflammation of the pancreas. Acute pancreatitis is characterized by the sudden onset of severe upper abdominal pain, often accompanied by nausea and vomiting (173). Although most attacks of acute pancreatitis require only supportive care, a small percentage of people may experience serious or life-threatening complications. Studies estimate that 19%-32% of acute pancreatitis cases have an alcoholic etiology (reviewed in 174).

Chronic pancreatitis results in progressive destruction of the pancreas, leading to loss of pancreatic function (175). An estimated 60%-72% of chronic pancreatitis cases have an alcoholic etiology. The risk of developing chronic pancreatitis increases with the quantity and duration of alcohol consumed: an increased risk of chronic pancreatitis is observed with long-term consumption of five or more alcoholic drinks per day (174). Only a small percentage (<10%) of alcoholics develop clinical pancreatitis; thus, hereditary and environmental factors are also thought to play a role. The disease is more common in men than in women, in Blacks compared to Whites, and in smokers versus nonsmokers (176, 177).

Bone health

Chronic alcoholism has deleterious effects on bone health, including decreased bone mineral density and increased risk of fracture. Consumption of large quantities of alcohol (100-200 grams/day) directly impairs activity of osteoblasts — the bone-forming cells. Negative effects on bone health are also indirectly caused by the malnutrition experienced by alcoholics (92).

Accidents, injury, and violence

Alcohol use is associated with an increased risk of injury in a number of circumstances, including motor vehicle accidents, falls, and fires (178). Data from hospital emergency departments indicate that consuming as little as one or two alcoholic drinks in the previous six hours significantly increases the risk of injury (179). Thirty-one percent of all traffic fatalities in the US are alcohol-related (180). Although the legal blood alcohol concentration (BAC) limit for drivers is 0.08 (grams of alcohol/deciliter of blood) in the US, most scientific studies have found significant impairment of driving-related skills at a BAC of 0.05 (181). For reference, a BAC of 0.05 might be achieved by a 175-pound male consuming three standard alcoholic drinks in one hour or a 120-pound female consuming two drinks in one hour (182).

Excessive alcohol use is associated with all forms of violence, including suicide, homicide, domestic violence, sexual assault, and gang violence. Although the reasons for alcohol-associated violence are complex, alcohol use appears to increase the risk of violent behavior in some populations (183).

Mortality

Heavy alcohol consumption increases the risk of mortality (4, 16). As mentioned above, the relationship between alcohol consumption and mortality is often described as J-shaped, meaning those with high intakes of alcohol have a higher risk of mortality than nondrinkers. A 2011 meta-analysis of eight prospective cohort studies found that consumption of >60 grams/day of alcohol was associated with a 30% increase in mortality from all causes (16).


Authors and Reviewers

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

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

Updated in August 2015 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in August 2015 by:
Arthur L. Klatsky, M.D.
Senior Consultant in Cardiology
Adjunct Investigator, Division of Research
Kaiser Permanente Medical Care Program
Oakland, CA

Copyright 2004-2017  Linus Pauling Institute


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