Benefits and risks of caffeine and caffeinated beverages

Official reprint from UpToDate® www.uptodate.com

©2023 UpToDate®

Benefits and risks of caffeine and caffeinated beverages

Authors: Bryan Bordeaux, DO, MPH, Harris R Lieberman, PhD
Section Editor: David Seres, MD
Deputy Editor: Sara Swenson, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2023. | This topic last updated: Jul 20, 2023.

INTRODUCTION

Caffeinated coffee and tea are the most consumed, socially accepted stimulants in the world.
Approximately 90 percent of all adults in the world consume caffeine daily. In their natural
forms, coffee and tea contain several chemical components that may confer both beneficial
and adverse health effects, including caffeine and antioxidants (eg, polyphenols, catechins,
and flavonoids).

Most of the data on the health benefits and risks of caffeine are from observational studies in
which self-reported consumption of beverages and foods is associated with health outcomes.
Such studies make it difficult to identify caffeine itself as the causative agent and to exclude
residual confounding. Based on available data, there is insufficient evidence for promoting or
discouraging regular coffee and/or tea consumption. Caffeine has multiple systemic effects
on the neuropsychiatric, cardiovascular, endocrine, and gastrointestinal systems. The impact
on health may be modified by genetic factors, age, sex, medications, and other
environmental exposures.

This review will focus on the effects of caffeine and caffeinated beverages on specific disease
processes, including insulin resistance, cancer, and all-cause mortality. The specific effects of
caffeine on the cardiovascular system, as well as the effects of caffeine on pregnancy, are
discussed separately. (See "Cardiovascular effects of caffeine and caffeinated beverages" and
- Page 1 of 32 -
Benefits and risks of caffeine and caffeinated beverages

"Nutrition in pregnancy: Dietary requirements and supplements".)

CONSUMPTION

Safe levels — For most adults, consumption of up to 400 mg of caffeine a day appears to be

safe [1-3]. A list of commonly consumed caffeinated beverages and average caffeine content
is shown in the table ( table 1).

Limited data are available about safe levels of caffeine consumption in children and
adolescents. A systematic review found that intake of 2.5 mg caffeine/kg of body weight per
day is not associated with adverse effects [3]. Young adults need to be cautioned about using
caffeinated energy drinks in excess and not mixing them with other substances. (See
'Dependence and abuse' below.)

Coffee and tea

● Coffee – More than 150 million people in the United States drink coffee on a daily basis,
making it an important environmental exposure. Coffee is preferred over tea in the
developed countries, particularly in Europe (except in England and Ireland), Australia,
and the Americas. The developed world accounts for 71.5 percent of worldwide coffee
consumption [4].The average United States adult's coffee consumption is approximately
two cups per day, which is the equivalent of approximately 280 mg of caffeine, although
coffee varies greatly in caffeine content ( table 1). Individuals who consume four or
more cups of coffee daily are considered by some investigators to be heavy coffee users
[5]. In the United States, coffee consumption is higher among males than females, and
among smokers than nonsmokers, but much lower in African Americans compared with
White Americans [6,7].

● Tea – Tea consumption in the United States is increasing and varies greatly by type of
tea. In the United States, 87 percent of total tea consumption is black tea and 12.5
percent is green tea, with the remainder coming from oolong and herbal teas [8]. Tea is
preferred over coffee in Asia and in the Southern Cone (Argentina, Chile, Paraguay, and
Uruguay), accounting for 76.6 percent of worldwide tea consumption [4]. Tea is second

- Page 2 of 32 -
Benefits and risks of caffeine and caffeinated beverages

only to water in worldwide beverage consumption, with the overall quantity of tea
consumed being three times greater than coffee [4]. The range of caffeine in tea varies
( table 1).

● Additives – Coffee and black tea are often consumed with cream, sugar, and/or milk.
Non-dairy creamers often contain partially hydrogenated oils and, when used in large
amounts, could be a significant dietary source of trans-fatty acids [9]. Added sugar may
contribute to the dietary glycemic load and thus negate some of the potential benefits
of caffeinated beverages [10]. Sugar and nondairy creamer may also reduce the
antioxidant concentrations of these beverages [11]. It is unclear whether milk or other
additives alter the effects of coffee or tea on disease endpoints. A prospective cohort
study of the relationship between tea consumption and mortality found a modest
association between tea intake and all-cause mortality that was most consistent among
those who drank tea with added milk but not sugar [12].

Soft drinks — Caffeinated soft drinks are another significant source of caffeine intake
( table 1), particularly in children. Some soft drinks that are not typically associated with
caffeine by the public do contain it, such as some lemon-lime and orange-flavored soft drinks.

Energy drinks and "shots" — Energy beverages and “shots” are other forms of caffeine-
containing beverages. Energy drinks typically contain about 100 to 200 mg of caffeine per
serving, although some contain more. Male adolescents and young adults are the typical
consumers [13]. Energy shots contain particularly high levels of caffeine (about 200 mg) given
their small serving size. Consumption of caffeinated energy drinks and reports of caffeine
toxicity from abusing energy drinks, especially in the male adolescent population, have
increased from 2004 to 2010 [13]. Hundreds of different brands of caffeinated energy
beverages exist, with caffeine content varying from 50 to over 500 mg per can or bottle [14].
Case studies of serious adverse events in adults (eg, atrial fibrillation and seizures) from
caffeinated energy drinks have observed that total doses of caffeine consumed per day by
individuals were more than 480 mg [15]. (See "Cardiovascular effects of caffeine and
caffeinated beverages", section on 'Other arrhythmias'.)

Other forms — Caffeine is also as an over-the-counter drug and is frequently added to

certain types of dietary supplements. Some supplements, especially those for workouts or
- Page 3 of 32 -
Benefits and risks of caffeine and caffeinated beverages

weight loss, are associated with various adverse events reported to the US Food and Drug
Administration (FDA). Caffeine is often a common ingredient in them and some of the
cardiovascular adverse effects could be due to high doses of caffeine in the supplements [16].
However, due to the nature of the FDA’s reporting system, these adverse events cannot be
definitively attributed to caffeine [17]. (See "Nutritional and non-medication supplements
permitted for performance enhancement", section on 'Caffeine'.)

Powdered caffeine is 100 percent caffeine and can lead to accidental overdose [18]. Small
amounts of caffeine can also be found in chocolate and coffee-flavored ice cream ( table 1).

CAFFEINE METABOLISM

Caffeine is rapidly absorbed in the gastrointestinal tract and undergoes demethylation in the
liver via the enzyme cytochrome P450 1A2 (CYP1A2) [19,20]. Defects in the CYP1A2 enzyme
are associated with impaired caffeine metabolism and prolonged caffeine half-life [20].
Genetic polymorphisms in the CYP1A2 pathway may in part explain inconsistencies in studies
of coffee and its effects on health.

Caffeine physiology — Caffeine is a potent antagonist of central and peripheral nervous

system adenosine receptors, thereby stimulating the release of excitatory neurotransmitters
[21]. The behavioral effects of caffeine are attributed to its effects on adenosine receptors
[22].

In addition to caffeine, other compounds in coffee and tea have pharmacologic effects.
Recognized components include:

● Chlorogenic acid, found in both coffee and black tea, raises homocysteine
concentrations in plasma [23,24]. In addition, polyphenols in coffee such as caffeic acid
and chlorogenic acid inhibit DNA methylation in a dose-dependent manner, which
prevents downregulation of tumor suppressor proteins and DNA repair enzymes
involved in carcinogenesis [25].

● Diterpenoids in unfiltered coffee may raise plasma low-density lipoprotein (LDL)

cholesterol and lower high-density lipoprotein (HDL) cholesterol [26].
- Page 4 of 32 -
Benefits and risks of caffeine and caffeinated beverages
● Induction of detoxifying enzymes (eg, glutathione S-transferase) that protect against
oxidative insults has been identified in vitro studies with rat liver cells exposed to coffee
[27].

● Unidentified compounds in coffee, other than caffeine, activate the sympathetic system
and may increase blood pressure [28]. This effect is brief and occurs primarily in non-
habitual coffee drinkers.

● Several other antioxidants in coffee, cocoa, and teas may contribute to beneficial effects
[29,30]. Antioxidants do pass through coffee filters.

Caffeine-drug interactions — Although there are data showing that the intake of coffee or
its constituent products interferes with absorption and metabolism of dietary and
pharmacologic products, the available evidence is generally from small studies.

Acebrophylline, doxofylline, and stiripentol have strong interactions with caffeine, and
patients taking these medications should completely avoid caffeine-containing products.
There are weaker interactions between caffeine and many more commonly prescribed drugs
including atomoxetine, bupropion, ciprofloxacin, clozapine, linezolid, lithium, and tizanidine;
moderate caffeine consumption (the equivalent of 1 to 2 cups of coffee per day) is unlikely to
lead to serious drug interactions, but prescribers should use caution when prescribing these
medications to higher caffeine consumers.

In addition, coffee can decrease the absorption of alendronate [31,32] and iron [33,34].

SPECIFIC HEALTH EFFECTS

Caffeine's physiologic and behavioral effects are dose dependent, and research on caffeine
must be interpreted with this in mind. In addition, epidemiologic studies of caffeine may be
confounded by several variables: healthy individuals are more likely to use caffeine than
unhealthy persons, and caffeine use is highly correlated with tobacco use, so tobacco use
should be carefully controlled and measured in both epidemiologic and experimental studies.

Cognitive/neuropsychiatric — Caffeine has been shown to influence cognition and mood,

- Page 5 of 32 -
Benefits and risks of caffeine and caffeinated beverages

both acutely and chronically [21]. Its effects, however, vary depending on the study
population and the amount and duration of caffeine consumed. In rested individuals, caffeine
in low and moderate doses, approximately 30 to 300 mg, improves vigilance and reaction
time [35-39]. In sleep-deprived individuals, caffeine's positive effects generalize to a wide
variety of functions, including learning and decision-making and real-world activities such as
automobile and aircraft operation [22,40-43]. Individuals who are habitual consumers of
coffee and tea perform better on various tests of cognitive performance, such as reaction
time and visuospatial reasoning [44].

Alertness — Caffeine consumption leads to increased alertness, mental energy, and ability

to concentrate, particularly when subjects are fatigued or working at night [45-47]. This is
probably the fundamental reason why so many humans regularly consume caffeine.

Caffeine mitigates the adverse effects of sleep deprivation on a wide variety of cognitive
functions [22,38,48,49]. A systematic review of 13 randomized trials of persons with jet lag or
shift work disorder found that caffeine significantly improved concept formation, reasoning,
memory, orientation, attention, and perception when compared with placebo [50]. Caffeine
was also found to be better than placebo in preventing errors and was similarly effective in
comparison to other active interventions such as using modafinil or bright light.

Headache — Caffeine has significant pharmacologic properties that can alleviate or

generate headache symptoms. Caffeine has long been used for its analgesic properties in the
treatment of headache and is frequently used alone or in combination with other
medications. Randomized trials have found that combination medications that include
caffeine (aspirin, acetaminophen, and caffeine) are more effective for tension and migraine
headaches than acetaminophen or low-dose ibuprofen alone [51,52]. (See "Tension-type
headache in adults: Acute treatment", section on 'Combination analgesics with caffeine' and
"Acute treatment of migraine in adults".)

Habitual caffeine consumption is associated with chronic migraine and analgesic rebound
headache. In a case-control study, patients with daily caffeine consumption were more likely
to have chronic migraines (odds ratio [OR] 2.9, 95% CI 1.5-5.3) and analgesic rebound
headaches (OR 2.2, 95% CI 1.2-3.9) than patients who did not regularly consume caffeine [53].
Headaches are the most common symptom of caffeine withdrawal. (See 'Caffeine withdrawal'
- Page 6 of 32 -
Benefits and risks of caffeine and caffeinated beverages

below and "Medication overuse headache: Etiology, clinical features, and diagnosis".)

Parkinson disease — The relationship between coffee or tea and the risk of Parkinson
disease has been described in several studies [54-56]. A meta-analysis found evidence of a
dose-response relationship between coffee or tea intake and decreased risk for Parkinson
disease [56]. The mechanism of how caffeine might protect against Parkinson disease is not
known.

This apparent protective effect is not observed in females who are taking postmenopausal
hormone therapy, in whom caffeine seems to increase the risk for Parkinson disease,
suggesting interactions between coffee and hormone use [57,58]. Among postmenopausal
hormone users in the Nurses' Health Study, high intake of coffee (≥6 cups) was associated
with a fourfold increased risk of Parkinson disease [58].

Alzheimer disease — There are very few studies examining the relationship between coffee
and Alzheimer disease. In a pooled analysis of two cohort and two case control studies on
coffee and Alzheimer disease, coffee consumption was associated with a small protective
effect against Alzheimer disease (relative risk [RR] 0.70, 95% CI 0.55-0.90) [59]. These findings
are supported by data from Alzheimer transgenic mice in which supplementation with
caffeine was associated with lower or delayed risk of Alzheimer disease [60].

Psychiatric — Caffeine intake is associated with a wide range of psychiatric symptoms and

disorders, but there is no evidence of causality. Acute caffeine intake is associated with
anxiety, nervousness, insomnia, irritability, and even panic attacks in healthy volunteers
[61,62]. Patients with preexisting anxiety disorders may be more susceptible to the
anxiogenic effects of caffeine [63]. In one United States study of over 3600 adult twins,
caffeine intake was associated with increased prevalence of generalized anxiety disorder,
depression, panic disorder, antisocial behavior, and substance abuse, particularly for those
with heavy caffeine intake (>5 cups of coffee per day) [64]. After controlling for genetic and
environmental factors, the association between psychiatric disorders and caffeine was
nonsignificant. By contrast, a prospective cohort study of >50,000 females free of depressive
symptoms found that increasing caffeinated coffee consumption was associated with a
decreased risk of incident depression in a dose-dependent fashion (RR 0.80, 95% CI 0.68-0.95,
≥4 compared with ≤1 cup per day) [65]. In this study, decaffeinated coffee was not associated
- Page 7 of 32 -
Benefits and risks of caffeine and caffeinated beverages

with incident depression.

Cardiovascular — Low to moderate coffee consumption (up to three cups per day) may
protect against myocardial infarction. Heavy coffee intake may trigger coronary and
arrhythmic events in susceptible individuals, although coffee intake is not considered a long-
term risk factor for myocardial disease. Drinking two or more cups per day of tea may also be
associated with a lower risk of cardiovascular mortality. The association between caffeinated
beverages and cardiovascular disease is discussed in detail separately. (See "Cardiovascular
effects of caffeine and caffeinated beverages".)

Endocrine — Caffeine consumption is associated with a reduced risk of diabetes, although

causality has not been established. (See "Type 2 diabetes mellitus: Prevalence and risk
factors".)

Insulin resistance — The evidence for the effects of caffeine consumption on glucose

metabolism is mixed. Although short-term studies have shown that the acute administration
of caffeine can induce insulin resistance and impaired glucose tolerance [66-68], several
prospective long-term studies have shown that consumption of coffee or tea is associated
with improved insulin sensitivity and better control of postprandial glycemia in patients with
diabetes [10,69-75]. However, in a randomized trial including 126 overweight Chinese,
Malaysian, and Indian adults, consumption of four cups of coffee daily for 24 weeks had no
effect on insulin sensitivity or fasting blood glucose compared with placebo [76].

Several mechanisms have been proposed to explain how caffeine might influence glucose
metabolism, including:

● Increased intake of caffeinated coffee is associated with an increase in plasma

adiponectin concentration, which leads to decreased insulin resistance [77].

● Caffeinated, but not decaffeinated, coffee is associated with increased sex hormone
binding globulin levels in plasma [78], which modulate the biologic effects of sex
hormones (testosterone and estrogen) on peripheral tissues and glucose homeostasis
[79].

● Caffeine acutely activates 5' adenosine monophosphate-activated protein kinase and

- Page 8 of 32 -
Benefits and risks of caffeine and caffeinated beverages

insulin-independent glucose transport in skeletal muscle [80].

● Long-term caffeine consumption upregulates insulin-like growth factor 1 signaling,

which in turn enhances insulin sensitivity as well as insulin secretion in a rat model [81].

Type 2 diabetes mellitus — There is a dose-dependent inverse association between

consumption of coffee (both caffeinated and decaffeinated) or tea and risk of type 2 diabetes
[82]. Decaffeinated coffee is also associated with lower hemoglobin A1c (A1C) concentrations
[83]. This is discussed in detail separately. (See "Type 2 diabetes mellitus: Prevalence and risk
factors".)

Gastrointestinal

Constipation — Caffeine is a potent stimulator of smooth muscles and thus might have an

impact on bowel function. In an observational study of 1705 females, coffee consumption was
associated with a modest decrease in constipation [84]. In the same study, however,
consumption of Chinese and Japanese tea was associated with an increased incidence of
constipation, suggesting that other components in the tea mitigated the effect of caffeine on
smooth muscle stimulation.

Cirrhosis — Coffee consumption has been associated with a decreased risk for cirrhosis. In a
meta-analysis including 16 observational studies, compared with nondrinkers, coffee drinkers
were less likely to develop cirrhosis (OR 0.61, 95% CI 0.45-0.84) [85].

Regular coffee consumption was also associated with a lower rate of disease progression in
patients with advanced hepatitis C infection. (See "Clinical manifestations and natural history
of chronic hepatitis C virus infection".)

Cancer — Despite a 2018 ruling by a California court requiring that coffee be labeled as

containing a cancer-causing agent, this recommendation is premature. While roasted coffee
contains acrylamide, a known carcinogen in animals, most human data suggest that there is
no association of coffee or other caffeinated beverages with any type of cancer [86-88].
Coffee and tea may reduce the risk of cancer because of their antioxidant properties,
although the data are inconsistent. In addition, a systematic review found conflicting evidence
for the association of green tea and prostate, gastrointestinal, breast, lung, ovarian, and
- Page 9 of 32 -
Benefits and risks of caffeine and caffeinated beverages

bladder cancer.

Breast cancer — The relationship between caffeine consumption and breast cancer is

uncertain. While some studies suggest a lower risk for breast cancer with coffee
consumption, this finding was not observed in all studies, and there are no randomized trials.

● In a matched case-control study of 1690 females with a BRCA1 or BRCA2 mutation,

coffee intake was associated with 69 percent lower risk for breast cancer [89].

● In another case-control study of 1932 cases of incident breast cancer and 1895 hospital-
based controls, consumption of caffeinated coffee was associated with 40 percent lower
risk for breast cancer [90]. No adverse or protective effects were reported for black tea
or decaffeinated beverages in these studies.

● In the French vitamin supplementation study of 4396 cancer-free females at baseline,

herbal tea but not coffee or black tea was associated with a decreased risk for breast
cancer after an average of 6.6 years of follow-up [91].

● In a prospective cohort from the Women's Health Study, there was no association
between breast cancer and intakes of coffee, tea, caffeinated cola, chocolate, or
decaffeinated beverages [92].

Lung cancer — Meta-analyses suggest that caffeinated coffee is associated with an

increased risk for lung cancer [93], while decaffeinated coffee [93] and green tea [94] are
associated with a decreased risk. However, the association for nonsmokers between coffee
and lung cancer became only marginally significant when the analysis was stratified by
smoking status. The authors stated that the results should be interpreted with caution due to
confounding by smoking.

● In a meta-analysis of five prospective and eight case-control studies, coffee

consumption was associated with an increased risk of lung cancer (RR 1.27, 95% CI 1.04-
1.54) [93].

● The same meta-analysis reported that decaffeinated coffee consumption was associated
with decreased lung cancer risk in data from two available studies (RR 0.66, 0.54-0.81)

- Page 10 of 32 -
Benefits and risks of caffeine and caffeinated beverages

[93].

● In a meta-analysis of eight prospective cohort studies and 14 retrospective case-control

studies, there was a borderline significant association between green tea consumption
and reduced risk of lung cancer (RR 0.78, 95% CI 0.61-1.00) [94]. There was no
statistically significant association for black tea (RR 0.86, 0.70-1.05).

Gastrointestinal cancer — Observational studies have found that coffee consumption may

be associated with a decreased risk of gastrointestinal cancers, particularly oropharyngeal
and hepatic cancer. Confounding and reverse causation are always possible in such studies.

● Oropharyngeal cancer – A meta-analysis of one cohort and eight case-control studies

found that coffee consumption was associated with a lower risk of cancers of the oral
cavity and pharynx (RR 0.64, 95% CI 0.51-0.80) [95].

● Hepatocellular carcinoma – Several observational studies have found coffee

consumption to be a protective factor against liver cancer, including hepatocellular
carcinoma. This is discussed in detail elsewhere. (See "Epidemiology and risk factors for
hepatocellular carcinoma".)

● Colorectal cancer – Observational studies have found conflicting evidence on the

relationship between coffee consumption and risk of colorectal cancer (CRC). A link
between high rates of coffee consumption and a reduced risk of CRC has been noted in
some reports but not others. (See "Colorectal cancer: Epidemiology, risk factors, and
protective factors", section on 'Coffee intake'.)

Endometrial cancer — An association between caffeine consumption and endometrial

cancer risk is questionable. A 2015 meta-analysis of 16 observational studies found that
coffee consumption was associated with decreased risk of endometrial cancer [96]. The meta-
analysis examined prospective and retrospective studies and identified a greater decrease in
the latter (for each cup of coffee, prospective studies RR 0.96, 95% CI 0.95-0.98, retrospective
studies RR 0.91, 95% CI 0.87-0.95). An older meta-analysis also found a risk reduction, with an
apparent dose relationship (compared with nondrinkers, RR 0.87, 95% CI 0.78-0.97 for low to
moderate coffee consumption and 0.64, 95% CI 0.48-0.86 for heavy coffee consumption) [97].
A 2015 meta-analysis of 12 observational studies of tea consumption did not find an
- Page 11 of 32 -
Benefits and risks of caffeine and caffeinated beverages

association with endometrial cancer risk (RR 0.97, 95% CI 0.93-1.01) [96]. Findings of the
above meta-analyses are limited by heterogeneity of main study results, as well as lack of
adjustment for reproductive and menstrual variables, which can be risk factors for
endometrial cancer.

Ovarian cancer — A meta-analysis of 11 prospective cohort studies (five of coffee drinking,

six of tea drinking) found no association between coffee or tea drinking and risk of epithelial
ovarian cancer (hazard ratios [HRs] 1.13, 95% CI 0.89-1.43 and 0.88, 95% CI 0.71-1.09,
respectively) [98].

Bladder cancer — Previous studies examining caffeine consumption and urinary tract

cancers found a small increase in bladder cancer risk among coffee drinkers [99]. However,
there is no relationship with caffeine dose, indicating the relationship may not be causal.
Furthermore, the association between coffee consumption and increased risk of bladder
cancer has been partly attributed to concomitant smoking among coffee drinkers [100,101].

Prostate cancer — Both coffee and green tea consumption are associated with a dose-
dependent reduction in risk of prostate cancer [102-105].

A prospective analysis of almost 48,000 males from the Health Professionals Follow-up Study
identified 5035 individuals with confirmed prostate cancer, including 642 who died or had
metastatic disease over a 20-year period [106]. Men who consumed six or more cups of coffee
per day had a lower risk of prostate cancer compared with nondrinkers (RR 0.82, 95% CI 0.68-
0.98). Coffee consumption was also associated with a dose-dependent reduction in risk of
fatal or metastatic prostate cancer. The inverse relationship appeared to be related to coffee
components other than caffeine as a similar level of protection was seen for those drinking
caffeinated and decaffeinated coffee.

One prospective cohort study of nearly 50,000 Japanese males identified 404 cases of
prostate cancer over more than 10 years of follow-up [102]. Green tea consumption was
associated with a dose-dependent reduction in risk of advanced prostate cancer (RR 0.52, 95%
CI 0.28-0.96) in those drinking five or more cups of green tea per day, compared with less
than one cup per day.

Musculoskeletal
- Page 12 of 32 -
Benefits and risks of caffeine and caffeinated beverages

Osteoporosis — Data suggest that high coffee intake may be associated with lower bone
mineral density and increased fracture risk in females, particularly those with low calcium
intake.

Several longitudinal studies have found an inverse correlation between caffeine intake and
bone density for at least some females [107-109]. One cohort study in older females (70 to 73
years) found that consumption of five or more cups of coffee per day was associated with
decreased bone mineral density only among lean females [109]. Another study found no
effect of caffeine on bone density for females whose calcium intake was at least 800 mg daily,
but there was an inverse correlation for females with lower calcium intake [108]. Similar to
results in bone mineral density, studies examining osteoporotic fractures demonstrate no to
modestly increased risk of fracture with high caffeine intake [110-113]. (See "Osteoporotic
fracture risk assessment".)

Tea consumption, on the other hand, was associated with higher bone density in several
studies [114-116], although this increased bone density did not decrease fracture risk [113]. It
is postulated that higher flavonoids in tea, compared with coffee, may be responsible for the
preservation of bone mineral.

Arthritis — Although one study suggested an increased risk for rheumatoid arthritis for
people who drank four cups of decaffeinated coffee daily [117], several large studies have not
found an association between caffeinated coffee consumption and rheumatoid arthritis
[118,119].

There was a strong inverse association between coffee intake and serum uric acid and
hyperuricemia [120]. In a 12-year prospective study of 45,869 males without a history of gout,
coffee consumption was inversely associated with incidence of gout in a dose-dependent
manner [121]. A similar relationship was observed for decaffeinated coffee, but not tea.

Urinary frequency and incontinence — Caffeine intake is associated with increased urinary

frequency and volume [122], while caffeine reduction has been shown to reduce urgency and
frequency [123]. However, the diuretic property of caffeine was not demonstrated in one
study in which controlled caffeine intake over a four-day period did not impact measures of
urine osmolality or volume [124]. Higher caffeine intake may also be associated with
- Page 13 of 32 -
Benefits and risks of caffeine and caffeinated beverages

increased incidence of urgency incontinence, but not stress or mixed incontinence [125].

Athletic performance enhancement — The performance-enhancing effects of caffeine have

been demonstrated across a wide range of athletic activities [126]. These include endurance
events, stop-and-go events, and high-intensity, short-duration activities. The beneficial effects
of caffeine supplementation on athletic performance are discussed in detail elsewhere. (See
"Nutritional and non-medication supplements permitted for performance enhancement",
section on 'Caffeine'.)

MORTALITY

All-cause mortality — Many, but not all, observational studies show an inverse relationship
between coffee or tea consumption and all-cause mortality [2,12,127-137]. A possible
explanation for these observations is that healthy individuals are more likely to select and
have access to caffeine-containing beverages than those who are ill.

● Coffee – The association of coffee consumption with lower mortality rates exhibits a
dose-response relationship in some studies [132,138,139]. As an example, a 2014 meta-
analysis of 18 prospective studies found that consuming four cups of coffee a day was
associated with a 16 percent decreased risk of all-cause mortality [86]. The largest study
in the meta-analysis was the National Institutes of Health-AARP Diet and Health Study,
which involved over 229,000 males and 173,000 females followed for up to 13 years
[131]. After adjustment for smoking status and other potential confounders, there was a
decreased risk of all-cause mortality for those who consumed two to three cups of
coffee a day (relative risk [RR] 0.90 in males and 0.87 in females). The apparent benefit of
coffee was similar for individuals with high levels of coffee consumption, including those
who drank six or more cups of coffee per day.

However, some studies have reported different results. An association of coffee with
decreased mortality was not seen in a study of caffeinated coffee consumption among
females with known cardiovascular disease from the Nurses' Health Study, in which
caffeine intake was not associated with either all-cause or cardiovascular mortality [140].
Additionally, in the Aerobics Center Longitudinal Study including 43,727 participants
- Page 14 of 32 -
Benefits and risks of caffeine and caffeinated beverages

followed for a median of 17 years, consuming more than twenty-eight cups of

caffeinated coffee per week was associated with increased all-cause mortality in men
and women younger than age 55 (hazard ratio [HR] 1.56 and 2.13, respectively) [5].

● Tea – A study of almost 500,000 individuals in the United Kingdom showed a modest
relationship between drinking two or more cups of tea per day and a lower risk of all-
cause mortality at a median follow-up of 11.2 years [12]. The association persisted after
adjustment for multiple risk factors, including smoking, self-reported health status, and
genetic variation in caffeine metabolism. Most participants (89 percent) drank black tea;
seven percent drank green tea. The association was most consistent among participants
who reported drinking tea with added milk or not adding sugar to their tea.  

Cardiovascular mortality — The association of caffeine and caffeinated beverages with

cardiovascular mortality is presented elsewhere. (See "Cardiovascular effects of caffeine and
caffeinated beverages", section on 'Mortality'.)

CAFFEINE DEPENDENCE, ABUSE, AND WITHDRAWAL

Many individuals use caffeine regularly to maintain their active, busy lifestyles, since caffeine
enhances mental performance and mood [141].

Adverse effects of excessive caffeine — Excessive caffeine intake can have several adverse
effects. In one observational study of 217 individuals (median age 17) who contacted a poison
control center after use of caffeinated energy drinks, common nonserious adverse effects
included palpitations, tremor, agitation, and gastrointestinal upset [13]. Less commonly,
individuals demonstrated serious neurologic or cardiac signs (arrhythmias, ischemia,
seizures, hallucinations). More than 125 were hospitalized for adverse effects, and of these 57
consumed caffeinated energy drinks alone.

Dependence and abuse — Caffeine use disorder is identified as a research diagnosis in the

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; eg, meant to
encourage studies but not be used in clinical settings) but does not meet full criteria for
dependence or abuse [142]. Abuse implies that the pattern of use interferes with normal life

- Page 15 of 32 -
Benefits and risks of caffeine and caffeinated beverages

patterns. Although the terms "caffeine dependence" and "caffeine abuse" are used frequently
in the literature, clinical indicators of dependence and abuse have not been conclusively
demonstrated [143,144].

Dependence is generally diagnosed for patients who meet three or more of the following
criteria:

● Tolerance
● Withdrawal
● Substance taken in larger quantity than intended
● Persistent desire to cut down or control use
● Time is spent obtaining, using, or recovering from the substance
● Social, occupational, or recreational tasks are sacrificed
● Use continues despite physical and psychological problems

Difficulty stopping caffeine intake and ongoing caffeine use despite harm have not been well
documented [144]. Several case studies demonstrate that high caffeine intake can lead to
dependence in a manner similar to other psychoactive substances [145]. It has also been
reported that clinicians are frequently unaware of patients who may have elements of
caffeine abuse, leading to emergency department visits and hospitalization [146].

Mechanisms leading to heavy coffee use are unknown. Data from animal studies suggest that
the psychostimulatory effects of caffeine may occur through blockade of the A2A adenosine
receptor and weak activation of extracellular signal-regulated kinase (ERK) in the striatum
[147]. This would be consistent with the finding that individuals homozygous for the variant
allele (T) in the adenosine receptor A2A gene are less likely to consume large amounts of
coffee [148].

Heavy caffeine use is associated with increased risk for other addictive behaviors, including
tobacco and alcohol abuse, as illustrated by the following studies:

● The proportion of current smokers is significantly higher (43 versus 12 percent) among
Costa Ricans who consumed four or more cups of coffee per day compared with less
than one cup per day [20]. Findings were similar for a prospective Finnish study, in which
the proportion of smokers was higher (30 versus 3 percent) for people who consumed
- Page 16 of 32 -
Benefits and risks of caffeine and caffeinated beverages

more than seven cups of coffee daily, compared with those who drank one to two cups.

● In the Nurses' Health Study, alcohol consumption was 50 percent higher among females
who drank six or more cups per day compared with those who consumed less than one
cup per day [130]. In the Health Professionals Follow-up Study, alcohol consumption was
doubled among males who drank six or more cups per day compared with those who
consumed less than one cup per day [130].

● In a survey of high school students in Italy, caffeine use was associated with alcohol use,
gambling, internet addiction, and illicit substance abuse [149].

● In young adults, caffeinated energy drinks are sometimes mixed with alcohol [14],
perhaps due in part to the belief that caffeine counteracts alcohol's sedative effects.
However, this may be erroneous. For example, in one randomized trial of 127 adults
(ages 21 to 30), adding caffeine to alcohol did not improve driving performance,
measured by a driving simulator and performance of sustained attention/reaction times
on the Psychomotor Vigilance Task (PVT) [150].

Caffeine withdrawal — Although there has been some question raised about the existence
of a caffeine withdrawal syndrome based upon nonrandomized trials, subsequent
randomized trials do support the existence of a caffeine withdrawal syndrome [151]. A
genetic propensity for caffeine withdrawal has been shown in studies comparing
monozygotic and dizygotic twins [152].

A comprehensive review of caffeine withdrawal validated 10 symptom categories [151]:

● Headache
● Tiredness/fatigue
● Decreased energy/activeness
● Decreased alertness/attentiveness
● Drowsiness/sleepiness
● Decreased contentedness/wellbeing
● Depressed mood
● Difficulty concentrating
● Irritability
- Page 17 of 32 -
Benefits and risks of caffeine and caffeinated beverages
● Fuzzy/foggy/not clearheaded

Flu-like symptoms, nausea, and muscle pain may also be experienced. Headache is the most
common symptom (50 percent incidence). Caffeine withdrawal can occur with abstinence
from daily doses as low as 100 mg per day, but the incidence and severity of symptoms
increases with higher daily dose [151]. Withdrawal symptoms typically occur within 12 to 24
hours after discontinuing caffeine, peak at one to two days, and may persist for up to nine
days. The minimum duration of caffeine maintenance leading to withdrawal symptoms is
three days. Readministration of caffeine has been shown to rapidly reverse withdrawal
symptoms within 30 to 60 minutes.

When caffeine abstinence in a chronic caffeine user is necessary (eg, prior to an elective
medical procedure), we suggest a gradual reduction in caffeine intake over the week
preceding the planned abstinence. However, in experimental studies, only 50 percent of
individuals acutely abstaining from caffeine experience withdrawal symptoms [151].
Therefore, if an unplanned abstinence occurs (eg, in an emergent procedure), caffeine
replacement is not indicated.

SUMMARY AND RECOMMENDATIONS

● Caffeine is the most consumed stimulant in the world, usually in the form of coffee and
tea. Based on available data, there is insufficient evidence for promoting or
discouraging coffee and/or tea consumption in the daily diet. (See 'Introduction' above.)

● For the majority of healthy adults, consuming less than 400 mg of caffeine a day
appears to be safe ( table 1). In children and adolescents, consumption of less than
2.5 mg/kg per day appears to be safe. Individuals, especially adolescents, need to be
cautioned about excessive caffeine intake and mixing caffeine with alcohol and other
drugs. (See 'Consumption' above.)

● Consumption of caffeinated beverages is associated with some short-term benefits,

including increased mental alertness; improvements in certain aspects of cognitive
performance, especially vigilance and reaction time; and improved athletic performance.

- Page 18 of 32 -
Benefits and risks of caffeine and caffeinated beverages

Caffeine, in moderate doses, mitigates many of the adverse effects of sleep deprivation
and jet lag on cognitive performance and mental alertness. (See 'Alertness' above and
"Nutritional and non-medication supplements permitted for performance
enhancement", section on 'Caffeine'.)

● Consumption of high levels of caffeine can be associated with short-term adverse

effects, including headache, anxiety, tremors, and insomnia, depending on prior
patterns of caffeine use. Chronic users are less sensitive to the adverse behavioral
effects of caffeine than non-users. In the long term, caffeine is also associated with
generalized anxiety disorder and substance abuse disorders, although causality has not
been established. (See 'Cognitive/neuropsychiatric' above.)

● Possible long-term benefits of caffeinated beverages are dose dependent. Caffeine is

associated with a reduced risk of Parkinson disease, Alzheimer disease, alcoholic
cirrhosis, and gout. Both caffeinated and decaffeinated coffee are also associated with a
lower risk of type 2 diabetes. (See 'Specific health effects' above.)

● Although several studies have linked coffee consumption with increase or decrease in
risk of various cancers, definitive data are lacking. (See 'Cancer' above.)

● Heavy coffee intake may trigger coronary and arrhythmic events in susceptible
individuals, although coffee intake is not considered a long-term risk factor for
myocardial disease. (See "Cardiovascular effects of caffeine and caffeinated beverages".)

● The majority of studies show that there may be a modest inverse relationship between
coffee and tea consumption and all-cause mortality. (See 'Mortality' above.)

● Although the existence of caffeine dependence and abuse are controversial, caffeine
withdrawal is a well-documented clinical syndrome, with headache being the most
common symptom. (See 'Caffeine dependence, abuse, and withdrawal' above.)

ACKNOWLEDGMENTS

The author and editorial staff at UpToDate, Inc. thank Edmond Kabagambe, DVM, MS, PhD

- Page 19 of 32 -
Benefits and risks of caffeine and caffeinated beverages

and Melissa Wellons, MD, MHS for their contributions to previous versions of this topic.

REFERENCES

1. Heckman MA, Weil J, Gonzalez de Mejia E. Caffeine (1, 3, 7-trimethylxanthine) in foods: a

comprehensive review on consumption, functionality, safety, and regulatory matters. J
Food Sci 2010; 75:R77.

2. Poole R, Kennedy OJ, Roderick P, et al. Coffee consumption and health: umbrella review
of meta-analyses of multiple health outcomes. BMJ 2017; 359:j5024.

3. Wikoff D, Welsh BT, Henderson R, et al. Systematic review of the potential adverse effects
of caffeine consumption in healthy adults, pregnant women, adolescents, and children.
Food Chem Toxicol 2017; 109:585.

4. Grigg D. The worlds of tea and coffee: Patterns of consumption. Geojournal 2002; 57:283.
5. Liu J, Sui X, Lavie CJ, et al. Association of coffee consumption with all-cause and
cardiovascular disease mortality. Mayo Clin Proc 2013; 88:1066.

6. Lieberman HR, Stavinoha T, McGraw S, et al. Caffeine use among active duty US Army
soldiers. J Acad Nutr Diet 2012; 112:902.

7. Ettinger B, Sidney S, Cummings SR, et al. Racial differences in bone density between
young adult black and white subjects persist after adjustment for anthropometric,
lifestyle, and biochemical differences. J Clin Endocrinol Metab 1997; 82:429.
8. Tea Fact Sheet. Tea association of the USA, Inc. Available at: www.teausa.com/general/tea
factsheet-updated2-10-06.pdf (Accessed on October 11, 2011).

9. Lorenz M, Jochmann N, von Krosigk A, et al. Addition of milk prevents vascular protective
effects of tea. Eur Heart J 2007; 28:219.

10. Arnlöv J, Vessby B, Risérus U. Coffee consumption and insulin sensitivity. JAMA 2004;
291:1199.

11. Renouf M, Marmet C, Guy P, et al. Nondairy creamer, but not milk, delays the appearance
of coffee phenolic acid equivalents in human plasma. J Nutr 2010; 140:259.

12. Inoue-Choi M, Ramirez Y, Cornelis MC, et al. Tea Consumption and All-Cause and Cause-
Specific Mortality in the UK Biobank : A Prospective Cohort Study. Ann Intern Med 2022;

- Page 20 of 32 -
Benefits and risks of caffeine and caffeinated beverages

175:1201.

13. Gunja N, Brown JA. Energy drinks: health risks and toxicity. Med J Aust 2012; 196:46.

14. Reissig CJ, Strain EC, Griffiths RR. Caffeinated energy drinks--a growing problem. Drug
Alcohol Depend 2009; 99:1.

15. Wolk BJ, Ganetsky M, Babu KM. Toxicity of energy drinks. Curr Opin Pediatr 2012; 24:243.

16. Jagim AR, Harty PS, Fischer KM, et al. Adverse Events Reported to the United States Food
and Drug Administration Related to Caffeine-Containing Products. Mayo Clin Proc 2020;
95:1594.

17. Lieberman HR. Why Are Certain Caffeine-Containing Products Associated With Serious
Adverse Effects? Mayo Clin Proc 2020; 95:1562.
18. US Food and Drug Administration. FDA Consumer Advice on Powdered Pure Caffeine. ww
w.fda.gov/Food/RecallsOutbreaksEmergencies/SafetyAlertsAdvisories/ucm405787.htm (A
ccessed on July 28, 2014).

19. Olthof MR, Hollman PC, Katan MB. Chlorogenic acid and caffeic acid are absorbed in
humans. J Nutr 2001; 131:66.

20. Cornelis MC, El-Sohemy A, Kabagambe EK, Campos H. Coffee, CYP1A2 genotype, and risk
of myocardial infarction. JAMA 2006; 295:1135.
21. Fredholm BB, Bättig K, Holmén J, et al. Actions of caffeine in the brain with special
reference to factors that contribute to its widespread use. Pharmacol Rev 1999; 51:83.

22. Carvey CE, Thompson LA, Lieberman HR. Caffeine: Mechanism of action, genetics and be
havioral studies conducted in simulators and in the field. In: Sleep Deprivation, Stimulant
Medications, and Cognition, Wesensten NJ (Ed), Cambridge University Press, Cambridge,
United Kingdom 2012. p.93.

23. Olthof MR, Hollman PC, Zock PL, Katan MB. Consumption of high doses of chlorogenic
acid, present in coffee, or of black tea increases plasma total homocysteine
concentrations in humans. Am J Clin Nutr 2001; 73:532.

24. Saw SM. Homocysteine and atherosclerotic disease: the epidemiologic evidence. Ann
Acad Med Singapore 1999; 28:565.
25. Lee WJ, Zhu BT. Inhibition of DNA methylation by caffeic acid and chlorogenic acid, two

- Page 21 of 32 -
Benefits and risks of caffeine and caffeinated beverages

common catechol-containing coffee polyphenols. Carcinogenesis 2006; 27:269.

26. Jayasuriya H, Herath KB, Ondeyka JG, et al. Diterpenoid, steroid, and triterpenoid
agonists of liver X receptors from diversified terrestrial plants and marine sources. J Nat
Prod 2005; 68:1247.
27. Cavin C, Marin-Kuan M, Langouët S, et al. Induction of Nrf2-mediated cellular defenses
and alteration of phase I activities as mechanisms of chemoprotective effects of coffee in
the liver. Food Chem Toxicol 2008; 46:1239.

28. Corti R, Binggeli C, Sudano I, et al. Coffee acutely increases sympathetic nerve activity
and blood pressure independently of caffeine content: role of habitual versus
nonhabitual drinking. Circulation 2002; 106:2935.

29. Richelle M, Tavazzi I, Offord E. Comparison of the antioxidant activity of commonly

consumed polyphenolic beverages (coffee, cocoa, and tea) prepared per cup serving. J
Agric Food Chem 2001; 49:3438.

30. Yen WJ, Wang BS, Chang LW, Duh PD. Antioxidant properties of roasted coffee residues. J
Agric Food Chem 2005; 53:2658.
31. Benvenga S, Bartolone L, Pappalardo MA, et al. Altered intestinal absorption of L-
thyroxine caused by coffee. Thyroid 2008; 18:293.

32. Gertz BJ, Holland SD, Kline WF, et al. Studies of the oral bioavailability of alendronate. Clin
Pharmacol Ther 1995; 58:288.

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

34. Mascitelli L, Goldstein MR. Does inhibition of iron absorption by coffee reduce the risk of
gout? Int J Clin Pract 2011; 65:713.

35. Lieberman HR, Wurtman RJ, Emde GG, Coviella IL. The effects of caffeine and aspirin on
mood and performance. J Clin Psychopharmacol 1987; 7:315.
36. Amendola CA, Gabrieli JD, Lieberman HR. Caffeine's Effects on Performance and Mood
are Independent of Age and Gender. Nutr Neurosci 1998; 1:269.

37. Smith A, Sturgess W, Gallagher J. Effects of a low dose of caffeine given in different drinks
on mood and performance. Hum Psychopharmacol Clin Exp 1999; 14:473.

- Page 22 of 32 -
Benefits and risks of caffeine and caffeinated beverages

38. Smith A, Sutherland D, Christopher G. Effects of repeated doses of caffeine on mood and
performance of alert and fatigued volunteers. J Psychopharmacol 2005; 19:620.
39. Childs E, de Wit H. Subjective, behavioral, and physiological effects of acute caffeine in
light, nondependent caffeine users. Psychopharmacology (Berl) 2006; 185:514.

40. Lieberman HR, Tharion WJ, Shukitt-Hale B, et al. Effects of caffeine, sleep loss, and stress
on cognitive performance and mood during U.S. Navy SEAL training. Sea-Air-Land.
Psychopharmacology (Berl) 2002; 164:250.

41. Magill RA, Waters WF, Bray GA, et al. Effects of tyrosine, phentermine, caffeine D-
amphetamine, and placebo on cognitive and motor performance deficits during sleep
deprivation. Nutr Neurosci 2003; 6:237.

42. Kamimori GH, Johnson D, Thorne D, Belenky G. Multiple caffeine doses maintain vigilance
during early morning operations. Aviat Space Environ Med 2005; 76:1046.

43. Doan BK, Hickey PA, Lieberman HR, Fischer JR. Caffeinated tube food effect on pilot
performance during a 9-hour, simulated nighttime U-2 mission. Aviat Space Environ Med
2006; 77:1034.

44. Jarvis MJ. Does caffeine intake enhance absolute levels of cognitive performance?
Psychopharmacology (Berl) 1993; 110:45.

45. Smith A. Effects of caffeine on human behavior. Food Chem Toxicol 2002; 40:1243.

46. Lorist MM, Snel J, Kok A, Mulder G. Influence of caffeine on selective attention in well-
rested and fatigued subjects. Psychophysiology 1994; 31:525.

47. McLellan TM, Caldwell JA, Lieberman HR. A review of caffeine's effects on cognitive,
physical and occupational performance. Neurosci Biobehav Rev 2016; 71:294.

48. Lieberman HR. Foods and Food Constituents, Effects on Human Behavior. In: The Encyclo
pedia of Neuroscience, 3rd ed, Adelman G, Smith B (Eds), Elsevier Science, The Netherlan
ds 2004.

49. Lieberman HR, Carvey CE, Thompson LA. Caffeine. In: Encyclopedia of Dietary Supplemen
ts, Coates PM (Ed), Informa Health Care, New York 2010. p.90.

50. Ker K, Edwards PJ, Felix LM, et al. Caffeine for the prevention of injuries and errors in shift
workers. Cochrane Database Syst Rev 2010; :CD008508.

- Page 23 of 32 -
Benefits and risks of caffeine and caffeinated beverages

51. Goldstein J, Silberstein SD, Saper JR, et al. Acetaminophen, aspirin, and caffeine in
combination versus ibuprofen for acute migraine: results from a multicenter, double-
blind, randomized, parallel-group, single-dose, placebo-controlled study. Headache 2006;
46:444.

52. Diener HC, Gold M, Hagen M. Use of a fixed combination of acetylsalicylic acid,
acetaminophen and caffeine compared with acetaminophen alone in episodic tension-
type headache: meta-analysis of four randomized, double-blind, placebo-controlled,
crossover studies. J Headache Pain 2014; 15:76.

53. Bigal ME, Sheftell FD, Rapoport AM, et al. Chronic daily headache: identification of factors
associated with induction and transformation. Headache 2002; 42:575.
54. Ragonese P, Salemi G, Morgante L, et al. A case-control study on cigarette, alcohol, and
coffee consumption preceding Parkinson's disease. Neuroepidemiology 2003; 22:297.

55. Abbott RD, Ross GW, White LR, et al. Environmental, life-style, and physical precursors of
clinical Parkinson's disease: recent findings from the Honolulu-Asia Aging Study. J Neurol
2003; 250 Suppl 3:III30.

56. Hernán MA, Takkouche B, Caamaño-Isorna F, Gestal-Otero JJ. A meta-analysis of coffee

drinking, cigarette smoking, and the risk of Parkinson's disease. Ann Neurol 2002;
52:276.

57. Ascherio A, Weisskopf MG, O'Reilly EJ, et al. Coffee consumption, gender, and Parkinson's
disease mortality in the cancer prevention study II cohort: the modifying effects of
estrogen. Am J Epidemiol 2004; 160:977.
58. Ascherio A, Chen H, Schwarzschild MA, et al. Caffeine, postmenopausal estrogen, and
risk of Parkinson's disease. Neurology 2003; 60:790.

59. Barranco Quintana JL, Allam MF, Serrano Del Castillo A, Fernández-Crehuet Navajas R.
Alzheimer's disease and coffee: a quantitative review. Neurol Res 2007; 29:91.

60. Arendash GW, Schleif W, Rezai-Zadeh K, et al. Caffeine protects Alzheimer's mice against
cognitive impairment and reduces brain beta-amyloid production. Neuroscience 2006;
142:941.
61. Griffiths RR. Principles of Addiction Medicine, Graham AW (Ed), 2003. p.193.

62. Uhde TW. Neurobiology of Panic Disorder, Ballenger JC (Ed), p.219.

- Page 24 of 32 -
Benefits and risks of caffeine and caffeinated beverages

63. Bruce M, Scott N, Shine P, Lader M. Anxiogenic effects of caffeine in patients with anxiety
disorders. Arch Gen Psychiatry 1992; 49:867.

64. Kendler KS, Myers J, O Gardner C. Caffeine intake, toxicity and dependence and lifetime
risk for psychiatric and substance use disorders: an epidemiologic and co-twin control
analysis. Psychol Med 2006; 36:1717.
65. Lucas M, Mirzaei F, Pan A, et al. Coffee, caffeine, and risk of depression among women.
Arch Intern Med 2011; 171:1571.
66. van Dam RM, Pasman WJ, Verhoef P. Effects of coffee consumption on fasting blood
glucose and insulin concentrations: randomized controlled trials in healthy volunteers.
Diabetes Care 2004; 27:2990.

67. Keijzers GB, De Galan BE, Tack CJ, Smits P. Caffeine can decrease insulin sensitivity in
humans. Diabetes Care 2002; 25:364.
68. Lane JD, Feinglos MN, Surwit RS. Caffeine increases ambulatory glucose and postprandial
responses in coffee drinkers with type 2 diabetes. Diabetes Care 2008; 31:221.
69. van Dam RM, Feskens EJ. Coffee consumption and risk of type 2 diabetes mellitus. Lancet
2002; 360:1477.

70. Rosengren A, Dotevall A, Wilhelmsen L, et al. Coffee and incidence of diabetes in Swedish
women: a prospective 18-year follow-up study. J Intern Med 2004; 255:89.
71. van Dam RM, Willett WC, Manson JE, Hu FB. Coffee, caffeine, and risk of type 2 diabetes: a
prospective cohort study in younger and middle-aged U.S. women. Diabetes Care 2006;
29:398.
72. Pereira MA, Parker ED, Folsom AR. Coffee consumption and risk of type 2 diabetes
mellitus: an 11-year prospective study of 28 812 postmenopausal women. Arch Intern
Med 2006; 166:1311.

73. Iso H, Date C, Wakai K, et al. The relationship between green tea and total caffeine intake
and risk for self-reported type 2 diabetes among Japanese adults. Ann Intern Med 2006;
144:554.

74. Salazar-Martinez E, Willett WC, Ascherio A, et al. Coffee consumption and risk for type 2
diabetes mellitus. Ann Intern Med 2004; 140:1.

- Page 25 of 32 -
Benefits and risks of caffeine and caffeinated beverages

75. MacKenzie T, Comi R, Sluss P, et al. Metabolic and hormonal effects of caffeine:
randomized, double-blind, placebo-controlled crossover trial. Metabolism 2007; 56:1694.
76. Alperet DJ, Rebello SA, Khoo EY, et al. The effect of coffee consumption on insulin
sensitivity and other biological risk factors for type 2 diabetes: a randomized placebo-
controlled trial. Am J Clin Nutr 2020; 111:448.
77. Williams CJ, Fargnoli JL, Hwang JJ, et al. Coffee consumption is associated with higher
plasma adiponectin concentrations in women with or without type 2 diabetes: a
prospective cohort study. Diabetes Care 2008; 31:504.

78. Goto A, Song Y, Chen BH, et al. Coffee and caffeine consumption in relation to sex
hormone-binding globulin and risk of type 2 diabetes in postmenopausal women.
Diabetes 2011; 60:269.

79. Ding EL, Song Y, Manson JE, et al. Sex hormone-binding globulin and risk of type 2
diabetes in women and men. N Engl J Med 2009; 361:1152.
80. Egawa T, Hamada T, Kameda N, et al. Caffeine acutely activates 5'adenosine
monophosphate-activated protein kinase and increases insulin-independent glucose
transport in rat skeletal muscles. Metabolism 2009; 58:1609.
81. Park S, Jang JS, Hong SM. Long-term consumption of caffeine improves glucose
homeostasis by enhancing insulinotropic action through islet insulin/insulin-like growth
factor 1 signaling in diabetic rats. Metabolism 2007; 56:599.

82. Huxley R, Lee CM, Barzi F, 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.

83. Zhang WL, Lopez-Garcia E, Li TY, et al. Coffee consumption and risk of cardiovascular
events and all-cause mortality among women with type 2 diabetes. Diabetologia 2009;
52:810.
84. Murakami K, Okubo H, Sasaki S. Dietary intake in relation to self-reported constipation
among Japanese women aged 18-20 years. Eur J Clin Nutr 2006; 60:650.
85. Liu F, Wang X, Wu G, et al. Coffee Consumption Decreases Risks for Hepatic Fibrosis and
Cirrhosis: A Meta-Analysis. PLoS One 2015; 10:e0142457.

86. Crippa A, Discacciati A, Larsson SC, et al. Coffee consumption and mortality from all
- Page 26 of 32 -
Benefits and risks of caffeine and caffeinated beverages

causes, cardiovascular disease, and cancer: a dose-response meta-analysis. Am J

Epidemiol 2014; 180:763.

87. Bøhn SK, Blomhoff R, Paur I. Coffee and cancer risk, epidemiological evidence, and
molecular mechanisms. Mol Nutr Food Res 2014; 58:915.
88. Boehm K, Borrelli F, Ernst E, et al. Green tea (Camellia sinensis) for the prevention of
cancer. Cochrane Database Syst Rev 2009; :CD005004.

89. Nkondjock A, Ghadirian P, Kotsopoulos J, et al. Coffee consumption and breast cancer
risk among BRCA1 and BRCA2 mutation carriers. Int J Cancer 2006; 118:103.
90. Baker JA, Beehler GP, Sawant AC, et al. Consumption of coffee, but not black tea, is
associated with decreased risk of premenopausal breast cancer. J Nutr 2006; 136:166.
91. Hirvonen T, Mennen LI, de Bree A, et al. Consumption of antioxidant-rich beverages and
risk for breast cancer in French women. Ann Epidemiol 2006; 16:503.

92. Ishitani K, Lin J, Manson JE, et al. Caffeine consumption and the risk of breast cancer in a
large prospective cohort of women. Arch Intern Med 2008; 168:2022.
93. Tang N, Wu Y, Ma J, et al. Coffee consumption and risk of lung cancer: a meta-analysis.
Lung Cancer 2010; 67:17.

94. Tang N, Wu Y, Zhou B, et al. Green tea, black tea consumption and risk of lung cancer: a
meta-analysis. Lung Cancer 2009; 65:274.
95. Turati F, Galeone C, La Vecchia C, et al. Coffee and cancers of the upper digestive and
respiratory tracts: meta-analyses of observational studies. Ann Oncol 2011; 22:536.
96. Yang TO, Crowe F, Cairns BJ, et al. Tea and coffee and risk of endometrial cancer: cohort
study and meta-analysis. Am J Clin Nutr 2015; 101:570.

97. Bravi F, Scotti L, Bosetti C, et al. Coffee drinking and endometrial cancer risk: a
metaanalysis of observational studies. Am J Obstet Gynecol 2009; 200:130.
98. Braem MG, Onland-Moret NC, Schouten LJ, 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; 95:1172.
99. Zeegers MP, Tan FE, Goldbohm RA, van den Brandt PA. Are coffee and tea consumption
associated with urinary tract cancer risk? A systematic review and meta-analysis. Int J

- Page 27 of 32 -
Benefits and risks of caffeine and caffeinated beverages

Epidemiol 2001; 30:353.

100. Pelucchi C, La Vecchia C. Alcohol, coffee, and bladder cancer risk: a review of
epidemiological studies. Eur J Cancer Prev 2009; 18:62.
101. Villanueva CM, Silverman DT, Murta-Nascimento C, et al. Coffee consumption, genetic
susceptibility and bladder cancer risk. Cancer Causes Control 2009; 20:121.

102. Kurahashi N, Sasazuki S, Iwasaki M, et al. Green tea consumption and prostate cancer
risk in Japanese men: a prospective study. Am J Epidemiol 2008; 167:71.
103. Severson RK, Nomura AM, Grove JS, Stemmermann GN. A prospective study of
demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii.
Cancer Res 1989; 49:1857.
104. Bettuzzi S, Brausi M, Rizzi F, et al. Chemoprevention of human prostate cancer by oral
administration of green tea catechins in volunteers with high-grade prostate
intraepithelial neoplasia: a preliminary report from a one-year proof-of-principle study.
Cancer Res 2006; 66:1234.
105. Wilson KM, Kasperzyk JL, Rider JR, et al. Coffee consumption and prostate cancer risk and
progression in the Health Professionals Follow-up Study. J Natl Cancer Inst 2011; 103:876.

106. Wilson KM, Kasperzyk JL, Rider JR, et al. Coffee consumption and prostate cancer risk and
progression in the Health Professionals Follow-up Study. J Natl Cancer Inst 2011; 103:876.
107. Rapuri PB, Gallagher JC, Kinyamu HK, Ryschon KL. Caffeine intake increases the rate of
bone loss in elderly women and interacts with vitamin D receptor genotypes. Am J Clin
Nutr 2001; 74:694.
108. Harris SS, Dawson-Hughes B. Caffeine and bone loss in healthy postmenopausal women.
Am J Clin Nutr 1994; 60:573.

109. Korpelainen R, Korpelainen J, Heikkinen J, et al. Lifestyle factors are associated with
osteoporosis in lean women but not in normal and overweight women: a population-
based cohort study of 1222 women. Osteoporos Int 2003; 14:34.
110. Kanis JA, Johnell O, Oden A, et al. Ten-year risk of osteoporotic fracture and the effect of
risk factors on screening strategies. Bone 2002; 30:251.
111. Cauley JA, Hochberg MC, Lui LY, et al. Long-term risk of incident vertebral fractures. JAMA

- Page 28 of 32 -
Benefits and risks of caffeine and caffeinated beverages

2007; 298:2761.
112. De Laet CE, Van Hout BA, Burger H, et al. Hip fracture prediction in elderly men and
women: validation in the Rotterdam study. J Bone Miner Res 1998; 13:1587.
113. Hallström H, Wolk A, Glynn A, Michaëlsson K. Coffee, tea and caffeine consumption in
relation to osteoporotic fracture risk in a cohort of Swedish women. Osteoporos Int 2006;
17:1055.

114. Hegarty VM, May HM, Khaw KT. Tea drinking and bone mineral density in older women.
Am J Clin Nutr 2000; 71:1003.
115. Devine A, Hodgson JM, Dick IM, Prince RL. Tea drinking is associated with benefits on
bone density in older women. Am J Clin Nutr 2007; 86:1243.
116. Chen Z, Pettinger MB, Ritenbaugh C, et al. Habitual tea consumption and risk of
osteoporosis: a prospective study in the women's health initiative observational cohort.
Am J Epidemiol 2003; 158:772.

117. Mikuls TR, Cerhan JR, Criswell LA, et al. Coffee, tea, and caffeine consumption and risk of
rheumatoid arthritis: results from the Iowa Women's Health Study. Arthritis Rheum 2002;
46:83.

118. Pedersen M, Stripp C, Klarlund M, et al. Diet and risk of rheumatoid arthritis in a
prospective cohort. J Rheumatol 2005; 32:1249.
119. Karlson EW, Mandl LA, Aweh GN, Grodstein F. Coffee consumption and risk of
rheumatoid arthritis. Arthritis Rheum 2003; 48:3055.

120. Choi HK, Curhan G. Coffee, tea, and caffeine consumption and serum uric acid level: the
third national health and nutrition examination survey. Arthritis Rheum 2007; 57:816.
121. Choi HK, Willett W, Curhan G. Coffee consumption and risk of incident gout in men: a
prospective study. Arthritis Rheum 2007; 56:2049.
122. Bird ET, Parker BD, Kim HS, Coffield KS. Caffeine ingestion and lower urinary tract
symptoms in healthy volunteers. Neurourol Urodyn 2005; 24:611.

123. Bryant CM, Dowell CJ, Fairbrother G. Caffeine reduction education to improve urinary
symptoms. Br J Nurs 2002; 11:560.
124. Armstrong LE, Pumerantz AC, Roti MW, et al. Fluid, electrolyte, and renal indices of

- Page 29 of 32 -
Benefits and risks of caffeine and caffeinated beverages

hydration during 11 days of controlled caffeine consumption. Int J Sport Nutr Exerc
Metab 2005; 15:252.

125. Jura YH, Townsend MK, Curhan GC, et al. Caffeine intake, and the risk of stress, urgency
and mixed urinary incontinence. J Urol 2011; 185:1775.
126. Burke LM. Caffeine and sports performance. Appl Physiol Nutr Metab 2008; 33:1319.

127. Happonen P, Läärä E, Hiltunen L, Luukinen H. Coffee consumption and mortality in a 14-
year follow-up of an elderly northern Finnish population. Br J Nutr 2008; 99:1354.
128. Paganini-Hill A, Kawas CH, Corrada MM. Non-alcoholic beverage and caffeine
consumption and mortality: the Leisure World Cohort Study. Prev Med 2007; 44:305.
129. 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.

130. Lopez-Garcia E, van Dam RM, Willett WC, et al. Coffee consumption and coronary heart
disease in men and women: a prospective cohort study. Circulation 2006; 113:2045.
131. Freedman ND, Park Y, Abnet CC, et al. Association of coffee drinking with total and cause-
specific mortality. N Engl J Med 2012; 366:1891.
132. Lopez-Garcia E, van Dam RM, Li TY, et al. The relationship of coffee consumption with
mortality. Ann Intern Med 2008; 148:904.

133. Saito E, Inoue M, Sawada N, et al. Association of coffee intake with total and cause-
specific mortality in a Japanese population: the Japan Public Health Center-based
Prospective Study. Am J Clin Nutr 2015; 101:1029.
134. Ding M, Satija A, Bhupathiraju SN, et al. Association of Coffee Consumption With Total
and Cause-Specific Mortality in 3 Large Prospective Cohorts. Circulation 2015; 132:2305.
135. Loftfield E, Freedman ND, Graubard BI, et al. Association of Coffee Consumption With
Overall and Cause-Specific Mortality in a Large US Prospective Cohort Study. Am J
Epidemiol 2015; 182:1010.

136. Park SY, Freedman ND, Haiman CA, et al. Association of Coffee Consumption With Total
and Cause-Specific Mortality Among Nonwhite Populations. Ann Intern Med 2017;
167:228.

- Page 30 of 32 -
Benefits and risks of caffeine and caffeinated beverages

137. Gunter MJ, Murphy N, Cross AJ, et al. Coffee Drinking and Mortality in 10 European
Countries: A Multinational Cohort Study. Ann Intern Med 2017; 167:236.
138. Sugiyama K, Kuriyama S, Akhter M, et al. Coffee consumption and mortality due to all
causes, cardiovascular disease, and cancer in Japanese women. J Nutr 2010; 140:1007.
139. Tsujimoto T, Kajio H, Sugiyama T. Association Between Caffeine Intake and All-Cause and
Cause-Specific Mortality: A Population-Based Prospective Cohort Study. Mayo Clin Proc
2017; 92:1190.

140. Lopez-Garcia E, Rodriguez-Artalejo F, Li TY, et al. Coffee consumption and mortality in

women with cardiovascular disease. Am J Clin Nutr 2011; 94:218.
141. Lieberman HR. Mental energy: Assessing the cognition dimension. Nutr Rev 2006;
64:S10.
142. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders,
Fifth Edition (DSM-5), American Psychiatric Association, Arlington, VA 2013.

143. Satel S. Is caffeine addictive?--a review of the literature. Am J Drug Alcohol Abuse 2006;
32:493.
144. Hughes JR, Oliveto AH, Helzer JE, et al. Should caffeine abuse, dependence, or withdrawal
be added to DSM-IV and ICD-10? Am J Psychiatry 1992; 149:33.

145. Ogawa N, Ueki H. Clinical importance of caffeine dependence and abuse. Psychiatry Clin
Neurosci 2007; 61:263.
146. McCarthy DM, Mycyk MB, DesLauriers CA. Hospitalization for caffeine abuse is associated
with abuse of other pharmaceutical products. Am J Emerg Med 2008; 26:799.
147. Valjent E, Pagès C, Hervé D, et al. Addictive and non-addictive drugs induce distinct and
specific patterns of ERK activation in mouse brain. Eur J Neurosci 2004; 19:1826.

148. Cornelis MC, El-Sohemy A, Campos H. Genetic polymorphism of the adenosine A2A
receptor is associated with habitual caffeine consumption. Am J Clin Nutr 2007; 86:240.
149. Pallanti S, Bernardi S, Quercioli L. The Shorter PROMIS Questionnaire and the Internet
Addiction Scale in the assessment of multiple addictions in a high-school population:
prevalence and related disability. CNS Spectr 2006; 11:966.
150. Howland J, Rohsenow DJ, Arnedt JT, et al. The acute effects of caffeinated versus non-

- Page 31 of 32 -
Benefits and risks of caffeine and caffeinated beverages

caffeinated alcoholic beverage on driving performance and attention/reaction time.

Addiction 2011; 106:335.

151. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of
symptoms and signs, incidence, severity, and associated features. Psychopharmacology
(Berl) 2004; 176:1.

152. Kendler KS, Prescott CA. Caffeine intake, tolerance, and withdrawal in women: a
population-based twin study. Am J Psychiatry 1999; 156:223.

Topic 5369 Version 64.0

© 2023 UpToDate, Inc. All rights reserved.

- Page 32 of 32 -