Benefits and risks of caffeine and caffeinated beverages

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 "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 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 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].

●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, 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' 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 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 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 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) [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 "Epidemiology and risk factors for colorectal cancer", 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 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

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 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 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 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 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

●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. 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 UpToDate editorial staff acknowledges Edmond Kabagambe, DVM, MS, PhD, Melissa Wellons, MD, MHS, and Harris Lieberman, PhD, who contributed to earlier versions of this topic review.