Scientific Opinion on the safety of caffeine

There are no studies on the health effects of single doses of caffeine consumed by pregnant women prior to intense physical exercise.

“There are no studies on the health effects of single doses of caffeine consumed by pregnant women prior to intense physical exercise.”

• Also stated in: § 5.2. Pregnant women 5.2.1. Single doses of caffeine · plain

  “There are no studies on the health effects of single doses of caffeine consumed by pregnant women prior to intense physical exercise.”

Data to characterise the risk of habitual caffeine consumption in pregnant women are scarce.

“Data to characterise the risk of habitual caffeine consumption in this population subgroup are scarce.”

At doses of up to 200 mg consumed by lactating women, daily caffeine intakes by the breastfed infant would not exceed 0.3 mg/kg bw, which is 10-fold below the lowest dose of 3 mg/kg bw tested in a dose finding study and at which no adverse effects were observed in the majority of infants.

“At these doses of caffeine, daily caffeine intakes by the breastfed infant would not exceed 0.3 mg/kg bw, which is 10-fold below the lowest dose of 3 mg/kg bw tested in a dose finding study and at which no adverse effects were observed in the majority of infants.”

In 7 out of 13 countries, the 95th percentile of daily caffeine intake from foods and beverages exceeded 400 mg.

“In 7 out of 13 countries, the 95 th percentile of daily caffeine intake from foods and beverages exceeded 400 mg.”

Single doses of 100 mg (about 1.4 mg/kg bw for a 70-kg adult) of caffeine may increase sleep latency and reduce sleep duration in some adult individuals, particularly when consumed close to bedtime.

“Single doses of 100 mg (about 1.4 mg/kg bw for a 70-kg adult) of caffeine may increase sleep latency and reduce sleep duration in some adult individuals, particularly when consumed close to bedtime.”

Like for adults, caffeine doses of about 1.4 mg/kg bw may increase sleep latency and reduce sleep duration in some children and adolescents, particularly when consumed close to bedtime.

“Like for adults, caffeine doses of about 1.4 mg/kg bw may increase sleep latency and reduce sleep duration in some children and adolescents, particularly when consumed close to bedtime.”

• Also stated in: § 5.4.1. Single doses of caffeine · hedged

  “The Panel notes that, like for adults, caffeine doses of about 1.4 mg/kg bw may increase sleep latency and reduce sleep duration in some children and adolescents, particularly when consumed close to bedtime.”

There are no data available to characterise the risk of single doses of caffeine from all sources consumed by children and adolescents.

“There are no data available to characterise the risk of single doses of caffeine from all sources consumed by children and adolescents.”

No new data have become available on these or other clinical outcomes which could justify modifying the conclusions on habitual caffeine consumption up to 400 mg per day.

“and no new data have become available on these or other clinical outcomes which could justify modifying these conclusions.”

In these studies, the contribution of energy drinks to total caffeine intake was low (about 2%).

“In these studies, the contribution of”

In Ireland and the UK, tea was the main source of caffeine, contributing 59% and 57%, respectively, to total caffeine consumption.

“In Ireland and the UK, tea was the main source of caffeine, which contributed 59 and 57 %, respectively, to total caffeine consumption (Appendix E).”

Data on pregnant women are available for Latvia only (n = 1002).

“Data on pregnant women are available for Latvia only (n = 1 002).”

For toddlers, 95th percentile caffeine intake ranged from 0.1 to 3.5 mg/kg bw per day.

“The 95 th percentile ranged from 0.1 to 3.5 mg/kg bw per day.”

Daily caffeine intake from all sources could be estimated for adults from 16 Member States.

“Daily caffeine intake from all sources could be estimated for adults from 16 Member States.”

Mean daily caffeine intake for toddlers in Belgium was 1.1 mg/kg bw per day.

“Mean daily caffeine intake was 1.1 mg/kg bw per day in this country (Appendix B).”

For children aged 3 to <10 years, mean daily caffeine intake from all sources ranged from 0.2 to 2.0 mg/kg bw per day.

“Mean daily intake of caffeine from all sources ranged from 0.2 to 2.0 mg/kg bw per day.”

The main sources of caffeine in the diet include coffee, tea, caffeinated soft drinks (including 'energy drinks') and chocolate.

“The main sources of caffeine in the diet include coffee, tea, caffeinated soft drinks (including “energy drinks”) and chocolate.”

For children aged 3 to <10 years, 17 surveys were available.

“For children aged 3 to < 10 years, 17 surveys were available.”

Data on lactating women are available from only a small survey in Greece (n = 65).

“Data on lactating women are available from only a small survey in Greece (n = 65).”

For toddlers, the highest 95th percentile of caffeine intake per kg bw on a single day when considering all days recorded was 7.1 mg/kg bw.

“For toddlers, the highest 95 th percentile of caffeine intake per kg bw on a single day when considering all days recorded was 7.1 mg/kg bw (Appendices C and D).”

When considering only coffee consumption days, the highest 95th percentile of caffeine intake from coffee on a single day for adolescents was 445 mg.

“When considering only coffee consumption days, the highest 95 th percentile of caffeine intake from coffee on a single day was 445 mg (Appendix C).”

For children aged 3 to <10 years, 95th percentile caffeine intake ranged from 1.2 to 4.6 mg/kg bw per day.

“The 95 th percentile ranged from 1.2 to 4.6 m/kg bw per day.”

For adults, the highest 95th percentile of caffeine intake on a single day was 809 mg (10.8 mg/kg bw).

“For adults, the highest 95 th percentile of caffeine intake on a single day was 809 mg (10.8 mg/kg bw) (Appendices C and D).”

Cola beverages and energy drinks were negligible as sources of caffeine in the elderly and very elderly in all surveys.

“Cola beverages and energy drinks were negligible as sources of caffeine in these population groups in all surveys.”

For toddlers, mean daily caffeine intake ranged from 0 to 2.1 mg/kg bw per day.

“Mean daily intakes of caffeine ranged from 0 to 2.1 mg/kg bw per day (Table 2, Appendix B).”

Daily caffeine intakes from all sources could be estimated for adolescents from 13 Member States.

“Daily caffeine intakes from all sources could be estimated for adolescents from 13 Member States.”

Variability in caffeine levels for different foods and beverages, in particular for coffee drinks, espresso coffee and tea, has been noticed within the same product and for the same country.

“Variability in caffeine levels for different foods and beverages, in particular for coffee drinks, espresso coffee and tea, have been noticed within the same product and for the same country.”

There were large differences among countries regarding the contribution of different food sources to total caffeine intake in adolescents.

“There were large differences among countries regarding the contribution of different food sources to total caffeine intake (Appendix E).”

For children aged 3 to 10 years, the highest 95th percentile of caffeine intake from all sources on a single day was estimated to be 5.7 mg/kg bw.

“For children aged 3 to 10 years, the highest 95 th percentile of caffeine intake from all sources on a single day was estimated to be 5.7 mg/kg bw (Appendices C and E).”

Data on caffeine intakes from energy drinks in a single session were available from 16 Member States.

“Data were available from 16 Member States (Zucconi et al., 2013).”

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Even using a conservative approach, the contribution of 'energy drinks' to total caffeine intakes was very low in all surveys published before 2000.

“Even using this conservative approach, the contribution of “energy drinks” to total caffeine intakes was very low in all surveys published before 2000.”

On a per kg bw basis, these intakes for adolescent energy drink consumers were estimated to be 2.9 and 7.2 mg.

“On a per kg bw basis, these intakes were estimated to be 2.9 and 7.2 mg, respectively.”

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On a per kg bw per day basis, mean caffeine intakes for adolescents ranged from 0.4 to 1.4 mg/kg bw per day.

“On a per kg bw per day basis, the mean intakes ranged from 0.4 to 1.4 mg/kg bw per day.”

In most surveys, coffee was the predominant source of caffeine for the adult population, contributing between 40 and 94% to total caffeine intake.

“In most surveys, coffee was the predominant source of caffeine for the adult population and contributed between 40 and 94 % to total caffeine intake.”

The scientific publications identified almost exclusively reported no relationship or an inverse relationship between habitual caffeine intake and other adverse health effects.

“The scientific publications identified almost exclusively reported no relationship or an inverse relationship between habitual caffeine intake and other adverse health effects.”

When considering only coffee consumption days, the highest 95th percentile of caffeine intake from coffee on a single day for adults was 890 mg.

“When considering only coffee consumption days, the highest 95 th percentile of caffeine intake from coffee on a single day was 890 mg.”

There were no major differences among surveys and publications from different countries regarding average caffeine levels in foods and beverages.

“The Panel notes that there were no major differences among surveys and publications from different countries regarding average caffeine levels in foods and beverages (Table 1).”

The 95th percentile of caffeine intake for adolescents varied between 1.5 and 4.1 mg/kg bw per day.

“The 95 th percentile varied between 1.5 and 4.1 mg/kg bw per day (Appendix B).”

About 41% of adolescent energy drink consumers (about 28% of all respondents) declared that they usually consume energy drinks in relation to sport activities.

“About 41 % of adolescent”

About 52% of adult energy drink consumers (15% of all respondents) declared that they usually consume energy drinks before/in association with/after sports activities.

“About 52 % of adult”

No single prospective cohort study reported an increased risk of heart failure associated with habitual coffee consumption.

“The Panel also notes that no single prospective cohort study reported an increased risk of heart failure associated with habitual coffee consumption.”

No single prospective cohort study reported an increased risk of stroke associated with habitual coffee or tea consumption in the general adult population.

“The Panel also notes that no single prospective cohort study reported an increased risk of stroke associated with habitual coffee or tea consumption in the general adult population.”

The estimated proportion of children with intakes exceeding 3 mg/kg bw per day of caffeine from foods and beverages in the countries where the 95th percentile exceeded 3 mg/kg bw ranged from 6% to about 13%.

“The estimated proportion of children with intakes exceeding 3 mg/kg bw per day of caffeine from foods and beverages in these countries ranged from 6 % to about 13 % (Appendix B).”

In the countries where the 95th percentile of caffeine intake exceeded 3 mg/kg bw per day for adolescents, the estimated proportion of the adolescent population exceeding caffeine intakes of 3 mg/kg bw per day from food and beverages ranged from 5 to 10%.

“In these countries, the estimated proportion of the adolescent population exceeding caffeine intakes of 3 mg/kg bw per day from food and beverages ranged from 5 to 10 % (Appendix B).”

For only one out of nine Member States did the 95th percentile of caffeine intake from all sources exceed 3 mg/kg bw per day for toddlers.

“For only one out of nine Member States did the 95 th percentile of caffeine intake from all sources exceed 3 mg/kg bw per day.”

The proportion of days in which daily intakes of caffeine from all sources exceed 3 mg/kg bw ranges from 7% to 37% for toddlers.

“The proportion of days in which daily intakes of caffeine from all sources exceeds 3 mg/kg bw ranges from 7 % to 37 % (Appendix D).”

Coffee was the main source of dietary caffeine in the seven countries for which the 95th percentile of daily caffeine intake exceeded 400 mg.

“The Panel notes that coffee was the main source of dietary caffeine in the seven countries for which the 95 th percentile of daily caffeine intake exceeded 400 mg, and that the use of a mean value for the caffeine content in coffee on a volume basis may not accurately reflect caffeine intakes in all countries.”

The proportion of days on which daily intakes of caffeine from food and beverages exceed 3 mg/kg bw in the countries where the 95th percentile exceeded 3 mg/kg bw ranges from about 7% to about 12% for adolescents.

“The proportion of days on which daily intakes of caffeine from food and beverages exceeds 3 mg/kg bw in these countries ranges from about 7% to about 12 % (Appendix D).”

About 6% of the toddlers had a daily consumption greater than 3 mg/kg bw in the country where the 95th percentile of caffeine intake from all sources exceeded 3 mg/kg bw per day.

“About 6 % of the toddlers had a daily consumption > 3 mg/kg bw in that country (Appendix B).”

In the countries where the 95th percentile of daily caffeine intake exceeded 400 mg, the estimated proportion of the adult population exceeding daily intakes of 400 mg ranged from about 6% to almost one-third (32.9%).

“In these countries, the estimated proportion of the adult population exceeding daily intakes of 400 mg ranged from about 6 % to almost one-third (32.9 %) (Appendix B).”

For 3 out of 10 Member States, the estimated 95th percentile of caffeine intake from all sources on a single day exceeded 3 mg/kg bw for toddlers.

“For 3 out of 10 Member States, the estimated 95 th percentile of caffeine intake from all sources on a single day exceeded 3 mg/kg bw.”

For 6 out of 16 Member States, the estimated 95th percentile of caffeine intake from foods and beverages on a single day exceeded 3 mg/kg bw for adolescents.

“For 6 out of 16 Member States, the estimated 95 th percentile of caffeine intake from foods and beverages on a single day exceeded 3 mg/kg bw.”

For 7 out of 13 Member States, estimates of the 95th percentile of daily caffeine intake from foods and beverages exceeded 400 mg.

“For 7 out of 13 Member States, estimates of the 95 th percentile of daily caffeine intake from foods and beverages exceeded 400 mg.”

For 9 out of 16 Member States, the estimated 95th percentile of caffeine intake from foods and beverages on a single day exceeded 3 mg/kg bw for children.

“For 9 out of 16 Member States, the estimated 95 th percentile of caffeine intake from food and beverages on a single day exceeded 3 mg/kg bw.”

There are no data available to characterise the risk of single doses of caffeine consumed by adults in relation to physical exercise.

“There are no data available to characterise the risk of single doses of caffeine consumed by adults in relation to physical exercise.”

For 5 out of 13 Member States, the 95th percentile of caffeine intake from food and beverages exceeded 3 mg/kg bw per day for adolescents.

“For 5 out of 13 Member States, the 95 th percentile of caffeine intake from food and beverages exceeded 3 mg/kg bw per day.”

As only single doses of caffeine of 200 mg have been tested in relation to MBF, a dose-response relationship cannot be derived on the basis of the data available.

“As only single doses of caffeine of 200 mg have been tested in relation to this outcome, a dose-response relationship cannot be derived on the basis of the data available.”

The proportion of days on which daily intakes of caffeine from food and beverages exceed 3 mg/kg bw in the countries where the 95th percentile exceeded 3 mg/kg bw ranges from about 6% to about 15% for children.

“The proportion of days on which daily intakes of caffeine from food and beverages exceeds 3 mg/kg bw in these countries ranges from about 6 % to about 15 % (Appendix D).”

No women in the small survey of lactating women (n = 65) consumed more than 400 mg of caffeine per day.

“No women in that small survey (n = 65) consumed more than 400 mg of caffeine per day.”

About 6.5% of the women in the only survey available for pregnant women (n = 1002) had daily caffeine intakes greater than 200 mg per day.

“About 6.5 % of the women in that survey (n = 1 002) had daily caffeine intakes > 200 mg per day.”

No studies are available in pregnant women or middle-aged/elderly subjects undertaking intense physical exercise.

“The Panel also notes that no studies are available in pregnant women or middle-aged/elderly subjects undertaking intense physical exercise.”

Chocolate beverages were important contributors to total caffeine intakes in children and toddlers in most countries.

“The Panel notes that chocolate beverages were important contributors to total caffeine intakes in this age group in most countries, and that the use of a conservative caffeine value for this food category may have led to an overestimation of caffeine intakes in children.”

The information available for children and adolescents on the relationship between caffeine intakes and health outcomes is insufficient to derive a safe level of caffeine intake.

“The Panel notes that the information available for this population subgroup on the relationship between caffeine intakes and health outcomes is insufficient to derive a safe level of caffeine intake.”

There is an absence of data for repeated caffeine doses in relation to the majority of health outcomes discussed for single doses of caffeine.

“The Panel notes the absence of data for repeated caffeine doses in relation to the majority of health outcomes discussed for single doses of caffeine.”

No health concerns in relation to acute toxicity, bone status, cardiovascular health, cancer risk or male fertility have been raised by other bodies in previous assessments for habitual caffeine consumption up to 400 mg per day.

“No health concerns in relation to acute toxicity, bone status, cardiovascular health, cancer risk or male fertility have been raised by other bodies in previous assessments for this level of habitual caffeine consumption”

The same amount of caffeine (up to 200 mg) does not give rise to safety concerns when consumed less than two hours prior to intense physical exercise under normal environmental conditions.

“The same amount does not give rise to safety concerns when consumed < 2 hours prior to intense physical exercise under normal environmental conditions.”

• Also stated in: § Single doses of caffeine · plain

  “The same amount of caffeine does not give rise to safety concerns when consumed less than two hours prior to intense physical exercise under normal environmental conditions.”

A level of no safety concern of 3 mg/kg bw per day (i.e. the level of no concern derived for single doses of caffeine for adults) is proposed for habitual caffeine consumption by children and adolescents.

“A level of no safety concern of 3 mg/kg bw per day (i.e. the level of no concern derived for single doses of caffeine for adults) is proposed for habitual caffeine consumption by children and adolescents.”

• AssumptionRests on an assumption: Caffeine clearance in children and adolescents is at least that of adults.

Other common constituents of energy drinks at typical concentrations (about 300-320, 4 000 and 2 400 mg/L of caffeine, taurine and D-glucurono-γ-lactone, respectively) would not affect the safety of single doses of caffeine up to 200 mg.

“Other common constituents of”

Alcohol consumption at doses up to about 0.65 g/kg bw, leading to a blood alcohol concentration of about 0.08%, would not affect the safety of single doses of caffeine up to 200 mg from any dietary source, including energy drinks.

“Alcohol consumption at doses up to about 0.65 g/kg bw, leading to a blood alcohol concentration of about 0.08 %, would not affect the safety of single doses of caffeine up to 200 mg from any dietary source, including”

For children and adolescents, the information available is insufficient to derive a safe caffeine intake.

“For children and adolescents, the information available is insufficient to derive a safe caffeine intake.”

• Also stated in: § Children and adolescents · plain

  “The information available for this population subgroup on the relationship between caffeine intakes and health outcomes is insufficient to derive a safe level of caffeine intake.”

The human intervention studies on which the conclusions on single doses are based were primarily conducted with caffeine supplements for most of the outcomes assessed (changes in myocardial blood flow, hydration status, body temperature, perceived exertion/effort during exercise, sleep).

“The human intervention studies on which these conclusions are based were primarily conducted with caffeine supplements for most of the outcomes assessed (i.e.changes in myocardial blood flow, hydration status, body temperature, perceived exertion/effort during exercise, sleep).”

Up to alcohol doses of about 0.65 g/kg bw, caffeine is unlikely to mask the subjective perception of alcohol intoxication.

“Up to these levels of intake, caffeine is unlikely to mask the subjective perception of alcohol intoxication.”

• Also stated in: § 5.1.2. Single doses of caffeine in combination with other common constituents of "energy drinks", alcohol and p-synephrine · hedged

  “Up to these levels of intake, caffeine is unlikely to mask the subjective perception of alcohol intoxication.”

Habitual caffeine consumption up to 400 mg per day does not give rise to safety concerns for non-pregnant adults.

“Habitual caffeine consumption up to 400 mg per day does not give rise to safety concerns for non-pregnant adults.”

• Also stated in: § Habitual caffeine consumption · plain

  “Caffeine intakes from all sources up to 400 mg per day (about 5.7 mg/kg bw per day for a 70-kg adult) consumed throughout the day do not give rise to safety concerns for healthy adults in the general population, except pregnant women (see below).”

Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) from all sources do not give rise to safety concerns for the general healthy adult population.

“Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) do not give rise to safety concerns.”

• Also stated in: § Single doses of caffeine · plain

  “Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) from all sources do not give rise to safety concerns for the general healthy adult population.”

Up to the levels of typical energy drink constituents, other common constituents are not expected to adversely interact with caffeine on its effects on the cardiovascular system, the central nervous system or hydration status.

“Up to these levels of intake, other common constituents of”

Caffeine intakes of no concern derived for acute caffeine consumption by adults (3 mg/kg bw per day) may serve as a basis to derive single doses of caffeine and daily caffeine intakes of no concern for children and adolescents.

“The Panel considers that caffeine intakes of no concern derived for acute caffeine consumption by adults (3 mg/kg bw per day) may serve as a basis to derive single doses of caffeine and daily caffeine intakes of no concern for these population subgroups.”

• Also stated in: § Single doses of caffeine · hedged

  “Single doses of caffeine of no concern derived for adults (3 mg/kg bw per day) may also apply to children, considering that caffeine clearance in children and adolescents is at least that of adults, and that the limited studies available on the acute effects of caffeine on anxiety and behaviour in children and adolescents support this level of no concern.”

• AssumptionRests on an assumption: Caffeine clearance in children and adolescents is at least that of adults.

Habitual caffeine consumption up to 200 mg per day by pregnant women does not give rise to safety concerns for the fetus.

“Habitual caffeine consumption up to 200 mg per day by pregnant women does not give rise to safety concerns for the fetus.”

• Also stated in: § Habitual caffeine consumption · plain

  “Caffeine intakes from all sources up to 200 mg per day consumed throughout the day by pregnant women in the general population do not give rise to safety concerns for the fetus.”

Single doses of caffeine and habitual caffeine intakes up to 200 mg consumed by lactating women do not give rise to safety concerns for breastfed infants.

“Single doses of caffeine and habitual caffeine intakes up to 200 mg consumed by lactating women do not give rise to safety concerns for breastfed infants.”

• Also stated in: § Single doses of caffeine and habitual caffeine consumption · plain

  “Single doses of caffeine up to 200 mg and habitual caffeine consumption at doses of 200 mg per day consumed by lactating women in the general population do not give rise to safety concerns for the breastfed infant.”

Single doses of caffeine which are of no safety concern for non-pregnant adults do not apply to pregnant women performing physical exercise.

“With regard to the different kinetics of caffeine in this population subgroup, single doses of caffeine which are of no safety concern for non-pregnant adults do not apply to pregnant women performing physical exercise.”

Only two studies (the Netherlands and Ireland) with a sufficient number (≥ 60) of subjects who had consumed 'energy drinks' were available to estimate statistically robust 95th percentiles.

“(e): Only two studies (the Netherlands and Ireland) with a sufficient number (≥ 60) of subjects who had consumed “energy drinks”, were available to estimate statistically robust 95 th percentiles.”

These surveys do not provide information about the consumption of caffeine-containing food supplements.

“These surveys do not provide information about the consumption of caffeine-containing food supplements.”

Only one study (the Netherlands) with a sufficient number (≥ 60) of subjects who had consumed 'energy drinks' was available to estimate a statistically robust 95th percentile.

“(d): Only one study (the Netherlands) with a sufficient number (≥ 60) of subjects who had consumed “energy drinks”, was available to estimate a statistically robust 95 th percentile.”

The highly variable caffeine concentrations in coffee beverages depend on the manufacturing process, on the type of coffee beans used and on the type of preparation (e.g. drip coffee, espresso).

“The highly variable caffeine concentrations in coffee beverages depend on the manufacturing process, on the type of coffee beans used and on the type of preparation (e.g.drip coffee, espresso) (Waizenegger et al., 2011).”

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Differences between surveys regarding contribution of different caffeine sources to total caffeine intakes in adolescents could be explained, at least in part, by different mean age of adolescents studied and by dietary habits.

“Differences between surveys regarding the contribution of different caffeine sources to total caffeine intakes could be explained, at least in part, by the different mean age of the adolescents studied in the different surveys and by dietary habits.”

'Energy drink consumers' may not be representative of the general population with respect to caffeine intake from all sources.

“(i) “energy drink consumers” may not be representative of the general population with respect to caffeine intake from all sources;”

The volume of distribution of caffeine is 0.671 L/kg bw.

“The volume of distribution is 0.671 L/kg bw (Abernethy and Todd, 1985).”

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In normotensive subjects, a single caffeine dose of 200-250 mg increases systolic blood pressure by 3-14 mmHg and diastolic blood pressure by 4-13 mmHg.

“A single dose of caffeine (200-250 mg, equivalent to two to three cups of coffee) was found to increase systolic blood pressure (SBP) by 3-14 mmHg and diastolic blood pressure (DBP) by 4-13 mmHg in normotensive subjects.”

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Lower CYP1A2 activity was found in women taking oral contraceptives.

“A lower CYP1A2 activity was found in women taking oral contraceptives.”

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In subjects with hypertension, single caffeine doses of 200 to 300 mg induce a mean increase in systolic blood pressure of 8.1 mmHg and diastolic blood pressure of 5.7 mmHg, observed in the first 60 minutes after intake and persisting up to 180 minutes afterwards.

“single caffeine doses of 200 to 300 mg induced a mean increase in SBP and DBP of 8.1 mmHg (95 % confidence interval (CI) = 5.7-10.6 mmHg) and 5.7 mmHg (95 % CI = 4.1-7.4mmHg), respectively, which was observed in the first 60 minutes after intake and persisted up to 180 minutes afterwards.”

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The Panel considers that, from the information available, no conclusions can be drawn on whether or not the simultaneous consumption of p-synephrine modulates the pressor effects of caffeine, and if so to what extent or at what doses this occurs.

“The Panel considers that, from the information available, no conclusions can be drawn on whether or not the simultaneous consumption of p-synephrine modulates the pressor effects of caffeine, and if so to what extent or at what doses this occurs.”

No significant changes in blood pressure were found with p-synephrine (12-13 mg) and lower doses of caffeine (150-176 mg).

“Conversely, no significant changes in BP were found with p-synephrine (12-13 mg) and lower doses of caffeine (150-176 mg).”

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The main route of caffeine metabolism in humans (70-80%) is via N-3 demethylation to paraxanthine catalysed by CYP1A2 in the liver.

“The main route of metabolism in humans (70-80 %) is via N-3 demethylation to paraxanthine (also known as 1,7-dimethylxanthine or 17X) catalysed by cytochrome (CYP) 1A2 in the liver.”

Significant increases in systolic and diastolic blood pressure were reported for p-synephrine from C. aurantium extracts when consumed at doses of 54 mg, but not at lower doses (13.5-50 mg).

“Significant increases in SBP and DBP were reported for p-synephrine from C. aurantium extracts when consumed at doses of 54 mg, but not at lower doses (13.5-50 mg).”

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Acute increases in systolic blood pressure, diastolic blood pressure or both, as well as in pulse pressure and mean arterial blood pressure, have been reported after single caffeine doses ranging from 80 to 250 mg in coffee abstainers, in habitual caffeine consumers after 12-48 hours' withdrawal, and after caffeine habituation (300-600 mg per day for six days).

“Acute increases in SBP, DBP or both, as well as in pulse pressure and mean arterial blood pressure (MABP), have been reported after single doses of caffeine ranging from 80 to 250 mg in coffee abstainers, in habitual caffeine consumers after 12-48 hours' withdrawal and after caffeine habituation (300-600 mg per day for six days)”

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The clinical relevance of acute changes in endothelial function and arterial compliance following an intervention is unclear, particularly when simultaneous changes in blood pressure occur.

“The clinical relevance of acute changes in endothelial function and arterial compliance following an intervention is unclear, particularly when simultaneous changes in BP occur (Anderson, 2006;McCall et al., 2011).”

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The kinetics of caffeine have been reported to be linear in doses up to 10 mg/kg bw.

“The kinetics of caffeine have been reported to be linear in doses up to 10 mg/kg bw (Bonati et al., 1982), whereas a later study claimed non-linearity beginning at doses as high as 500 mg, corresponding to about 7.1 mg/kg bw (Kaplan et al., 1997).”

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Acute changes in endothelial function and arterial compliance following caffeine consumption are vascular phenomena concordant with the acute increase in blood pressure, which can be predicted from arterial physiology.

“The acute changes in endothelial function and arterial compliance following caffeine consumption are vascular phenomena concordant with the acute increase in BP, which can be predicted from arterial physiology.”

Caffeine consumption acutely increases blood pressure in virtually all adult population subgroups tested, regardless of baseline blood pressure, regular caffeine consumption or time of caffeine withdrawal, age, sex or hormonal status.

“The Panel notes that caffeine consumption acutely increases BP in virtually all adult population subgroups tested, regardless of baseline BP, regular caffeine consumption/time of caffeine withdrawal, age, sex or hormonal status.”

CYP1A2 polymorphism has been reported to be a source of variability in caffeine metabolism between individuals measured by caffeine metabolites in urine.

“CYP1A2 polymorphism has been reported to be a source of variability in the metabolism of caffeine between individuals measured by caffeine metabolites in urine (Rasmussen et al., 2002).”

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The Panel notes that none of the available studies has investigated the effects on blood pressure of single doses of caffeine alone, of p-synephrine alone, or of their combination.

“The Panel notes that none of the available studies has investigated the effects on BP of single doses of caffeine alone, of p-synephrine alone or of their combination.”

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The Panel considers the effect of caffeine-induced changes in blood pressure and myocardial blood flow to be of low clinical relevance for healthy individuals in the general population under normal environmental conditions.

“the Panel considers the effect to be of low clinical relevance for healthy individuals in the general population under normal environmental conditions.”

Studies suggest an increased risk of acute cardiovascular events in the hour following consumption of caffeinated coffee, particularly in subjects with low habitual coffee intake.

“The Panel notes that these studies suggest an increased risk of acute cardiovascular events in the hour following consumption of caffeinated coffee, particularly in subjects with low habitual coffee intake.”

In habitual coffee consumers consuming three to six cups of coffee per day, 4 mg/kg body weight per day of caffeine from coffee consumed for three consecutive days did not lead to significant changes in hydration measures compared with placebo.

“and 4 mg/kg bw per day of caffeine from coffee were consumed for three consecutive days by habitual coffee consumers (three to six cups of coffee per day) (Killer et al., 2014).”

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Studies in subjects with an established cardiovascular event do not provide information about the risk of acute cardiovascular events following caffeine consumption in the general population.

“and do not provide information about the risk of acute cardiovascular events following caffeine consumption in the general population”

Baylin et al. 2006 found that the relative risk of myocardial infarction in the hour after drinking coffee was 1.49 (95% CI 1.17-1.89).

“The relative risk (RR) of MI in the hour after drinking coffee was 1.49 (95 % CI = 1.17-1.89).”

• cites Baylin et al., 2006 sourceNot checked yet

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A single dose of 200 mg of caffeine decreases myocardial blood flow if consumed approximately one hour prior to endurance exercise, when the blood-pressure-raising effect of caffeine reaches its peak.

“A single dose of 200 mg of caffeine also decreases MBF if consumed approximately one hour prior to endurance exercise (i.e. when the BP-raising effect of caffeine reaches its peak).”

In a study of cyclists, no significant differences among trials were found regarding measures of hydration status, relative dehydration, fluid retention, urine output or sweat rate.

“No significant differences among trials were found regarding measures of hydration status, relative dehydration, fluid retention, urine output or sweat rate.”

• cites Millard-Stafford et al., 2007Not checked yet

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Changes in blood pressure and myocardial blood flow induced by caffeine could increase the risk of acute cardiovascular events in subjects with an increased risk of cardiovascular disease, such as those with underlying hypertension and/or advanced atherosclerosis.

“Although such changes could increase the risk of acute cardiovascular 18314732, 2015, 5, Downloaded from https://efsa.onlinelibrary.wiley.com/doi/10.2903/j.efsa.2015.4102,Wiley Online Library on [26/08/2026].See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions)on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License”

In a study of nonhabitual caffeine consumers, tympanic body temperature increased significantly pre-exercise only following caffeine consumption.

“whereas tympanic body temperature increased significantly pre-exercise only (by 0.12 C).”

• cites Kim et al., 2011 sourceNot checked yet

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Studies conducted in subjects with an established fatal or non-fatal cardiovascular event included few cases, which may limit the value of sensitivity and subgroup analyses conducted to explore modifying factors.

“The Panel also notes that these studies conducted in subjects with an established (fatal or non-fatal) cardiovascular event included few cases, which may limit the value of the sensitivity and subgroup analyses conducted to explore modifying factors (e.g.influence of other risk factors of the event, such as disease conditions or physical activity prior to the event)”

A single dose of 200 mg of caffeine consumed one to two hours pre-exercise significantly increases blood pressure during resistance training in habitual coffee consumers after 24-48 hours of caffeine withdrawal.

“as well as in habitual coffee consumers after 24-48 hours of caffeine withdrawal.”

Studies in subjects with an established cardiovascular event do not provide information on the dose of caffeine which could trigger such events.

“or on the dose of caffeine which could trigger such events.”

Any diuretic effects resulting from chronic caffeine consumption are unlikely to have adverse health consequences for healthy individuals in the general population.

“However, any diuretic effects resulting from chronic caffeine consumption are unlikely to have adverse health consequences for healthy individuals in the general population.”

The acute effects of lower caffeine doses and/or caffeine taken at longer time intervals on blood pressure have not been tested in the studies available.

“The acute effects of lower caffeine doses and/or taken at longer time intervals on BP have not been tested in the studies available.”

A single dose of 200 mg of caffeine consumed one to two hours pre-exercise significantly increases blood pressure during resistance training in caffeine-naive subjects.

“A single dose of 200 mg of caffeine consumed one to two hours pre-exercise significantly increases BP during resistance training in caffeine-naive subjects”

Doses of caffeine up to 6 mg/kg body weight per day consumed for four days by habitual caffeine consumers, after a one-week run-in with doses of 3 mg/kg body weight per day, did not lead to significant changes in body mass, urine osmolality, urine specific gravity, urine colour, 24-hour urine volume, 24-hour sodium and potassium excretion, 24-hour creatinine, blood urea nitrogen, serum sodium and钾

“In addition, doses of caffeine up to 6 mg/kg bw per day consumed for four days by habitual caffeine consumers (one week run-in with doses of 3 mg/kg bw per day) did not lead to significant changes in body mass, urine osmolality, urine specific gravity, urine colour, 24-hour urine volume, 24-hour Na + and K + excretion, 24-hour creatinine, blood urea nitrogen, serum Na + and K + , serum osmolality,”

• cites Armstrong et al., 2005 sourceNot checked yet

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In the Stroke Onset Study, the relative risk of stroke in the hour after consuming coffee was 2.0 (95% CI 1.4-2.8; p < 0.001).

“The RR of stroke in the hour after consuming coffee was 2.0 (95 % CI = 1.4-2.8;p < 0.001).”

• cites Mostofsky et al., 2010a, bNot checked yet

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In a study of nonhabitual caffeine consumers, mean body temperature was significantly higher before and after exercise following caffeine consumption than following water consumption.

“Mean body temperature (calculated from tympanic and skin temperatures) was significantly higher in pre-(by 0.08 C) and post exercise (by 0.14 C) following caffeine consumption than following water consumption”

• cites Kim et al., 2011 sourceNot checked yet

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In a study of endurance-trained cyclists, no significant differences in fluid losses, serum osmolality or core temperature were observed between the water and carbohydrate-electrolyte groups with caffeine and without caffeine.

“No significant differences in fluid losses, serum osmolality or core temperature were observed between the WAT and CES groups with caffeine and without caffeine.”

• cites Del Coso et al., 2008 sourceNot checked yet

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In Selb Semerl and Selb 2004, alcohol drinking did not appear to influence the risk in coffee drinkers.

“Alcohol drinking did not appear to influence the risk in coffee drinkers.”

• cites Selb Semerl and Selb, 2004Not checked yet

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In a study of endurance-trained cyclists, rehydration with water or carbohydrate-electrolyte solution, with or without caffeine, prevented the significant losses of body fluid, the increase in serum osmolality and the significant rise in core temperature observed with no fluid replacement, with or without caffeine.

“Rehydration with WAT or CES, with or without caffeine, prevented the significant losses of body fluid, the increase in serum osmolality and the significant rise in core temperature observed with no fluid replacement, with or without caffeine.”

• cites Del Coso et al., 2008 sourceNot checked yet

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The Panel notes that the Millard-Stafford et al. study does not show a clinically significant effect of caffeine on core rectal temperature or hydration status at doses of 5.3 mg/kg body weight consumed during physical exercise and hot and humid conditions.

“The Panel notes that this study does not show a clinically significant effect of caffeine on core (rectal) temperature or hydration status at doses of 5.3 mg/kg bw consumed during physical exercise and hot and humid conditions.”

• cites Millard-Stafford et al., 2007Not checked yet

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Caffeine has a diuretic effect.

“It is well established that caffeine has a diuretic effect (SCF, 1983;EFSA, 2009).”

• cites SCF, 1983Not checked yet

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• cites EFSA, 2009Not checked yet

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Higher doses of caffeine (≥400-500 mg) consumed either on a single occasion or within short periods of time have been reported to increase anxiety upon oral consumption, mostly in patients with psychiatric anxiety disorders, but also in healthy adults, particularly if they are non-habitual caffeine consumers.

“Higher doses (≥ 400-500 mg) consumed either on a single occasion or within short periods of time have been reported to increase anxiety upon oral consumption, mostly in patients with psychiatric anxiety disorders, but also in healthy adults, particularly if they are non-habitual caffeine consumers (FSANZ, 2000;Nawrot et al., 2003;Childs and de Wit, 2006;NNT, 2008;SHC, 2012).”

• cites FSANZ, 2000Not checked yet

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• cites Nawrot et al., 2003 sourceNot checked yet

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• cites Childs and de Wit, 2006 sourceNot checked yet

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The Panel notes that caffeine at doses of 3 mg/kg body weight, equivalent to 210 mg for a 70-kg adult, ingested about one hour prior to endurance exercise appears to induce only a modest increase in body temperature compared with placebo.

“The Panel notes that caffeine at doses of 3 mg/kg bw (equivalent to 210 mg for a 70-kg adult) ingested about one hour prior to endurance exercise appear to induce only a modest increase in body temperature compared with placebo.”

The Panel notes that the studies do not show an effect of single doses of caffeine ranging from 2.5 to 10 mg/kg body weight on most self-reported measures of anxiety in children.

“The Panel notes that these studies (Elkins et al., 1981;Rapoport et al., 1981b;Bernstein et al., 1994) do not show an effect of single doses of caffeine ranging from 2.5 to 10 mg/kg bw on most selfreported measures of anxiety in children.”

• cites Elkins et al., 1981 sourceNot checked yet

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• cites Rapoport et al., 1981bNot checked yet

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• cites Bernstein et al., 1994 sourceNot checked yet

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In adults, single doses of caffeine of about 100 mg, about 1.4 mg/kg body weight per day in a 70-kg adult, have been shown to increase sleep latency and reduce sleep duration when consumed close to bedtime.

“In adults, single doses of caffeine of about 100 mg (1.4 mg/kg bw per day in a 70-kg adult) have been shown to increase sleep latency and reduce sleep duration when consumed close to bedtime (Landolt et al., 1995)”

• cites Landolt et al., 1995 sourceNot checked yet

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The Panel notes that the results from prospective cohort studies on the association between habitual caffeine consumption and long-term changes in blood pressure are mixed.

“The Panel notes that the results from prospective cohort studies on the association between habitual caffeine consumption and long-term changes in BP are mixed.”

The Panel notes that 100 mg of caffeine, about 1.4 mg/kg body weight for a 70-kg adult, may increase sleep latency and reduce sleep duration in some individuals, particularly when consumed close to bedtime.

“The Panel notes that 100 mg of caffeine (about 1.4 mg/kg bw for a 70-kg adult) may increase sleep latency and reduce sleep duration in some individuals, particularly when consumed close to bedtime.”

• cites Landolt et al., 1995 sourceNot checked yet

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The Panel notes that regular consumption of caffeine up to about 3 mg/kg body weight per day does not appear to induce behavioural changes in children and adolescents.

“The Panel notes that regular consumption of caffeine up to about 3 mg/kg bw per day does not appear to induce behavioural changes in children and adolescents”

Doses of caffeine less than 100 mg do not appear to have an effect on sleep.

“whereas doses < 100 mg do not appear to have such an effect on sleep (Dorfman and Jarvik, 1970).”

• cites Dorfman and Jarvik, 1970 sourceNot checked yet

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Single doses of caffeine up to about 200 mg do not alter the subjective perception of alcohol intoxication when alcohol is consumed at doses of about 0.65 g/kg body weight.

“or alter the subjective perception of alcohol intoxication when alcohol is consumed at doses of about 0.65 g/kg bw.”

Single doses of caffeine up to about 200 mg, 3 mg/kg body weight for a 70-kg adult, do not appear to induce anxiety in unselected adult subjects from the general population.

“Single doses of caffeine up to about 200 mg (3 mg/kg/bw for a 70-kg adult) do not appear to induce anxiety in unselected adult subjects from the general population”

The Panel notes that the Steffen et al. (2012) meta-analysis does not show a significant increase in fasting BP following consumption of caffeinated coffee for >7 days at doses of about three to six cups per day.

“The Panel notes that this meta-analysis does not show a significant increase in fasting BP following consumption of caffeinated coffee for > 7 days at doses of about three to six cups per day.”

• cites Steffen et al., 2012 sourceNot checked yet

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The Panel also notes that higher doses of caffeine (5-6 mg/kg body weight) ingested one hour before and during prolonged endurance exercise in a hot environment do not affect body temperature or hydration status significantly beyond what could be expected from the testing conditions.

“The Panel also notes that higher doses of caffeine (5-6 mg/kg bw) ingested one hour before and during prolonged endurance exercise in a hot environment do not affect body temperature or hydration status significantly beyond what could be expected from the testing conditions.”

In adults, tolerance to the anxiogenic effect of caffeine develops with frequent consumption, even in genetically susceptible individuals.

“In adults, tolerance to the anxiogenic effect of caffeine develops with frequent consumption, even in genetically susceptible individuals (Rogers et al., 2010).”

• cites Rogers et al., 2010 sourceNot checked yet

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The Panel considers that the results of these studies cannot be used on their own to derive single doses of caffeine of no concern for children or adolescents.

“The Panel considers that the results of these studies cannot be used on their own to derive single doses of caffeine of no concern for children or adolescents.”

Single doses of caffeine up to about 200 mg do not reduce the perceived exertion or effort during exercise when consumed one hour prior to exercise after 12-24 hours of caffeine withdrawal.

“reduce the perceived exertion/effort during exercise when consumed one hour prior to exercise after 12-24 hours of caffeine withdrawal”

The Panel notes that single doses of caffeine which have been observed to reduce the rated perceived exertion or effort during exercise (≥4 mg/kg body weight) are equivalent to 280 mg of caffeine for a 70-kg adult.

“The Panel notes that single doses of caffeine which have been observed to reduce the rated perceived exertion/effort during exercise (≥ 4 mg/kg bw) are equivalent to 280 mg of caffeine for a 70-kg adult.”

In Steffen et al. (2012), coffee drinking was not significantly associated with an increased risk of hypertension at any category of coffee intake compared with the reference category.

“Coffee drinking was not significantly associated with an increased risk of hypertension at any category of coffee intake compared with the reference category.”

• cites Steffen et al., 2012 sourceNot checked yet

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Palatini et al. (2009) reported an increased risk of developing sustained hypertension requiring pharmacological treatment with increasing caffeinated coffee consumption in carriers of the slow CC or CA allele (59%) of the CYP1A2 gene, but not in carriers of the fast AA allele.

“A subsequent study by the same authors (Palatini et al., 2009) reported an increased risk of developing sustained hypertension requiring pharmacological treatment with increasing caffeinated coffee consumption in carriers of the slow CC or CA allele (59 %) of the CYP1A2 gene, but not in carriers of the fast AA allele”

• cites Palatini et al., 2009 sourceNot checked yet

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Bertoia et al. (2013) found no association between total caffeine, caffeinated coffee, decaffeinated coffee or caffeinated tea and risk of sudden cardiac death.

“No association between total caffeine, caffeinated (regular) coffee, decaffeinated coffee or caffeinated tea and the risk of SCD was found.”

• cites Bertoia et al., 2013 sourceNot checked yet

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The Panel notes that caffeine intakes at doses of about 400 mg/day did not raise fasting BP significantly after caffeine habituation in human intervention studies.

“The Panel notes that caffeine intakes at doses of about 400 mg per day did not raise fasting BP significantly after caffeine habituation in human intervention studies.”

In NHS I and II, no linear association between caffeine consumption and risk of incident hypertension was observed after multivariate adjustment.

“In both cohorts, no linear association between caffeine consumption and the risk of incident hypertension was observed after multivariate adjustment.”

• cites Winkelmayer et al., 2005 sourceNot checked yet

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The Panel notes that three meta-analyses and the vast majority of the 56 prospective cohort studies reported no increased risk of CHD associated with habitual coffee consumption at any level of intake.

“The Panel notes that three meta-analyses and the vast majority of the 56 prospective cohort studies included in these review publications reported no increased risk of CHD associated with habitual coffee consumption at any level of intake.”

The Panel notes that the NHS study shows an inverse U-shaped relationship between total caffeine intake from dietary sources and incident hypertension.

“The Panel notes that this study shows an inverse U-shaped relationship between total caffeine intake from dietary sources and incident hypertension.”

• cites Winkelmayer et al., 2005 sourceNot checked yet

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Two studies (Murray et al., 1981; Stensvold and Tverdal, 1995) were not adjusted for any confounding variable.

“Two studies (Murray et al., 1981;Stensvold and Tverdal, 1995) were not adjusted for any confounding variable.”

• cites Murray et al., 1981 sourceNot checked yet

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• cites Stensvold and Tverdal, 1995Not checked yet

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Among 56 prospective cohort studies, eight studies (seven published in or before 1995) reported a positive association between coffee consumption and risk of CHD, including fatal and non-fatal CAD, fatal ischaemic heart disease and fatal and non-fatal MI.

“Among the 56 prospective cohort studies included in the meta-analyses above, eight studies, seven of which were published in or before 1995, reported a positive association between coffee consumption and the risk of CHD, including fatal and non-fatal CAD, fatal ischaemic heart disease and fatal and non-fatal MI.”

Compared with the reference category, the pooled RR for hypertension was 1.09 (95% CI 1.01-1.18) for low coffee consumption (one to three cups/day).

“Compared with the reference category, the pooled RRs (95 % CI) for hypertension were 1.09 (1.01-1.18)for the low category (one to three cups per day)”

• cites Zhang et al., 2011 sourceNot checked yet

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In the AF meta-analyses, there was no significant association between caffeine exposure and AF risk in primary or subgroup analyses considering age, sex, race, study quality, caffeine from coffee versus all sources, caffeine dose or duration of follow-up.

“There was no significant association between caffeine exposure and AF risk in primary or subgroup analyses, considering age, sex, race, study quality, caffeine from coffee versus caffeine from all sources, caffeine dose or duration of follow-up.”

• cites Caldeira et al., 2013 sourceNot checked yet

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• cites Cheng et al., 2014 sourceNot checked yet

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In Wu et al. (2009), stratified analyses by sex, region, study quality, duration of follow-up and adjustment for confounding variables did not affect the results significantly.

“Stratified analyses by sex, region, study quality and duration of follow-up and adjustment for confounding variables did not affect the results significantly.”

• cites Wu et al., 2009Not checked yet

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An inverse relationship was found between habitual caffeine intake and risk of AF in a dose-response analysis (Cheng et al., 2014).

“An inverse relationship was found between habitual caffeine intake and the risk of AF in a dose-response analysis (Cheng et al., 2014).”

• cites Cheng et al., 2014 sourceNot checked yet

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The Panel notes that the risk of hypertension did not increase significantly at any dose of coffee consumption in the dose-response analysis.

“The Panel notes that the risk of hypertension did not increase significantly at any dose of coffee consumption in this dose-response analysis.”

In Lopez-Garcia et al. (2006), after adjustment for confounders, neither coffee nor total caffeine intake were significantly associated with risk of CHD in men or women.

“After adjustment for confounders, neither coffee nor total caffeine intake were significantly associated with the risk of CHD in either men or women.”

• cites Lopez-Garcia et al., 2006Not checked yet

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The Panel notes that the available studies do not provide sufficient information to conclude on whether or not consumption of p-synephrine modifies the effects of daily caffeine consumption on fasting BP.

“The studies available do not provide sufficient information to conclude on whether or not consumption of p-synephrine modifies the effects of daily caffeine consumption on fasting BP.”

In NHS I and II, significant positive associations between intake of sugar-containing and sugar-free caffeinated cola drinks and incident hypertension were observed in both cohorts.

“A significant positive association between the intake of sugar-containing (p for trend = 0.03 and < 0.001 in NHS I and NHS II, respectively) and sugar-free (p for trend = 0.03 and < 0.001 in NHS I and NHS II, respectively) caffeinated cola drinks and incident hypertension was observed in both cohorts.”

• cites Winkelmayer et al., 2005 sourceNot checked yet

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In Klag et al. (2002), no association between caffeinated coffee consumption and risk of incident hypertension was observed after adjusting for confounding variables in normotensive young males.

“No association between caffeinated coffee consumption and the risk of incident hypertension was observed after adjusting for confounding variables in the study by Klag et al. (2002) in normotensive young males.”

• cites Klag et al., 2002 sourceNot checked yet

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One meta-analysis (Arab et al., 2009) of tea consumption and stroke risk found similar results.

“One meta-analysis (Arab et al., 2009) of prospective cohort studies which assessed the relationship between green and black tea consumption and the risk of stroke and included data from nine individual studies involving 4 378 strokes among 194 965 individuals in total found similar results.”

• cites Arab et al., 2009 sourceNot checked yet

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In the dose-response meta-analysis by Ding et al. (2014), coffee consumption up to about four cups per day was inversely associated with the risk of stroke.

“Coffee consumption up to about four cups per day was inversely associated with the risk of stroke.”

• cites Ding et al. (2014) sourceNot checked yet

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Among the prospective cohort studies included in the meta-analyses, none reported a positive association between coffee consumption and the risk of stroke of any type.

“Among the prospective cohort studies included in the meta-analyses above, none reported a positive association (increased risk) between coffee consumption and the risk of stroke of any type.”

• cites Larsson and Orsini, 2011Not checked yet

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• cites Kim et al., 2012 sourceNot checked yet

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In the Sengpiel et al. (2013) study, total caffeine and coffee caffeine were significantly associated with increased gestational length.

“total caffeine and coffee caffeine were significantly associated with increased gestational length.”

• cites Sengpiel et al., 2013 sourceNot checked yet

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Total caffeine intake was not associated with an increased CVD risk in any of the studies that investigated all sources of caffeine.

“However, total caffeine intake was not associated with an increased CVD risk in any of the studies that investigated all sources of caffeine.”

In the study by Larsson et al. (2008), consumption of caffeinated coffee, caffeinated tea or total caffeine was not associated with an increased risk of ischaemic or haemorrhagic stroke.

“Consumption of caffeinated coffee, caffeinated tea or total caffeine (from coffee and tea) was not associated with an increased risk of ischaemic or haemorrhagic stroke.”

• cites Larsson et al. (2008) sourceNot checked yet

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The Panel notes that the Bakker et al. (2010) study did not assess caffeine intake during pregnancy from all dietary sources.

“The Panel notes that this study did not assess caffeine intake during pregnancy from all dietary sources.”

In the Bakker et al. (2010) study, no clear dose-response associations were found for caffeine intakes during pregnancy and fetal growth.

“No clear dose-response associations were found for caffeine intakes during pregnancy and fetal growth.”

• cites Bakker et al., 2010 sourceNot checked yet

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In the Bech et al. (2007) RCT, the adjusted difference in length of gestation between the decaffeinated and caffeinated coffee groups was -1.31 days (95% CI -2.87 to 0.25).

“The adjusted difference in length of gestation between the decaffeinated and caffeinated coffee groups was -1.31 days (-2.87 to 0.25).”

• cites Bech et al., 2007 sourceNot checked yet

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In the CARE Study Group, caffeine intake was associated with an increased risk of late miscarriage or stillbirth.

“Caffeine intake was also associated with an increased risk of late miscarriage or stillbirth (Greenwood et al., 2010).”

• cites Greenwood et al., 2010 sourceNot checked yet

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In the dose-response meta-analysis by Ding et al. (2014), no association was observed between coffee consumption and CVD risk at higher intake.

“No association was observed between coffee consumption and CVD risk at higher intake.”

• cites Ding et al. (2014) sourceNot checked yet

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In the dose-response meta-analysis by Ding et al. (2014), no association was observed between coffee consumption of higher intakes and the risk of stroke.

“No association was observed between coffee consumption of higher intakes and the risk of stroke.”

• cites Ding et al. (2014) sourceNot checked yet

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In the CARE Study Group, after adjustment for confounding variables, the relationship between total caffeine intake in pregnancy and FGR showed a significant trend with increasing caffeine intake (p for trend = 0.02).

“After adjustment for confounding variables, the relationship between total caffeine intake in pregnancy and FGR showed a significant trend with increasing caffeine intake (p for trend = 0.02).”

• cites CARE Study Group, 2008 sourceNot checked yet

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In the dose-response meta-analysis by Ding et al. (2014), coffee consumption was inversely associated with the risk of CVD up to six cups per day.

“In the dose-response analysis, coffee consumption was inversely associated with the risk of CVD up to six cups per day.”

• cites Ding et al. (2014) sourceNot checked yet

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In Mostofsky et al. (2012), a non-linear association between coffee consumption and heart failure risk was found (p for non-linearity=0.02; p for overall significance=0.02).

“A non-linear association between coffee consumption and heart failure risk was found (p for non-linearity = 0.02; p for overall significance of curve = 0.02).”

• cites Mostofsky et al., 2012Not checked yet

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In the meta-analysis, coffee intake up to 11 cups per day, corresponding to about 1100 mg of caffeine, was not significantly associated with an increased risk of heart failure.

“The Panel notes that coffee intake up to 11 cups per day, corresponding to about 1 100 mg of caffeine, were not significantly associated with an increased risk of heart failure in this meta-analysis.”

In the meta-analysis by Larsson and Orsini (2011), a non-linear inverse association between coffee consumption and stroke risk was observed (p for non-linearity = 0.005).

“A non-linear inverse association between coffee consumption and stroke risk was observed (p for non-linearity = 0.005).”

• cites Larsson and Orsini (2011)Not checked yet

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Habitual caffeinated coffee consumption has not been associated with an increased risk of total CVD or CVD subtypes in the general adult population at any level of intake in any summary publication.

“Habitual caffeinated coffee consumption has not been associated with an increased risk of total CVD or CVD subtypes in the general adult population at any level of intake in any summary publication.”

The Panel notes that habitual caffeine consumption from all sources up to about 1,000 mg/day was not significantly associated with an increased risk of AF in the two meta-analyses.

“The Panel notes that habitual caffeine consumption from all sources up to about 1 000 mg per day was not significantly associated with an increased risk of AF in these two meta-analyses.”

• cites Caldeira et al., 2013 sourceNot checked yet

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• cites Cheng et al., 2014 sourceNot checked yet

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In the Sengpiel et al. (2013) study, an additional 100 mg total caffeine per day was associated with a 21- to 28-g birth weight decrease.

“An additional 100 mg total caffeine per day was associated with a 21-to 28-g birth weight decrease, depending on the growth curve.”

• cites Sengpiel et al., 2013 sourceNot checked yet

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In the Sengpiel et al. (2013) study, black tea caffeine was associated with increased risk of early spontaneous pre-term delivery (OR 1.61, 95% CI 1.10-2.35, p = 0.01).

“black tea caffeine was associated with increased risk of early spontaneous pre-term delivery (OR 1.61, 95 % CI = 1.10-2.35,p = 0.01).”

• cites Sengpiel et al., 2013 sourceNot checked yet

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The Panel notes that the relationship between caffeine intake and outcomes related to the length of gestation is inconsistent.

“The Panel also notes that the relationship between caffeine intake and outcomes related to the length of gestation is inconsistent.”

Loomba et al. (2014) reported no association between coffee consumption and CVD mortality in multivariate analysis adjusted for confounding variables at any level of intake among 8 608 subjects > 45 years of age.

“An additional prospective cohort study published thereafter (Loomba et al., 2014) using data from the US National Health and Nutrition Examination Survey III (NHANES III) reported no association between coffee consumption and CVD mortality (including stroke, congestive heart failure and ischaemia-related mortality) in multivariate analysis adjusted for confounding variables at any level of intake”

• cites Loomba et al., 2014Not checked yet

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The Panel notes that the Bech et al. (2007) study did not report an effect of decreasing caffeine consumption from about 300 mg per day to about 100 mg per day in the last four months of pregnancy on length of gestation or birth weight.

“The Panel notes that this study did not report an effect of decreasing caffeine consumption from about 300 mg per day to about 100 mg per day in the last four months of pregnancy on length of gestation or birth weight.”

The Panel notes that coffee intake up to 8-11 cups per day, corresponding to about 800-1100 mg of caffeine per day, was not significantly associated with an increased risk of stroke in the meta-analyses considered.

“The Panel notes that coffee intake up to 8-11 cups per day, corresponding to about 800-1 100 mg of caffeine per day, were not significantly associated with an increased risk of stroke in the meta-analyses considered.”

In the Bakker et al. (2010) study, caffeine intake was positively associated with the risks of delivering an SGA child.

“Caffeine intake was positively associated with the risks of delivering an SGA child.”

• cites Bakker et al., 2010 sourceNot checked yet

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The Panel considers that habitual caffeine intake up to about 400 mg per day from all sources does not increase the risk of CVD in habitual alcohol drinkers from the general adult population.

“the Panel considers that habitual caffeine intake up to about 400 mg per day from all sources does not increase the risk of CVD in habitual alcohol drinkers from the general adult population.”

The Panel also notes that no single prospective cohort study reported an increased risk of AF associated with habitual caffeine consumption.

“The Panel also notes that no single prospective cohort study reported an increased risk of AF associated with habitual caffeine consumption.”

The Panel notes that genetic polymorphisms for genes involved in caffeine metabolism may explain only a small proportion of the inter-individual variability in caffeine intake.

“The Panel notes that genetic polymorphisms for genes involved in caffeine metabolism may explain only a small proportion of the inter-individual variability in caffeine intake.”

In the Bech et al. (2007) RCT, after adjustment, the mean birth weight of babies born to women in the decaffeinated coffee group was 16 g (95% CI -40 to 73 g) higher than those born to women in the caffeinated group.

“After adjustment for length of gestation, parity, pre-pregnancy body mass index and smoking at baseline, the mean birth weight of babies born to women in the decaffeinated coffee group was 16 g (95 % CI = -40 to 73 g), which was higher than those born to women in the caffeinated group.”

• cites Bech et al., 2007 sourceNot checked yet

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Data from RCTs suggest that caffeine intake (from coffee or supplements) at doses ≤ 400 mg per day does not raise fasting BP significantly after caffeine habituation takes place.

“Data from RCTs suggest that caffeine intake (from coffee or supplements) at doses ≤ 400 mg per day does not raise fasting BP significantly after caffeine habituation takes place.”

No single prospective cohort study reported an increased risk of AF associated with habitual caffeine or coffee consumption.

“No single prospective cohort study reported an increased risk of AF associated with habitual caffeine or coffee consumption.”

Incidence of AF decreased by 6% (RR=0.94, 95% CI 0.90-0.99) for every 300 mg/day increment in habitual caffeine intake up to about 1,000 mg/day.

“Incidence of AF decreased by 6 % (RR = 0.94, 95 % CI = 0.90-0.99)for every 300 mg per day increment in habitual caffeine intake up to about 1 000 mg per day.”

• cites Cheng et al., 2014 sourceNot checked yet

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Higher doses of caffeine could lead to prolonged physical exercise that might compromise the cardiovascular and/or musculoskeletal systems.

“Higher doses could lead to prolonged physical exercise that might compromise the cardiovascular and/or musculoskeletal systems.”

A level of no safety concern for habitual caffeine consumption by children and adolescents of 3 mg/kg bw per day is appropriate.

“The Panel, therefore, considers a level of no safety concern for habitual caffeine consumption by children and adolescents of 3 mg/kg bw per day (i.e. the level of no safety concern derived for single doses of caffeine for adults) as appropriate.”

• AssumptionRests on an assumption: Caffeine clearance in children and adolescents is at least that of adults.

Moderate habitual alcohol consumption would not affect the safety of habitual caffeine consumption up to 400 mg per day.

“In addition, the Panel considers that moderate habitual alcohol consumption would not affect the safety of habitual caffeine consumption up to 400 mg per day.”

Single doses of caffeine up to 200 mg consumed by lactating women in the general population do not give rise to safety concerns for the breastfed infant.

“Single doses of caffeine up to 200 mg consumed by lactating women in the general population do not give rise to safety concerns for the breastfed infant.”

Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) are unlikely to mask the subjective perception of alcohol intoxication when alcohol is consumed at doses up to about 0.65 g/kg bw.

“Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) are also unlikely to mask the subjective perception of alcohol intoxication when alcohol is consumed at doses up to about 0.65 g/kg bw.”

The Panel notes that the relationship between caffeine intakes and adverse birth weight-related outcomes is observed at all levels of intake, with no threshold below which the relationship is not observed.

“The Panel also notes that the relationship between caffeine intakes and adverse birth weight-related outcomes is observed at all levels of intake, with no threshold below which the relationship is not observed.”

The Panel considers that the risk becomes clinically relevant at daily doses of about 200 mg of caffeine from all sources.

“However, the Panel considers that the risk becomes clinically relevant at daily doses of about 200 mg of caffeine from all sources.”

Taking into account the different kinetics of caffeine in pregnant women, single doses of caffeine which are of no safety concern for non-pregnant adults may not apply to pregnant women performing physical exercise.

“Taking into account the different kinetics of caffeine in this population subgroup, the Panel considers that single doses of caffeine which are of no safety concern for non-pregnant adults may not apply to pregnant women performing physical exercise.”

The human intervention studies on which these conclusions are based were primarily conducted with caffeine supplements for most of the outcomes assessed, namely changes in MBF, hydration status, body temperature, perceived exertion/effort during exercise, and sleep.

“The human intervention studies on which these conclusions are based (Section 4.4) were primarily conducted with caffeine supplements for most of the outcomes assessed (i.e.changes in MBF, hydration status, body temperature, perceived exertion/effort during exercise, sleep).”

Caffeine intakes from all sources up to 400 mg per day (corresponding to about 5.7 mg/kg bw for a 70-kg adult) consumed throughout the day do not give rise to safety concerns for healthy adults in the general population, except for pregnant women.

“Caffeine intakes from all sources up to 400 mg per day (corresponding to about 5.7 mg/kg bw for a 70-kg adult) consumed throughout the day do not give rise to safety concerns for healthy adults in the general population, except for pregnant women (see Section 5.2).”

Because information on caffeine intake is not available for other sources of caffeine or for caffeine from all sources including food supplements, the percentage of adults exceeding 200 mg caffeine in a single sports session may be underestimated.

“On the one hand, the Panel notes that this information is not available for other sources of caffeine, or for caffeine from all sources, including food supplements, and thus the percentage of adults exceeding 200 mg caffeine in a single sports session may be underestimated.”

Single doses of caffeine up to 200 mg are unlikely to induce clinically relevant changes in blood pressure, hydration status or body temperature, both at rest and when consumed less than two hours prior to intense physical exercise under normal environmental conditions.

“Single doses of caffeine up to 200 mg are also unlikely to induce clinically relevant changes in blood pressure, hydration status or body temperature.This is the case both at rest or when consumed less than two hours prior to intense physical exercise under normal environmental conditions.”

100 mg (about 1.4 mg/kg bw for a 70-kg adult) of caffeine may increase sleep latency and reduce sleep duration in some adult individuals, particularly when consumed close to bedtime.

“The Panel notes that 100 mg (about 1.4 mg/kg bw for a 70-kg adult) of caffeine may increase sleep latency and reduce sleep duration in some adult individuals, particularly when consumed close to bedtime.”

Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult), or the same amount consumed within a short period, are unlikely to induce clinically relevant changes in MBF in the general healthy adult population, either at rest or when consumed less than two hours prior to intense physical exercise under normal environmental conditions.

“Single doses of caffeine up to 200 mg, corresponding to about 3 mg/kg bw for a 70-kg adult, or the same amount consumed within a short period of time, are unlikely to induce clinically relevant changes in MBF in the general healthy adult population, either at rest or when consumed less than two hours prior to intense physical exercise, under normal environmental conditions.”

The use of a mean value for the caffeine content in coffee on a volume basis may not accurately reflect caffeine intakes in all countries.

“The Panel notes that coffee was the main source of dietary caffeine in the seven countries for which the 95 th percentile of daily caffeine intake exceeded 400 mg, and that the use of a mean value for the caffeine content in coffee on a volume basis may not accurately reflect caffeine intakes in all countries.”

Two prospective cohort studies (CARE Study Group, 2008; Sengpiel et al., 2013) show a dose-dependent positive association between caffeine intakes during pregnancy and the risk of adverse birth weight-related outcomes, namely fetal growth restriction and small for gestational age.

“This conclusion is based on two prospective cohort studies (CARE Study Group, 2008;Sengpiel et al., 2013) showing a dose-dependent positive association between caffeine intakes during pregnancy and the risk of adverse birth weight-related outcomes (i.e.FGR, SGA).”

• cites CARE Study Group, 2008 sourceNot checked yet

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• cites Sengpiel et al., 2013 sourceNot checked yet

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Caffeine intakes from all sources up to 200 mg per day consumed throughout the day by pregnant women in the general population do not give rise to safety concerns for the fetus.

“Caffeine intakes from all sources up to 200 mg per day consumed throughout the day by pregnant women in the general population do not give rise to safety concerns for the fetus.”

• AssumptionThe authors state this as an assumption: The relationship between caffeine intake during pregnancy and adverse birth weight-related outcomes is causal in the context of this safety assessment.

Decreasing caffeine intake from about 300 mg per day to about 100 mg per day in the third trimester of pregnancy does not decrease the risk, as observed in one human intervention study (Bech et al., 2007).

“decreasing caffeine intake from about 300 mg per day to about 100 mg per day in the third trimester of pregnancy does not decrease the risk, as observed in one human intervention study (Bech et al., 2007).”

• cites Bech et al., 2007 sourceNot checked yet

  Not checked in the free run.

The conclusion that single doses of caffeine up to 200 mg are unlikely to induce clinically relevant changes in blood pressure, hydration status or body temperature applies to non-habitual caffeine consumers, caffeine-deprived subjects and habitual caffeine consumers.

“This applies to non-habitual caffeine consumers, to caffeine-deprived subjects and to habitual caffeine consumers.”

Doses of 200 mg per day from all sources consumed throughout the day by lactating women do not give rise to safety concerns for the breastfed infant.

“In this context, the Panel considers that doses of 200 mg per day from all sources consumed throughout the day by lactating women do not give rise to safety concerns for the breastfed infant.”

• AssumptionRests on an assumption: The half-life of caffeine in women is mean four hours, range two to eight hours, and the half-life in infants is longer, namely 50-103 hours in neonates with no CYP1A2 activity and about 14 hours at three to four months of age.

The association between caffeine intakes and other adverse pregnancy-related outcomes is less consistent.

“The association between caffeine intakes and other adverse pregnancy-related outcomes is less consistent.”

The Panel notes that two prospective cohort studies show a dose-dependent positive association between caffeine intake during pregnancy from all dietary sources and the risk of adverse birth weight-related outcomes (i.e. FGR, SGA).

“The Panel notes that two prospective cohort studies (CARE Study Group, 2008;Sengpiel et al., 2013) show a dose-dependent positive association between caffeine intake during pregnancy from all dietary sources and the risk of adverse birth weight-related outcomes (i.e.FGR, SGA).”

Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) are unlikely to reduce the perceived exertion/effort during exercise.

“Single doses of caffeine up to 200 mg (about 3 mg/kg bw for a 70-kg adult) are unlikely to reduce the perceived exertion/effort during exercise.”

Prospective cohort studies cannot provide evidence for a causal association between caffeine and adverse birth weight-related outcomes.

“The Panel notes that prospective cohort studies cannot provide evidence for a causal association between caffeine and adverse birth weight-related outcomes.”