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Caffeine

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{{DISPLAYTITLE:Caffeine and Running}}[[File:Caffeine.jpg|right|thumb|500px|Common sources of Caffeine.]]Caffeine can improve athletic performance, but it's as widely misunderstood as it is widely consumed by the general public and athletes, and moderate used. * Moderate levels of caffeine can improve athletic performanceby about 2%, which is about 5 minutes on a 4 hour marathon. This improvement appears to happen regardless of how regularly caffeine is used. * For running, the best recommendation is a dose of 3 to 5 mg/kg before exercise, followed by 1 to 2 mg/kg periodically after that. For runners, a [[Comparison of Energy Gels| caffeinated energy gel]] is probably the best source. * While it's commonly believed that caffeine causes dehydration, this is only true when high doses are given to those not used to it. Drinking a caffeinated beverage will produce about the same amount of urine, which is probably the source of the myth. Caffeine does People will drink caffeinated beverages when they're not cause dehydrationthirsty, but so they assume it 's the caffeine that's causing them to need to urinate, not the fluid they've drunk. * Obviously caffeine can interfere with sleep, but this effect can last much longer than you might expect. Even caffeine taken early in the morning can impact your nights' sleep. * Caffeine in coffee does not seem as effectiveat improving performance, so other sources should be used. * Caffeine increases blood pressure, and should be avoided during exercise by those with high blood pressure.* There may be genetic differences in the effect of caffeine; see the section on "Caffeine and Genetics" below for details.
=Introduction=
Man has been searching for ways of improving athletic performance since at least 400 BC, when the hearts of lion were believed to impart benefits<ref name="CaffLionHeart"/>. Today, caffeine can improve performance in endurance running, and three of every four elite athletes take caffeine when competing<ref name="CaffUse"/>. Caffeine is one of the most widely used drugs in the world<ref name="CaffWorld"/>, with average daily intakes worldwide of 70mg/day, but higher in the US (~200mg/day) and the UK (~400mg/day)<ref name="CaffDependence"/>. Caffeine has many effects on many different tissue types, directly and through its metabolites, as well as stimulating adrenaline release<ref name="CaffMetaAndPerf"/>.
=Performance =
Studies have shown caffeine can improve performance by ~2%<ref name="CaffMeta"/>. Though much greater improvements (~12%) have been shown in laboratory conditions, these are not likely to be seen in real world race conditions<ref name="CaffMeta"/>. That ~2% represents 3.5 minutes on a 3 hour marathon, nearly 5 minutes on a 4 hour marathon. For the 5K, that represents 25 seconds on a 21 minute 5K, or 18 seconds on a 15 minute 5K. Caffeine tends to benefit fitter individuals more<ref name="CaffMeta"/>. Caffeine may improve performance by reducing the [[Rating of Perceived Exertion|RPE]]<ref name="CafRPE"/> and muscle [[Muscle]] pain<ref name="CafMusclePain"/>.
==Green Tea and Performance==
There is relatively little research concerning the effect of tea on athletic performance. However, one study did show that the green tea extract increased fat burning and glucose tolerance during cycling at 60% [[VO2max|V̇O<sub>2</sub>max]] without affecting [[Heart Rate]] or overall energy consumption<ref name="Venables-2008"/>.
=How much?=
Most studies use 3-13mg/Kg, average 6mg, but within that dose range there was no obvious dose response<ref name="CaffMeta"/>. A smaller intake of 3 to 5 mg/kg dose before exercise and then 1 to 2 mg/kg intakes during prolonged exercise has been recommended<ref name="CaffMetaAndPerf"/>. Too much caffeine (9 mg/kg), especially for those that do not regularly take caffeine, can cause impairment, such as becoming talkative, giddy, and unable to perform simple tasks such as telling the time<ref name="CaffMetaAndPerf"/>. Low levels of exercise (30% [[VO2max|V̇O<sub>2</sub>max]]) seem to increase the metabolism of caffeine<ref name="CafModEx"/>, but higher intensities have no impact<ref name="CafExThermal"/>. Below is a listing of caffeine in common beverages.
{| class="wikitable" style="margin-left: auto; margin-right: auto; border: none;"
! '''Source'''
! '''Caffeine (mg) '''
| 80 per 8.3oz Can
|}
=Caffeine and Genetics=
There is some research indicating that there are genetic differences that change how caffeine effects people, but the research is a little unclear. However, it seems that having your genome tested could provide valuable information into how to use caffeine. The enzyme CYP1A2 metabolizes many drugs, and it's been shown to be responsible for over 95% of the metabolism of caffeine<ref name="BegasKouvaras2007"/>. The CYP1A2 enzyme is produced by the CYP1A2 gene, and a genetic change at rs762551 impacts how the enzyme is produced, with AA having greater activity than the AC or CC genotypes<ref name="snpe_rs76"/>. Sometimes the subjects with the AA variant are called "fast metabolizers". (I had my genome tested using 23andme.com which showed I have the AA variant of CYP1A2/rs762551.)
* A study of 101 recreationally competitive male athletes on a 10K cycling time trial with 2 or 4 mg/Kg caffeine, there was an improvement only in those with the AA variant of CYP1A2, with no effect on the AC and diminished performance for the CC<ref name="Guest-2018"/>.
* A study of 21 active subjects given 3 mg/Kg of caffeine and tested using a 30 second Wingate test showed performance improvements did not vary between AA and AC/CC variants, though AC/CC reported increased nervousness while the AA variants did not<ref name="Salinero-2017"/>.
* A study of caffeine and basketball related performance (jump, change of direction) in 19 elite basketball players found that caffeine benefited the AA variants slightly more than the AC/CC variants<ref name="Puente-2018"/>. Strangely, the AA variants suffered tended to suffer from insomnia in the 24 hours after the test (I'd have expected AA variants to clear the caffeine faster and thus not suffer from insomnia as much as other variants.)
* A study of 35 male recreationally competitive cyclists performing a simulated 40K time trial following 6 mg/Kg of caffeine showed the AA variants improved more (4.9%) with caffeine than the AC/CC variants (1.8%)<ref name="WomackSaunders2012"/>. Beyond those averages, 15 of 16 AA variants improved their time by at least 60 seconds, while that only happened for 10 of the 19 C variants.
* A study of 20 healthy but untrained subjects did not show any statistically significant improvement in performance with 225mg caffeine in either AA or C variants<ref name="AlgrainThomas2016"/>. Looking at the data, it appears that a larger group of subjects might be needed to provide the statistical power required.
* A study of 20 collage level tennis players showed that 6 mg/Kg caffeine improved intermittent treadmill performance with no differences between AA and C variants<ref name="KleinClawson2012"/>.
* Other factors beyond genetics impact CYP1A2 enzyme activity, with exercise, caffeine intake, broccoli all increasing it<ref name="Vistisen-1992"/>.
It seems rather counterintuitive to me that the faster you metabolize caffeine, the greater the benefit. It suggests that maybe it's a metabolite of caffeine that improves performance rather than the caffeine itself, but that's pure supposition on my part.
=Caffeine, Blood Pressure and Heart Rate=
Caffeine increases blood pressure at rest and under stress, including exercise stress. The effect of caffeine on heart rate is unclear, with both increases and decreases observed in studies. Generally caffeine decreases heart rate at rest and moderate intensity exercise, but increases it at maximal workloads.
==Confounding factors==
Understanding the effect of caffeine on blood pressure and heart rate is complicated by a number of factors. Do the subjects regularly use caffeine or are they caffeine naive? Do they have normal blood pressure or hypotension? How does exercise or non-exercise stress change the effect of caffeine? Should we look at acute or long term changes? There may be other underlying factors that influence the response to caffeine, such as nicotine consumption<ref name="Perkins-1994"/>, or taking caffeine with food<ref name="HasenfratzJaquet1991"/>.
==Acute Changes at Rest ==
At rest, caffeine increases blood pressure, but it may lower or slightly raise heart rate.
* Systolic blood pressure is increased by 3-7 mmHg<ref name="Sondermeijervan Marle2002"/><ref name="Hartley-2004"/><ref name="TurleyGerst2006"/>.
** A meta-analysis showed that coffee increased systolic blood pressure by 2.4 mmHg, with each additional cup of coffee increasing by a further 0.8 mmHg<ref name="Jee-1999"/>.
* Diastolic blood pressure is increased by 2-4 mmHg<ref name="Sondermeijervan Marle2002"/><ref name="Hartley-2004"/><ref name="TurleyGerst2006"/>.
** Coffee increases diastolic blood pressure by 1.2 mmHg, with each additional cup of coffee increasing by a further 0.5 mmHg<ref name="Jee-1999"/>.
* The change in blood pressure is due to an increase in peripheral vascular resistance rather than increased cardiac output<ref name="Pincomb-1996"/><ref name="Pincomb-1985"/><ref name="SungLovallo1990"/>.
* Most<ref name="Pincomb-1996"/><ref name="Sung-1995"/><ref name="HartleySung2000"/>, but not all<ref name="Lovallo-1991"/> studies show that blood pressure increases are generally greater in people with borderline hypotension.
* The rise in blood pressure is seen while the subjects went about their normal activities<ref name="Green-1996"/>.
* At rest, heart rate decreases with caffeine<ref name="Whitsett-1984"/><ref name="Sung-1995"/><ref name="TurleyGerst2006"/> though one study showed no change<ref name="Sondermeijervan Marle2002"/>.
* Most studies show that [[Heart Rate Variability]] is increased at rest<ref name="Yeragani-2005"/><ref name="Kolodiĭchuk-1991"/><ref name="Nishijima-2002"/>, but one study showed no change in habitual caffeine users<ref name="RauhBurkert2006"/>, and another showed a reduction in the caffeine naive<ref name="Sondermeijervan Marle2002"/>.
* Caffeine withdrawal can reduce blood pressure by 5-6 mmHg<ref name="Phillips-Bute1997"/>.
* A review of the available research indicated that 7 studies showed that habitual caffeine users had a lower Blood Pressure response to acute caffeine compared with caffeine naive individuals, but 21 studies found no difference<ref name="GreenKirby1996"/>. One study showed a reduced increase in blood pressure after regular coffee drinking for four weeks<ref name="Ammon-1983"/>.
* Older individuals may have a greater rise in blood pressure<ref name="Izzo-1983"/>.
* Taking caffeine with food dampens the effect of the caffeine, probably because it decreases the absorption rate<ref name="HasenfratzJaquet1991"/>.
==Acute Changes During Exercise==
Caffeine raises blood pressure during exercise, increasing the possibility of excessively high blood pressure. Caffeine can increase or decrease heart rate during exercise, possibly lowering it during lower intensity exercise and increasing it at highest intensities.
* The effect of Caffeine on heart rate during exercise is ambiguous, with some studies showing an increase in heart rate<ref name="Bell-1998"/><ref name="Mcnaughton1987"/><ref name="Sasaki-1987"/><ref name="Sung-1995"/><ref name="Bell-2002"/>, while others show a decrease<ref name="Sullivan-1992"/><ref name="TurleyGerst2006"/><ref name="Gaesser-1985"/><ref name="McClaranWetter2007"/><ref name="SungLovallo1990"/>. Examining the studies in more detail however, and it appears that the increase in heart rate may be mostly at the highest intensities, with caffeine reducing heart rate at the lower intensities. The effect does not appear different for those that are caffeine habituated or those that are caffeine naïve.
{| class="wikitable" style="margin-left: auto; margin-right: auto; border: none;"
! Study
! Subjects
! Caffeine
! Exercise
! Caffeine's effect on Heart Rate
|-
| Bell 1998<ref name="Bell-1998"/>
| Caffeine Habituated
| 5mg/Kg
| 85% [[VO2max|V̇O<sub>2</sub>max]]
| Increased at 5 min but not 10 min
|-
| McNaughton 1987<ref name="Mcnaughton1987"/>
| Caffeine Naïve
|
| Incremental to exhaustion
| HR Increased
|-
| Bell 2002<ref name="Bell-2002"/>
| Both Habituated and Naïve
| 5mg/Kg
| 80% [[VO2max|V̇O<sub>2</sub>max]]
| HR Increased in both groups
|-
| Sasaki 1987<ref name="Sasaki-1987"/>
|
| 200mg
| Incremental to exhaustion
| HR Increased
|-
| Sung 1995<ref name="Sung-1995"/>
| Caffeine Habituated
|
| 30 min cycling
| HR Increase in hypotensive, not normotensive
|-
| Sullivan 1992<ref name="Sullivan-1992"/>
|
| 3.3mg/Kg
| 45% [[VO2max|V̇O<sub>2</sub>max]]
| No change
|-
| Turley 2006<ref name="TurleyGerst2006"/>
|
| 5mg/Kg
| 25 and 50watt cycling (children)
| No change
|-
| Gaesser 1985<ref name="Gaesser-1985"/>
| Caffeine Habituated
| 200mg
| Incremental to exhaustion
| HR lower at moderate work rates, no change at high work rates
|-
| McClaran 2007<ref name="McClaranWetter2007"/>
| Caffeine Naïve, Trained
| 1.5 or 3.0 mg/Kg
| Incremental and maximal
| HR lower at submaximal (30-63% [[VO2max|V̇O<sub>2</sub>max]]) but not maximum workloads
|}
* The effect of caffeine on blood pressure is more consistent, with most studies showing an increase<ref name="Sung-1995"/><ref name="Sullivan-1992"/><ref name="TurleyGerst2006"/>.
* Blood pressure during exercise can become excessive (> 230 for systolic or > 120 for diastolic). Caffeine increases the risk of excessive blood pressure in normotensive individuals<ref name="SungLovallo1990"/>, but the risk is greater in people who are hypertensive <ref name="Sung-1995"/>. There are recommendations that hypertensive individuals avoid caffeine during exercise<ref name="PincombWilson1991"/>.
* [[Heart Rate Variability]] goes down with exercise, but this decrease is reduced with caffeine<ref name="Yeragani-2005"/><ref name="Nishijima-2002"/>.
* Caffeine did not alter [[Maximum Heart Rate]] in one study<ref name="SungLovallo1990"/>.
==Caffeine Changes During Non-Exercise Stress==
Non-exercise stress includes things like mental arithmetic, rapid information processing, final exams. An analysis of 21 studies that looked at caffeine and non-exercise stress found that<ref name="GreenKirby1996"/>:
* Heart rate changes:
** 13 showed no change in heart rate, both at rest and under stress.
** 3 decrease in heart rate at rest, but an increase under stress.
** 3 no change in heart rate at rest, but an increase under stress.
** 2 showed a decrease both at rest and under stress.
* Nearly all studies showed an increase in blood pressure for both the at rest and stress conditions.
=Caffeine and Dehydration=
Caffeine does not impact performance in hot/humid conditions, nor act as a diuretic when running<ref name="CaffDiuretic"/>. Caffeine at 360mg is a diuretic at rest, but not at 180mg or less<ref name="CaffDiureticDose"/>. Caffeine does not cause long term dehydration<ref name="Caff11day"/>, and black tea has been shown to hydrate as well as water<ref name="CaffTea"/>. Caffeine does result in increased sodium excretion in the urine<ref name="CaffSodium"/>, but the significance of this unclear.
* While caffeine could reduce the altitude problems that prevent sleep, the stimulant nature of caffeine may offset these benefits.
Caffeine has a shorter duration of effect at high altitude, possibly due to increased blood flow to the liver, and withdrawal from caffeine would likely make altitude problems more severe<ref name="CafAltitude"/>.
=Caffeine clearance=
Caffeine is rapidly absorbed, and its clearance varies with multiple variables, including exercise. It seems that exercise might increase clearance, which in turn might increase the needed dosage for ultra-endurance events.
* About 99% of consumed caffeine is absorbed within 45 minutes, with peak concentrations after about 30 minutes<ref name="NehligAlexander2018"/>.
* Caffeine half-life is generally 2.5-5 hours with some dose dependency and individual variability<ref name="CamandolaPlick2018"/>.
* A study found that lean subjects cleared caffeine faster than the obese, with the half life of 2.6 hours rather than 4.4 hours<ref name="Kamimori-1987"/>.
* An hour's light exercise (30% [[VO2max|V̇O<sub>2</sub>max]]) reduced the half life from 4 hours to 2.3 hours in healthy subjects<ref name="Collomp-1991"/>.
* A study of 14 active ([[VO2max|V̇O2max]] of 50) subjects (8 women) found no change in caffeine clearance with exercise<ref name="McLeanGraham2002"/>. Subjects exercised for 1.5 hours at 60-65% of [[VO2max|V̇O<sub>2</sub>max]], starting 1 hour after ingesting 6 mg/Kg of caffeine. Half life was ~6 hours.
* The half-life of caffeine seems dose dependent<ref name="ChengMurphy1990"/>. In healthy subjects, the half-life at 70mg was 4.5 hours, at 200mg was 60 hours, and at 300mg was 6.4 hours. (Impaired liver function can dramatically increase the half-life to 25-30 hours.)
* Caffeine is metabolized by the liver enzyme CYP1A2<ref name="KalowTang1993"/> and the activity of this enzyme can be affected by drugs and diet, with tobacco and chargrilled meat increasing levels<ref name="Flockhart-2007"/>.
Things may not be so simple, as about 85% of caffeine is metabolized to Paraxanthine <ref name="GuerreiroToulorge2008"/> and Paraxanthine in mice is a stronger stimulant than caffeine<ref name="Okuro-2010"/>, while similar in humans<ref name="BenowitzJacob1995"/>. Paraxanthine has a half-life of 3.1-4.1 hours<ref name="CamandolaPlick2018"/>, and levels become higher than caffeine after 8-10 hours<ref name="NehligAlexander2018"/>
(There is a common genetic mutation in dogs that prevents the formation of CYP1A2, making these dogs unable to metabolize caffeine and some other substances<ref name="AretzGeyer2011"/>.)
=Glucose Absorption, Insulin Resistance and Glycemic index =
Caffeine changes the way glucose is absorbed, but this effect is different for those at rest compared with those exercising.
==Soda==
The caffeine levels in soda vary widely, with some common values shown below.
{| class="wikitable" style="margin-left: auto; margin-right: auto; border: none;"
! Soda
! Caffeine per 12oz<ref name="ChouBell2007"/>
==Caffeine and Irregular Heart Beats==
[http://en.wikipedia.org/wiki/Cardiac_arrhythmia Cardiac arrhythmias] (irregular heartbeats) are a group of conditions where the heart does not beat normally and can be a life threatening emergency. There is a common belief that caffeine is linked to some types of arrhythmias, but this does not seem scientifically supported for <ref name="RashidHines2006"/><ref name="Katan-2005"/><ref name="Pelchovitz-2011"/>. In fact, an animal study showed that moderate caffeine reduces the risk of atrial fibrillation<ref name="RashidHines2006"/>. A study giving recent heart attacks 450mg of caffeine showed no change in the risk of arrythmia<ref name="Myers-1990"/>. Giving 200mg of caffeine before a bicycle stress test to patients who have malignant ventricular arrhythmias made no difference<ref name="Graboys-1989"/>. However, there are anecdotal reports of people having arrhythmia triggered by caffeine. Note that a caffeine overdoes can result in heart problems<ref name="Pelchovitz-2011"/>.
==Caffeine and Blood Pressure==
As noted above, blood pressure during exercise rise to an excessive level (> 230 for systolic or > 120 for diastolic). Taking caffeine can increase the risk of excessive blood pressure in people with normal blood pressure<ref name="SungLovallo1990"/>, but the risk is greater in people who already have high blood pressure<ref name="Sung-1995"/>. Some authorities recommendation that individuals with high blood pressure do not take caffeine with exercise<ref name="PincombWilson1991"/>.
==Evaluating the risks==
Because coronary artery disease may not have any initial symptoms<ref name="MayoCAD"/>, risk evaluation is tricky. Some runners who died suddenly had high cholesterol, high blood pressure or chest pains<ref name="WallerRoberts1980"/>. Other risk factors include diabetes, smoking, family history of heart attacks, obesity, long term alcohol use. If you have any risk factors for coronary artery disease, it would be prudent to talk to a healthcare professional.
* A milk intake of 500 to 900 ml/day<ref name="CaffBabyMilk"/>
* The nursing mother's caffeine intake of 200mg/day (one double shot espresso),
We get a resulting caffeine concentration in the milk of 4ug/ml to 8ug/ml<ref name="Stavchansky-"/>, which is a total caffeine intake of between 2mg to 13mg, or 0.6 to 4 mg/Kg body weight. The upper end of that level is quite high. However, the baby's half-life for caffeine is 31-132 hours (average 82 hours)<ref name="Parsons-1981"/>, compared with an adult's 2-10 hour half-life, so the caffeine will build up over time. A 24 hour half live (which is easier to calculate) would result in about a 3mg to 26mg, which is 1 to 8 mg/Kg. I'm guessing that would result in the baby not sleeping well! Conversely, a baby whose mother takes caffeine during pregnancy and is then given formula milk may undergo caffeine withdrawal after birth<ref name="McGowan-1988"/>. Even if the mother breast feeds, the varying levels of caffeine may cause withdrawal symptoms<ref name="Martín-2007"/>. Also, caffeine has been shown to increase fetal [[Heart Rate]]<ref name="Buscicchio-2012"/>. There is research indicating that Caffeine may not reduce to subtherapeutic levels until around 11-12 days<ref name="Doyle-2016"/>.
=References=
<references>
<ref name="Doyle-2016">J. Doyle, D. Davidson, S. Katz, M. Varela, D. Demeglio, J. DeCristofaro, Apnea of prematurity and caffeine pharmacokinetics: potential impact on hospital discharge., J Perinatol, volume 36, issue 2, pages 141-4, Feb 2016, doi [http://dx.doi.org/10.1038/jp.2015.167 10.1038/jp.2015.167], PMID [http://www.ncbi.nlm.nih.gov/pubmed/26562367 26562367]</ref>
<ref name="Martín-2007">I. Martín, MA. López-Vílchez, A. Mur, O. García-Algar, S. Rossi, E. Marchei, S. Pichini, Neonatal withdrawal syndrome after chronic maternal drinking of mate., Ther Drug Monit, volume 29, issue 1, pages 127-9, Feb 2007, doi [http://dx.doi.org/10.1097/FTD.0b013e31803257ed 10.1097/FTD.0b013e31803257ed], PMID [http://www.ncbi.nlm.nih.gov/pubmed/17304161 17304161]</ref>
<ref name="McGowan-1988">JD. McGowan, RE. Altman, WP. Kanto, Neonatal withdrawal symptoms after chronic maternal ingestion of caffeine., South Med J, volume 81, issue 9, pages 1092-4, Sep 1988, PMID [http://www.ncbi.nlm.nih.gov/pubmed/3420441 3420441]</ref>
<ref name="Pasman-1995">WJ. Pasman, MA. van Baak, AE. Jeukendrup, A. de Haan, The effect of different dosages of caffeine on endurance performance time., Int J Sports Med, volume 16, issue 4, pages 225-30, May 1995, doi [http://dx.doi.org/10.1055/s-2007-972996 10.1055/s-2007-972996], PMID [http://www.ncbi.nlm.nih.gov/pubmed/7657415 7657415]</ref>
<ref name="CaffRedBull">Nutrition Facts and Analysis for Energy drink, RED BULL, with added caffeine, niacin, pantothenic acid, vitamins B6 and B12 http://nutritiondata.self.com/facts/beverages/7399/2 </ref>
<ref name="Macfarlane">author Alan Macfarlane, Iris Macfarlane !!coauthors!!, The Empire of Tea, publisher The Overlook Press, isbn 1-58567-493-1, page 32 !!page!!, 2004</ref>
<ref name="Lin-2003">YS. Lin, YJ. Tsai, JS. Tsay, JK. Lin, Factors affecting the levels of tea polyphenols and caffeine in tea leaves., J Agric Food Chem, volume 51, issue 7, pages 1864-73, Mar 2003, doi [http://dx.doi.org/10.1021/jf021066b 10.1021/jf021066b], PMID [http://www.ncbi.nlm.nih.gov/pubmed/12643643 12643643]</ref>
<ref name="ShishikuraKhokhar2005">Yoko Shishikura, Santosh Khokhar, Factors affecting the levels of catechins and caffeine in tea beverage: estimated daily intakes and antioxidant activity, Journal of the Science of Food and Agriculture, volume 85, issue 12, 2005, pages 2125–2133, ISSN [http://www.worldcat.org/issn/0022-5142 0022-5142], doi [http://dx.doi.org/10.1002/jsfa.2206 10.1002/jsfa.2206]</ref>
<ref name="Pettitt-2012"> RW. Pettitt, JD. Niemeyer, PJ. Sexton, A. Lipetzky, SR. Murray, Do the non-caffeine ingredients of energy drinks affect metabolic responses to heavy exercise?, J Strength Cond Res, Oct 2012, doi [http://dx.doi.org/10.1519/JSC.0b013e3182736e31 10.1519/JSC.0b013e3182736e31], PMID [http://www.ncbi.nlm.nih.gov/pubmed/23037611 23037611]</ref>
<ref name="Parsons-1981">Parsons, William D., and Allen H. Neims. "Prolonged half-life of caffeine in healthy term newborn infants." Journal of Pediatrics 98.4 (1981): 640-641.</ref>
<ref name="HasenfratzJaquet1991">M. Hasenfratz, F. Jaquet, D. Aeschbach, K. Bättig, Interactions of smoking and lunch with the effects of caffeine on cardiovascular functions and information processing, Human Psychopharmacology: Clinical and Experimental, volume 6, issue 4, 1991, pages 277–284, ISSN [http://www.worldcat.org/issn/0885-6222 0885-6222], doi [http://dx.doi.org/10.1002/hup.470060403 10.1002/hup.470060403]</ref>
<ref name="PincombWilson1991">Gwendolyn A. Pincomb, Michael F. Wilson, Bong Hee Sung, Richard B. Passey, William R. Lovallo, Effects of caffeine on pressor regulation during rest and exercise in men at risk for hypertension, American Heart Journal, volume 122, issue 4, 1991, pages 1107–1115, ISSN [http://www.worldcat.org/issn/00028703 00028703], doi [http://dx.doi.org/10.1016/0002-8703(91)90479-2 10.1016/0002-8703(91)90479-2]</ref>
<ref name="SungLovallo1990">Bong Hee Sung, William R. Lovallo, Gwendolyn A. Pincomb, Michael F. Wilson, Effects of caffeine on blood pressure response during exercise in normotensive healthy young men, The American Journal of Cardiology, volume 65, issue 13, 1990, pages 909–913, ISSN [http://www.worldcat.org/issn/00029149 00029149], doi [http://dx.doi.org/10.1016/0002-9149(90)91435-9 10.1016/0002-9149(90)91435-9]</ref>
<ref name="HartleySung2000">T. R. Hartley, B. H. Sung, G. A. Pincomb, T. L. Whitsett, M. F. Wilson, W. R. Lovallo, Hypertension Risk Status and Effect of Caffeine on Blood Pressure, Hypertension, volume 36, issue 1, 2000, pages 137–141, ISSN [http://www.worldcat.org/issn/0194-911X 0194-911X], doi [http://dx.doi.org/10.1161/01.HYP.36.1.137 10.1161/01.HYP.36.1.137]</ref>
<ref name="Lovallo-1991">WR. Lovallo, GA. Pincomb, BH. Sung, SA. Everson, RB. Passey, MF. Wilson, Hypertension risk and caffeine's effect on cardiovascular activity during mental stress in young men., Health Psychol, volume 10, issue 4, pages 236-43, 1991, PMID [http://www.ncbi.nlm.nih.gov/pubmed/1915209 1915209]</ref>
<ref name="Pincomb-1985">GA. Pincomb, WR. Lovallo, RB. Passey, TL. Whitsett, SM. Silverstein, MF. Wilson, Effects of caffeine on vascular resistance, cardiac output and myocardial contractility in young men., Am J Cardiol, volume 56, issue 1, pages 119-22, Jul 1985, PMID [http://www.ncbi.nlm.nih.gov/pubmed/4014015 4014015]</ref>
<ref name="Pincomb-1996">GA. Pincomb, WR. Lovallo, BS. McKey, BH. Sung, RB. Passey, SA. Everson, MF. Wilson, Acute blood pressure elevations with caffeine in men with borderline systemic hypertension., Am J Cardiol, volume 77, issue 4, pages 270-4, Feb 1996, PMID [http://www.ncbi.nlm.nih.gov/pubmed/8607407 8607407]</ref>
<ref name="TurleyGerst2006">Kenneth R. Turley, Jonathan W. Gerst, Effects of Caffeine on Physiological Responses to Exercise in Young Boys and Girls, Medicine & Science in Sports & Exercise, volume 38, issue 3, 2006, pages 520–526, ISSN [http://www.worldcat.org/issn/0195-9131 0195-9131], doi [http://dx.doi.org/10.1249/01.mss.0000191189.40436.73 10.1249/01.mss.0000191189.40436.73]</ref>
<ref name="Sullivan-1992">Sullivan, James J., Knowlton, Ronald G., Brown, Dale D., 1992, Journal of Cardiopulmonary Rehabilitation and Prevention, Caffeine Affects Heart Rate and Blood Pressure Response to Prolonged Walking, http://journals.lww.com/jcrjournal/Fulltext/1992/11000/Caffeine_Affects_Heart_Rate_and_Blood_Pressure.8.aspx</ref>
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