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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