- What is coffee ?
- Is coffee good or bad for you
- Coffee and Pregnancy outcomes
- Coffee Effect on Bone and Calcium
- Coffee and Total Mortality
- Coffee and Cardiovascular Disease
- Coffee and Cholesterol
- Coffee and Blood Pressure & Hypertension
- Coffee and Type 2 Diabetes
- Coffee and Cancer
- Coffee and Parkinson’s Disease
- Coffee and Cognitive Function
- Coffee and Headache
- Coffee and Gastro-oesophageal Reflux
- Caffee and Mental Illness
What is coffee ?
According to the 2008 coffee market report of the International Coffee Organization, over 2.5 billion cups (30 mL/cup) of coffee are consumed per day worldwide; it is the world’s second most popular drink after water 1). Coffee is a brewed drink prepared from roasted coffee beans, which are the seeds of berries from the Coffea plant. The genus Coffea is native to tropical Africa (specifically having its origin in Ethiopia and Sudan) and Madagascar, the Comoros, Mauritius, and Réunion in the Indian Ocean. Several species of shrub of the genus Coffea produce the berries from which coffee is extracted. The two main species commercially cultivated are Coffea canephora (predominantly a form known as ‘Robusta’) and Coffea Arabica 2). Coffea arabica, the most highly regarded species, is native to the southwestern highlands of Ethiopia and the Boma Plateau in southeastern Sudan and possibly Mount Marsabit in northern Kenya 3). Coffea canephora is native to western and central Subsaharan Africa, from Guinea to Uganda and southern Sudan 4). Less popular species are Coffea liberica, Coffea stenophylla, Coffea mauritiana, and Coffea racemosa.
Once ripe, coffee berries are picked, processed, and dried. Dried coffee seeds (referred to as beans) are roasted to varying degrees, depending on the desired flavor. Roasted beans are ground and brewed with near-boiling water to produce coffee as a beverage.
The degree of roast has an effect upon coffee flavor and body. Darker roasts are generally bolder because they have less fiber content and a more sugary flavor. Lighter roasts have a more complex and therefore perceived stronger flavor from aromatic oils and acids otherwise destroyed by longer roasting times. Roasting does not alter the amount of caffeine in the bean, but does give less caffeine when the beans are measured by volume because the beans expand during roasting.
Roasted coffee beans contain 0.8–2.5% caffeine. Generally, dark-roast coffee has less caffeine than lighter roasts because the roasting process reduces the bean’s caffeine content. Arabica coffee normally contains less caffeine than the Robusta variety. In general, one serving of coffee ranges from 64 mg for a single cup (30 ml) of espresso to about 145 mg for an 8-oz. ounce cup (237 ml) of automatic drip coffee.
A small amount of chaff is produced during roasting from the skin left on the seed after processing. Chaff is usually removed from the seeds by air movement, though a small amount is added to dark roast coffees to soak up oils on the seeds. Depending on the color of the roasted beans as perceived by the human eye, they will be labeled as light, medium light, medium, medium dark, dark, or very dark. A more accurate method of discerning the degree of roast involves measuring the reflected light from roasted seeds illuminated with a light source in the near-infrared spectrum. This elaborate light meter uses a process known as spectroscopy to return a number that consistently indicates the roasted coffee’s relative degree of roast or flavor development.
Coffee is best stored in an airtight container made of ceramic, glass, or non-reactive metal. Higher quality prepackaged coffee usually has a one-way valve which prevents air from entering while allowing the coffee to release gases. Coffee freshness and flavor is preserved when it is stored away from moisture, heat, and light. The ability of coffee to absorb strong smells from food means that it should be kept away from such smells. Storage of coffee in the refrigerator is not recommended due to the presence of moisture which can cause deterioration. Exterior walls of buildings which face the sun may heat the interior of a home, and this heat may damage coffee stored near such a wall. Heat from nearby ovens also harms stored coffee.
Decaffeination may also be part of the processing that coffee seeds undergo. Seeds are decaffeinated when they are still green. Many methods can remove caffeine from coffee, but all involve either soaking the green seeds in hot water (often called the “Swiss water process”) or steaming them, then using a solvent to dissolve caffeine-containing oils. Decaffeination is often done by processing companies, and the extracted caffeine is usually sold to the pharmaceutical industry.
Table 1. Ground coffee beans nutritional content
BEAN BAG 8 g
Value per 100 g
|Total lipid (fat)||g||0.00||0.00|
|Carbohydrate, by difference||g||0.00||0.00|
|Fiber, total dietary||g||0.0||0.0|
|Vitamin C, total ascorbic acid||mg||0.0||0.0|
|Vitamin A, IU||IU||0||0|
|Fatty acids, total saturated||g||0.000||0.000|
|Fatty acids, total trans||g||0.000||0.000|
What is Caffeine ?
Caffeine (1,3,7-trimethylxanthine) is an adenosine and benzodiazepine receptor antagonist, phosphodiesterase inhibitor, and central nervous system stimulant 6), 7). Caffeine is a pharmacologically active component of many foods, beverages, dietary supplements, and drugs; it is also used to treat very ill newborns afflicted with apnea (temporary cessation of breathing) 8). Caffeine occurs naturally in some plant leaves, seeds, and fruits, where it serves as an herbicide, insect repellant, and even attractant for pollination 9). This botanically sourced compound is the most commonly consumed stimulant worldwide 10). Caffeine enters the human food chain through plant-derived foods such as coffee beans, tea leaves, guarana, cocoa beans, and kola nuts 11). In healthy adults, a caffeine intake of ≤400 mg/day is considered safe; acute clinical toxicity begins at 1 g, and 5 to 10 g can be lethal 12).
Caffeine is the world’s most popular drug, and coffee is possibly the second most valuable product after oil. The common dietary sources of caffeine are coffee, chocolate, tea, and some soft drinks. The amount of caffeine in food products varies, depending on the serving size, the type of product and the preparation method 13). Up to 90% of Americans of all ages consume some caffeine daily with more than 50% consuming coffee daily 14). More than 50% average 300mg caffeine per day, with an average daily dosage for all consumers of about 200mg. One report estimates nearly 95% of Brazil’s population consumes caffeine daily, whereas only about 63% of Canadian adults do so. The average dietary caffeine consumption in some Scandinavian countries is more than 400 mg per person per day. It is not hard to reach 200-300mg of caffeine daily since a standard eight-ounce cup of coffee made by the American drip method contains between 125mg and 250mg of caffeine. A 12-ounce can of Coca-Cola contains 34mg. Also, the usual ‘cup’ of coffee for many individuals is often actually 12 or even 16 ounces and sometimes more.
Most people consume caffeine from drinks. The amounts of caffeine in different drinks can vary a lot, but it is generally
- An 8-ounce cup of coffee: 95-200 mg
- A 12-ounce can of cola: 35-45 mg
- An 8-ounce energy drink: 70-100 mg
- An 8-ounce cup of tea: 14-60 mg
Caffeine has many effects on your body’s metabolism
- Caffeine stimulates your central nervous system, which can make you feel more awake and give you a boost of energy.
- Caffeine is a diuretic, meaning that it helps your body get rid of extra salt and water by urinating more.
- Caffeine increases the release of acid in your stomach, sometimes leading to an upset stomach or heartburn.
- Caffeine may interfere with the absorption of calcium in the body.
- Caffeine increases your blood pressure.
Within one hour of eating or drinking caffeine, it reaches its peak level in your blood. You may continue to feel the effects of caffeine for four to six hours.
For most people, it is not harmful to consume up to 400mg of caffeine a day. If you do eat or drink too much caffeine, it can cause health problems, such as:
- Restlessness and shakiness
- Insomnia. Most adults need seven to eight hours of sleep each night. But caffeine, even in the afternoon, can interfere with this much-needed sleep. Chronically losing sleep — whether it’s from work, travel, stress or too much caffeine — results in sleep deprivation. Sleep loss is cumulative, and even small nightly decreases can add up and disturb your daytime alertness and performance. Using caffeine to mask sleep deprivation can create an unwelcome cycle. For example, you may drink caffeinated beverages because you have trouble staying awake during the day. But the caffeine keeps you from falling asleep at night, shortening the length of time you sleep.
- Rapid or abnormal heart rhythm
- Stomach upset
- Dependency, so you need to take more of it to get the same results.
Some people are more sensitive to the effects of caffeine than others. If you’re susceptible to the effects of caffeine, just small amounts — even one cup of coffee or tea — may prompt unwanted effects, such as restlessness and sleep problems. How you react to caffeine may be determined in part by how much caffeine you’re used to drinking. People who don’t regularly drink caffeine tend to be more sensitive to its negative effects. Other factors may include genetics, body mass, age, medication use and health conditions, such as anxiety disorders.
Do not underestimate the power or potency of caffeine. An abrupt decrease in caffeine may cause withdrawal symptoms, such as headaches, fatigue, irritability and difficulty focusing on tasks. Fortunately, these symptoms are usually mild and resolve after a few days. Caffeine dependency can occur after as little as seven days of exposure. 100mg per day can sustain dependency. In fact, many individuals can avoid caffeine withdrawal symptoms by as little as 25mg—the equivalent of about two tablespoons of most “gourmet” coffees. Carefully controlled studies show that caffeine doses as low as about 10mg can be reliably noticed by particularly sensitive people. These studies also show that more than 30 percent of people can feel the effects of 18mg or less.
Studies of caffeine dependency and tolerance show that daily caffeine users are actually more motivated to consume it to avoid withdrawal symptoms, than to experience the lift that its stimulant properties may provide. Caffeine’s combination of a punishing syndrome of withdrawal, along with a rewarding sense of wakefulness, has made coffee, tea, and chocolate, some of humanity’s best-loved foods. One might say that caffeine-producing plants have succeeded in motivating humans to cultivate them widely and with very great care.
Not everyone consuming daily caffeine is equally likely to develop dependency and withdrawal syndrome. Studies indicate that genetics make some people more likely than others. Scientists do not know whether the inherited tendency to experience caffeine withdrawal syndrome relates to the genetic factors that cause migraine. In summary, caffeine may lead to the development of medication-overuse headache (so-called “rebound” headache). As such, patients should limit caffeine use as recommended for other acute medications for migraine. This use should not exceed two days per week. Removing caffeine alone is rarely enough to solve the problem. For patients with high daily caffeine intake, this reduction in use should be achieved over a gradual taper of days or even weeks to limit the impact of withdrawal syndrome.
Coffee and Caffeine
Coffee is one of the major contributors of caffeine to the diet 15); since the late 1980s, the energy drink market has emerged as another source of caffeine in the diet 16). Consumption practices were recently investigated by Mitchell et al. 17), who reported that 85% of the US population ingests at least one caffeine-containing beverage per day, and by Fulgoni et al. 18), who reported that 89% of the population uses caffeine in some form. In addition to standard beverages, a number of other caffeinated products, such as maple syrup, beef jerky, and donuts, have entered the market, suggesting substantial consumer interest in diverse sources of caffeine. Because of the variation in caffeine content of beverages due to a wide range in dose and infusion times as well as unexpected sources of caffeine appearing on the market, assessing exposure to caffeine has a great deal of uncertainty. This, in combination with uncertainty in the use of dietary intake surveys, as well as simultaneous exposure to many substances when consuming the various caffeine sources, are well-known limitations in the evidence base.
Caffeine is generally recognized as safe by the US Food and Drug Administration (FDA) at a use level not to exceed 200 ppm (0.02%) in cola-type beverages for the specific intended use of flavor (21CFR§182.1180). Caffeinated beverages, like coffee, have been consumed for centuries. Current estimates suggest that the mean consumption of caffeine (all ages) is 165 mg/day, ∼105 mg of which is associated with coffee consumption 19). Emergence of other products containing caffeine, particularly energy drinks, combined with controversies regarding the potential for increased consumption by nonadult populations 20), has been accompanied by concerns regarding the impact of these products on consumer health. Regulatory agencies worldwide, including those in the United States 21), 22), Europe 23), Canada 24), New Zealand, India, and Australia, have evaluated caffeine safety, and several agencies have issued guidance regarding daily intake amounts 25), 26). The most widely cited of these values is from Health Canada 27), in which the agency authors conducted a comprehensive (but not systematic) literature search and concluded in a peer-reviewed publication that an intake dose of up to 400 mg caffeine/day was not associated with adverse effects in healthy adults. Nawrot et al. 28) also concluded that consumption of up to 300 mg/day for pregnant women and 2.5 mg/kg/day for children is not associated with adverse effects 29).
What is caffeine withdrawal ?
If you have been consuming caffeine on a regular basis and then suddenly stop, you may have caffeine withdrawal. Symptoms can include
- Difficulty concentrating
These symptoms usually go away after a couple of days.
Who should avoid or limit caffeine ?
You should check with your health care provider about whether you should limit or avoid caffeine if you:
- Are pregnant, since caffeine passes through the placenta to your baby
- Are breastfeeding, since a small amount of caffeine that you consume is passed along to your baby
- Have sleep disorders, including insomnia
- Have migraines or other chronic headaches
- Have anxiety
- Have GERD (gastro-esophageal reflux disease) or ulcers
- Have fast or irregular heart rhythms
- Have high blood pressure
- Take certain medicines or supplements, including stimulants, certain antibiotics, asthma medicines, and heart medicines. Check with your health care provider about whether there might be interactions between caffeine and any medicines and supplements that you take.
- Are a child or teen. Neither should have as much caffeine as adults. Children can be especially sensitive to the effects of caffeine.
How much caffeine in coffee
The caffeine content in coffee depends on the type of coffee and method of preparation. The actual caffeine content of a single cup of coffee can vary considerably because of factors such as origin, the variety of seed, processing and preparation method, including brewing method and brewing time 30). While the percent of caffeine content in coffee seeds themselves diminishes with increased roast level, the opposite is true for coffee brewed from different grinds and brewing methods using the same proportion of coffee to water volume.
According to the USDA National Nutrient Database, an 8-ounce (237 ml) cup of “coffee brewed from grounds with water” contains 95 mg caffeine, whereas an espresso (25 ml) contains 63 mg 31).
According to an article in the Journal of the American Dietetic Association, coffee has the following caffeine content, depending on how it is prepared.
The charts below show typical caffeine content in popular beverages. Drink sizes are in fluid ounces (oz.) and milliliters (mL). Caffeine is shown in milligrams (mg).
Table 2. Caffeine content in coffee
|Coffee drinks||Size in oz. (mL)||Caffeine (mg)|
|Brewed, decaf||8 (237)||2-5|
|Espresso, decaf||1 (30)||0|
|Instant, decaf||8 (237)||2|
|Latte or mocha||8 (237)||63-126|
Is coffee good or bad for you
Coffee is one of the most widely consumed beverages in the world, and contains caffeine and phenolic compounds.
Caffeine, a major component of coffee, elevates blood pressure by raising peripheral vascular resistance 33), 34).
The Dietary Guidelines for Americans 35) recommends that women who are pregnant and those who are breast-feeding check with their health care providers for advice concerning caffeine.
The Dietary Guidelines for Americans doesn’t include guidelines for safe caffeine consumption for children. However, the American Academy of Pediatrics takes the position that stimulant-containing energy drinks have no place in the diets of children or adolescents.
According to a dose-response meta-analysis of trials assessing the relationship between habitual coffee consumption and risk of hypertension, consumption of 1 to 3 cups a day moderately increased the risk of developing hypertension 36), while consumption of more than 3 cups or less than 1 cup did not pose an increased risk. There are also numerous amounts of studies in progress seeking for the effects that coffee has on cardiovascular disease. Several studies found no statistically significant relationship between the two variables 37), 38), 39), while some demonstrated a prophylactic effect of coffee on cardiovascular diseases 40). Coffee has been reported to increase insulin sensitivity, thus helping to prevent the development of type 2 diabetes mellitus 41), 42), 43). Consumption of coffee not only ameliorates inflammatory responses, but also improves vascular endothelial function 44).
Hypertension, cardiovascular diseases, and diabetes mellitus are risk factors of stroke. In light of the evidence of association between the above risk factors and coffee consumption, one can suggest that coffee intake may directly or indirectly have some influence on stroke.
Among studies assessing the relationship between coffee consumption and risk of stroke, 2 cohort studies reported prophylactic effects of coffee consumption on the development of stroke 45), 46) while 6 studies showed no significant relationship between the two 47), 48), 49), 50), 51), 52). In one cohort study, despite the statistically insignificant relationship between coffee consumption and risk of stroke, stroke risk tended to decrease as coffee consumption increased in women 53). Likewise, a number of studies have been published, but the prophylactic effects of coffee consumption on development of stroke still remains controversial.
The association between coffee consumption and chronic diseases such as hypertension 54), coronary artery disease 55), 56) or diabetes mellitus 57), 58) has been further verified by meta-analyses, but those clarifying the relationship between coffee consumption and the risk of stroke are still lacking.
Although coffee consumption has been known to decrease cerebral blood flow and pose a risk for hypertension, analysis of 3 articles of high quality showed that there was no significant relationship between coffee consumption and risk of stroke and that of 6 articles of relatively low quality showed a prophylactic effect of coffee consumption on stroke incidence.
Coffee and Pregnancy outcomes
What is the relationship between usual caffeine consumption and pregnancy outcomes ?
There is a consistent evidence from observational studies indicating that caffeine intake in pregnant women is not associated with risk of preterm delivery. Higher caffeine intake (especially >=300 mg/day ) is associated with a small increased risk of miscarriage, stillbirth, low birth weight, and small for gestational age births. However, these data should be interpreted cautiously due to potential recall bias in the case-control studies and confounding by smoking and pregnancy signal symptoms.
Consumption of caffeine from various sources was associated with a significantly increased risk of spontaneous abortion and low birth weight 59). Control for confounders such as maternal age, smoking, and ethanol use was not possible.
Two studies assessed observational studies on the association of caffeine intake with adverse pregnancy outcomes 60), 61). The pregnancy outcomes included miscarriage, pre-term birth, stillbirth, small for gestational age and low birth-weight. The most recent study by Greenwood et al. 62) quantified the association between caffeine intake and adverse pregnancy outcomes from 60 publications from 53 separate cohort and case-control studies. The evidence covered a variety of countries with caffeine intake categories that ranged from non-consumers to those consuming >1,000mg/day. They found that an increment of 100 mg caffeine was associated with a 14% increased risk of miscarriage, 19% increased risk of stillbirth, 10% increased risk of SGA, and 7% increased risk of low birth weight. There was no significant increase in risk of preterm delivery. The magnitude of these associations was relatively small within the range of caffeine intakes of the majority women in the study populations, and the associations became more pronounced at higher range (>=300 mg/day). The authors also note the substantial heterogeneity observed in the meta-analyses shows that interpretation of the results should be cautious. In addition, the results from prospective cohort studies and case-control studies were mixed together. Since coffee consumption is positively correlated with smoking, residual confounding by smoking may have biased the results toward a positive direction 63).
The other studies did not cover all of the above pregnancy outcomes, but for those adverse outcomes covered, the results were in agreement with Greenwood et al., Maslova 64) reviewed 22 studies (15 cohort and 7 case-control studies) and found no significant association between caffeine intake and risk of pre-term birth in either case-control or cohort studies. For all of the observational studies assessed across the three studies, most studies did not adequately adjust for the pregnancy signal phenomenon, i.e. that nausea, vomiting, and other adverse symptoms are associated with a healthy pregnancy that results in a live birth, whereas pregnancy signal symptoms occur less frequently when the result is miscarriage. Coffee consumption decreases with increasing pregnancy signal symptoms, typically during the early weeks of pregnancy, and this confounds the association. Greenwood et al. 65) state that this potential bias is the most prominent argument against a causal role for caffeine in adverse pregnancy outcomes. Only one randomized controlled trial of caffeine/coffee reduction during pregnancy has been conducted to date. The study found that a reduction of 200 mg of caffeine intake per day did not significantly influence birth weight or length of gestation. The trial did not examine other outcomes.
Coffee Effect on Bone and Calcium
With respect to fracture and fall, most studies reported a lack of effects, both above and below the comparator of 400 mg/day 66), 67), 68), 69), 70). Hallstrom et al. 71) reported that consumption of ≥560 mg caffeine (≥8 cups) was not associated with a higher rate of any fracture or of hip fracture in a comprehensive evaluation of long-term coffee consumption in relation to fracture risk and BMD in women. In a recent systematic review and meta-analysis for coffee consumption and risk of fractures 72), an insignificant relative risk for coffee consumption and risk of fracture was reported for all studies combined. Results of subgroup analyses indicated contrasting findings by sex; men consuming 760 mg/day had a 24% lower risk of fractures, whereas women consuming 190 mg/day had a 2% higher risk of fractures, relative to those who did not drink coffee 73). Estimates increased based on increased consumption; 8 cups of coffee per day was reported to be associated with a 54% higher risk of fractures. This study did not evaluate interactions between caffeine/coffee consumption and calcium intake. Hallstrom et al. 74) also reported effects below the comparator. The authors reported that a daily intake of ≥330 mg caffeine may be associated with a modestly increased risk of osteoporotic fractures 75), especially in women with a low intake of calcium; when stratified by calcium intake, the increased risk was only significant when calcium intake was low (<700 mg/day). No trend in increased risk was observed with higher caffeine intake in participants with high calcium intake.
The majority, although not all, of the data on risk of fracture or fall demonstrate a lack of effects of caffeine consumption at levels both above (up to 760 mg/day) and below 400 mg/day. Evidence of effects below 400 mg/day was of low magnitude and was confounded by calcium intake; the potential interaction of calcium intake was not accounted for in the study reporting the lowest effect level 76) and the other study 77) reporting an effect level below the comparator found in stratified analyses that increased risk was only observed under conditions of low calcium intake. Confidence in these data is moderate 78); findings were generally consistent, and most, although not all, studies controlled for calcium intake. As such, the evidence in this review 79) supports that an intake of 400 mg caffeine/day in healthy adult populations, particularly those with adequate calcium intake, is not associated with significant concern regarding the risk of fracture and fall.
In summary, the systematic review of 14 studies provided evidence to evaluate potential impacts of the consumption of 400 mg caffeine/day on the bone and calcium outcome in healthy adults; these studies included assessment of the risk of fracture and fall, BMD (bone mineral density) and osteoporosis, and altered calcium homeostasis 80). When the weight of evidence was considered, the comparator, 400 mg/day, was found to be an acceptable intake that is not associated with significant concern regarding overt, adverse effects on bone or calcium endpoints, particularly under conditions of adequate calcium intake 81). Although effects were observed at exposures below the comparator they were often limited to physiological effects following acute exposure (altered calcium homeostasis), and subgroups in analyses of clinical endpoints, including those with low calcium intake. Such effects were generally of low magnitude, and/or were of overall low/negligible consequence to downstream events. Several studies also reported on a lack of effect on the clinical endpoints following chronic consumption below the comparator, as well as above the comparator. Based on the underlying study type (11 observational, 2 randomised controlled trials, 1 meta-analysis) that constitute this evidence base, there is a moderate level of confidence in the research, which supports this conclusion. Key limitations that precluded a higher level of confidence were the inability to fully accommodate for calcium intake, the high level of indirectness, as well as an uncertainty in exposure estimates 82).
Coffee and Total Mortality
According to the Office of Disease Prevention and Health Promotion and U.S. Department of Health and Human Services, there is strong and consistent evidence showing that consumption of coffee within the moderate range (3 to 5 cups/d or up to 400 mg/d caffeine) is not associated with increased risk of major chronic diseases, such as cardiovascular disease (CVD) and cancer and premature death in healthy adults 83). The key findings from their study are shown below:
- Coffee consumption was associated with reduced risk of total mortality (3-4% lower mortality with 1 cup/day), especially cardiovascular mortality.
- Decaffeinated coffee consumption was associated with a lower risk of death (5 studies only).
- The limited number of studies on decaffeinated coffee indicates that protective association of coffee consumption may not be due to caffeine alone.
Two systematic reviews and/or meta-analyses of 20 and 23 prospective cohort studies 84), 85). Je et al. 86) examined total mortality and Malerba et al. 87) examined total, cardiovascular disease and cancer mortality.
Evidence suggests a significant inverse relationship between coffee consumption of 1-4 cups/day with total mortality, especially cardiovascular disease mortality. This evidence is based on three meta-analyses of more than 20 prospective cohort studies 88), 89), 90). In general, results were similar for men and women. The risk reduction associated with each cup of coffee per day was between 3-4 percent. In addition, Je 91) found a significant inverse association between coffee consumption and cardiovascular disease mortality. This association was stronger in women (16% lower risk) than in men (8% lower risk). However, no association was found for cancer mortality. Crippa et al. found that the lowest risk was observed for 4 cups/d for all-cause mortality and 3 cups/d for CVD mortality 92).
Coffee and Cardiovascular Disease
There is consistent observational evidence indicating that moderate coffee consumption is associated with reduced risk of type 2 diabetes and cardiovascular disease in healthy adults 93). Collectively, the majority of evidence support that 400 mg caffeine/day in healthy adult populations is an acceptable intake which is not associated with significant concern for cardiovascular mortality. Even at higher intakes up to ∼855 mg/day, there are no consistently reported effects on mortality; further, several studies, reported findings that are suggestive of protective effects 94).
- Non-linear association between coffee intake and risk of cardiovascular disease
- Moderate coffee consumption was inversely associated with cardiovascular disease risk
- Lowest risk at 3-5 cups/d
- Heavy consumption was not associated with higher cardiovascular disease risk.
- When the evidence for potential changes to heart rate is considered collectively, data support that the comparator of 400 mg caffeine/day in healthy adults is acceptable as an intake which is not associated with meaningful concern regarding adverse effects on heart rate 95). There is a moderate to high level of confidence in this evidence base 96). For children and adolescents, data support a relationship between caffeine exposure and decreased heart rate; however, further characterization of exposures associated with such were difficult, given that changes were observed in studies both below and above the Nawrot et al. 97) comparator of 2.5 mg/kg— yet no changes were observed in a study involving exposure to 6 mg/kg. Thus, it was determined that the evidence base was insufficient to render a conclusion regarding appropriateness of the comparator for potential impacts of caffeine consumption on heart rate in children and adolescents 98).
- Non-linear association between coffee intake and risk of stroke
- Moderate coffee consumption was inversely associated with stroke
- Lowest risk at 3-4 cups/day
- Higher intakes were not associated with higher stroke risk
Coronary Heart Disease
- Moderate coffee consumption was associated with lower coronary heart disease risk
- Higher intakes were not associated with higher coronary heart disease risk
- Moderate (1-5 cups/d) coffee consumption was inversely associated with risk of heart failure
- The largest inverse association observed for 4 cups/day.
- Caffeine was not associated with increased risk of atrial fibrillation.
- Low-dose caffeine exposure (<350 mg) may have a protective effect.
Coffee and Cholesterol
- Caffeinated, but not decaffeinated coffee, had significant effect on serum lipids. The effects were mostly found in unfiltered coffee.
- Coffee consumption increased total cholesterol, LDL (bad) cholesterol, and triglycerides
- Positive dose-response relation between coffee intake and total cholesterol, LDL (bad) cholesterol, and triglycerides.
Seven controlled trials were identified that evaluated the effects of 180–475 mg caffeine/day on serum cholesterol 99), 100), 101), 102), 103), 104), 105). Increased total serum or low-density lipoprotein (LDL) cholesterol is a well-recognized risk factor for cardiovascular disease 106). Three studies were of caffeine, and the remaining studies were of caffeinated coffee or tea. A significant increase in total cholesterol was observed following consumption of ≥380 mg/day caffeine in filtered coffee for 4–6 weeks (no effects at 95–285 mg/day) 107). In contrast, Kempf et al. 108) reported no significant effects of consumption of 238 or 475 mg caffeine on total cholesterol or LDL “bad” cholesterol, respectively, and reported significant increases in high-density lipoprotein (HDL) cholesterol (considered a beneficial effect) at consumption of 238 mg/day 109). A significant increase in the HDL/total cholesterol ratio, which is also considered a beneficial effect, was observed following consumption of 283 mg or 392 mg caffeine (in females and males, respectively) 110). The magnitude of observed change in these studies was on the order of 10–20 mg/dL. No changes or significant decreases in cholesterol (in the latter case, total or LDL cholesterol) were observed in the remaining four studies of caffeine, coffee, or tea associated with lower caffeine intakes of 180–250 mg/day for a single day or up to 12 weeks.
The results of three cohort studies are inconsistent. Vlachopoulos et al. 111) observed a significant increase in total cholesterol in participants with self-reported consumption of <80, 80–180, and >180 mg caffeine/day in coffee; however, no dose-response was observed. LDL cholesterol was significantly higher only in the highest exposure category (>180 mg caffeine/day in coffee). In contrast, Trovato et al. 112) did not observe changes in total, HDL, or LDL cholesterol in participants with self-reported consumption averaging 95 mg caffeine/day in espresso. Del Brutto et al. 113) also did not observe changes in total cholesterol in participants with self-reported caffeine consumption of up to >200 mg/day. Thus, for the controlled trials, a significant increase in total cholesterol was observed only in the two studies of relatively high caffeine consumption (≥380–475 mg/day), and one of the three cohort studies reported a statistically significant increase in total cholesterol following self-reported exposures to <80, 80–180, and >180 mg caffeine.
More than other endpoints evaluated, data are relatively consistent in showing a lack of effect of caffeine consumption on cholesterol at intakes below and above the comparator, thus supporting that for cholesterol, caffeine 400 mg/kg is an acceptable comparator in healthy adults 114). There is a moderate to high level of confidence in the evidence base supporting this conclusion.
Lastly, European pressed coffee has become more fashionable in the U.S. And it may have a negative impact on health if you drink too much, according to nutrition expert Eric Rimm of Harvard T.H. Chan School of Public Health. Pressed coffee is made by mixing ground coffee beans with boiled water in a special glass pitcher called a French press. After the coffee steeps, you press a mesh plunger down to strain the liquid and trap the coffee grounds. There’s no coffee filter, so some of the grounds can wind up in your cup—and they contain oily substances called diterpenes (cafestol and kahweol) that may pose a health risk. Coffee aficionados say these oils make the brew taste better. But you should know that diterpenes have been shown to have a negative impact on health.
The coffee diterpene cafestol occurs in both robusta and arabica beans. It is present in unfiltered coffee brews and raises serum concentrations of cholesterol, triacylglycerols, and alanine aminotransferase in humans 115). The effects are linear with the cafestol dose. Unfiltered coffee also contains the related compound kahweol, which occurs only in the major coffee strain arabica. The activity of kahweol is unknown. In a randomized, double-blind crossover study 116), 10 healthy male volunteers receive either pure cafestol (61-64 mg/d) or a mixture of cafestol (60 mg/d) and kahweol (48-54 mg/d) for 28 day. Relative to baseline values, cafestol raised total serum cholesterol concentrations by 31 +/- 5 mg/dL, low-density-lipoprotein (LDL) cholesterol by 22 +/- 5 mg/dL, fasting triglycerides by 58 +/- 11 mg/dL, and alanine aminotransferase by 18 +/- 2 U/L. Relative to cafestol alone, the mixture of cafestol plus kahweol increased total cholesterol by another 9 +/- 6 mg/dL, LDL cholesterol by 9 +/- 6 mg/dL, triglycerides by 8 +/- 9 mg/dL and alanine aminotransferase by 35 +/- 11 U/L. Thus, the effect of cafestol on serum lipid concentrations was much larger than the additional effect of kahweol, and the hyperlipidemic potential of unfiltered coffee mainly depends on its cafestol content 117). Both cafestol and kahweol raised alanine aminotransferase concentrations, and their hyperlipidemic effect thus seems not to be coupled with their effect on liver cells.
In another study on the effect of unfiltered coffee and cholesterol and liver enzyme (alanine aminotransferase), 46 healthy men and women aged 19 to 69 were given five to six strong cups (0.9 litres) a day of either unfiltered (pressed coffee) coffee (22 subjects) or filtered coffee (24 subjects) for 24 weeks 118). Cafetière (pressed unfiltered coffee) coffee raised alanine aminotransferase concentration by up to 80% above baseline values relative to filtered coffee. After 24 weeks the rise was still 45%. Alanine aminotransferase concentration exceeded the upper limit of normal in eight of the 22 subjects drinking cafetière coffee, being twice the upper limit of normal in three of them. Cafetière coffee raised low density lipoprotein (LDL) cholesterol concentrations by 9-14%. After 24 weeks the rise was 0.26 mmol/l relative to filtered coffee 119). Triglyceride concentrations initially rose by 26% with cafetière coffee but returned close to baseline values within six months. All increases were reversible after the intervention was stopped 120). In study conclusion was that daily consumption of five to six cups of strong cafetière (unfiltered pressed coffee) coffee affects the integrity of liver cells as suggested by small increases in serum alanine aminotransferase concentration. The effect does not subside with prolonged intake. High intakes of coffee brews rich in cafestol and kahweol may thus be responsible for unexplained increases in this enzyme activity in apparently healthy subjects. Cafetière coffee also raises low density lipoprotein cholesterol concentration and thus the risk of coronary heart disease.
The take home message ? If you drink unfiltered Cafetière coffee (European pressed coffee), it is recommended that you check your cholesterol levels regularly to make sure your LDL levels don’t get too high, and make sure to check your liver function test too.
Coffee and Blood Pressure & Hypertension
- No effect of coffee on long-term blood pressure or risk of hypertension
- For habitual coffee consumption, consumption of >3 cups/d was not associated with increased risk of hypertension compared with <1 cup/day
- There was a slightly elevated risk of hypertension for light to moderate consumption (1-3 cups/day)
- In hypertensive individuals, caffeine intake produces an acute increase in blood pressure for ≥3 h, but there is no evidence of an association between long-term coffee consumption and increased blood pressure.
- Regular caffeine intake (median 410 mg/d) increases blood pressure in short-term randomised controlled trials, although when ingested through coffee, blood pressure effect of caffeine was smaller but significant.
Taken together, studies were relatively consistent in demonstrating that exposures to caffeine, at intakes both below and above the comparator (up to 400 mg caffeine/day), have the potential to result in an increase in blood pressure (often only a few mmHg) in all populations evaluated. The long-term effects of transient caffeine-mediated blood pressure increase are unknown relative to the potential impact on known cardiovascular risk factors, such as chronic hypertension.
Lastly, some data indicate the potential for unique subgroups of individuals to demonstrate greater blood pressure sensitivity to caffeine than other subgroups. When the evidence is considered collectively, findings suggest that the comparator of 400 mg/day in healthy adults is too high if one is only considering the potential for caffeine to cause a physiological change in blood pressure (which may or may not be adverse) 121). When considering the small magnitude of changes in this physiological parameter, as well as the lack of information demonstrating an association between chronic caffeine-mediated blood pressure increases relative to known cardiovascular risk factors, the comparator of 400 mg/day is likely acceptable 122). There is a moderate to high level of confidence in the underlying data for this endpoint, primarily driven by the low risk of bias and use of controlled exposures (RCTs). However, confidence in determining conclusions relative to the comparator is limited by the inability to ascertain the conditions and magnitude of change that would be considered adverse in a clinical or toxicological context (which is beyond the scope of this assessment).
Similar to the findings in adults, some data suggest that the comparator of 2.5 mg/kg/day in children is too high if only the potential for caffeine to cause a physiological change in blood pressure (which may or may not be adverse) is being considered 123); other data suggested that the comparator was too low, as no changes were observed following ingestion of 5 mg/kg. When considering the small magnitude of changes in this physiological parameter, as well as the lack of information demonstrating an association between chronic caffeine-mediated blood pressure increases relative to known cardiovascular risk factors, evidence shifts to support the comparator of 2.5 mg caffeine/kg/day 124). There is a moderate to high level of confidence in this body of evidence; confidence is limited by inconsistency of findings. Thus, results indicate that it would be prudent to evaluate blood pressure in children and/or adolescents with significant caffeine intake and consider limiting this for those with significant caffeine-mediated blood pressure rise.
Twelve studies examined Cardiovascular Disease 125), 126), 127), 128), 129), 130), 131), 132), 133), 134), 135), 136). Some SR/MAs covered only RCTs (Cai 2013). Others included only prospective cohort studies (Larsson 2011, Zhang 2011, Kim2012, Mostofsky 2012, Wu 2009).
A large and current body of evidence directly addressed the relationship between normal coffee consumption and risk of cardiovascular disease (CVD). The evidence included 12 systematic reviews with meta-analyses, all of which had high quality ratings. Cardiovascular disease incidence and mortality, as well as coronary heart disease (CHD), stroke, heart failure, and hypertension were assessed by meta-analyses that consisted primarily of prospective cohort studies; intermediate outcomes such as blood pressure, blood lipids, and blood glucose were assessed by meta-analyses of randomized controlled trials.
Cardiovascular disease risk was assessed by a current meta-analysis of 36 prospective cohort studies on long-term coffee consumption 137). This analysis showed a non-linear association, such that the lowest risk of cardiovascular disease was seen with moderate coffee consumption (3-5 cups/day), but higher intakes (>5 cups/day) were neither protective nor harmful. Overall, moderate consumption of caffeinated, but not decaffeinated, coffee was associated with a 12 percent lower risk of cardiovascular disease.
Results from the assessment of coronary heart disease risk in three meta-analyses 138), 139), 140) were inconsistent. Ding 141) found 10 percent lower coronary heart disease risk with moderate coffee consumption (3-5 cups/day) in a meta-analysis of 30 prospective cohort studies, whereas Wu 142) and Sofi 143) in meta-analyses of 21 and 10 prospective cohort studies, respectively, found no association between coffee consumption and coronary heart disease risk. However, in sub-group analysis, Wu 144) found that habitual moderate coffee consumption (1-4 cups/day) was associated with an 18 percent lower risk among women. Overall, the meta-analyses of Sofi 145) and Wu 146) were conducted with smaller bodies of evidence and Ding 147) assessed several more recent studies. One reason for the inconsistent associations may be that coffee brewing methods have changed over time and the filter method has become more widely used, replacing unfiltered forms of coffee such as boiled coffee that were more widely consumed by participants in earlier studies.
Risk of stroke was assessed in two systematic reviews with meta-analyses of prospective cohort studies 148), 149) with consistent findings. Kim 150) found that coffee intake of 4 or more cups/day had a protective effect on risk of stroke. Larsson 151) documented a non-linear association such that coffee consumption ranging from 1 to 6 cups/day was associated with an 8 percent-13 percent lower risk of stroke, and higher intakes were not associated with decreased or increased risk. The inverse associations were limited to ischemic stroke and no association was seen with hemorrhagic stroke.
Regarding blood pressure, three meta-analyses evaluated the effect of coffee and caffeine on systolic and diastolic blood pressure using controlled trials 152), 153), 154). The most recent meta-analysis of 10 randomized controlled trials by Steffen et al. 155) showed no effect of coffee on either systolic or diastolic blood pressure. Similarly, in another meta-analysis of 11 coffee trials and 5 caffeine trials, caffeine doses of <410 mg/day had no effect on systolic and diastolic blood pressure while doses of 410 or more mg/day resulted in a net increase 156). A third meta-analysis showed that among individuals with hypertension, 200-300 mg of caffeine (equivalent to ~2-3 cups filtered coffee) resulted in an acute increase of systolic and diastolic blood pressure 157). Additionally, two meta-analyses quantified the effect of coffee on incidence of hypertension 158), 159) and found no association between habitual coffee consumption and risk of hypertension. However, Zhang et al. 160) documented a slightly elevated risk for light to moderate consumption (1-3 cups/day) of coffee compared to less than 1 cup/day. Regarding blood lipids, in a quantitative analysis of short-term randomized controlled trials, Cai et al. 161) revealed that coffee consumption contributed significantly to an increase in total cholesterol, LDL-cholesterol, and triglycerides, and that unfiltered coffee had a greater effect than filtered coffee. Interestingly, caffeinated, but not decaffeinated (more likely to be filtered), coffee had this effect on serum lipids.
In a meta-analysis of observational study data, including prospective, retrospective, and case-control studies, higher amounts of coffee or caffeine had no association with risk of atrial fibrillation, but low doses of caffeine (<350 mg/day) appeared to have a protective effect 162). In contrast, coffee consumption of 1-5 cups/day was found to be inversely associated with risk of heart failure in a meta-analysis of 5 prospective studies 163). A non-linear association was documented and the lowest risk was observed for 4 cups/day 164).
Coffee and Type 2 Diabetes
There is a consistent observational evidence indicating that moderate coffee consumption is associated with reduced risk of type 2 diabetes and cardiovascular disease in healthy adults 165). In addition, consistent observational evidence indicates that regular consumption of coffee is associated with reduced risk of cancer of the liver and endometrium, and slightly inverse or null associations are observed for other cancer sites.
- Coffee consumption was inversely associated with type 2 diabetes risk in a dose-response manner
- Both caffeinated and decaffeinated coffee were associated with lower type 2 diabetes risk
- Increased coffee consumption by 1 cup/d was associated with 7% lower type 2 diabetes risk
- Similar associations were seen in men and women
- A smaller number of studies on decaffeinated coffee indicate that protective association of coffee consumption is unlikely to be due to caffeine alone
- In type 2 diabetes individuals, ingestion of caffeine (~200-500 mg) significantly increased blood glucose, serum insulin, and lowered insulin sensitivity in those with type 2 diabetes in short-term randomised controlled trials.
Five studies examined coffee and type 2 diabetes 166), 167), 168), 169), 170). Coffee consumption has consistently been associated with a reduced risk of type 2 diabetes. In four meta-analyses of prospective cohort studies 171), 172), 173), 174) and cross-sectional studies 175), coffee consumption was inversely associated with risk of type 2 diabetes in a dose-response manner. Risk for type 2 diabetes was 33 percent lower for those consuming 6 cups/day in the analysis by Ding et al. 176) while the risk was 37 percent lower for those consuming 10 cups/day in the analysis by Jiang et al. 177). Using a sub-set of the prospective cohorts in the Ding et al. 178) and Jiang et al. 179) meta-analyses, Huxley 180) documented that each cup of coffee was associated with a 7 percent lower risk of type 2 diabetes. Similarly, van Dam 181) noted that consumption of ≥6 or ≥7 cups/day was associated with a 35 percent lower risk of type 2 diabetes. Three meta-analyses 182), 183), 184) found protective associations for decaffeinated coffee. Moderate decaffeinated coffee consumption (3-4 cups/day) was associated with a 36 percent lower risk of type 2 diabetes 185). Each cup of decaffeinated coffee was associated with a 6 percent lower risk 186) while every 2 cups were associated with a 11 percent lower risk 187). Both reports also documented a dose-response association between caffeine and type 2 diabetes risk such that every 140 mg/day was associated with an 8 percent lower risk in the Ding et al 188) meta-analysis while every 200 mg/day was associated with a 14 percent lower risk in the analysis by Jiang et al 189). However, it remains unclear if this inverse association is independent of coffee consumption as Ding et al 190) indicated that none of the studies included in the caffeine dose-response analysis adjusted for total coffee.
Only one systematic review of 9 randomized controlled trials examined the effects of caffeine on blood glucose and insulin concentrations among those with type 2 diabetes 191). Ingestion of 200-500 mg of caffeine acutely increased blood glucose concentrations by 16-28 percent of the area under the curve and insulin secretions by 19-48 percent of the area under the curve when taken prior to a glucose load. At the same time, these trials also noted a decrease in insulin sensitivity by 14-37 percent. Although it is not clear if the acute effects of caffeine on blood glucose and insulin persist in the long term, evidence from prospective cohorts indicate that caffeine may have no adverse effect on the risk of type 2 diabetes.
Coffee and Cancer
What is the relationship between usual caffeine consumption and cancer developing ?
There is a consistent observational evidence indicating that regular consumption of coffee is associated with reduced risk of cancer of the liver and endometrium, and slightly inverse or null associations are observed for other cancer sites 192).
- Total Cancer Coffee drinkers had a modestly lower total cancer incidence compared to nondrinkers or those with the lowest intakes.
- Coffee consumption was associated with higher risk of lung cancer, but the association was mainly explained by smoking. An association was not founder among nonsmokers.
- Significant inverse association between coffee consumption and liver cancer risk seen in both case-control and cohort studies (after adjustment for existing liver disease).
- Risk of hepatocelluar carcinoma was reduced by 40% for any coffee consumption versus no coffee consumption.
- No association between caffeine, coffee, or decaffeinated coffee and breast cancer risk.
- An inverse association was seen in postmenopausal women and a strong inverse association seen in BRCA1 mutation carriers.
- Borderline lower risk for highest versus lowest coffee consumption.
- For all studies together, an increase of 2 cups of coffee per day was associated with a 2% marginally lower breast cancer risk.
- Regular coffee consumption associated with modestly lower risk of prostate cancer.
- Significant inverse association documented for cohort studies. For case-control studies, a 2 cup increment was associated with a higher risk of prostate cancer.
- Dose-response meta-analysis of coffee consumption showed inverse association with prostate cancer mortality, but not incidence.
- No association between coffee consumption and ovarian cancer risk in high versus low or dose-response meta-analysis.
- Increased coffee intake was associated with a reduced risk of endometrial cancer in both cohort and case-control studies.
- A reduction of ~20% in endometrial cancer risk among coffee drinkers; >20% and >30% reduction in risk among low to mod and heavy drinkers, respectively.
- Data from case-control studies suggest that consumption of coffee is associated with an increased risk for bladder cancer, but no significant association was seen in prospective cohort studies.
- Meta-analysis of prospective cohort studies showed that coffee drinking was inversely associated with pancreatic cancer risk (in sub-group analyses, there was a reduced risk in men but not women).
- A positive association was found between coffee intake and pancreatic cancer in case-control studies that did not adjust for smoking. An inverse association was found in prospective cohort studies.
Upper Digestive & Respiratory Cancer
- Coffee drinking was inversely related to oral/pharyngeal cancer risk while there was no relation with laryngeal cancer, ESCC, and EAC.
- Coffee consumption was inversely, but non-significantly, associated with risk of esophageal cancer.
- No association between coffee consumption and gastric cancer risk in cohort or case-control studies.
- Case-control studies suggest coffee consumption decreases risk of colorectal and colon cancer, especially in women; the association was inverse, but marginally non-significant, for cohort studies for colorectal and colon cancer.
- Prospective cohort studies showed no association between coffee consumption on colorectal cancer risk (a suggestive inverse association was slightly stronger in studies that adjusted for smoking and alcohol).
A large number of studies addressed cancer, including total cancer 193), lung cancer 194), liver cancer 195), 196), breast cancer 197), 198), 199), prostate cancer 200), 201), 202), 203), ovarian cancer 204), endometrial cancer 205), 206), bladder cancer 207), pancreatic cancer 208), 209), upper digestive and respiratory tract cancer 210), esophageal cancer 211), gastric cancer 212), and colorectal cancer 213), 214), 215). Several systematic reviews and meta-analyses examined the association between coffee consumption and risk of cancer. Types of cancer examined by the Committee included total cancer, cancers of the lung, liver, breast, prostate, ovaries, endometrium, bladder, pancreas, upper digestive and respiratory tract, esophagus, stomach, colon, and rectum.
In a quantitative summary of 40 prospective cohort studies with an average follow-up of 14.3 years, Yu 216) found a 13 percent lower risk of total cancer among coffee drinkers compared to non-drinkers or those with lowest intakes. Risk estimates were similar for men and women. In sub-group analyses, the authors noted that coffee drinking was associated with a reduced risk of bladder, breast, buccal and pharyngeal, colorectal, endometrial, esophageal, hepatocellular, leukemic, pancreatic, and prostate cancers.
Tang et al 217) evaluated 5 prospective cohorts and 8 case-control studies and found that overall those with the highest levels of coffee consumption had a 27 percent higher risk for lung cancer compared to never drinkers or those with least consumption. An increase in coffee consumption of 2 cups/day was associated with a 14 percent higher risk of developing lung cancer. However, because smoking is an important confounder, when analyses were stratified by smoking status, coffee consumption was marginally protective in non-smokers and was not associated with lung cancer among smokers. When estimates from 2 studies that examined decaffeinated coffee were summarized, there was a protective association with lung cancer. No association was seen with lung cancer when only case-control studies were considered.
Results from two meta-analyses indicate the coffee consumption is associated with a 50 percent lower risk of liver cancer 218) and a 40 percent lower risk of hepatocellular carcinoma 219) when considering both cohort and case-control studies. Associations were significant in men but not in women 220).
Three meta-analyses of observational studies found no association between coffee consumption 221), 222), 223), caffeine consumption 224) or decaffeinated coffee consumption 225) and risk of breast cancer. In all 3 reports, each 2 cup/day of coffee was marginally associated with a 2 percent lower risk of breast cancer. However, in sub-group analyses, coffee consumption was protective against breast cancer risk in postmenopausal women 226), BRCA1 mutation carriers 227) and women with estrogen receptor negative status 228).
The association between coffee consumption and risk of prostate cancer was mixed. Cao 229) and Zhong 230) found that regular or high coffee consumption, compared to non- or lowest levels of consumption, was associated with a 12 percent-17 percent lower risk of prostate cancer in prospective cohort studies. Further, each 2 cups of coffee per day was associated with a 7% lower risk of prostate cancer. However, no associations were seen with case-control data alone or when these studies were examined together with prospective cohort studies. Using a combination of both prospective cohort and case-control data, Discacciati 231) found that each 3 cups/day of coffee was associated with a 3% lower risk of localized prostate cancer and an 11% lower risk of mortality from prostate cancer. On the other hand, after summarizing data from 12 prospective cohort and case-control studies, Park 232) found a 16% higher risk of prostate cancer. However, in sub-group analyses by study design, the higher risk was observed in case-control but not in cohort studies.
Consumption of coffee was not associated with risk of ovarian cancer in a meta-analysis of 7 prospective cohort studies with over 640,000 participants 233).
Two meta-analyses confirmed an inverse association between coffee consumption and risk of endometrial cancer 234), 235). In the most recent and updated meta-analysis of prospective cohort and case-control studies, compared to those in the lowest category of coffee consumption, those with the highest intakes of coffee had a 29% lower risk of endometrial cancer 236). Each cup of coffee per day was associated with an 8% lower risk of endometrial cancer. Similar results were found in the meta-analysis by Bravi 237) that included a sub-set of the studies in Je 238) and documented a 20% lower risk of endometrial cancer overall, and a 7% decrease for each cup of coffee per day. However, the association was significant only in case-control studies but not in cohort studies, most likely due to lower statistical power.
A recent meta-analysis of 23 case-control studies by Zhou 239) found coffee was a risk factor for bladder cancer. There was a smoking-adjusted increased risk of bladder cancer for those in the highest (45%), second highest, (21%), and third highest (8%) groups of coffee consumption, compared to those in the lowest group. No association was, however, seen in cohort studies.
Two meta-analyses of coffee consumption and pancreatic cancer risk provided mixed results 240), 241). Using both prospective cohort and case-control studies, Turati 242) found that coffee consumption was not associated with risk of pancreatic cancer. However, an increased risk was seen in case-control studies that did not adjust for smoking. Using a sub-set of prospective cohorts included in the Turati 243) meta-analysis, Dong 244) found that coffee drinking was inversely associated with pancreatic cancer risk but did not separate studies based on their adjustment for smoking status. Sub-group analyses revealed a protective association in men, but not in women.
Turati 245) quantified the association between coffee consumption and various upper digestive and respiratory tract cancers using data from observational studies. Coffee consumption was associated with a 36% lower risk of oral and pharyngeal cancer but not with risk of laryngeal cancer, esophageal squamous cell carcinoma, or esophageal adenocarcinoma. In a meta-analysis of prospective cohort and case-control studies, Zheng 246) noted that coffee was inversely, but non-significantly, associated with risk of esophageal cancer. Regarding gastric cancer, no association between coffee consumption and risk was seen in a meta-analysis of observational studies by Botelho 247).
Three meta-analyses on the association between coffee consumption and colorectal cancer risk 248), 249), 250) have yielded mixed findings. Results from case-control studies suggested coffee consumption was associated with lower risk of colorectal (15% lower) and colon cancer (21% lower), especially in women. However, this inverse association was non-significant for cohort studies. Using all but one of the case-control studies, Galeone 251) arrived at similar conclusions as the Li 252) analysis although associations were in general stronger. Galeone 253) also provided suggestive evidence for a dose-response relationship between coffee and colorectal cancer such that each cup of coffee was associated with a 6% lower risk of colorectal cancer, 5% lower risk of colon cancer, and 3% lower risk of rectal cancer. Using several prospective cohort studies as in the Li 254) meta-analysis, Je 255) found no significant association of coffee consumption with risk of colorectal cancer. Interestingly, no differences were seen by sex but the suggestive inverse associations were slightly stronger in studies that adjusted for smoking and alcohol.
Coffee and Parkinson’s Disease
There was a non-linear inverse association between coffee and Parkinson’s disease risk with maximum protection at ~3 cups/d (adjusted for smoking) 256). For caffeine consumption, a linear inverse association was found (adjusted for smoking); every 300 mg/day was associated with a 24% lower risk of Parkinson’s disease.
Evidence from two systematic reviews 257), 258) and one quantitative meta-analysis 259) confirmed an inverse association between coffee, caffeine, and risk of Parkinson’s disease. Qi 260) evaluated six case-control studies and seven prospective articles and documented a non-linear relationship between coffee and risk of Parkinson’s disease, overall. The lowest risk was observed at ~3 cups/day (smoking-adjusted risk reduction was 28%). For caffeine, a linear dose-response was found and every 200 mg/day increment in caffeine intake was associated with a 17% lower risk of Parkinson’s disease. Using a combination of cohort, case-control, and cross-sectional data, Costa 261) summarized that the risk of Parkinson’s disease was 25% lower among those consuming the highest versus lowest amounts of caffeine. Like Qi 262), Costa documented a linear dose-response with caffeine intake such that every 300 mg/day was associated with a 24% lower risk of Parkinson’s disease. In both reports, associations were weaker among women than in men.
Coffee and Cognitive Function
There is limited evidence indicates that caffeine consumption is associated with a modestly lower risk of cognitive decline or impairment and lower risk of Alzheimer’s disease. However, there was a trend toward a protective effect of caffeine from different sources and cognitive impairment/dementia. Two systematic reviews 263), 264) and one meta-analysis 265) examined the effects of caffeine from various sources, including coffee, tea, chocolate, on cognitive outcomes. Arab 266) systematically reviewed six longitudinal cohort studies evaluating the effect of caffeine or caffeine-rich beverages on cognitive decline. Most studies in this review used the Mini Mental State Examination Score as a global measure of cognitive decline. The review concluded that estimates of cognitive decline were lower among consumers, although there was no clear dose-response relationship. Studies also showed stronger effects among women than men. In a meta-analysis of nine cohort and two case-control studies, caffeine intake from various sources was associated with a 16% lower risk of various measures of cognitive impairment/decline. Specifically, data from four studies indicate that caffeine is associated with a 38% lower risk of Alzheimer’s disease 267).
Coffee and Headache
Pallarés et al. 268) studied adults participating in a weight-lifting protocol and assessed headache ratings the following day after administration of three different caffeine doses. Compared to a placebo, a slight increase in headache was seen with a 230-mg caffeine dose; higher single doses of approximately 459 mg and 689 mg caffeine/day increased the reports of headaches 24 h later, although it should be noted that this study did not fully describe the statistical significance 269).
For adults, the studies support that consumption of ≤400 mg caffeine is not associated with an increase in headaches. However, like the evidence presented in Nawrot et al. 270), observational studies do indicate a potential link between caffeine use and headache prevalence in some individuals, although some of this effect is likely due to withdrawal-related symptoms. In this regard, timing of the dose is important, since increases in reports of headache may only occur some significant time after ingestion (e.g., 12–24 h for habitual users) 271). Although these studies were relatively consistent among themselves, withdrawal-related effects may be a factor in the outcomes of these observational studies, in addition to some residual confounding in these data due to reverse causation – factors making integration and interpretation of the findings quite complex. When effects were observed, the overall strength of association, however, was generally small (i.e., small magnitude). The confidence in the body of evidence is moderate to high. So for those who have frequent headaches, avoidance of all caffeine is ideal, and at least until improvement in headache frequency is seen.
However, chronic daily headache patients are much more likely to use daily dietary caffeine and/or prefer caffeine-containing headache medications. Moreover, people who occasionally experience migraine attacks are at a higher risk of developing chronic daily headache when they also consume caffeine daily as well. In one study, consumers of 100mg caffeine daily had nearly three times higher likelihood of developing chronic daily headache than those drinking less 272). This association is particularly notable for young women—a group already at greater risk for migraine and the march or progression to daily headache.
The effect of caffeine on headache in children and adolescents was assessed in two controlled trials, both of which suggest an effect of consumer status on this endpoint. In the first study, Heatherley et al. 273) found that 1.3 mg/kg caffeine administered to children (aged 9–11 years) had no effect on headache ratings among those who were typically non- or low consumers (mean consumption of 12 mg/day); however, in regular consumers (mean consumption of 109 mg/day), caffeine reduced headache ratings compared to placebo 274). The authors suggest that these results indicate a reversal of the adverse effects, which may occur following overnight abstinence. In the second study, Temple et al. 275) analyzed the effects of caffeine intake on irritability, hunger, and headaches in adolescents aged 12–17 years. Compared to the placebo group, changes in headache ratings did not reach statistical significance after consumption of 2.32 mg/kg caffeine/day; however, both male and female participants who were regular high-caffeine consumers (considered by the authors to be ≥ 50 mg/day) self-reported significantly more headaches than low consumers 276).
One observational study was also identified that evaluated the relationship between caffeine consumption and headache in children. Kristjansson et al. 277) reported on the physical complaints (e.g., headache, problems sleeping, and low appetite) that were associated with the daily intake of cola and energy drinks in Icelandic children (aged 10–12 years). Girls appeared to be more sensitive than boys to the caffeine-related headaches and <0.6 mg/kg caffeine/day (less than one cola drink day) was associated with an increase in headaches. For boys, significant increases in headaches were linked with consumption of more than one cola and less than one energy drink per day (i.e., >0.6 mg/kg to <1.4 mg/kg caffeine/day).
For children and adolescents, there was insufficient evidence to make conclusions regarding the appropriateness of the comparator. The limited evidence available, however, suggests that the comparator may be acceptable for headache; however, the data show that the relationship between headache and caffeine in children and adolescents is likely dependent on the timing of the dose and the subject’s typical consumption.
Coffee and Gastro-oesophageal Reflux
Although coffee often mentioned as a cause of dyspeptic symptoms, no association between coffee and dyspepsia is found. Heartburn is the most frequently reported symptom after coffee drinking. It is demonstrated that coffee promotes gastro-oesophageal reflux. Coffee stimulates gastrin release and gastric acid secretion, but studies on the effect on lower oesophageal sphincter pressure yield conflicting results. Coffee also prolongs the adaptive relaxation of the proximal stomach, suggesting that it might slow gastric emptying. However, other studies indicate that coffee does not affect gastric emptying or small bowel transit. Coffee induces cholecystokinin release and gallbladder contraction, which may explain why patients with symptomatic gallstones often avoid drinking coffee. Coffee increases rectosigmoid motor activity within 4 min after ingestion in some people. Its effects on the colon are found to be comparable to those of a 1000 kCal meal. Since coffee contains no calories, and its effects on the gastrointestinal tract cannot be ascribed to its volume load, acidity or osmolality, it must have pharmacological effects. Caffeine cannot solely account for these gastrointestinal effects. This review concluded that coffee promotes gastro-oesophageal reflux, but is not associated with dyspepsia 278). Coffee stimulates gallbladder contraction and colonic motor activity. Caffeinated coffee stimulates colonic motor activity. Its magnitude is similar to a meal, 60% stronger than water and 23% stronger than decaffeinated coffee 279). In another study 280) coffee consumption may have helped to prevent symptomatic gallstone disease.
Caffee and Mental Illness
The mechanism of action by which coffee induce or exacerbate mental illness is thought to be by way of caffeine and its effects on neurotransmitters 281). Through adenosine A1 and A2A receptor antagonism, caffeine inhibits the inhibitory effects of adenosine on dopamine, thus increasing the psychoactivity of dopaminergic systems (D1 and D2 receptors acted on by A1 and A2A, respectively) affecting mood, executive functioning, salience attribution, cognition, and regulation of behaviors 282). This appears to be true as caffeine has been shown to induce manic symptoms in those without bipolar disorder, and psychosis in those without a previously diagnosed psychotic disorder 283), 284), 285). These symptoms tend to resolve with discontinuation or significant reduction of caffeine consumption 286), 287).
It has also been hypothesized that the mechanism by which caffeine-containing beverages induce psychiatric relapse is via competitive binding at CYP450 sites. With increased caffeine intake, these binding sites are overwhelmed by caffeine molecules, thus inhibiting binding by psychotropic medications. By this process, many antipsychotics and antidepressants will not be metabolized, thereby inducing relapse by decreasing efficacy of psychotropic medications 288).
In a case report by Cerimele, Stern, and Jutras-Aswad 289), an individual diagnosed with schizophrenia was noted to experience psychotic symptoms resulting in readmission to the hospital after increased consumption of energy drinks. After his first beverage, the subject reported an increased interest in activities and improved mood. Eventually, the subject increased his consumption of energy drinks to 8 to 10 cans (16oz per can) daily. After two months, the subject was hospitalized with symptoms of paranoia, internal preoccupations, constricted affect, and delusional religious beliefs. Ten days after hospitalization and discontinuation of the excess dietary caffeine, the degree of paranoia, preoccupations, and other psychotic symptoms displayed while consuming the energy drinks decreased to pre-study levels without an increase in maintenance antipsychotic medication 290). The authors were convinced that the temporal evidence gathered by this case report demonstrates enough evidence to prove their hypothesis correct, although more studies are necessary to confirm these findings.
Chelben et al. 291) reported on three patients who also demonstrated increased psychiatric symptomatology leading to inpatient hospitalization with use of energy drinks. The first case described a 41-year-old woman with cluster B personality traits consistent with borderline personality disorder who drank five or more energy drinks per day for one week. Upon dissolution of monetary assets, she abruptly stopped her energy drink intake and was hospitalized the following day with signs and symptoms of hypervigilance, aggression, psychomotor agitation, and impulsivity. The second case described in this report was of a 38-year-old woman with a psychiatric history significant for comorbid bipolar disorder, borderline personality disorder, and polysubstance dependence. She began drinking 5 to 10 energy drinks per day with a resultant “high, like on drugs,” and improved affective control with better control over her anger. Like the previous case, on hospital admission she exhibited impulsivity and psychomotor aggitation with additional onset of self-injurious behaviors and beginning insomnia. The final case described a 25-year-old man with schizophrenia who, for one month prior to hospitalization, had been consuming 8 to 9 energy drinks in one sitting. He too exhibited signs of hypervigilance, aggression, and psychomotor agitation, as well as thoughts of self-harm. These authors also acknowledge that while the temporal relationship between intensification of energy drink consumption and mental deterioration appears to be associated, this does not confirm a causal relationship 292). However, there are several reports of caffeine-induced mania in patients with bipolar disorder 293) and suicidality in those with depression 294) with doses of caffeine greater than 300mg per day. At doses greater than 450mg per day, caffeine has been shown to induce or exacerbate anxiety 295), especially in patients with panic disorder 296), and in family studies, the same effect was detected in first-degree relatives 297). Caffeine was also shown to exacerbate anxiety in depression 298), generalized anxiety disorder 299), and social anxiety disorder-performance subtype 300). Paradoxically, in a double-blind, placebo-controlled study, Koran et al. 301) showed that a single large dose (300mg) of caffeine daily may provide added symptom reduction when used to augment a selective serotonin reuptake inhibitor in those with treatment-resistant obsessive compulsive disorder (OCD). Caffeine may be beneficial in obsessive compulsive disorder as compared to other anxiety disorders due to the differential symptomatology 302). Whereas most anxiety disorders consist of irrational or disabling worries and fears, in OCD, individuals suffer from ruminative thoughts leading to compulsive behaviors. Koran et al. 303) hypothesized that the caffeine-induced increase in dopamine may lead to increased D1 receptor binding in the prefrontal cortex resulting in enhanced attention and working memory. Thus, individuals with OCD should be able to divert their attention away from intrusive thoughts, which then decreases reactive compulsive behaviors. By the same mechanism—increased D1 activity in the prefrontal cortex—caffeine may be beneficial in attention deficit hyperactivity disorder (ADHD) by increasing the ability to sustain attention, resulting in decreased reaction times, enhanced executive functioning, and increased processing speed 304).
At moderate doses, defined as less than 150 to 200mg of caffeine per day, caffeine has been shown to have neuroprotective effects as well as positive effects on mental illness. Moderate intake has been associated with fewer signs and symptoms of depression 305), including decreased risk of suicide 306), and cognitive improvement/delay of cognitive decline 307). However the mood-enhancing effect of caffeine appears only to occur in regular consumers of caffeine, whereas caffeine-naive consumers tend to derive performance-enhancing benefits 308).
Coffee is Bad:
- If you are sensitive to caffeine, coffee (caffeine) may cause restlessness and shakiness, insomnia, headaches, dizziness, rapid or abnormal heart rhythm, stomach upset, dehydration, anxiety, dependency, so you need to take more of it to get the same results.
- If you are a child or teen. Neither should have as much caffeine as adults. Children can be especially sensitive to the effects of caffeine (commonly found in energy drinks).
- If you have sleep disorders, including insomnia.
- If you suffer from migraines or other chronic headaches.
- If you have anxiety or mood disorders. High caffeine intakes (e.g. more than 5 mg/kg body weight per day) were associated with an increased risk of anxiety and withdrawal symptoms 309).
- Caffeine may be related to psychotic or mood symptoms but may also aggravate pre-existing psychotic or mood disorders 310).
- If you have GERD (gastro-esophageal reflux disease) or ulcers.
- If you have fast or irregular heart rhythms.
- Coffee can raise your blood pressure, so if you have high blood pressure it’s best to avoid or reduce your coffee and caffeine consumption.
- Unfiltered (European pressed) coffee or cafetière coffee contain oily substances called diterpenes (cafestol and kahweol), which can raise your cholesterol (both total and LDL bad cholesterol) level and affect your liver. So if you like your coffee unfiltered European style, it is recommended that you have your cholesterol levels regularly checked to make sure your LDL levels don’t get too high and also your liver enzyme checked to ensure your liver function is within normal.
- If you have been consuming coffee (caffeine) on a regular basis and then suddenly stop, you may have caffeine withdrawal. Symptoms can include headaches, drowsiness, irritability, nausea and difficulty concentrating.
You should check with your health care provider about whether you should limit or avoid caffeine if you:
- Are pregnant, since caffeine passes through the placenta to your baby
- Are breastfeeding, since a small amount of caffeine that you consume is passed along to your baby
- Take certain medicines or supplements, including stimulants, certain antibiotics, asthma medicines, and heart medicines. Check with your health care provider about whether there might be interactions between caffeine and any medicines and supplements that you take. For example, ephedrine – mixing caffeine with this medication, which is used in decongestants — might increase your risk of high blood pressure, heart attack, stroke or seizure. Theophylline, this medication, used to open up bronchial airways, tends to have some caffeine-like effects. So taking it with caffeine might increase the adverse effects of caffeine, such as nausea and heart palpitations. Echinacea. This herbal supplement, which is sometimes used to prevent colds or other infections, may increase the concentration of caffeine in your blood and may increase caffeine’s unpleasant effects.
Coffee is Good:
- The evidence generally supported consumption of up to 400 mg coffee (caffeine) per day in healthy adults is not associated with overt, adverse cardiovascular, behavioral, reproductive, acute, or bone status effects.
- Intakes of up to 300 mg coffee (caffeine) per day in pregnant women and up to 2.5 mg/kg-day in children and adolescents remain acceptable. It should be noted that additional research are required and valuable in this area.
- Recognizing that individuals may differ in their own level of sensitivity to caffeine, the caffeine intake values of up to 400 mg caffeine per day in healthy adults, of up to 300 mg caffeine per day in pregnant women and up to 2.5 mg/kg-day in children and adolescents were originally intended to provide guidance on safe levels of consumption to healthy consumers.
- Findings of this review, however, highlight that there is no “bright line,” as potential effects are dependent on many conditional factors; furthermore, there is some limited evidence that self-regulation reduces consumption.
References [ + ]
|1, 2.||↵||International Coffee Organization. http://www.ico.org/|
|3, 4.||↵||Clifford, M. N.; Wilson, K. C., eds. (1985). Coffee: Botany, Biochemistry and Production of Beans and Beverage. Westport, Connecticut: AVI Publishing. ISBN 0-7099-0787-7.|
|5, 31.||↵||United States Department of Agriculture Agricultural Research Service. USDA Branded Food Products Database. https://ndb.nal.usda.gov/ndb/|
|6, 12.||↵||Caffeine-induced cardiac arrhythmia: an unrecognised danger of healthfood products. Cannon ME, Cooke CT, McCarthy JS. Med J Aust. 2001 May 21; 174(10):520-1. https://www.ncbi.nlm.nih.gov/pubmed/11419773/|
|7.||↵||Greenwood MRC, Oria M. Use of dietary supplements by military personnel. Available at: www.nap.edu/catalog/12095.html Accessed January 17, 2011|
|8.||↵||Food and Chemical Toxicology 21 April 2017; 1-64. https://doi.org/10.1016/j.fct.2017.04.002. Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children. http://www.sciencedirect.com/science/article/pii/S0278691517301709|
|9.||↵||G.A. Wright, D.D. Baker, M.J. Palmer, D. Stabler, J.A. Mustard, E.F. Power, A.M. Borland, P.C. Stevenson. Caffeine in floral nectar enhances a pollinator’s memory of reward. Science, 339 (2013), pp. 1202-1204. http://science.sciencemag.org/content/339/6124/1202|
|10.||↵||B.B. Fredholm, K. Battig, J. Holmen, A. Nehlig, E.E. Zvartau. Actions of caffeine in the brain with special reference to factors that contribute to its widespread use. Pharmacol. Rev., 51 (1999), pp. 83-133.|
|11.||↵||J.J. Barone, H.R. Roberts. Caffeine consumption. Food Chem. Toxicol., 34 (1996), pp. 119-129. http://www.sciencedirect.com/science/article/pii/0278691595000933|
|13.||↵||US Food and Drug Administration. Caffeine Intake by the U.S. Population. https://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofFoods/CFSAN/CFSANFOIAElectronicReadingRoom/UCM333191.pdf|
|14, 272.||↵||American Migraine Foundation. Caffeine and Migraine. https://americanmigrainefoundation.org/understanding-migraine/caffeine-and-migraine/|
|15.||↵||D.C. Mitchell, J. Hockenberry, R. Teplansky, T.J. Hartman. Assessing dietary exposure to caffeine from beverages in the U.S. population using brand-specific versus category-specific caffeine values. Food Chem. Toxicol., 80 (2015), pp. 247-252. http://dx.doi.org/10.1016/j.fct.2015.03.024. http://www.sciencedirect.com/science/article/pii/S0278691515001039|
|16.||↵||G. Richards, A.P. Smith. A review of energy drinks and mental health, with a focus on stress, anxiety, and depression. J. Caffeine Res., 6 (2016), pp. 49-63. https://doi.org/10.1089/jcr.2015.0033|
|17.||↵||D.C. Mitchell, C.A. Knight, J. Hockenberry, R. Teplansky, T.J. Hartman. Beverage caffeine intakes in the US. Food Chem. Toxicol., 63 (2014), pp. 136-142. http://dx.doi.org/10.1016/j.fct.2013.10.042|
|18.||↵||V.L. Fulgoni, D.R. Keast, H.R. Lieberman. Trends in intake and sources of caffeine in the diets of US adults: 2001-2010. Am. J. Clin. Nutr., 101 (2015), pp. 1081-1087, 10.3945/ajcn.113.080077|
|19.||↵||D.C. Mitchell, J. Hockenberry, R. Teplansky, T.J. Hartman. Assessing dietary exposure to caffeine from beverages in the U.S. population using brand-specific versus category-specific caffeine values. Food Chem. Toxicol., 80 (2015), pp. 247-252. http://dx.doi.org/10.1016/j.fct.2015.03.024|
|20.||↵||A. Drewnowski, C.D. Rehm. Sources of caffeine in diets of US children and adults: trends by beverage type and purchase location. Nutrients, 8 (2016), p. 154, 10.3390/nu8030154|
|21.||↵||DGAC Scientific Report of the 2015 Dietary Guidelines Advisory Committee, Part B, Chapter 2 (2015). https://health.gov/dietaryguidelines/2015-scientific-report/04-integration.asp|
|22.||↵||B.E. Millen, S. Abrams, L. Adams-Campbell, C.A. Anderson, J.T. Brenna, W.W. Campbell, S. Clinton, F. Hu, M. Nelson, M.L. Neuhouser, R. Perez-Escamilla, A.M. Siega-Riz, M. Story, A.H. Lichtenstein. The 2015 dietary guidelines advisory committee scientific report: development and major conclusions. Adv. Nutr., 7 (2016), pp. 438-444. http://advances.nutrition.org/content/7/3/438.full|
|23.||↵||EFSA Scientific Opinion on the safety of caffeine. EFSA J., 13 (2015), pp. 4102-4120. http://onlinelibrary.wiley.com/doi/10.2903/j.efsa.2015.4102/epdf|
|24, 26, 27, 28, 29, 97, 270.||↵||P. Nawrot, S. Jordan, P. EastNawrot, S. Jordan, J. Eastwood, J. Rotstein, A. Hugenholtz, M. Feeley. Effects of caffeine on human health. Food Addit. Contam., 20 (2003), pp. 1-30. http://www.tandfonline.com/doi/abs/10.1080/0265203021000007840|
|25.||↵||S. Milanez. Adverse Health Effects of Caffeine: Review and Analysis of Recent Human and Animal Research. Oak Ridge National Laboratory, Oak Ridge, TN (2011).|
|30, 32.||↵||Mayo Foundation for Medical Education and Research. Caffeine content for coffee, tea, soda and more. http://www.mayoclinic.org/healthy-lifestyle/nutrition-and-healthy-eating/in-depth/caffeine/art-20049372|
|33.||↵||Pincomb GA, Lovallo WR, Passey RB, Whitsett TL, Silverstein SM, Wilson MF. Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men. Am J Cardiol. 1985;56:119–122. https://www.ncbi.nlm.nih.gov/pubmed/4014015|
|34.||↵||Hartley TR, Lovallo WR, Whitsett TL. Cardiovascular effects of caffeine in men and women. Am J Cardiol. 2004;93:1022–1026. https://www.ncbi.nlm.nih.gov/pubmed/15081447|
|35.||↵||Office of Disease Prevention and Health Promotion. The Dietary Guidelines for Americans. https://health.gov/dietaryguidelines/|
|36.||↵||Zhang Z, Hu G, Caballero B, Appel L, Chen L. Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies. Am J Clin Nutr. 2011;93:1212–1219. https://www.ncbi.nlm.nih.gov/pubmed/21450934|
|37.||↵||Lopez-Garcia E, van Dam RM, Willett WC, Rimm EB, Manson JE, Stampfer MJ, et al. Coffee consumption and coronary heart disease in men and women: a prospective cohort study. Circulation. 2006;113:2045–2053. https://www.ncbi.nlm.nih.gov/pubmed/16636169|
|38.||↵||Reis JP, Loria CM, Steffen LM, Zhou X, van Horn L, Siscovick DS, et al. Coffee, decaffeinated coffee, caffeine, and tea consumption in young adulthood and atherosclerosis later in life: the CARDIA study. Arterioscler Thromb Vasc Biol. 2010;30:2059–2066. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940975/|
|39.||↵||Sugiyama K, Kuriyama S, Akhter M, Kakizaki M, Nakaya N, Ohmori-Matsuda K, et al. Coffee consumption and mortality due to all causes, cardiovascular disease, and cancer in Japanese women. J Nutr. 2010;140:1007–1013. https://www.ncbi.nlm.nih.gov/pubmed/20335629|
|40.||↵||Woodward M, Tunstall-Pedoe H. Coffee and tea consumption in the Scottish Heart Health Study follow up: conflicting relations with coronary risk factors, coronary disease, and all cause mortality. J Epidemiol Community Health. 1999;53:481–487. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756940/|
|41.||↵||Arnlov J, Vessby B, Riserus U. Coffee consumption and insulin sensitivity. JAMA. 2004;291:1199–1201. https://www.ncbi.nlm.nih.gov/pubmed/15010440|
|42.||↵||van Dam RM, Feskens EJ. Coffee consumption and risk of type 2 diabetes mellitus. Lancet. 2002;360:1477–1478. https://www.ncbi.nlm.nih.gov/pubmed/12433517|
|43, 57.||↵||van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA. 2005;294:97–104. https://www.ncbi.nlm.nih.gov/pubmed/15998896|
|44.||↵||Lopez-Garcia E, van Dam RM, Qi L, Hu FB. Coffee consumption and markers of inflammation and endothelial dysfunction in healthy and diabetic women. Am J Clin Nutr. 2006;84:888–893. https://www.ncbi.nlm.nih.gov/pubmed/17023717|
|45.||↵||Larsson SC, Mannisto S, Virtanen MJ, Kontto J, Albanes D, Virtamo J. Coffee and tea consumption and risk of stroke subtypes in male smokers. Stroke. 2008;39:1681–1687. https://www.ncbi.nlm.nih.gov/pubmed/18369170|
|46.||↵||Larsson SC, Virtamo J, Wolk A. Coffee consumption and risk of stroke in women. Stroke. 2011;42:908–912. https://www.ncbi.nlm.nih.gov/pubmed/21393590|
|47.||↵||Silletta MG, Marfisi R, Levantesi G, Boccanelli A, Chieffo C, Franzosi M, et al. Coffee consumption and risk of cardiovascular events after acute myocardial infarction: results from the GISSI (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico)-Prevenzione trial. Circulation. 2007;116:2944–2951. https://www.ncbi.nlm.nih.gov/pubmed/18056527|
|48.||↵||Greenberg JA, Chow G, Ziegelstein RC. Caffeinated coffee consumption, cardiovascular disease, and heart valve disease in the elderly (from the Framingham Study) Am J Cardiol. 2008;102:1502–1508. https://www.ncbi.nlm.nih.gov/pubmed/19026304|
|49.||↵||Zhang WL, Lopez-Garcia E, Li TY, Hu FB, van Dam RM. Coffee consumption and risk of cardiovascular events and all-cause mortality among women with type 2 diabetes. Diabetologia. 2009;52:810–817. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2666099/|
|50.||↵||Zhang W, Lopez-Garcia E, Li TY, Hu FB, van Dam RM. Coffee consumption and risk of cardiovascular diseases and all-cause mortality among men with type 2 diabetes. Diabetes Care. 2009;32:1043–1045. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681042/|
|51.||↵||Mukamal KJ, Hallqvist J, Hammar N, Ljung R, Gemes K, Ahlbom A, et al. Coffee consumption and mortality after acute myocardial infarction: the Stockholm Heart Epidemiology Program. Am Heart J. 2009;157:495–501. https://www.ncbi.nlm.nih.gov/pubmed/19249420|
|52.||↵||de Koning Gans JM, Uiterwaal CS, van der Schouw YT, Boer JM, Grobbee DE, Verschuren WM, et al. Tea and coffee consumption and cardiovascular morbidity and mortality. Arterioscler Thromb Vasc Biol. 2010;30:1665–1671. https://www.ncbi.nlm.nih.gov/pubmed/20562351|
|53.||↵||Lopez-Garcia E, Rodriguez-Artalejo F, Rexrode KM, Logroscino G, Hu FB, van Dam RM. Coffee consumption and risk of stroke in women. Circulation. 2009;119:1116–1123. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2729465/|
|54.||↵||Zhang Z, Hu G, Caballero B, Appel L, Chen L. Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies. Am J Clin Nutr. 2011;93:1212–1219. https://www.ncbi.nlm.nih.gov/pubmed/21450934|
|55.||↵||Wu JN, Ho SC, Zhou C, Ling WH, Chen WQ, Wang CL, et al. Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies. Int J Cardiol. 2009;137:216–225. https://www.ncbi.nlm.nih.gov/pubmed/18707777|
|56.||↵||Sofi F, Conti AA, Gori AM, Eliana Luisi ML, Casini A, Abbate R, et al. Coffee consumption and risk of coronary heart disease: a meta-analysis. Nutr Metab Cardiovasc Dis. 2007;17:209–223. https://www.ncbi.nlm.nih.gov/pubmed/17156982|
|58.||↵||Huxley R, Lee CM, Barzi F, Timmermeister L, Czernichow S, Perkovic V, et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: a systematic review with meta-analysis. Arch Intern Med. 2009;169:2053–2063. https://www.ncbi.nlm.nih.gov/pubmed/20008687|
|59, 83, 93, 165, 192, 256.||↵||Office of Disease Prevention and Health Promotion. Usual Caffeine Consumption and Health. https://health.gov/dietaryguidelines/2015-scientific-report/14-appendix-e2/e2-39a.asp|
|60, 64.||↵||Maslova E, Bhattacharya S, Lin SW, Michels KB. Caffeine consumption during pregnancy and risk of preterm birth: a meta-analysis. Am J Clin Nutr. 2010;92(5):1120-32. PMID: 20844077. http://www.ncbi.nlm.nih.gov/pubmed/20844077|
|61, 62, 63, 65.||↵||Greenwood DC, Thatcher NJ, Ye J, Garrard L, Keogh G, King LG, et al. Caffeine intake during pregnancy and adverse birth outcomes: a systematic review and dose-response meta-analysis. Eur J Epidemiol. 2014;29(10):725-34. PMID: 25179792. http://www.ncbi.nlm.nih.gov/pubmed/25179792|
|66.||↵||G. Albrand, F. Munoz, E. Sornay-Rendu, F. DuBoeuf, P.D. Delmas. Independent predictors of all osteoporosis-related fractures in healthy postmenopausal women: the OFELY study. Bone, 32 (2003), pp. 78-85, 10.1016/S8756-3282(02)00919-5|
|67.||↵||T.T. Fung, M.H. Arasaratnam, F. Grodstein, J.N. Katz, B. Rosner, W.C. Willett, D. Feskanich. Soda consumption and risk of hip fractures in postmenopausal women in the Nurses’ Health Study. Am. J. Clin. Nutr., 100 (2014), pp. 953-958, 10.3945/ajcn.114.083352|
|68, 71.||↵||H. Hallstrom, L. Byberg, A. Glynn, E.W. Lemming, A. Wolk, K. Michaelsson. Long-term coffee consumption in relation to fracture risk and bone mineral density in women. Am. J. Epidemiol., 178 (2013), pp. 898-909. https://academic.oup.com/aje/article-lookup/doi/10.1093/aje/kwt062|
|69.||↵||R.M. Jha, A. Mithal, N. Malhotra, E.M. Brown. Pilot case-control investigation of risk factors for hip fractures in the urban Indian population. BMC Musculoskelet. Disord., 11 (2010), p. 49. https://bmcmusculoskeletdisord.biomedcentral.com/articles/10.1186/1471-2474-11-49|
|70, 72, 73, 76.||↵||D.R. Lee, J. Lee, M. Rota, J. Lee, H.S. Ahn, S.M. Park, D. Shin. Coffee consumption and risk of fractures: a systematic review and dose–response meta-analysis. Bone, 63 (2014), pp. 20-28. http://www.thebonejournal.com/article/S8756-3282(14)00044-1/fulltext|
|74, 75, 77.||↵||H. Hallstrom, A. Wolk, A. Glynn, K. Michaëlsson. Coffee, tea and caffeine consumption in relation to osteoporotic fracture risk in a cohort of Swedish women. Osteoporos. Int., 17 (2006), pp. 1055-1064. https://link.springer.com/article/10.1007%2Fs00198-006-0109-y|
|78.||↵||OHAT Handbook for Conducting a Literature-Based Health Assessment Using OHAT Approach for Systematic Review and Evidence Integration (2015). https://ntp.niehs.nih.gov/ntp/ohat/pubs/handbookjan2015_508.pdf|
|79, 80, 81, 82, 94, 95, 96, 98, 114, 121, 122, 123, 124.||↵||Food and Chemical Toxicology 21 April 2017. https://doi.org/10.1016/j.fct.2017.04.002. Systematic review of the potential adverse effects of caffeine consumption in healthy adults, pregnant women, adolescents, and children. http://www.sciencedirect.com/science/article/pii/S0278691517301709|
|84, 86, 88, 91.||↵||Je Y, Giovannucci E. Coffee consumption and total mortality: a meta-analysis of twenty prospective cohort studies. Br J Nutr. 2014;111(7):1162-73. PMID: 24279995. http://www.ncbi.nlm.nih.gov/pubmed/24279995|
|85, 87, 89.||↵||Malerba S, Turati F, Galeone C, Pelucchi C, Verga F, La Vecchia C, et al. A meta-analysis of prospective studies of coffee consumption and mortality for all causes, cancers and cardiovascular diseases. Eur J Epidemiol. 2013;28(7):527-39. PMID: 23934579. http://www.ncbi.nlm.nih.gov/pubmed/23934579|
|90, 92.||↵||Crippa A, Discacciati A, Larsson SC, Wolk A, Orsini N. Coffee consumption and mortality from all causes, cardiovascular disease, and cancer: a dose-response meta-analysis. Am J Epidemiol. 2014;180(8):763-75. PMID: 25156996. http://www.ncbi.nlm.nih.gov/pubmed/25156996|
|99.||↵||R.J. Bloomer, T.M. Farney, I.C. Harvey, R.J. Alleman. Safety profile of caffeine and 1,3-dimethylamylamine supplementation in healthy men. Hum. Exp. Toxicol., 32 (2013), pp. 1126-1136. http://journals.sagepub.com/doi/10.1177/0960327113475680|
|100, 107.||↵||B. Christensen, A. Mosdol, L. Retterstol, S. Landaas, D.S. Thelle. Abstention from filtered coffee reduces the concentrations of plasma homocysteine and serum cholesterol–a randomized controlled trial. Am. J. Clin. Nutr., 74 (2001), pp. 302-307.|
|101.||↵||M.J. Davies, J.T. Judd, D.J. Baer, B.A. Clevidence, D.R. Paul, A.J. Edwards, S.A. Wiseman, R.A. Muesing, S.C. Chen. Black tea consumption reduces total and LDL cholesterol in mildly hypercholesterolemic adults. J. Nutr., 133 (2003), pp. 3298S-3302S.|
|102, 108, 109.||↵||K. Kempf, C. Herder, I. Erlund. Effects of coffee consumption on subclinical inflammation and other risk factors for type 2 diabetes: a clinical trial. Am. J. Clin. Nutr., 91 (2010), pp. 950-957. http://ajcn.nutrition.org/content/91/4/950.full|
|103, 110.||↵||V. Mougios, S. Ring, A. Petridou, M.G. Nikolaidis. Duration of coffee- and exercise-induced changes in the fatty acid profile of human serum. J. Appl. Physiol., 94 (2003), pp. 476-484. http://jap.physiology.org/content/94/2/476|
|104.||↵||M. Namdar, P. Koepfli, R. Grathwohl, P.T. Siegrist, M. Klainguti, T. Schepis, R. Delaloye, C.A. Wyss, S.P. Fleischmann, O. Gaemperli, P.A. Kaufmann. Caffeine decreases exercise-induced myocardial flow reserve. J. Am. Coll. Cardiol., 47 (2006), pp. 405-410. http://www.sciencedirect.com/science/article/pii/S0735109705025003|
|105.||↵||G.S. Yukawa, M. Mune, H. Otani, Y. Tone, X.M. Liang, H. Iwahashi, W. Sakamoto. Effects of coffee consumption on oxidative susceptibility of low-density lipoproteins and serum lipid levels in humans. Biochem, 69 (2004), pp. 70-74.|
|106.||↵||D. Mozaffarian, E.J. Benjamin, A.S. Go, D.K. Arnett, M.J. Blaha, M. Cushman, S.R. Das, S. de Ferranti, J.-P. Després, H.J. Fullerton, V.J. Howard, M.D. Huffman, C.R. Isasi, M.C. Jiménez, S.E. Judd, B.M. Kissela, J.H. Lichtman, L.D. Lisabeth, S. Liu, R.H. Mackey, D.J. Magid, D.K. McGuire, E.R. Mohler, C.S. Moy, P. Muntner, M.E. Mussolino, K. Nasir, R.W. Neumar, G. Nichol, L. Palaniappan, D.K. Pandey, M.J. Reeves, C.J. Rodriguez, W. Rosamond, P.D. Sorlie, J. Stein, A. Towfighi, T.N. Turan, S.S. Virani, D. Woo, R.W. Yeh, M.B. Turner. Heart disease and stroke Statistics-2016 update: a report from the American heart association. Circulation, 133 (2016), pp. e38-e360. http://circ.ahajournals.org/content/133/4/e38|
|111.||↵||C. Vlachopoulos, D. Panagiotakos, N. Ioakeimidis, I. Dima, C. Stefanadis. Chronic coffee consumption has a detrimental effect on aortic stiffness and wave reflections. Am. J. Clin. Nutr., 81 (2005), pp. 1307-1312.|
|112.||↵||G.M. Trovato, C. Pirri, G.F. Martines, F. Trovato, D. Catalano. Coffee, nutritional status, and renal artery resistive index. Ren. Fail., 32 (2010), pp. 1137-1147. http://www.tandfonline.com/doi/full/10.3109/0886022X.2010.516853|
|113.||↵||O.H. Del Brutto, R.M. Mera, M. Zambrano. Cardiovascular health and caffeine consumption. A population-based study in rural Ecuador. Int J. Cardiol., 172 (2014), pp. 284-285. http://www.internationaljournalofcardiology.com/article/S0167-5273(14)00112-0/fulltext|
|115, 116, 117.||↵||Urgert R, Essed N, van der Weg G, Kosmeijer-Schuil TG, Katan MB. Am J Clin Nutr. 1997 Feb;65(2):519-24. Separate effects of the coffee diterpenes cafestol and kahweol on serum lipids and liver aminotransferases. https://www.ncbi.nlm.nih.gov/pubmed/9022539|
|118, 119, 120.||↵||Urgert R, Meyboom S, Kuilman M, et al. Comparison of effect of cafetière and filtered coffee on serum concentrations of liver aminotransferases and lipids: six month randomised controlled trial. BMJ : British Medical Journal. 1996;313(7069):1362-1366. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2352912/|
|125, 137, 138, 141, 147.||↵||Ding M, Bhupathiraju SN, Satija A, van Dam RM, Hu FB. Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies. Circulation. 2014;129(6):643-59. PMID: 24201300. http://www.ncbi.nlm.nih.gov/pubmed/24201300|
|126, 162.||↵||Caldeira D, Martins C, Alves LB, Pereira H, Ferreira JJ, Costa J. Caffeine does not increase the risk of atrial fibrillation: a systematic review and meta-analysis of observational studies. Heart. 2013;99(19):1383-9. PMID: 24009307. http://www.ncbi.nlm.nih.gov/pubmed/24009307|
|127, 161.||↵||Cai L, Ma D, Zhang Y, Liu Z, Wang P. The effect of coffee consumption on serum lipids: a meta-analysis of randomized controlled trials. Eur J Clin Nutr. 2012;66(8):872-7. PMID: 22713771. http://www.ncbi.nlm.nih.gov/pubmed/22713771|
|128.||↵||Kim B, Nam Y, Kim J, Choi H, Won C. Coffee Consumption and Stroke Risk: A Meta-analysis of Epidemiologic Studies. Korean J Fam Med. 2012;33(6):356-65. PMID: 23267421. http://www.ncbi.nlm.nih.gov/pubmed/23267421|
|129, 163, 164.||↵||Mostofsky E, Rice MS, Levitan EB, Mittleman MA. Habitual coffee consumption and risk of heart failure: a dose-response meta-analysis. Circ Heart Fail. 2012;5(4):401-5. PMID: 22740040. http://www.ncbi.nlm.nih.gov/pubmed/22740040|
|130, 154, 155, 158.||↵||Steffen M, Kuhle C, Hensrud D, Erwin PJ, Murad MH. The effect of coffee consumption on blood pressure and the development of hypertension: a systematic review and meta-analysis. J Hypertens. 2012;30(12):2245-54. PMID: 23032138. http://www.ncbi.nlm.nih.gov/pubmed/23032138|
|131, 159, 160.||↵||Zhang Z, Hu G, Caballero B, Appel L, Chen L. Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies. Am J Clin Nutr. 2011;93(6):1212-9. PMID: 21450934. http://www.ncbi.nlm.nih.gov/pubmed/21450934|
|132, 152, 157.||↵||Mesas AE, Leon-Munoz LM, Rodriguez-Artalejo F, Lopez-Garcia E. The effect of coffee on blood pressure and cardiovascular disease in hypertensive individuals: a systematic review and meta-analysis. Am J Clin Nutr. 2011;94(4):1113-26. PMID: 21880846. http://www.ncbi.nlm.nih.gov/pubmed/21880846|
|133, 149, 151.||↵||Larsson SC, Orsini N. Coffee consumption and risk of stroke: a dose-response meta-analysis of prospective studies. Am J Epidemiol. 2011;174(9):993-1001. PMID: 21920945. http://www.ncbi.nlm.nih.gov/pubmed/21920945|
|134.||↵||Wu JN, Ho SC, Zhou C, Ling WH, Chen WQ, Wang CL, et al. Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies. Int J Cardiol. 2009;137(3):216-25. PMID: 18707777. http://www.ncbi.nlm.nih.gov/pubmed/18707777|
|135, 139, 143, 145.||↵||Sofi F, Conti AA, Gori AM, Eliana Luisi ML, Casini A, Abbate R, et al. Coffee consumption and risk of coronary heart disease: a meta-analysis. Nutr Metab Cardiovasc Dis. 2007;17(3):209-23. PMID: 17156982. http://www.ncbi.nlm.nih.gov/pubmed/17156982|
|136, 153, 156.||↵||Noordzij M, Uiterwaal CS, Arends LR, Kok FJ, Grobbee DE, Geleijnse JM. Blood pressure response to chronic intake of coffee and caffeine: a meta-analysis of randomized controlled trials. J Hypertens. 2005;23(5):921-8. PMID: 15834273. http://www.ncbi.nlm.nih.gov/pubmed/15834273|
|140, 142, 144, 146.||↵||Wu JN, Ho SC, Zhou C, Ling WH, Chen WQ, Wang CL, et al. Coffee consumption and risk of coronary heart diseases: a meta-analysis of 21 prospective cohort studies. Int J Cardiol. 2009;137(3):216-25. PMID: 18707777. http://www.ncbi.nlm.nih.gov/pubmed/18707777|
|148, 150.||↵||Kim B, Nam Y, Kim J, Choi H, Won C. Coffee Consumption and Stroke Risk: A Meta-analysis of Epidemiologic Studies. Korean J Fam Med. 2012;33(6):356-65. PMID: 23267421. http://www.ncbi.nlm.nih.gov/pubmed/23267421|
|166, 171, 176, 178, 182, 186, 188, 190.||↵||Ding M, Bhupathiraju SN, Chen M, van Dam RM, Hu FB. Caffeinated and decaffeinated coffee consumption and risk of type 2 diabetes: a systematic review and a dose-response meta-analysis. Diabetes Care. 2014;37(2):569-86. PMID: 24459154. http://www.ncbi.nlm.nih.gov/pubmed/24459154|
|167, 172, 180, 184, 185.||↵||Huxley R, Lee CM, Barzi F, Timmermeister L, Czernichow S, Perkovic V, et al. Coffee, decaffeinated coffee, and tea consumption in relation to incident type 2 diabetes mellitus: a systematic review with meta-analysis. Arch Intern Med. 2009;169(22):2053-63. PMID: 20008687. http://www.ncbi.nlm.nih.gov/pubmed/20008687|
|168, 173, 177, 179, 183, 187, 189.||↵||Jiang X, Zhang D, Jiang W. Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies. Eur J Nutr. 2014;53(1):25-38. PMID: 24150256. http://www.ncbi.nlm.nih.gov/pubmed/24150256|
|169, 174, 191.||↵||Whitehead N, White H. Systematic review of randomised controlled trials of the effects of caffeine or caffeinated drinks on blood glucose concentrations and insulin sensitivity in people with diabetes mellitus. J Hum Nutr Diet. 2013;26(2):111-25. PMID: 23331476. http://www.ncbi.nlm.nih.gov/pubmed/23331476|
|170, 175, 181.||↵||van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic review. Jama. 2005;294(1):97-104. PMID: 15998896. http://www.ncbi.nlm.nih.gov/pubmed/15998896|
|193, 216.||↵||Yu X, Bao Z, Zou J, Dong J. Coffee consumption and risk of cancers: a meta-analysis of cohort studies. BMC Cancer. 2011;11:96. PMID: 21406107. http://www.ncbi.nlm.nih.gov/pubmed/21406107|
|194, 217.||↵||Tang N, Wu Y, Ma J, Wang B, Yu R. Coffee consumption and risk of lung cancer: a meta-analysis. Lung Cancer. 2010;67(1):17-22. PMID: 19362749. http://www.ncbi.nlm.nih.gov/pubmed/19362749|
|195, 218, 220.||↵||Sang LX, Chang B, Li XH, Jiang M. Consumption of coffee associated with reduced risk of liver cancer: a meta-analysis. BMC Gastroenterol. 2013;13:34. PMID: 23433483. http://www.ncbi.nlm.nih.gov/pubmed/23433483|
|196, 219.||↵||Bravi F, Bosetti C, Tavani A, Gallus S, La Vecchia C. Coffee reduces risk for hepatocellular carcinoma: an updated meta-analysis. Clin Gastroenterol Hepatol. 2013;11(11):1413-21.e1. PMID: 23660416. http://www.ncbi.nlm.nih.gov/pubmed/23660416|
|197, 221, 224, 225, 226, 227.||↵||Jiang W, Wu Y, Jiang X. Coffee and caffeine intake and breast cancer risk: an updated dose-response meta-analysis of 37 published studies. Gynecol Oncol. 2013;129(3):620-9. PMID: 23535278. http://www.ncbi.nlm.nih.gov/pubmed/23535278|
|198, 222, 228.||↵||Li XJ, Ren ZJ, Qin JW, Zhao JH, Tang JH, Ji MH, et al. Coffee consumption and risk of breast cancer: an up-to-date meta-analysis. PLoS One. 2013;8(1):e52681. PMID: 23308117. http://www.ncbi.nlm.nih.gov/pubmed/23308117|
|199, 223.||↵||Tang N, Zhou B, Wang B, Yu R. Coffee consumption and risk of breast cancer: a metaanalysis. Am J Obstet Gynecol. 2009;200(3):290.e1-9. PMID: 19114275. http://www.ncbi.nlm.nih.gov/pubmed/19114275|
|200, 229.||↵||Cao S, Liu L, Yin X, Wang Y, Liu J, Lu Z. Coffee consumption and risk of prostate cancer: a meta-analysis of prospective cohort studies. Carcinogenesis. 2014;35(2):256-61. PMID: 24343360. http://www.ncbi.nlm.nih.gov/pubmed/24343360|
|201, 230.||↵||Zhong S, Chen W, Yu X, Chen Z, Hu Q, Zhao J. Coffee consumption and risk of prostate cancer: an up-to-date meta-analysis. Eur J Clin Nutr. 2014;68(3):330-7. PMID: 24300907. http://www.ncbi.nlm.nih.gov/pubmed/24300907|
|202, 231.||↵||Discacciati A, Orsini N, Wolk A. Coffee consumption and risk of nonaggressive, aggressive and fatal prostate cancer–a dose-response meta-analysis. Ann Oncol. 2014;25(3):584-91. PMID: 24276028. http://www.ncbi.nlm.nih.gov/pubmed/24276028|
|203, 232.||↵||Park CH, Myung SK, Kim TY, Seo HG, Jeon YJ, Kim Y. Coffee consumption and risk of prostate cancer: a meta-analysis of epidemiological studies. BJU Int. 2010;106(6):762-9. PMID: 20590551. http://www.ncbi.nlm.nih.gov/pubmed/20590551|
|204, 233.||↵||Braem MG, Onland-Moret NC, Schouten LJ, Tjonneland A, Hansen L, Dahm CC, et al. Coffee and tea consumption and the risk of ovarian cancer: a prospective cohort study and updated meta-analysis. Am J Clin Nutr. 2012;95(5):1172-81. PMID: 22440851. http://www.ncbi.nlm.nih.gov/pubmed/22440851|
|205, 235, 236, 238.||↵||Je Y, Giovannucci E. Coffee consumption and risk of endometrial cancer: findings from a large up-to-date meta-analysis. Int J Cancer. 2012;131(7):1700-10. PMID: 22190017. http://www.ncbi.nlm.nih.gov/pubmed/22190017|
|206, 234, 237.||↵||Bravi F, Scotti L, Bosetti C, Gallus S, Negri E, La Vecchia C, et al. Coffee drinking and endometrial cancer risk: a metaanalysis of observational studies. Am J Obstet Gynecol. 2009;200(2):130-5. PMID: 19110217. http://www.ncbi.nlm.nih.gov/pubmed/19110217|
|207, 239.||↵||Zhou Y, Tian C, Jia C. A dose-response meta-analysis of coffee consumption and bladder cancer. Prev Med. 2012;55(1):14-22. PMID: 22564775. http://www.ncbi.nlm.nih.gov/pubmed/22564775|
|208, 240.||↵||Turati F, Galeone C, Edefonti V, Ferraroni M, Lagiou P, La Vecchia C, et al. A meta-analysis of coffee consumption and pancreatic cancer. Ann Oncol. 2012;23(2):311-8. PMID: 21746805. http://www.ncbi.nlm.nih.gov/pubmed/21746805|
|209, 241, 244.||↵||Dong J, Zou J, Yu XF. Coffee drinking and pancreatic cancer risk: a meta-analysis of cohort studies. World J Gastroenterol. 2011;17(9):1204-10. PMID: 21448427. http://www.ncbi.nlm.nih.gov/pubmed/21448427|
|210, 242, 243, 245.||↵||Turati F, Galeone C, La Vecchia C, Garavello W, Tavani A. Coffee and cancers of the upper digestive and respiratory tracts: meta-analyses of observational studies. Ann Oncol. 2011;22(3):536-44. PMID: 20943597. http://www.ncbi.nlm.nih.gov/pubmed/20943597|
|211, 246.||↵||Zheng JS, Yang J, Fu YQ, Huang T, Huang YJ, Li D. Effects of green tea, black tea, and coffee consumption on the risk of esophageal cancer: a systematic review and meta-analysis of observational studies. Nutr Cancer. 2013;65(1):1-16. PMID: 23368908. http://www.ncbi.nlm.nih.gov/pubmed/23368908|
|212, 247.||↵||Botelho F, Lunet N, Barros H. Coffee and gastric cancer: systematic review and meta-analysis. Cad Saude Publica. 2006;22(5):889-900. PMID: 16680342. http://www.ncbi.nlm.nih.gov/pubmed/16680342|
|213, 248, 251, 253.||↵||Galeone C, Turati F, La Vecchia C, Tavani A. Coffee consumption and risk of colorectal cancer: a meta-analysis of case-control studies. Cancer Causes Control. 2010;21(11):1949-59. PMID: 20680435. http://www.ncbi.nlm.nih.gov/pubmed/20680435|
|214, 249, 255.||↵||Je Y, Liu W, Giovannucci E. Coffee consumption and risk of colorectal cancer: a systematic review and meta-analysis of prospective cohort studies. Int J Cancer. 2009;124(7):1662-8. PMID: 19115212. http://www.ncbi.nlm.nih.gov/pubmed/19115212|
|215, 250, 252, 254.||↵||Li G, Ma D, Zhang Y, Zheng W, Wang P. Coffee consumption and risk of colorectal cancer: a meta-analysis of observational studies. Public Health Nutr. 2013;16(2):346-57. PMID: 22694939. http://www.ncbi.nlm.nih.gov/pubmed/22694939|
|257.||↵||Ishihara L, Brayne C. A systematic review of nutritional risk factors of Parkinson’s disease. Nutr Res Rev. 2005;18(2):259-82. PMID: 19079910. http://www.ncbi.nlm.nih.gov/pubmed/19079910|
|258, 261.||↵||Costa J, Lunet N, Santos C, Santos J, Vaz-Carneiro A. Caffeine exposure and the risk of Parkinson’s disease: a systematic review and meta-analysis of observational studies. J Alzheimers Dis. 2010;20 Suppl 1:S221-38. PMID: 20182023. http://www.ncbi.nlm.nih.gov/pubmed/20182023|
|259, 260, 262.||↵||Qi H, Li S. Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson’s disease. Geriatr Gerontol Int. 2014;14(2):430-9. PMID: 23879665. http://www.ncbi.nlm.nih.gov/pubmed/23879665|
|263, 266, 267.||↵||Arab L, Khan F, Lam H. Epidemiologic evidence of a relationship between tea, coffee, or caffeine consumption and cognitive decline. Adv Nutr. 2013;4(1):115-22. PMID: 23319129. http://www.ncbi.nlm.nih.gov/pubmed/23319129|
|264, 265.||↵||Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N. Caffeine intake and dementia: systematic review and meta-analysis. J Alzheimers Dis. 2010;20 Suppl 1:S187-204. PMID: 20182026. http://www.ncbi.nlm.nih.gov/pubmed/20182026|
|268, 269.||↵||J.G. Pallarés, V.E. Fernández-Elías, J.F. Ortega, G. Muñoz, J. Muñoz-Guerra, R. Mora-Rodríguez. Neuromuscular responses to incremental caffeine doses: performance and side effects. Med. Sci. Sports Exerc, 45 (2013), pp. 2184-2192. http://journals.lww.com/acsm-msse/Fulltext/2013/11000/Neuromuscular_Responses_to_Incremental_Caffeine.21.aspx|
|271.||↵||S. Cappelletti, P. Daria, G. Sani, M. Aromatario. Caffeine: cognitive and physical performance enhancer or psychoactive drug? Curr. Neuropharmacol., 13 (2015), pp. 71-88. http://www.eurekaselect.com/126862/article|
|273, 274.||↵||S.V. Heatherley, K.M.F. Hancock, P.J. Rogers. Psychostimulant and other effects of caffeine in 9- to 11-year-old children. J. Child. Psychol. Psychiatry Allied Discip., 47 (2006), pp. 135-142. http://onlinelibrary.wiley.com/doi/10.1111/j.1469-7610.2005.01457.x/abstract|
|275, 276.||↵||J.L. Temple, A.M. Bulkley, L. Briatico, A.M. Dewey. Sex differences in reinforcing value of caffeinated beverages in adolescents. Behav. Pharmacol., 20 (2009), pp. 731-741. http://journals.lww.com/behaviouralpharm/pages/articleviewer.aspx?year=2009&issue=12000&article=00007&type=abstract|
|277.||↵||A.L. Kristjansson, I.D. Sigfusdottir, M.J. Mann, J.E. James. Caffeinated sugar-sweetened beverages and common physical complaints in Icelandic children aged 10-12years. Prev. Med. Balt., 58 (2014), pp. 40-44.|
|278.||↵||Boekema PJ, Samsom M, van Berge Henegouwen GP, Smout AJ. Scand J Gastroenterol Suppl. 1999;230:35-9. Coffee and gastrointestinal function: facts and fiction. A review. https://www.ncbi.nlm.nih.gov/pubmed/10499460|
|279.||↵||Rao SS, Welcher K, Zimmerman B, Stumbo P. Eur J Gastroenterol Hepatol. 1998 Feb;10(2):113-8. Is coffee a colonic stimulant? https://www.ncbi.nlm.nih.gov/pubmed/9581985|
|280.||↵||Leitzmann MF, Willett WC, Rimm EB, Stampfer MJ, Spiegelman D, Colditz GA, Giovannucci E. JAMA. 1999 Jun 9;281(22):2106-12. A prospective study of coffee consumption and the risk of symptomatic gallstone disease in men. https://www.ncbi.nlm.nih.gov/pubmed/10367821|
|281.||↵||Rizkallah E, Belanger M, Stavro K, et al. Could the use of energy drinks induce manic or depressive relapse among abstinent substance use disorder patients with comorbid bipolar spectrum disorder. Bipolar Disord. 2011;13(5-6):578–580. https://www.ncbi.nlm.nih.gov/pubmed/22017226|
|282.||↵||Cauli O, Morelli M. Caffeine and the dopaminergic system. Behav Pharmacol. 2005;16(2):63–77. https://www.ncbi.nlm.nih.gov/pubmed/15767841|
|283, 286.||↵||Ogawa N, Ueki H. Secondary mania caused by caffeine. Gen Hosp Psychiatry. 2003;25(2):138–139. https://www.ncbi.nlm.nih.gov/pubmed/12676429|
|284, 287.||↵||Hedges DW, Woon FL, Hoopes SP. Caffeine-induced psychosis. CNS Spectr. 2009;14(30):127–129. https://www.ncbi.nlm.nih.gov/pubmed/19407709|
|285, 302, 304, 305.||↵||Lara DR. Caffeine, mental health and psychiatric disorders. J Alzheimers Dis. 2010;20(Suppl 1):S239–248. https://www.ncbi.nlm.nih.gov/pubmed/20164571|
|288.||↵||Carrillo JA, Benitez J. Clinically significant pharmacokinetic interactions between dietary caffeine and medications. Clin Pharmacokinet. 2000;39(2):127–153. https://www.ncbi.nlm.nih.gov/pubmed/10976659|
|289, 290.||↵||Cerimele JM, Stern AP, Jutras-Aswad D. Psychosis following excessive ingestion of energy drinks in a patient with schizophrenia. Am J Psychiatry. 2010;167(3):353. https://www.ncbi.nlm.nih.gov/pubmed/20194494|
|291, 292.||↵||Chelben J, Piccone-Sapir A, Ianco I, et al. Effects of amino acid energy drinks leading to hospitalization in individuals with mental illness. Gen Hosp Psychiatry. 2008;30(2):187–189. https://www.ncbi.nlm.nih.gov/pubmed/18291302|
|293.||↵||Tondo L, Rudas N. The course of a seasonal bipolar disorder influenced by caffeine. J Affect Disord. 1991 Aug;22(4):249–251. https://www.ncbi.nlm.nih.gov/pubmed/1939933|
|294.||↵||Tanskanen J, Puska P. Heavy coffee drinking and the risk of suicide. Eur J Epidemiol. 2000;16(9):789–791. https://www.ncbi.nlm.nih.gov/pubmed/11297219|
|295.||↵||Childs E, de Wit H. Subjective, behavioral, and physiological effects of acute caffeine in light, nondependent caffeine users. Psychopharmacology. 2006;185(4):514–523. https://www.ncbi.nlm.nih.gov/pubmed/16541243|
|296, 298.||↵||Lee MA, Flegel P, Greden JF, Cameron OG. Anxiogenic effects of caffeine on panic and depressed patients. Am J Psychiatry. 1988;145:632–635. https://www.ncbi.nlm.nih.gov/pubmed/3358468|
|297.||↵||Nardi AE, Valenca AM, Nascimento I, et al. A caffeine challenge test in panic disorder patients, their healthy first-degree relatives and healthy controls. Depress Anxiety. 2008;25(10):847–853. https://www.ncbi.nlm.nih.gov/pubmed/17823963|
|299.||↵||Bruce M, Scott N, Shine P, Lader M. Anxiogenic effects of caffeine in patients with anxiety disorders. Arch Gen Psychiatry. 1992;49(11):867–869. https://www.ncbi.nlm.nih.gov/pubmed/1444724|
|300.||↵||Nardi AE, Lopes FL, Freire RC, et al. Panic disorder and social anxiety disorder subtypes in a caffeine challenge test. Psychiatry Res. 2009;169(2):149–153. https://www.ncbi.nlm.nih.gov/pubmed/19698996|
|301, 303.||↵||Koran LM, Aboujaoude E, Gamel NN. Double-blind study of dextroamphetamine versus caffeine augmentation for treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2009;70(11):1530–5153. https://www.ncbi.nlm.nih.gov/pubmed/19573497|
|306.||↵||Kawachi I, Willett WC, Colditz GA, et al. A prospective study of coffee drinking and suicide in women. Arch Int Med. 1996;156(5):521–525. https://www.ncbi.nlm.nih.gov/pubmed/8604958|
|307.||↵||Smith AP. Caffeine at work. Hum Psychopharmacol. 2005;20(6):441–445. https://www.ncbi.nlm.nih.gov/pubmed/16106485|
|308.||↵||Haskell CF, Kennedy DO, Wesnes KA, Scholey AB. Cognitive and mood improvements of caffeine in habitual consumers and habitual non-consumers of caffeine. Psychopharmacology. 2005;179(4):813–825. https://www.ncbi.nlm.nih.gov/pubmed/15678363|
|309.||↵||Journal of Human Nutrition and Dietetics Volume 27, Issue 4, pages 342–357, August 2014. The suitability of caffeinated drinks for children: a systematic review of randomised controlled trials, observational studies and expert panel guidelines. http://onlinelibrary.wiley.com/wol1/doi/10.1111/jhn.12172/abstract|
|310.||↵||Wang, Hee Ryung; Woo, Young Sup; Bahk, Won-Myong. International Clinical Psychopharmacology: July 2015 – Volume 30 – Issue 4 – p 179–182. Caffeine-induced psychiatric manifestations: a review. http://journals.lww.com/intclinpsychopharm/Abstract/2015/07000/Caffeine_induced_psychiatric_manifestations___a.1.aspx|