effects of caffeine on blood pressure

Effects of Caffeine on Blood PressureMartin G. Myers, MD, FRCPC

\s=b\Initial reports indicated that caffeine has a pressor effect,raising the possibility that it might contribute to hypertension.However, further studies have demonstrated that caffeine doesnot produce a persistent increase in blood pressure. Individ-uals who do not regularly consume caffeine may experiencea slight increase in blood pressure when they are exposed tocaffeine, but tolerance develops rapidly and blood pressurereturns to baseline.

(Arch Intern Med 1988;148:1189-1193)

Caffeine has been subject to a barrage of adverse criticism^ linking it to a wide variety of ills, including cancer,heart disease, hypertension, and cardiac arrhythmias.13Although initial reports of its adverse effects are oftenpublicized widely, such is not always the case when subse¬quent studies fail to confirm the original claims. A recentarticle in Discover4 described the plight of caffeine asfollows:"... caffeine has been let off the hook time and time

again. People are just waiting for somebody to nail it: ifcaffeine isn't bad for you, it should be."

The story behind the general belief that caffeine is linkedto high blood pressure is typical of caffeine's scientifichistory. Initial reports suggested a pressor effect of caf¬feine, raising the specter that this substance may be acause of hypertension. These reports provided a stimulusfor further studies in which the cardiac effects of caffeinewere examined in more detail; generally negative findingswere reported. The results of these recently publishedstudies have clarified much of the controversy surroundingthe effect of caffeine on blood pressure and make a reviewof the subject timely.

REVIEW OF THE LITERATUREThe literature on caffeine and high blood pressure is

summarized in the Table.Confusion regarding caffeine's effect on blood pressure

is long-standing. In reviewing the pre-1950 literature,Robertson and Curatolo5 noted that caffeine was originallythought to lower blood pressure, but subsequent studiessuggested that caffeine either raised it or had no effect.More recent studies615 uniformly reported an increase inblood pressure after caffeine ingestion, but only in subjectswho had abstained from caffeine beforehand.

Cardiovascular Studies WithSmall Populations

In one of the more widely quoted reports on the subject,Robertson et al6 administered caffeine (250 mg) to nine

Accepted for publication Dec 21, 1987.From the Division of Cardiology, Sunnybrook Medical Centre, Toronto.Reprint requests to Division of Cardiology, Sunnybrook Medical Centre,

2075 Bayview Ave, Toronto, Ontario, Canada M4N 3M5 (Dr Myers).

young, healthy subjects who had abstained from caffeinefor at least 21 days. The effects of caffeine on bloodpressure, heart rate, plasma renin activity, and plasmacatecholamines were compared with changes in thesemeasures after placebo administration in a randomized,double-blind study design. After caffeine ingestion, bloodpressure increased by a maximum of 14/10 mm Hg at onehour, with values returning toward baseline at three hours.The rise in blood pressure was accompanied by a declinein heart rate and an increase in plasma renin activity,epinephrine, and norepinephrine. Unfortunately, the pla¬cebo results were presented only for the biochemical data.Since blood pressure and heart rate tend to vary sponta¬neously, it is difficult to assess the apparent effect ofcaffeine on these measures. In addition, the statisticaltests used to compare the changes in blood pressure aftercaffeine and placebo ingestion were not stated. Othercomparisons were assessed by multiple Student's pairedt test, a method that would tend to overestimate thestatistical significance of any observed differences.

Extrapolation of the results from the study of Robertsonet al6 is also hampered by the experimental conditions andstudy population. The subjects, who were all young andcaffeine-naive, remained overnight in the clinical researchcenter before each study. At the start of the experiment,plasma norepinephrine values were exceptionally low, sug¬gesting that the subjects were under extreme basal con¬ditions with low levels of sympathetic nervous systemactivity. It is therefore not surprising that these individualsexperienced an increase in blood pressure (assuming no

changes with placebo) after caffeine ingestion coincidentwith increases in measurements of sympathetic activity.

The importance of previous caffeine ingestion and basalprecaffeine status can be seen from results of a secondstudy by Robertson and his coworkers.7 On this occasion,the subjects were also young (21 to 52 years) and hadabstained from caffeine for 21 days. Ingestion of caffeine(250 mg) was associated with an acute, statistically signif¬icant increase in blood pressure. However, the increasewas relatively small, and only the rise in systolic pressurewas reported. In addition, the blood pressure values aftercaffeine were compared with pretreatment levels, withoutany placebo data being presented.

Subsequent long-term administration of caffeine to thesesubjects for seven days demonstrated that the acute in¬crease in blood pressure was present only for the first twodoses. By the third day, blood pressure had returned toprecaffeine levels, and stopping caffeine ingestion afterseven days of repeated administration had no effect, withblood pressure remaining similar to precaffeine values.

Overlooking the méthodologie weaknesses of the twostudies of Robertson and his colleagues, we are left withthe following information about the cardiovascular effectsof caffeine. Young, healthy, caffeine-naive subjects experi-

Studies of the Effects of Caffeine on Blood Pressure After Acute or Long-term Administration

SourceAge, y/Characteristics

of Subjects Type of Study*Caffeine Dose,

mg/dEffect on

Blood PressureEffect on

Heart RateRobertson et al6

Robertson et al7

Ammon et al8

Izzo et al9

Whitsett et al10

Van Nguyen andMyers11

Pincomb et al12Smits et al13

Myers et al14

Smits et al15

Lang et al16

Lang et al17

Klatsky et al18

Prineas et al19

Periti et al20

Charney et al21

Piters et al25

9 21-30/caffeine-naive


10 20-30/7 d off caffeine

20 27±1(n = 12),62±2(n = 8)/caffeine-naive (n = 10),caffeine users ( = 10)

54 22-47/off caffeine 24 h


15 20-35/caffeine abstainers8 21-25/caffeine users

(1-2 doff caffeine)

70 36-75/7 d off caffeineafter myocardial infarction

12 17-38/caffeine users

1491 15-70/users and abstainers

6321 18-60/users and abstainers

80000

7311 37-57/male only

500 18-62

11 Mean, 37/caffeine users

17 40-74/angina patients,caffeine-users

DB, R, P,crossover,acute

DB, R, P,parallel,acute/long-term

DB, R, (DC),crossover,acute/long-term

DB, ( = 8 only),crossover,acute

Open-label, R,crossover,acute


DB, R, Open-label,

crossover,acute


DB, R, no P,acute

Cross-sectionalsurvey, long-term





Open-label,crossover

DB, R, (DC),crossover,acute

250

250

504

250

2.2 mg/kg

300

3.3 mg/kg250-350

(estimated)

300

350(estimated)

10 mg/kg

100-200(estimated)

Increase

Acute, increase;long-term, no change

Acute, increase;long-term, no change

Caffeine-naive,increase; caffeineusers, no change

Increase

Increase

IncreaseIncrease

Increase

Increase

Increase(diastolic only)

Increase(systolic only)

Negativelycorrelatedwith caffeine use

Negativelycorrelated withcaffeine use

Negativelycorrelated withcaffeine use

No change

No change

Increase/decrease

No change

No change

Decrease

Decrease

No change

No changeNo change

No change

Decrease

No change

No change

*DB indicates double-blind; R, randomized; P, placebo; and DC, decaffeinated coffee.

enee a small increase in blood pressure after ingesting oneor two doses of caffeine. The magnitude of this increase iscomparable with changes in blood pressure observed withconversation or other everyday activities. Thereafter, long-term caffeine administration is associated with a return ofblood pressure to normal. The acute increase in bloodpressure in the caffeine-naive state is accompanied by a

slight decline in heart rate, although this response may bedue to factors other than caffeine.

The importance of age, previous caffeine exposure, andthe role of the sympathetic nervous system in the cardio¬vascular effects of caffeine have been investigated exten¬sively by Izzo and his coworkers.9 Two groups of subjectswere recruited: individuals who did not regularly ingestcaffeine and those who had an average intake exceeding300 mg daily. The subjects were further divided into young(27 ± 1 years) and older (62 ± 2 years) subgroups. Using adouble-blind design, Izzo et al observed that caffeine

(250 mg) produced a significant increase in both systolicand diastolic blood pressure in caffeine-naive subjectscompared with individuals who regularly ingested caffeine.The increase in blood pressure showed a significant positivecorrelation (r = .69) with age. Heart rate declined slightlyby 2 to 3 beats per minute in both groups.

An apparent weakness in this study was the absence ofa placebo control for the changes in blood pressure andheart rate. The study conditions alone could have accountedfor some of the small changes in these measures, especiallyheart rate. However, there was a distinct difference in theblood pressure response in the caffeine-naive subjectscompared with those who ingested caffeine regularly.

Izzo et al9 also examined the effects of caffeine on plasmanorepinephrine, epinephrine, renin activity, and vasopres-sin. The only noteworthy finding was a significant increasein plasma epinephrine concentration in the caffeine-naivesubgroup similar to the changes reported earlier by Rob-

ertson et al. However, Izzo et al noted no significantchanges in norepinephrine concentration, plasma reninactivity, or vasopressin concentration in comparison withbaseline values. Further examination of the data revealedthat the increase in epinephrine concentration was morelikely to occur in younger subjects.

The acute pressor effect of caffeine in caffeine-naivesubjects has also been confirmed in a number of otherstudies. Ammon et al8 reported a caffeine-induced transientincrease in blood pressure after a period of abstention fromcaffeine-containing foods. Daily caffeine ingestion pro¬duced a small increase in blood pressure for several days,with levels falling thereafter and remaining at baseline forthe remainder of the four-week period of continued caffeineuse.

Whitsett et al10 administered caffeine after a minimum24-hour abstinence period to a varied group of subjectsranging from total caffeine abstainers to heavy coffeedrinkers. In this open, uncontrolled study, caffeine causeda slight increase in blood pressure and a decrease in heartrate. Previous caffeine use had little effect on the cardio¬vascular responses, suggesting that some of caffeine'stolerance may dissipate within 24 hours. However, theresults of this study must be interpreted with caution sincethere was no placebo control and measurements were madeby unblinded observers.

Smits et al13 also reported a small increase in bloodpressure (5/7 mm Hg) in young, healthy subjects who hadabstained from caffeine for one to two days. Despite therelatively small changes in blood pressure, there was a

significant negative correlation between basal plasma caf¬feine concentrations and a rise in systolic blood pressureafter acute dosing with caffeine, with patients who hadlow basal caffeine concentrations exhibiting the greatestincrease in blood pressure. However, their data suggestthat few regular consumers of caffeine-containing bever¬ages would have had a sufficiently low basal caffeineconcentration to show a pressor response to caffeineingested as part of their daily routine.

Pincomb et al12 also noted a small increase in bloodpressure after caffeine administration to young healthyvolunteers who had abstained from caffeine for one toseven days. Findings from two recently completed studiesare consistent with these observations. In one study,11 theadministration of caffeine (300 mg) to ten young, healthy,caffeine-naive subjects significantly increased blood pres¬sure by 11/9 mm Hg compared with placebo. In a secondstudy involving 70 relatively caffeine-naive patients sevento ten days after myocardial infarction, caffeine (300 mg)significantly increased blood pressure by 9/8 mm Hg incomparison with changes noted after placebo.14 Heart ratedeclined slightly after caffeine in both studies, but thechanges were not significantly different from the fall inheart rate noted after placebo.

Despite differences in methods, patient populations, andscientific rigor, there appears to be general agreement inthe literature with respect to caffeine's cardiovasculareffects. Caffeine administration causes a small increase inblood pressure that is most apparent in young caffeineabstainers given a single dose equivalent to several cupsof coffee. Individuals who regularly ingest caffeine showlittle or no blood pressure response after acute dosing.Even caffeine nonusers rapidly develop tolerance to caf¬feine's effects after two or three days of caffeine use. Oldersubjects may respond with less of an increase in bloodpressure regardless of previous caffeine status.

Although caffeine is generally recognized as a stimulant,most reports are in agreement that it does not increase

heart rate. Instead, its ingestion is almost uniformlyassociated with a small decline in resting heart rate,although the changes do not significantly differ from thoseobserved after placebo in studies with a placebo control.1114

Large Epidemiologie StudiesThe studies cited above examined the cardiovascular

effects of caffeine in relatively small groups of subjects.The possible relationship between caffeine intake and bloodpressure has also been the subject of several large epide¬miologie surveys with rather disparate findings.

Lang et al16 recorded coffee, tea, and cigarette consump¬tion in addition to blood pressure measurements in 1491residents of Algiers, Algeria. Both tea and coffee drinkersexhibited a slightly higher (2 to 3 mm Hg) diastolic bloodpressure than did abstainers, with the systolic bloodpressure being similar for both groups. The small differencein diastolic blood pressure was partly accounted for by agebut remained statistically significant after multivariateanalysis. In a similar survey in the Paris region involving6321 adults, Lang et al17 found no difference in diastolicblood pressure between coffee users and abstainers. How¬ever, systolic blood pressure was significantly correlatedwith coffee consumption, although the overall increase inblood pressure before adjustment for other variables wasonly 3.5 mm Hg.

Two large American surveys also reported on a possibleassociation between caffeine use and blood pressure. In80 000 persons enrolled in the Kaiser Permanente MedicalCare Program, coffee and tea use were both significantly"negatively" correlated with systolic but not diastolic bloodpressure.18 This association remained after correction forother variables. Similarly, Prineas et al19 recorded bloodpressure and coffee consumption in 7311 residents of themetropolitan Minneapolis-St Paul area. Once again, coffeeuse was "negatively" correlated with blood pressure, al¬though the results of multivariate analysis were not re¬ported. This rather surprising negative association be¬tween caffeine use and blood pressure was recentlyconfirmed in another cross-sectional survey of 500 Italianhealth care workers.20 In this study, there was a statisticallysignificant mean reduction in systolic and diastolic bloodpressure of 0.80 and 0.48 mm Hg, respectively, per cup ofcoffee ingested.

On balance, there is little epidemiologie evidence tosupport a link between caffeine use and increased bloodpressure. In the studies by Lang and his coworkers,contradictory findings were observed, whereas the largeAmerican surveys found either no significant relationshipbetween caffeine and blood pressure or a negative associ¬ation between these variables.

Continued Use of CaffeineThree small studies examined the effects of continued

caffeine use on blood pressure. Both Robertson et al7 andAmmon et al8 found that repeated ingestion of caffeine didnot affect blood pressure after two to three days or atseven and 28 days. Charney et al21 also found no significantchanges in blood pressure in 11 normal coffee-drinkingsubjects after a rather high dose (10 mg/kg) of caffeine incomparison with placebo.

Mechanisms of Presser EffectSeveral mechanisms have been proposed to explain

caffeine's putative pressor effect. Caffeine and other meth-ylxanthines appear to exert a positive inotropic effect oncardiac muscle. Theories that have been advanced toexplain this action include an increase in cyclic adenosine

monophosphate levels via inhibition of phosphodiesterase,caffeine-induced release of calcium from the sarcoplasmicreticulum, and antagonism of endogenous adenosine recep¬tors.2224 In humans, Pincomb et al12 reported that thepressor effect of caffeine was due to a progressive rise invascular resistance and not an increase in cardiac outputor contractility.

The pressor effect of caffeine has also been attributed toan increase in sympathetic activity. In their 1978 publica¬tion involving young, healthy, caffeine-naive subjects, Rob¬ertson et al6 reported a marked rise in both plasmanorepinephrine and epinephrine concentrations in associ¬ation with an acute increase in blood pressure. However,the subjects in this study appear to have been in an

extremely basal state, with the mean resting plasmanorepinephrine being less than half the value observed insimilar studies.7-914 Others have subsequently reportedlittle15 or no91314 increase in plasma norepinephrine concen¬tration after acute administration of caffeine, suggestingthat caffeine does not cause a clinically relevant increasein sympathetic activity. Unlike norepinephrine, plasmaepinephrine appears to exhibit a small but relativelyconsistent increase after caffeine administration in caf¬feine-naive subjects.91315 This increase may be due to adirect effect of caffeine on the adrenal medulla, since itdoes not seem to be mediated via the sympathetic nervous

system, and plasma norepinephrine values are unchanged.Further evidence against a clinically important sympa¬

thetic response to caffeine is the absence of any increasein heart rate after its acute administration. In almost everystudy, regardless of previous caffeine use, subjects haveexhibited either no change or a slight fall in heart rateafter caffeine.715·25 A marked caffeine-induced tachycardiadid occur after the ingestion of large amounts of caffeinewith suicidal intent.26

Interaction of Caffeine WithOther Agents

There are some special circumstances where caffeinemight affect blood pressure by interacting with otheragents. For instance, many coffee and tea drinkers alsosmoke cigarettes. It would be of interest to know ifcombined smoking and caffeine ingestion has any effect onblood pressure.

Looking first at the effects of smoking itself on bloodpressure, there is some evidence to suggest that inhalationof cigarette smoke may increase blood pressure.2729 Studieshave generally involved young subjects who smoked twocigarettes in rapid succession after a period of abstinencefrom smoking (usually eight to 12 hours).26·27 The resultsindicated that smoking causes a small, transient increasein blood pressure that persists for up to 15 minutes. Thisincrease has been attributed to nicotine.27 However, middle-aged and older smokers do not exhibit any increase in bloodpressure on resumption of smoking after eight to 12 hoursof abstinence, even after smoking a total of six cigarettesover 2V2 hours.30 Smoking is also not considered a cause ofhypertension, nor is stopping smoking recommended spe¬cifically as an antihypertensive therapy.31 Thus, only a

small, transient increase in blood pressure would be antic¬ipated after smoking one to two cigarettes, with no changesoccurring thereafter.

This expectation was confirmed in a study by Freestoneand Ramsay28 in which the cardiovascular effects of smok¬ing, coffee, and combined smoking and coffee were exam¬ined in 16 hypertensive patients who were all habitualcigarette smokers and caffeine consumers. Eight of thesubjects were being treated with a thiazide diuretic, and

the rest were receiving no medication. Using a 2x2factorial design, the investigators demonstrated the car¬diovascular effects of caffeine, smoking, both interventions,and placebo. Smoking alone increased blood pressure forup to 15 minutes, an observation consistent with findingsfrom other studies.27·28·30 Caffeine alone had little effect onblood pressure, but combined caffeine ingestion and smok¬ing significantly increased blood pressure by a mean of11/8 mm Hg over two hours. Thus, smoking and caffeine inhypertensive patients may increase blood pressure slightlyin the morning after overnight abstention from both habits.

Freestone and Ramsay28 noted that epidemiologie studiesdo not demonstrate a positive relationship between smok¬ing and blood pressure. Rather, smokers generally haveslightly lower blood pressure readings than do abstainers,a difference perhaps related to lower body weights. Datafrom the Framingham study32 do not support a link betweenblood pressure and combined smoking and caffeine use.

Heavy coffee drinkers who smoked had the same bloodpressure as did nonsmokers who did not consume caffeineregularly. Thus, the resumption of smoking and caffeine inthe morning may increase blood pressure slightly withoutbeing detected in large epidemiologie studies.

Caffeine and the Treatment of HypertensionIn the study of Freestone and Ramsay,28 the hypertensive

patients receiving diuretics exhibited the same bloodpressure responses as did untreated patients, suggestingthat thiazide diuretics do not interact with smoking orcaffeine. ß-Blockers are also commonly used in the treat¬ment of hypertension; Smits and coworkers15 examined theeffects of coffee ingestion in normotensive subjects receiv¬ing these drugs. In this study, a cup of percolated coffeecontaining 24 g of ground coffee was administered to 12normotensive subjects after pretreatment with the non-selective ß-blocker propranolol, the cardioselectiveß-blocker metoprolol, and placebo. All subjects had ab¬stained from caffeine for at least 17 hours. Caffeine wasassociated with a small increase in blood pressure on allthree days, with propranolol and metoprolol pretreatmenthaving no effect on the response to caffeine. Thus, blockadeof ß-adrenoeeptors, leaving "unopposed" a-adrenoceptorresponsiveness, did not augment the apparent pressorresponse to caffeine.

The Joint National Committee on Detection, Evaluation,and Treatment of High Blood Pressure recently reportedon nonpharmacologic approaches to the control of hyper¬tension.31 The committee acknowledged the small, tran¬sient increase in blood pressure after caffeine administra¬tion to caffeine-naive subjects but concluded that caffeineis not associated "with persistently elevated blood pressureor increased frequency of hypertension" and that it doesnot elevate levels of plasma catecholamines, vasopressin,or renin activity on a long-term basis.

If caffeine does not increase blood pressure and causethe heart to beat faster, why do so many13 assume thecontrary to be true? Several cups of coffee or tea doenhance mental alertness33 and perhaps increase cardiacinotropism,22·24 with a resultant subjective sensation thatthe heart is beating more vigorously, a situation in whichthe blood pressure could reasonably be expected to rise.This may explain why reviews of caffeine, especially in thelay press, are left to conclude that "if caffeine is not badfor you, it should be."4

Other Cardiovascular Effects

Although the main purpose of this article is to reviewthe effects of caffeine on blood pressure, some mention

should be made of its other effects on the cardiovascularsystem. Caffeine has long been suspected of causing cardiacarrhythmias; however, most of the supporting evidence hasbeen either anecdotal or derived from in vitro or animalstudies. In a recent report,14 my coworkers and I examinedthe effects of caffeine (300 mg) on the development ofventricular arrhythmias in 70 patients who had recentlyexperienced a myocardial infarction. In this randomized,prospective, placebo-controlled study, caffeine did notincrease the frequency or severity of ventricular arrhyth¬mias. There was also no evidence of any caffeine-inducedsupraventricular arrhythmias, although isolated atrial pre¬mature beats were not quantitated. In a similar study,Grayboys et al ( . . Grayboys, MD, unpublished data,1987) showed that caffeine did not increase arrhythmiaoccurrence in patients who were already experiencingventricular ectopie activity. It would now appear thatcaffeine does not generally cause cardiac arrhythmias,although the possibility that it might induce rhythm dis¬turbances in rare, susceptible individuals cannot be ex¬cluded.

Long-term ingestion of caffeine has also been considereda possible cause of increased cardiovascular mortality.La Croix et al34 reported that heavy coffee consumptionover a 19- to 35-year period increased the risk of develop¬ment of coronary artery disease by twofold to threefold.However, other epidemiologie studies3538 failed to find any

association between coffee use and the presence of cardio¬vascular disease. One of the méthodologie problems en¬countered in these studies is the separation of long-termcigarette use from caffeine consumption, since the two areoften closely associated in the same individual. On thebasis of current evidence, it would seem premature toimplicate long-term caffeine use as contributing factor inthe development of ischemie heart disease.

CONCLUSIONS

This review of the literature indicates that caffeine doesnot cause any persistent increase in blood pressure. Indi¬viduals who do not regularly consume caffeine in the dietmay experience slight increases in blood pressure whenexposed to caffeine, but tolerance rapidly develops, withthe blood pressure returning to previous levels.

What advice should a family physician offer to thehypertensive patient who regularly consumes caffeine andis worried about its effect on blood pressure? On the basisof existing scientific knowledge, it would seem most appro¬priate to permit moderate use of coffee, tea, and othercaffeine-containing beverages. Careful attention to otherlife-style factors, such as high sodium intake or obesity, isprobably much more important in promoting optimumcontrol of high blood pressure than is concern about caffeineconsumption.

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effects of caffeine on blood pressure

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