Coffee, an infusion of ground, roasted coffee beans, is among the most widely consumed beverages in the world. 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 (1).
Some Bioactive Compounds in Coffee
Chlorogenic Acid
Chlorogenic acids are actually a family of esters formed between quinic acid and phenolic compounds known as cinnamic acids (2). 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 acid. The chlorogenic acid content of a 200 ml (7-oz) cup of coffee has been reported to range from 70-350 mg, which would provide about 35-175 mg of caffeic acid. Although chlorogenic acid and caffeic acid have antioxidant activity in vitro (3), 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 (4).
Caffeine
Caffeine 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 (5). Adenosine is an endogenous compound that modulates the response of a 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 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 a recent 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 72-130 mg (6). Caffeine in espresso coffees ranged from 58-76 mg in a single shot. 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.
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 (7). 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 (6-12 mg/cup), while filtered coffee, percolated coffee and instant coffee contain low levels of cafestol and kahweol (0.2-0.6 mg/cup) (8, 9). 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 and LDL cholesterol.
Six out of nine prospective cohort studies have found higher coffee intakes to be associated with significant reductions in the risk of type 2 diabetes mellitus (DM) (10-14). The two largest prospective cohort studies to examine the relationship between coffee consumption and type 2 DM were the Health Professionals Follow-up Study (41,934 men) and the Nurses’ Health Study (84,276 women) in the US. Men who drank at least 6 cups of coffee daily had a risk of developing type 2 DM that was 54% lower than men who did not drink coffee, and women who drank at least 6 cups of coffee daily had a risk of type 2 DM that was 29% lower than women who did not drink coffee (12). In both cohorts, higher caffeine intakes were also associated with significant reductions in the risk of type 2 DM. Decaffeinated coffee consumption was associated with a more modest decrease in the risk of type 2 DM, suggesting that compounds other than caffeine may contribute to the reduction in risk. Recently, a systematic review of nine prospective cohort studies, including more than 193,000 men and women, found that the risk of type 2 DM was 35% lower in those who consumed at least 6 cups/d of coffee and 28% lower in those who consumed between 4-6 cups/d compared those who consumed less than 2 cups/d (15). The mechanism explaining the significant reductions in the risk for type 2 DM observed in the majority of prospective studies is unclear, since short-term clinical trials have found that caffeine administration impairs glucose tolerance and decreases insulin sensitivity (16, 17). Until the relationship between long-term coffee consumption and type 2 DM risk is better understood, it is premature to recommend coffee consumption as a means of preventing type 2 DM (12, 15).
Several large prospective cohort studies have found higher coffee and caffeine intakes to be associated with significant reductions in Parkinson’s disease risk in men (18-20). In a prospective study of 47,000 men, those who regularly consumed at least one cup of coffee daily had a risk of developing Parkinson’s disease over the next 10 years that was 40% lower than men who did not drink coffee (19). Caffeine consumption from other sources was also inversely associated with Parkinson’s disease risk in a dose-dependent manner. 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 (21). In contrast to the results of prospective studies in men, inverse associations between coffee or caffeine consumption and Parkinson’s disease risk were not observed in women (18, 19). The failure of prospective studies to find inverse associations between coffee or caffeine consumption and Parkinson’s disease in women may be due to the modifying effect of estrogen replacement therapy. Further analysis of a prospective study of more than 77,000 female nurses revealed that coffee consumption was inversely associated with Parkinson’s disease risk in women who had never used postmenopausal estrogen, but a significant increase in Parkinson’s disease risk was observed in postmenopausal estrogen users who drank at least 6 cups of coffee daily (22). 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 (18). It is not known how estrogen modifies the effect of caffeine on Parkinson’s disease risk (23). Although the results of epidemiological and animal studies suggest that caffeine may reduce the risk of developing Parkinson’s disease, it is premature to recommend increasing caffeine consumption to prevent Parkinson’s disease, particularly in women taking estrogen.
In general, coffee consumption has been inversely associated with the risk of colon cancer in case-control studies, but not in prospective cohort studies (24, 25). A meta-analysis that combined the results of 12 case-control studies and five prospective cohort studies found that those who drank 4 or more cups of coffee daily had a risk of colorectal cancer that was 24% lower than that of nondrinkers (25). However, coffee consumption was not associated with colorectal cancer risk when the results of only the prospective cohort studies were combined. Although case-control studies usually include more cancer cases than prospective cohort studies, they may be subject to recall bias with respect to coffee consumption and selection bias with respect to the control group. A more recent review of epidemiological studies also found evidence of an inverse association between coffee consumption and colon cancer risk from case-control studies but no evidence of such an association from prospective cohort studies (24). No overall associations between coffee and rectal cancer emerged in this review. In contrast, the two largest prospective cohort studies to examine the relationship between coffee and colorectal cancer to date found that American men and women who regularly consumed 2 or more cups of decaffeinated coffee daily had a risk of rectal cancer that was 48% lower than those who never consumed coffee (26). Consumption of caffeinated coffee, tea and caffeine were not associated with either colon or rectal cancer risk. Despite promising findings in case-control studies, it is unclear whether coffee consumption decreases colon or rectal cancer risk in humans.
Liver injury resulting from chronic inflammation may result in cirrhosis. In cirrhosis, the formation of fibrotic scar tissue results in progressive deterioration of liver function and other complications, including liver cancer (hepatocellular carcinoma) (27). The most common causes of cirrhosis in developed countries are alcohol abuse and viral hepatitis B and C infection. Coffee consumption was inversely associated with the risk of cirrhosis in several case-control studies (28-30) and with mortality from alcoholic cirrhosis in two prospective cohort studies (31, 32). An 8-year study of more than 120,000 men and women in the US found that the risk of death from alcoholic cirrhosis was 22% lower per cup of coffee consumed daily (33). A 17-year study of more than 51,000 men and women in Norway found that those who consumed at least 2 cups of coffee daily had a risk of death from cirrhosis that was 40% lower than those who never consumed coffee (32). Several case-control studies in Europe (34, 35) and two prospective cohort studies in Japan (36, 37) have found significant inverse associations between coffee consumption and the risk of hepatocellular carcinoma. In the prospective cohort studies, coffee consumption was associated with significant reductions in the risk of hepatocellular carcinoma in Japanese men and women with liver disease or hepatitis C infection (36, 37). In those high risk individuals, consumption of at least one cup of coffee daily was associated with a 50% reduction in the risk of hepatocellular carcinoma compared to those who never drank coffee.
Health Risks Associated with Coffee Consumption
Cardiovascular Disease
Coronary heart disease: Although limited by the potential for selection and recall bias, the results of most case-control studies suggest that people who consume 5 or more cups of coffee daily may be at increased risk of coronary heart disease (38, 39). In contrast, the majority of prospective cohort studies have not found significant associations between coffee intake and CHD risk. One exception was a prospective study in Norway, which found that high intakes of unfiltered boiled coffee were associated with increased risk of death from CHD before that population switched to filtered coffee (40). The results of two separate meta-analyses that combined the results of more than 10 prospective cohort studies did not support an association between coffee consumption and the risk of CHD (39, 41). Similarly most of the prospective cohort studies published since the last meta-analysis have not found significant associations between coffee consumption and CHD risk, including studies of large cohorts in the US, Scotland and Finland (42-44).
Hypertension: Hypertension is a well-recognized risk factor for cardiovascular disease. It has been well-established that caffeine consumption acutely raises blood pressure, particularly in individuals with hypertension (5). Although habitual consumption has been found to result in a degree of tolerance to the blood pressure-raising effect of caffeine, the results of several clinical trials suggest that this tolerance is not always complete even in those who consume caffeine daily (45-47). Two meta-analyses have examined the results of randomized controlled trials of coffee consumption for more than one week on blood pressure. A meta-analysis that included 11 randomized controlled trials, in which the median duration of coffee consumption was 56 days and the median intake was 5 cups/d, found that coffee consumption significantly increased systolic and diastolic blood pressure by 2.4 and 1.2 mm Hg, respectively (48). More recently, a meta-analysis that included 18 randomized controlled trials with a median duration of 43 days and a median intake of 725 ml/d (~3 cups/d) found that coffee consumption significantly increased systolic blood pressure by 1.2 mm Hg (49). Although the increases in systolic 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 CHD (50). The available evidence from randomized controlled trials suggests that chronic coffee and caffeine consumption modestly raises systolic blood pressure, which, given the widespread consumption of caffeine and coffee, may result in increased risk of stroke and CHD in the population, particularly in those with hypertension.
LDL cholesterol: A meta-analysis of 14 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 (51). Overall, the consumption of boiled coffee increased serum total cholesterol by 23 mg/dl and LDL cholesterol by 14 mg/dl, while the consumption of filtered coffee raised total cholesterol by only 3 mg/dl and did not affect LDL cholesterol. The cholesterol-raising factors in unfiltered coffee have been identified as cafestol and kahweol, diterpenes that are largely removed from coffee by paper filters (see Diterpenes above) (7).
Homocysteine: An elevated plasma total homocysteine
(tHcy) concentration is associated with increased risk of cardiovascular
disease, including CHD, stroke and peripheral
vascular disease, but it is unclear whether the relationship is causal
(52). Higher coffee intakes have been
associated with increased plasma tHcy concentrations in cross-sectional
studies conducted in Europe, Scandinavia and the US (53-57).
Controlled clinical trials have confirmed the homocysteine-raising effect
of coffee at intakes of about 4 cups/d (58-60).
In one clinical trial, supplementation of healthy men and women with 200
mcg/d of folic acid prevented
elevations in plasma tHcy induced by the consumption of 600 ml/d (2-3
cups/d) of filtered coffee for 4 weeks (61).
Cardiac arrhythmias: Clinical trials have not found coffee
or caffeine intake equivalent to 5-6 cups/d to increase the frequency
or severity of cardiac arrhythmias
in healthy people or people with CHD (62,
63). A large prospective study in the US that followed more than 128,000
people for 7 years found no association between coffee consumption and
sudden cardiac death. More recently, two prospective studies in Scandinavia
found no association between coffee consumption and the risk of developing
atrial fibrillation, a common supraventricular arrhythmia (64,
65).
Numerous epidemiological studies have examined relationships between coffee and caffeine intake and cancer risk in humans. In general, there is little evidence that coffee consumption increases the risk of cancer, especially when the analyses are adjusted for cigarette smoking [reviewed in (66)].
Miscarriage: The results of epidemiological studies that have examined the relationship between maternal coffee or caffeine intake and the risk of miscarriage (spontaneous abortion) have been conflicting. While some studies have observed significant associations between high caffeine intakes, particularly from coffee, and the risk of spontaneous abortion (67-70), other studies have not (71, 72). Most studies that observed significant associations between self-reported coffee or caffeine consumption and the risk of spontaneous abortion did so at intake levels of at least 300 mg/d of caffeine (66). The only 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 at least 600 mg/d (73). 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 (74). Nausea is more common in women with viable pregnancies than nonviable pregnancies, suggesting that women with viable pregnancies are more likely to avoid or limit caffeine consumption due to nausea. However, at least one study found that the significant increase in the risk of spontaneous abortion observed in women with caffeine intakes higher than 300 mg/d was independent of nausea in pregnancy (68), and two other studies found that caffeine consumption was associated with increased risk of spontaneous abortion in women who experienced nausea or aversion to coffee during pregnancy (67, 70). Although the topic remains controversial, the available epidemiological evidence suggests that maternal consumption of less than 300 mg/d of caffeine is unlikely to increase the risk of spontaneous abortion.
Fetal Growth: Epidemiological studies examining the effects of maternal caffeine consumption on fetal growth have assessed mean birth weight, low birth weight (less than 2500 g) and fetal growth retardation (less than the 10th percentile of birth weight for gestational age). Several studies found that maternal caffeine intakes ranging from 200-400 mg/d were associated with decreases in mean birth weight of about 100 g (3.5 oz) (75-77). However, a large prospective study found that caffeine-associated decreases in birth weight were unlikely to be clinically important in women with caffeine intakes of less than 600 mg/d (78). The results of epidemiological studies examining the association between maternal caffeine consumption and the risk of low birth weight or fetal growth retardation have been mixed [reviewed in (66)]. Moreover, some of the available epidemiological studies have been criticized for inadequately controlling for important risk factors for low birth weight and fetal growth retardation, particularly smoking (74). Although the relationship between maternal caffeine consumption and fetal growth requires further clarification, it appears unlikely that caffeine intakes less than 300 mg/d will adversely affect fetal growth in nonsmoking women.
Birth defects: At present, there is no convincing evidence from epidemiological studies that maternal caffeine consumption ranging from 300-1000 mg/d increases the risk of congenital malformations in humans [reviewed in (66, 79)].
Lactation
The American Academy of Pediatrics categorizes caffeine as a maternal medication that is usually compatible with breastfeeding (80). 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 2-3 cups of coffee daily.
Adverse Effects
Most adverse effects attributed to coffee consumption are related to caffeine. 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) (81). Very high caffeine intakes, not usually from coffee, may induce hypokalemia (abnormally low serum potassium) (82). Sudden cessation of caffeine consumption after long-term use may result in caffeine withdrawl symptoms (83). Commonly reported caffeine withdrawal symptoms include headaches, fatigue, drowsiness, irritability, difficulty concentrating, and depressed mood. Significant withdrawal symptoms have been observed at long-term intakes as low as 100 mg/d, although they are more common with higher intakes. Gradual withdrawal from caffeine appears less likely to result in withdrawal symptoms than abrupt withdrawal (84).
Habitual caffeine consumption increases hepatic cytochrome P450 (CYP) 1A2 activity, which has implications for the metabolism for a number of medications (85). Additionally, drugs that inhibit the activity of CYP1A2 interfere with the metabolism and elimination of caffeine, increasing the risk of adverse effects (86).
Drugs that Alter Caffeine Metabolism
The following medications may impair the hepatic metabolism of caffeine, decreasing its elimination and potentially increasing the risk of caffeine-related side effects: cimetidine (Tagamet), disulfiram (Antabuse), estrogens, fluconazole (Diflucan), fluvoxamine (Luvox), mexiletine (Mexitil), quinolone class antibiotics and terbinafine (Lamisil) (85). Phenytoin (Dilantin) and cigarette smoking increase the hepatic metabolism of caffeine, resulting in increased elimination and decreased plasma caffeine concentrations (81).
Caffeine Effects on Other Drugs
Caffeine and other methylxanthines may enhance the effects and side effects of beta-adrenergic stimulating agents, such as epinephrine and albuterol (81, 85). Caffeine may inhibit the hepatic metabolism of the antipsychotic medication, clozapine, potentially elevating serum clozapine levels and increasing the risk of toxicity. Caffeine consumption can decrease the elimination of theophylline, potentially increasing serum theophylline levels. Caffeine has been found to decrease the systemic elimination of acetaminophen and to increase the bioavailability of aspirin, which may partially explain its efficacy in enhancing their analgesic effects. Caffeine may decrease serum lithium concentrations by enhancing its elimination.
Calcium and Osteoporosis
The results of controlled studies in humans indicate that coffee and caffeine consumption decrease the efficiency of calcium absorption resulting in a loss of about 4-6 mg of calcium per cup of coffee (87, 88). Most studies have found no association between caffeine consumption and change in bone mineral density (BMD) over time [reviewed in (89)]. However, one study found that caffeine consumption was associated with accelerated loss of BMD only in women with calcium intakes less than 744 mg/d (90), while another found that consumption of more than 300 mg/d of caffeine was associated with accelerated bone loss in elderly women (91). Six prospective cohort studies have examined associations between caffeine (mainly from coffee) or coffee consumption and the risk of hip fracture in women. Two studies, one in Finland and one in Japan, found no association (92, 93). Another study in Norway found that women who consumed at least 9 cups of coffee daily tended to have an increased risk of hip fracture, but only 7% of women consumed this much coffee (94). However, three prospective cohort studies in the US found that coffee or caffeine consumption was positively associated with the risk of hip fracture in women (95-97). In the Framingham cohort, women who consumed more than 2 cups of coffee daily had a risk of hip fracture over the next 12 years that was 69% higher than women who did not consume caffeinated beverages (95). In the Nurses’ Health Study cohort, women who consumed 4 or more cups of coffee daily had a risk of hip fracture over the next 6 years that was three times the risk of those who did not drink coffee (96). A prospective cohort study of women 65 years of age and older found that a 190 mg increase in caffeine consumption increased the risk of osteoporotic fracture by about 20% (97). Given the multifactorial etiology of osteoporosis, the impact of coffee or caffeine consumption on the risk of osteoporosis is not clear. However, currently available evidence suggests that ensuring adequate calcium and vitamin D intake and limiting coffee consumption to 3 cups/d or less may help reduce the risk of osteoporosis and osteoporotic fracture, particularly in older adults.
Nonheme Iron
Phenolic compounds in coffee can bind nonheme iron and inhibit its intestinal absorption (98). Drinking 150-250 ml of coffee with a test meal has been found to inhibit the absorption of iron by 24-73% (99, 100). To maximize iron absorption from a meal or iron supplements, concomitant intake of coffee should be avoided.
Written by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed by:
Professor Martijn B. Katan Ph.D.
Wageningen Centre for Food Sciences
and
Wageningen University
The Netherlands
Last updated 08/16/2005 Copyright 2005-2008 Linus Pauling Institute
Disclaimer
The Linus Pauling Institute Micronutrient Information Center provides scientific information on health aspects of micronutrients and phytochemicals for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.
The information on micronutrients and phytochemicals contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.