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1、The new england journal of medicinen engl j med 383;4 nejm.org July 23,2020369Review ArticleFrom the Saw Swee Hock School of Pub-lic Health and Yong Loo Lin School of Medicine,National University of Singa-pore and National University Health Sys-tem,Singapore(R.M.V.D.);and the De-partments of Nutriti
2、on(R.M.V.D.,F.B.H.,W.C.W.)and Epidemiology(F.B.H.,W.C.W.),Harvard T.H.Chan School of Public Health,and the Channing Division of Network Medicine,Department of Medicine,Brigham and Womens Hospi-tal and Harvard Medical School(F.B.H.,W.C.W.)both in Boston.Address re-print requests to Dr.van Dam at the
3、Saw Swee Hock School of Public Health,Na-tional University of Singapore,Tahir Foun-dation,Bldg.12,Science Drive 2,Singa-pore 117549,Singapore,or at rob.van.dam nus.edu.sg.N Engl J Med 2020;383:369-78.DOI:10.1056/NEJMra1816604Copyright 2020 Massachusetts Medical Society.Coffee and tea are among the m
4、ost popular beverages world-wide and contain substantial amounts of caffeine,making caffeine the most widely consumed psychoactive agent.1 A variety of plants contain caf-feine in their seeds,fruits,and leaves.Besides coffee and tea,these plants include cacao beans(an ingredient of chocolate),yerba
5、matte leaves(used to make an herbal tea),and guarana berries(used in various beverages and supplements).1,2 Caffeine can also be synthesized and is added to foods and beverages,including soft drinks,energy drinks,and energy shots,and to tablets marketed for reducing fatigue.2 In addition,caffeine is
6、 widely used as a treatment for apnea of prematu-rity in infants,3 and caffeine and analgesic agents are used together in pain medications.4Coffee and tea have been consumed for hundreds of years and have become an important part of cultural traditions and social life.5 In addition,people use coffee
7、 beverages to increase wakefulness and work productivity.The caffeine content of commonly used sources of caffeine is shown in Table 1.For a typical serving,the caffeine content is highest in coffee,energy drinks,and caffeine tablets;interme-diate in tea;and lowest in soft drinks.In the United State
8、s,85%of adults consume caffeine daily,6 and average caffeine intake is 135 mg per day,which is equivalent to about 1.5 standard cups of coffee(with a standard cup defined as 8 fluid oz 235 ml).7 Coffee is the predominant source of caffeine ingested by adults,whereas soft drinks and tea are more impo
9、rtant sources of caffeine ingested by adolescents(Fig.1).Concerns have long existed that coffee and caffeine may increase the risks of cancer and cardiovascular diseases,but more recently,evidence of health benefits has also emerged.8 A key issue in research on caffeine and coffee is that coffee con
10、tains hundreds of other biologically active phytochemicals,including polyphe-nols such as chlorogenic acid and lignans,the alkaloid trigonelline,melanoidins formed during roasting,and modest amounts of magnesium,potassium,and vi-tamin B3(niacin).8 These coffee compounds may reduce oxidative stress,9
11、 improve the gut microbiome,10 and modulate glucose and fat metabolism.11,12 In contrast,the diterpene cafestol,which is present in unfiltered coffee,increases serum cho-lesterol levels.13 Thus,research findings for coffee and other dietary sources of caffeine should be interpreted cautiously,since
12、effects may not be due to caffeine itself.Metabolism,Physiological Effects,and Toxic EffectsAbsorption and MetabolismChemically,caffeine is a methylxanthine(1,3,7-trimethylxanthine).Caffeine ab-sorption is nearly complete within 45 minutes after ingestion,with caffeine blood Edward W.Campion,M.D.,Ed
13、itorCoffee,Caffeine,and HealthRob M.van Dam,Ph.D.,Frank B.Hu,M.D.,Ph.D.,and Walter C.Willett,M.D.,Dr.P.H.The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF BIRMINGHAM on July 22,2020.For personal use only.No other uses without permission.Copyright 2020 Massachusetts Medica
14、l Society.All rights reserved.n engl j med 383;4 nejm.org July 23,2020370The new england journal of medicinelevels peaking after 15 minutes to 2 hours.14 Caffeine spreads throughout the body and cross-es the bloodbrain barrier.In the liver,caffeine is metabolized by cytochrome P-450(CYP)en-zymes in
15、particular,CYP1A2.Caffeine me-tabolites include paraxanthine and,in smaller amounts,theophylline and theobromine,which are further metabolized to uric acid and eventu-ally excreted with urine.The half-life of caffeine in adults is typically 2.5 to 4.5 hours but is sub-ject to large variation from on
16、e person to an-other.14 Newborns have a limited capacity to metabolize caffeine,and the half-life is about 80 hours.After 5 to 6 months of age,the capac-ity for caffeine metabolism per kilogram of body weight does not change much with age.Smok-ing greatly accelerates caffeine metabolism,re-ducing th
17、e half-life by up to 50%,whereas oral contraceptive use doubles the half-life of caf-feine.Pregnancy greatly reduces caffeine me-tabolism,especially in the third trimester,when the half-life of caffeine can be up to 15 hours.The activity of caffeine-metabolizing enzymes is partly inherited.15 For ex
18、ample,a variant in the gene encoding CYP1A2 is associated with higher plasma caffeine levels and a lower ratio of pa-raxanthine to caffeine(which reflects slower caffeine metabolism),as well as with a lower caffeine intake.16 Persons with genetically deter-mined slower caffeine metabolism tend to co
19、m-Table 1.Caffeine Content of Commonly Consumed Foods,Beverages,and Over-the-Counter Drugs in the United States.*SourceServing SizeMilligrams of CaffeineCoffee,brewed,coffee shop12 fluid oz235Americano,coffee shop12 fluid oz150Coffee,brewed8 fluid oz92Coffee,instant8 fluid oz63Espresso1 fluid oz63De
20、caffeinated coffee8 fluid oz2Black tea,brewed8 fluid oz47Green tea,brewed8 fluid oz28Chamomile or peppermint tea8 fluid oz0Cola soft drink12 fluid oz32Energy drink8.5 fluid oz80Energy shot2 fluid oz200Dark chocolate1 oz24Milk chocolate1 oz6Over-the-counter drug for alertness1 tablet200Headache medic
21、ation with caffeine1 tablet65*Information is from FoodData Central.2 To convert fluid ounces to milliliters,multiply by 29.57.To convert ounces of chocolate to grams,multiply by 28.35.The caffeine content is shown for commonly used versions of energy drinks and shots,but the content may vary,particu
22、larly with different brands.Figure 1.Sources of Caffeine and Average Daily Intake in Adolescents and Middle-Aged Adults in the United States.Data are from the National Health and Nutrition Exami-nation Surveys,20112012.7 Panel A shows caffeine sources and daily intake for adolescents,and Panel B sho
23、ws sources and intake for adults 35 to 49 years of age.BTotal Caffeine Intake,3549 Yr of AgeATotal Caffeine Intake,1519 Yr of AgeCoffee,24.9%Tea,27.9%Soft drinks,32.9%Energydrinks,10.0%Other beverages,0.9%Food,3.4%Average daily intake,61 mgCoffee,65.0%Tea,16.0%Soft drinks,16.0%Energy drinks,1.0%Othe
24、r beverages,0.6%Food,1.4%Average daily intake,188 mgThe New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF BIRMINGHAM on July 22,2020.For personal use only.No other uses without permission.Copyright 2020 Massachusetts Medical Society.All rights reserved.n engl j med 383;4 nejm
25、.org July 23,2020371Coffee,Caffeine,and Healthpensate by having lower habitual caffeine intake than persons without this genetic predisposi-tion.17 In addition,medications from a range of drug classes(including several quinolone anti-biotics,cardiovascular drugs,bronchodilators,and antidepressant ag
26、ents)can slow caffeine clearance and increase its half-life,generally because they are metabolized by the same liver enzymes.14 Similarly,caffeine can affect the ac-tion of various drugs,and clinicians should consider possible caffeinedrug interactions when prescribing medications.14 Beneficial Effe
27、cts on Cognitive Performance and PainThe molecular structure of caffeine is similar to that of adenosine,which allows caffeine to bind to adenosine receptors,block adenosine,and inhibit its effects(Fig.S1 in the Supplementary Appendix,available with the full text of this article at NEJM.org).1 Accum
28、ulation of adenosine in the brain in-hibits arousal and increases drowsiness.In moder-ate doses(40 to 300 mg),caffeine can antagonize the effects of adenosine and reduce fatigue,increase alertness,and reduce reaction time(Fig.2).19,33Figure 2.Effects of Caffeine Intake on Health,According to Organ S
29、ystem.Information is from Schmidt et al.,3 Derry et al.,4 McLellan et al.,18 Clark et al.,19 Lara,20 Qi et al.,21 Kang et al.,22 Welsh et al.,23 Kennedy et al.,24,25 Wijarnpreecha et al.,26 Chen et al.,27,28 Armstrong et al.,29 Robertson et al.,30 Greer et al.,31 and Alperet et al.32 NSAIDs denotes
30、nonsteroidal antiinflammatory drugs.Endocrine systemReduces skeletal-muscle insulin sensitivity in the short term,but tolerance appears to develop with habitual intakeBrain Increases mental performance and vigilance owing to greater alertness Contributes to insomnia and induces anxiety(particularly
31、at high doses and in susceptible persons)May reduce the risk of depression Can augment the effect of NSAIDs and acetaminophen for treating headache and other causes of pain May reduce the risk of Parkinsons diseaseKidneys and urinary tractHigh doses can have a diuretic effect,but habitual moderate i
32、ntake does not substantially affect hydration statusLiverMay reduce the risk of liver fibrosis,cirrhosis,and cancerCardiovascular systemIncreases blood pressure in the short term,but at least partial tolerance develops with habitual intakeLungs Is effective for treating apnea of prematurity in infan
33、ts Slightly improves lung function in adultsReproductive systemMay reduce fetal growth and increase the risk of pregnancy lossThe New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF BIRMINGHAM on July 22,2020.For personal use only.No other uses without permission.Copyright 2020
34、 Massachusetts Medical Society.All rights reserved.n engl j med 383;4 nejm.org July 23,2020372The new england journal of medicineThese effects of caffeine have also been ob-served in persons who do not habitually con-sume caffeine and after short periods of absti-nence in habitual consumers.33 Caffe
35、ine intake can also improve vigilance during tasks of long duration that provide limited stimulation,such as working on an assembly line,long-distance driving,and flying aircraft.18 Although these mental benefits are most pronounced in sleep-deprived states,18,34 caffeine cannot compensate for the d
36、ecline in performance after long-term sleep deprivation.35Caffeine can contribute to pain relief when added to commonly used analgesic agents.Spe-cifically,a review of 19 studies showed that 100 to 130 mg of caffeine added to an analgesic modestly increased the proportion of patients with successful
37、 pain relief.4Effects on Sleep,Anxiety,and Hydration and Withdrawal SymptomsAs expected from its effects on fatigue,caffeine consumption later in the day can increase sleep latency and reduce the quality of sleep.19 In ad-dition,caffeine can induce anxiety,particularly at high doses(200 mg per occas
38、ion or 400 mg per day)and in sensitive persons,including those with anxiety or bipolar disorders.20 Interpersonal differences in the effects of caffeine on sleep and anxiety are large.These differences may reflect variation in the rate of caffeine metabo-lism and variants in the adenosine receptor g
39、ene.14,36 Caffeine consumers and physicians should be aware of these possible side effects of caffeine,and persons who drink caffeinated beverages should be advised to reduce caffeine intake or avoid intake later in the day,if these effects occur.High caffeine intake can stimulate urine output,but n
40、o detrimental effects on hy-dration status have been found with longer-term intake of moderate doses of caffeine(400 mg per day).29,37Quitting caffeine intake after habitual con-sumption can lead to withdrawal symptoms,including headaches,fatigue,decreased alert-ness,and depressed mood,as well as in
41、fluenza-like symptoms in some cases.38 These symptoms typically peak 1 to 2 days after cessation of caf-feine intake,with a total duration of 2 to 9 days,and can be reduced by gradually decreasing the caffeine dose.Toxic EffectsSide effects of caffeine at very high levels of in-take include anxiety,
42、restlessness,nervousness,dysphoria,insomnia,excitement,psychomotor agitation,and rambling flow of thought and speech.20 Toxic effects are estimated to occur with intakes of 1.2 g or higher,and a dose of 10 to 14 g is thought to be fatal.39 A recent review of blood caffeine levels in cases of fatal o
43、ver-doses showed that the median postmortem blood caffeine level was 180 mg per liter,which corresponds to an estimated intake of 8.8 g of caffeine.40 Caffeine poisoning from consump-tion of traditional sources of caffeine such as coffee and tea is rare because a very large amount(75 to 100 standard
44、 cups of coffee)would have to be consumed in a short time for the dose to be fatal.Caffeine-related deaths have generally been due to very high doses of caffeine from tablets or supplements in powdered or liquid form,mostly in athletes or patients with psychiatric disorders.41In case reports,high co
45、nsumption of energy drinks and shots,especially when mixed with alcohol,has also been linked to adverse cardio-vascular,psychological,and neurologic events,including fatal events.42 Caffeine in the form of energy drinks and shots may have more ad-verse effects than other caffeinated beverages for se
46、veral reasons:high episodic consumption of these forms of caffeine,which does not al-low the development of caffeine tolerance;popularity among children and adolescents,who may be more vulnerable to the effects of caffeine;lack of clarity on the part of consum-ers about caffeine content;possible syn
47、ergistic effects with other components of the energy drinks;and combination with alcohol con-sumption or vigorous exertion.High consump-tion of energy drinks(approximately 34 fluid oz 1 liter,containing 320 mg of caffeine),but not moderate consumption(200 mg of caf-feine),resulted in adverse short-t
48、erm cardiovas-cular effects(increased blood pressure,pro-longed QT interval corrected for heart rate,and palpitations)in several studies.42 Persons who consume energy drinks should thus be advised to check the caffeine content and avoid high consumption(200 mg of caffeine per occa-sion)or consumptio
49、n in combination with al-cohol.The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITY OF BIRMINGHAM on July 22,2020.For personal use only.No other uses without permission.Copyright 2020 Massachusetts Medical Society.All rights reserved.n engl j med 383;4 nejm.org July 23,2020373C
50、offee,Caffeine,and HealthCoffee,Caffeine,and the Risk of Chronic DiseaseMethodologic ConsiderationsStudies of caffeine intake and health outcomes can have several potential limitations.First,ob-servations of the acute effects of caffeine may not reflect long-term effects because tolerance of caffein