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LPI On Coffee and Caffeine

--contains significant chlorogenic acid and caffeine
--unfiltered coffee is a significant source of cafestol and kahweol
--cafestol and kahweol = diterpenes that incr serum total and LDL chol in humans
--assoc w/ decr risk of type 2 diabetes, Parkinson’s disease and liver disease
--little evidence that coffee consumption increases the risk of cancer
--some evidence coffee can increase blood pressure
--moderate coffee consumption appears to NOT be assoc with incr risk of cardiovascular disease
--SUMMARY: little evidence of health risk and some evidence of health benefits for adults consuming moderate amounts of filtered coffee (3-4 cups/d providing 300-400 mg/d of caffeine)
--some people are more sensitive:
----2-3 cups of coffee may raise blood pressure, esp in pts with borderline or high BP
----uncertain impact on risk of miscarriage and fetal growth (LPI recommends preg women limit to max 3 cups/day with no more than 300 mg/day caffeine
----adequate calcium and vitamin D intake and limiting coffe intake to limits for preg women may help reduce the risk of osteoporosis and osteoporotic fracture, particularly in older adults

--coffee = among the most widely consumed beverages in the world
--=complex mix of many chems: carbs, lipids, amino acids, vitamins, minerals, alkaloids, and phenols
--coffee is a rich source of chlorogenic acids
--chlorogenic acids = a family of esters formed between quinic acid and phenolic compounds (cinnamic acids) --most abundant chlorogenic acid acid = 5-O-caffeoylquinic acid
-- = an ester formed between quinic acid and caffeic acid
--200 ml (7-oz) cup of coffee contains 70-350 mg-->35-175 mg of caffeic acid
--chlorogenic and caffeic acid have ANTIOXIDANT activity in vitro, but in vivo uncertain
--they are extensively metabolized and the metabolites are not as strong antiox

--caffeine is a purine alkaloid that occurs naturally in coffee beans
--at coffee drinking levels, caffeine appears to work by antagonizing some types of adenosine receptors
--adenosine is endogenous, modulates the response of neurons to neurotransmitters, is mostly inhibitory in CNS
--blocking adenosine receptors is thus mostly stimulating
--caffeine is rapidly and almost completely absorbed in the stomach and small intestine
--once absorbed it goes through the body incl to the brain
--caff concentrations in coffee beverages are variable:
72-130mg/8 oz brewed cup by a recent analysis samples from specialty coffee shops in US
--espresso coffees ranged from 58-76 mg per shot
--outside the US coffee is often stronger but the volume is lower so intake/cup is not radically different

--Cafestol and kahweol
--raise serum total and LDL cholesterol concentrations in humans
--largely removed from coffee by paper filters
--more in Scandinavian boiled coffee, Turkish coffee, and French press (cafetiere) coffee (6-12 mg/cup)
--less in filtered coffee, percolated coffee, and instant coffee (0.2-0.6 mg/cup)
--relatively high in espresso coffee but small serving size--> (4 mg/cup)
--coffee beans/grounds are high in cafestol and kahweol, regular ingestion may also raise tot & LDL chol

--higher coffee intakes to be assoc w/ significant reductions in the risk of type 2 DM
--9 studies, 193,000 men and women: risk 35% lower drinking 6+ cups/d of coffee
--28% lower at 4-6 cups/d
--compared to less than 2 cups/d (16)
--three prospective cohort studies in the U.S.:
Health Professionals Follow-up Study (41,934 men)
Nurses’ Health Study (84,276 women)
Nurses' Health Study II (88,259 women)
--men who drank 6+ cups/day 54% lower risk of developing type 2 DM than men who did not drink coffee
--women at 6+ cups/day-->29% lower risk than non coffee drinkers
--women at 4+ cups a day-->39% lower risk, similar results at 2-3 cups/day
--in all three cohorts: higher caffeine intake also assoc w/ DM2 reduction
--decaff-->more modest decrease in the risk
--decaf was the only type of coffee sig assoc w/ lower DM2 risk in a cohort of 28,812 postmenopausal women
--mechanism unclear
--short-term clinical trials have found that caffeine administration impairs glucose tolerance and decreases insulin sensitivity
--relationship between long-term coffee consumption and DM2 not fully understood and coffee not recommended as preventative measure: YET

--several large studies have found high coffee/caffeine intake assoc with reduction in P dz risk in men
--prospective study of 47,000 men:1+ cup/day-->40% reduced risk for a decade
--caffeine consumption from other sources also inversely associated with Parkinson’s dz risk (dose-dependent)
--prospective study in 29,335 Finnish men and women: 1+ cups/day-->60% risk reduction
--three or more cups of tea also decreased the risk
--mechanism?: caffeine may protect dopaminergic neurons by acting as an adenosine A2A-receptor antagonist in the brain
--results not as strong for women, mbdt est replacement
--prospective study of more than 77,000 female nurses: coffee reduces Parkinson's in postmenopausal women who drink 6+ cups/day and have never used supplemental estrogen
--women who used estrogen not helped
--mechanism unknown


Some studies have shown that coffee drinking protects against development of colorectal cancer. In general, coffee consumption has been inversely associated with the risk of colon cancer in case-control studies, but not in prospective cohort studies (29, 30). A meta-analysis that combined the results of 12 case-control studies and five prospective cohort studies found that those who drank four or more cups of coffee daily had a risk of colorectal cancer that was 24% lower than that of nondrinkers (30). 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 (29). 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 two or more cups of decaffeinated coffee daily had a risk of rectal cancer that was 48% lower than those who never consumed coffee (31). Consumption of caffeinated coffee, tea, or total caffeine was not associated with either colon or rectal cancer risk in either study. More recently, prospective studies conducted in Sweden (32) and Japan (33-35) have generally not found consumption of caffeinated coffee to be associated with colon, rectal, or colorectal cancer in men or women; however, examination of two cohorts revealed an inverse association in women with respect to colon cancer (33) and invasive colon cancer (34). Despite promising findings in case-control studies, it is unclear whether coffee consumption decreases colon or rectal cancer risk in humans. Coffee drinking has not been found to increase the risk of colon or rectal cancer.

Cirrhosis and Liver Cancer

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) (36). 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 (37-39) and with mortality from alcoholic cirrhosis in two prospective cohort studies (40, 41). An 8-year study of more than 120,000 men and women in the U.S. found that the risk of death from alcoholic cirrhosis was 22% lower per cup of coffee consumed daily (42). A 17-year study of more than 51,000 men and women in Norway found that those who consumed at least two cups of coffee daily had a risk of death from cirrhosis that was 40% lower than those who never consumed coffee (41). A recent prospective cohort study in 125,580 U.S. adults found that coffee drinking was protective against alcoholic cirrhosis but not nonalcoholic cirrhosis (43). Specifically, risk of developing alcoholic cirrhosis was 40% lower in those who drank 1-3 cups/day of coffee and 80% lower in those who drank four or more cups daily (43). Several case-control studies in Europe (44-46) and Japan (47, 48) have found significant inverse associations between coffee consumption and the risk of hepatocellular carcinoma. Results of three prospective cohort studies in Japan (49-51) and one in Finland (52) have supported findings of case-control studies. In two of the prospective cohort studies, coffee consumption was associated with significant reductions in risk of hepatocellular carcinoma in Japanese men and women with liver disease or hepatitis C infection (49, 50). 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. Similarly, one of the prospective studies found that drinking at least one cup of coffee daily resulted in a 50% reduction in risk for death caused by hepatocellular cancer, but the association was not statistically significant in subjects without a history of liver diseases (51). Further, two meta-analyses have found inverse associations between coffee consumption and liver cancer (53, 54).


A prospective cohort study in U.S. adults (41,736 men and 86,214 women) participating in the Health Professionals Follow-up Study and Nurses' Health Study examined whether coffee drinking was associated with all-cause, cardiovascular disease, or cancer mortality. In both men and women, caffeinated coffee consumption was inversely associated with all-cause and cardiovascular-related mortality but not with cancer mortality (55). Other smaller cohort studies have reported habitual consumption of caffeinated coffee reduces all-cause mortality (56-59) and cardiovascular-related (57) mortality, but the associations have not always been consistent among women and men. Yet, other studies have found that coffee is not related to or may increase all-cause or cause-specific mortality (reviewed in (55)).

--5+ cups-->??increased risk of coronary heart disease, only some studies not all
--prospective study in Norway: high intakes of unfiltered boiled coffee were associated with increased risk of death from CHD before that population switched to filtered coffee
--two separate meta-analyses: no support for CHD conxn
--well-recognized risk factor for cardiovascular disease
--caffeine acutely raises blood pressure, particularly in individuals with hypertension
--habitual consumption increases tolerance
--tolerance is not always complete even in those who consume caffeine daily
--coffee consumption significantly increased systolic, diastolic BP by 2.4 an 1.2 mm Hg
--meta-analysis incl 18 RCT's: coffee consumption significantly increased systolic BP
--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
--caffeine in the form of a pill elevated blood pressure more than coffee
--other compounds in coffee may counteract caffeine's blood pressure-raising effect (ritual??)
--recent prospective study conducted in the Nurses' Health Studies I and II cohorts (140,544 women total) reported that caffeinated cola intake, but not habitual coffee intake, was linked to an increased risk for 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 (76). 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, two 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 coronary heart disease, stroke, and peripheral vascular disease, but it is unclear whether the relationship is causal (77). Higher coffee intakes have been associated with increased plasma tHcy concentrations in cross-sectional studies conducted in Europe, Scandinavia, and the United States (78-82). Controlled clinical trials have confirmed the homocysteine-raising effect of coffee at intakes of about 4 cups/d (83-85).

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 in people with coronary heart disease (86, 87). A large prospective study in the U.S. that followed more than 128,000 people for seven 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 (88, 89).


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 (90)].


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 (91-95), other studies have not (96-98). 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 (90). 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 (99). 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 (100). 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 risk of spontaneous abortion observed in women with caffeine intakes higher than 300 mg/d was independent of nausea in pregnancy (92). Additionally, 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 (91, 94). 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 and coffee consumption on fetal growth have assessed mean birth weight, incidence of low birth weight (less than 2,500 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) (101-103). 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 (104). 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 (90)]. 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 (100). More recently, a double-blind, intervention trial randomized women to drink decaffeinated (median caffeine intake of 117 mg/day) or caffeinated coffee (median coffee intake of 317 mg/day) throughout the second half of their pregnancy (105). No differences in length of gestation or infant birth weight were found between the two groups (105). Although the relationship between maternal caffeine consumption and fetal growth requires further clarification, it appears unlikely that caffeine intakes less than 300 mg/d would 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 300-1,000 mg/d increases the risk of congenital malformations in humans [reviewed in (90, 106, 107)].


The American Academy of Pediatrics categorizes caffeine as a maternal medication that is usually compatible with breast-feeding (108). 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) (109). Very high caffeine intakes, not usually from coffee, may induce hypokalemia (abnormally low serum potassium) (110). Sudden cessation of caffeine consumption after long-term use may result in caffeine withdrawal symptoms (111). Commonly reported caffeine withdrawal symptoms include headache, 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 (112).

Drug Interactions

Habitual caffeine consumption increases hepatic cytochrome P450 (CYP) 1A2 activity, which has implications for the metabolism for a number of medications (113). Additionally, drugs that inhibit the activity of CYP1A2 interfere with the metabolism and elimination of caffeine, thereby increasing the risk of adverse effects (114).

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) (113). Use of the drug phenytoin (Dilantin) or cigarette smoking increases the hepatic metabolism of caffeine, resulting in increased elimination and decreased plasma caffeine concentrations (109).

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 (109, 113). 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. This is important because many pain-relievers on the market today combine caffeine with aspirin and/or acetaminophen. Further, caffeine may decrease serum lithium concentrations by enhancing its elimination.

Nutrient Interactions

--coffee/caffeine decrease efficiency of calcium absorption
--loss of 4-6 mg of calcium per cup of coffee
--most studies have found no assoc btw caff & change in bone mineral density (BMD)
--1 study found caffeine consumption assoc w/ accelerated loss of BMD only in women with calcium intakes less than 744 mg/d
--another study found that consumption of more than 300 mg/d of caffeine was associated with accelerated bone loss in elderly women
--at least six prospective cohort studies have examined associations between caffeine (mainly from coffee) or coffee consumption and the risk of hip fracture in women
--2 studies, Finland & Japan, found no association
--Norway study: 9+ cups in women--> increased risk of hip fracture, only 7% drank so much
--3 studies in US find coffee assoc w/ risk of hip fracture in women
--Framingham cohort: women drinking 2+ cups of coffee/day-->69% higher hip fx rx in 12 yrs compared to noncoffee drinkers
--Nurses’ Health Study: women drinking 4+ cups had 3x risk over 6 yrs
--another study: women 65+ drinking 2cups-->incr hip fx risk
--31,527 older Swedish women 4+ cups-->only risk for hip fx w/ low Ca++ intake (< 700 mg/day)

Nonheme Iron

Phenolic compounds in coffee can bind nonheme iron and inhibit its intestinal absorption (127). Drinking 150-250 ml of coffee with a test meal has been found to inhibit the absorption of iron by 24-73% (128, 129). To maximize iron absorption from a meal or iron supplements, concomitant intake of coffee should be avoided.




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