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Caffeine

physician assistant

teensdrinkcoffeeIntroduction:

Caffeine is a central nervous system stimulant found naturally in the fruits, leaves, and seeds of coffee plants, Camelia senesis (tea plants), guarana, kola nut, and some others. The majority of adults in developed countries consume caffeine every day. Caffeine taken in moderation has been generally recognized as safe by the Food and Drug Administration (FDA) and American Medical Association (AMA). Caffeine interacts with hundreds of medications and affects the retention and secretion of many nutrients. The stimulant effects of caffeine cause many substantial adverse health effects. If more than 1-2 cups of caffeinated beverages are consumed per day, it is prudent to seek physician and/or pharmacist approval of caffeine consumption with any medications or supplements. The research represented here describes many of the risks and benefits to consuming caffeine and the beverages in which caffeine is found. The specific amounts of caffeine found to be potentially helpful or dangerous in various health conditions will also be discussed.

 

Caffeine intake limits:

Multiple sources in literature search quote that caffeine intake up to 300 mg per day is generally safe for healthy adults. Severe adverse reactions may occur with caffeine intake over 600 mg per day and death can occur with extremely high doses of caffeine if several grams or more are ingested. Caffeine intake in young children and adolescents should be limited much more than adults. The American Academy of Pediatrics recommends that adolescents consume no more than 100 mg of caffeine daily. Younger children should not drink caffeinated beverages on a regular basis (1).

 

Caffeine and adolescent health:

Consuming greater amounts of caffeine leads to shorter sleep duration, longer awake time, and increased sleep during the day, or napping, in adolescents. A total of 191 high school students took part in a 14-day study. Caffeine consumption ranged between 0 and 800 mg per day. The average over 2 weeks went up to 379.4 mg per day. Participants reported on the time they went to bed and woke up, any caffeine intake, and any naps they took. At the end of the study, the researchers found that teens with higher caffeine intake slept fewer hours at night and took more naps during the day than those who had less caffeine. (2)

 

Caffeine and insomnia:

Sleep disturbance by caffeine varies in individuals:

The way in which one’s body metabolizes caffeine may determine the way it influences a person’s sleep patterns. In a study by Levy M. et al, different individuals have been found to metabolize caffeine at different rates. Slower blood clearance and higher blood concentrations of caffeine at midnight were found in six healthy individuals with caffeine-induced wakefulness. Six other subjects in the study were not adversely affected by caffeine, indicating that differences in caffeine metabolism may be a cause of sleep disturbance. Participants with caffeine-induced wakefulness had a longer mean plasma half-life of 7.4 hours and a slower mean plasma clearance compared to those not affected by caffeine. (3)

 

Caffeine users and insomnia:

Participants in a study by Brown et al which were using caffeine were nearly twice as likely to report difficulty falling asleep (odds ratio [OR]=1.79) as those who did not use caffeine. The use of caffeine-containing nonprescription pain killers (analgesics) was associated with difficulty falling asleep while the use of comparable analgesics without caffeine was not. At the third annual follow-up, 2885 study participants aged 67 to 105 completed a survey that included questions about medication use and sleep problems. Only 5.4% of participants were taking caffeine-containing medications. However, these participants were nearly twice as likely to report difficulty falling asleep (odds ratio [OR]=1.79) as those who did not use caffeine containing-medications. This association persisted after taking into account depression, pain, use of multiple drugs or drugs known to interfere with sleep, and coffee consumption with a reported 60% increased risk of difficulty falling asleep (OR=1.60). (4)

 

Caffeine and exercise performance:

Caffeine prolonged time to exhaustion in cycling possibly by conserving potassium. Caffeine Researchers examined the effects of caffeine on athletic performance, including oxygen uptake, also known as VO2 max; oxygen deficit; and certain substances that are by-products of exercise. The researchers evaluated six trained cyclists who exercised to a level beyond aerobic capacity—the ability of the body to utilize oxygen—following consumption of 5 mg per kilogram of body weight of caffeine. There was a significant increase in exercise endurance of 14.8% and the ability of the athletes to exceed aerobic capacity by 6.5%; however, no change was observed for maximum oxygen uptake. Blood potassium levels were tested as a measure of metabolic efficiency and found to be decreased after caffeine consumption and prior to exercise by 13.4%, leading the researchers to suggest the possibility that caffeine had a conserving effect on potassium, thereby prolonging time to fatigue. (5)

Caffeine equivalent to about a cup of coffee improved performance by about 3% in a 60 minute cycling time trial. Investigator had 12 well-trained, regular caffeine users undertake 4 separate cycling trials. Subjects consumed either a measured caffeine dose or a placebo (caffeine withdrawal) for 4 days before a 60 minute cycle time trial. On the caffeine trial, subjects were provided with 1.5 mg of caffeine per kilogram body weight, which equaled about 120 mg of caffeine. On the withdrawal trial, subjects received a placebo tablet to ensure they were blinded to the intervention. Then, on the actual day of the exercise cycle time trial, subjects consumed either a placebo or a 3 mg per kilogram dose of caffeine 90 minutes before the start of the trial. Results found that regardless if subjects withdrew from caffeine or had caffeine daily for the 4 days leading into the cycle time trial, having a 3 mg per kilogram dose of caffeine 90 minutes before the trial, improved exercise performance by about 3%. (6)

In a randomized, double-blind study with10 moderately trained male athletes, it was found that caffeine ingestion may improve performance when athletes are both fresh and fatigued. Compared to placebo participants, individuals taking a 6mg/kg dose of caffeine 60 min before completing an 80-min (4 × 20 min) simulated team-game reported increased total time by 2.3%, reactive agility by 3.9%, movement time by 2.7%, decision time by 9.3%, and decision-making accuracy by 3.8% compared to placebo. However, the results were not significant. (7)

A study found that caffeine or sodium bicarb enhanced cycling performance but combining both did not result in further benefit. Ten well-trained cyclists (mean age, 24.2 yr) participated in this double-blind, crossover study that involved four 3-km cycling time-trial (TT) on a laboratory-based cycle ergometer performed on separate days. Before each TT, participants took either 3 mg/kg body mass (BM) of caffeine (CAFF), 0.3 g per kilogram of sodium bicarbonate (SB), a combination of the two (CAFF+SB), or a placebo (PLAC). Findings indicate that when taken individually, both CAFF and SB enhance high-intensity cycling TT. However, the effect on enhancing physical performance of these 2 popular supplements when taken together was not additive. (8)

In a study, caffeine improved cycling performance time in a surrounding temperature of 12°C but not in a 33°C temperature. The effects of ambient temperature (12°C and 33°C) on how caffeine affects performance during endurance cycling exercise were examined. Male cyclists (N = 11) completed four exercise trials. After cycling continuously for 90 minutes (15-minutes alternating intensities of ~60 and ~71% max oxygen consumption [VO2max]) in either a warm (~33°C, ~41% RH) or cool (~12°C, ~60% RH) environment, participants completed a 15-minute performance trial. Participants ingested 3 mg/kg of caffeine or placebo in capsules 60 minutes prior to exercise and after 45 minutes of exercise. Prior to, and at every 15 minutes of exercise, individuals drank water in equal volumes so that independent of ambient temperature were dehydrated less than 1% at the end of exercise (there was greater fluid intake in the 33°C condition compared to the 12°C condition). Total work accumulated during the performance trial was greater in 12°C than 33°C. Independent of temperature, caffeine increased performance time when compared to placebo. However, compared to placebo, caffeine increased performance time in the 12°C but not in the 33°C condition. Within the 12°C trial, significant differences between caffeine and placebo occurred from 0-5 minutes and 5-10 minutes, but not 10-15 minutes. (9)

 

Caffeine and muscle contraction:

Caffeine was found to increase short duration muscle contraction and muscle fiber conduction velocity in 14 male volunteers in a double-blind study using placebo or caffeine (6mg per kilogram). Measure of muscular function such as maximal voluntary isometric contractions, evoked maximal twitch, and maximal isokinetic contractions during elbow flexion were assessed. Mechanical and electromyographic signals from the biceps brachi muscles were recorded, and changes in the muscle-force velocity relationship and muscle fiber were evaluated. The toque-angular velocity curve improved after caffeine supplementation with an 8.7% increase in muscle conduction velocity. Caffeine was believed to improve motor unit muscle recruitment. (10)

 

Caffeine intake and risk of Alzheimer’s disease:

A case-control study on caffeine done by Maia et al, tested to see if caffeine intake protects against Alzheimer’s disease (AD). In a questionnaire about caffeine intake, researchers calculated the estimated intake depending on the amount of caffeine in different caffeinated products. There were also questions involving tobacco and alcohol consumption. This study reported a significant inverse association between caffeine intake and AD. In other words, an increase in caffeine intake decreased the risk of AD. Hypertension, diabetes, stroke, head trauma, smoking habits, alcohol consumption, non-steroid anti-inflammatory drugs, vitamin E, gastric disorders, heart disease, education and family history of dementia were not statistically significantly associated with AD. Patients with AD had an average daily intake of about 73.9 mg of caffeine during the 20 years prior to diagnosis. Meanwhile, the controls had about 198.7 mg of daily caffeine intake during the same 20 years as their matched pair in the study. These findings suggest that consuming caffeine may have a lower risk Alzheimer’s disease. (11)

 

A review of studies on coffee and Alzheimer’s disease:

A review of studies consistently supported coffee’s favorable effects against cognitive decline, dementia, and Alzheimer’s disease (AD). In a review done by Eskelinen et al., it was determined that moderate caffeine intake, coffee in particular, is associated with a decreased risk in the diagnosis of dementia/AD. This review included nine longitudinal studies and the CAIDE study (Cardiovascular risk factors, Aging and Dementia). The results from the longitudinal studies were inconsistent, but most studies (3 out of 5) support coffee’s favorable effects against cognitive decline. The CAIDE study showed that drinking 3 to 5 cups per day at midlife appears to decrease the risk of dementia/AD by about 65 percent later on. These findings suggest that coffee drinking may be associated with a decreased risk of dementia/AD. (12)

 

Caffeine, cognitive function, and mood:

Caffeine, mood, reaction time, attention, and memory: The ingestion of 250 mg caffeine, by 17 caffeine consumers (mean intake 375mg caffeine per day), after 30 hours of abstinence, had a greater effect than placebo on mood and choice reaction time. Caffeine also improved selective attention and memory in both those who had abstained from caffeine and those who had maintained their habitual intake levels, suggesting no evidence of withdrawal on these markers of mental performance. (13)

 

Caffeine, attention, cognitive function, mood, and performance:

Expectations of caffeine consumption on attention, reward response and mood were tested in 88 participants who were randomly assigned to caffeinated coffee, decaffeinated coffee or placebo. In both groups attention and cognitive/physical function speed increased. Alertness and reward responsiveness were improved in the placebo group. In all participants, self-reported depression increased, but less in the caffeine coffee group than the decaffeinated coffee group. (14)

 

Caffeine used by an introvert vs. extrovert personality:

Researchers suggest that the beneficial effects of caffeine intake on improving working memory (WM) may be linked to personality. Fifty-nine participants received caffeine (200 mg) or placebo prior to completing a N-Back WM task, similar to a memory which is used to measure working memory. Compared to placebo, caffeine improved working memory performance in extroverts but not in introverts. (35)

 

Caffeine and theanine:

Caffeine in combination with theanine present in black tea may improve cognitive function and mood.

 

Black tea, attention focus, accuracy, and alertness:

Drinking black tea was shown to improve the ability to focus attention in two double-blind, randomized, placebo-controlled, crossover studies. In both studies, black tea significantly enhanced accuracy on the switch task and self-reported alertness on the Bond-Lader questionnaire, a mood assessment which grades the degree of mental alertness, calmness and contentedness. The first study also reported better auditory and visual attention after black tea compared to placebo. The two compounds in tea most likely responsible for these effects are theanine, an amino acid found almost exclusively in tea, and caffeine. Both of these were higher in the first study, which corresponds to the stronger results reported in the first study. (15)

 

Caffeine, theanine, cognition, and mood:

Results from a randomized, placebo controlled, double-blind, balanced crossover study of the cognitive and mood effects of two compounds both alone [L-theanine (250 mg), caffeine (150 mg)] and in combination (250 mg/150 mg) suggest that beverages, like tea, containing L-theanine and caffeine may have a positive effect on cognition and mood. Twenty four undergraduate students (mean age 21.3 years) took part in the study and were asked to abstain from caffeine and alcohol 12 hours prior to the study. Participants were randomised to a treatment group and received 4 different beverages (250ml drinks as previously described) plus a placebo on separate occasions 7 days apart. On each occasion the tests were carried out before taking the drink, 30 minutes after the drink and 90 minutes post-drink. Each testing session lasted approximately 30 minutes. Compared to the isolated effects of caffeine and L-theanine, the combined action resulted in improvements in visual tasks and mental fatigue ratings. In addition the combination of caffeine and L-theanine also speeded up the completion of a number of cognitive tasks. Participants also reported fewer headache symptoms and felt more alert. Overall, L-theanine with caffeine was found to increasing alertness, reducing tiredness, and reducing headaches. (16)

 

Caffeine, lung function, and asthma:

Caffeine doses for asthma:

Caffeine at a dose of 7 mg/kg was reported to improve lung function in a study that included 10 individuals with bronchial asthma. Patients were given placebo and caffeine (3.5 mg/kg and 7 mg/kg ) two hours prior to exercise and a lung function test (spirometry) was administered  an hour and two hours after and at 5, 15, and 30 minutes post exercise. Forced expiratory volume (FEV1), a measure of lung function, improved significantly and stopped constriction of the airways in the lungs caused by exercise. (17)

 

Caffeine and pulmonary function testing:

A review examined seven available clinical trials on caffeine in asthma, specifically on caffeine’s effect on lung function tests. Of the 55 asthmatics in these studies, some were given caffeine and others were given placebos. The results showed that even small amounts of caffeine (< 5mg/kg body weight) helps asthmatics breathe more easily for 2 to 4 hours after ingestion. Forced expiratory volume (FEV1), a measure of lung function, showed a small mean improvement of 5% up to 2 hours after consumption of caffeine. In 2 separate studies mean FEV1 improvement were reported at 12% and 18% after caffeine. Another clinical trial looked at the effect of caffeine on exhaled nitric oxide levels and found that there is no significant effect. (18)

 

Tea and cardiovascular disease:

Despite drinking tea containing small amounts of caffeine, the risk of cardiovascular disease was reduced. This is likely attributed to the antioxidants in the tea as opposed to the caffeine which tea contains: In a population study researchers found that consumption of coffee, green tea and oolong tea and total caffeine intake was linked to a reduced risk of death from cardiovascular disease (CVD). Participants included 76,979 adults followed for 1,010,787 person years, all of whom were ages 40 to 79 and free of stroke, heart disease, and cancer at the start of the study. Compared with non-tea drinkers, women consuming 1-6 cups/week, 1-2 cups/day, 3-5 cups/day and ≥ 6 cups/day had a 66%, 72%, 61%, and 58% reduced rate of coronary heart disease compared to non-tea drinkers. Multivariable hazard ratios were 0.34 (0.06-1.75), 0.28 (0.07-1.11), 0.39 (0.18-0.85) and 0.42 (0.17-0.88) respectively (p = 0.038 for trend). Men drinking ≥ 1 cups/day of oolong tea benefited from a 61% reduced rate of CVD (the HR was 0.39, with range of 0.17-0.88) when compared to non-tea drinkers, (p = 0.049 for trend). Individuals in the second highest quintile of total caffeine intake had a total CVD risk reduction of 38% in men and 22% in women. (19)

 

Caffeine use in pregnancy:

Coffee consumption and spontaneous abortion (a.k.a. miscarriage):

Non-smoking pregnant women who drank coffee were found to have an increased risk of losing their baby through spontaneous abortion in a study of 1,515 women (spontaneous abortion: 562, no spontaneous abortion: 953). Risk of spontaneous abortion was related to quantity of caffeine consumed. At 100 to 299 mg/d, 300 to 499 mg/d, and 500 mg/d or more of caffeine consumption risk of spontaneous abortion increased by 30%, 40%, and 120%, respectively. No increased risk of spontaneous abortion from caffeine was reported among women who smoked. Additionally, moderate to high consumption of caffeine was associated with an excess risk of spontaneous abortion in fetuses with normal chromosomes than in those classified as abnormal. (20)

 

Safe level of caffeine consumption in pregnancy:

According to a study by Jarosz M, et al, entitled Maternal caffeine intake and its effect on pregnancy outcomes, caffeine intake of up to 300 mg per day may not affect pregnancy duration and condition of the newborn baby in a study, but intake should be kept at 200 mgs per day or lower in order to be safe. Research included in this publication by the author found that a study conducted on 509 pregnant women found no relationship between maternal caffeine intake during pregnancy and the risk of premature birth, birth weight or the Apgar score (a method of assessing health) of newborns. A majority of women (98.4%) consumed no more than 300 mg of caffeine per day. Most sources estimate that one 8 ounce cup of coffee contains between 60 and 200 mg of caffeine. In conclusion, during pregnancy caffeine consumption of no more than 300 mg per day does not affect pregnancy duration and the condition of the newborn. (21)

Caffeine consumption in small amounts (less than 200 mg/day) during pregnancy does not seem to be associated with miscarriage or preterm birth. However, caffeine’s effect on the growth of the fetus is not known. (34)

 

Caffeine and diabetes:

Caffeine may increase blood glucose levels by lowering insulin sensitivity. Lowering insulin sensitivity makes insulin less effective at lowering blood glucose levels.

Drinking caffeinated coffee with meals may decrease insulin sensitivity, according researchers.Ten healthy men 5 mg/kg of caffeinated coffee one hour before eating a meal (75-g oral glucose load) with either a high glycemic index (Crispex) — comprised of foods that raise blood sugar levels quickly, such as processed carbohydrates — or a low glycemic index meal (All Bran). Caffeinated coffee before a high glycemic index meal resulted in significant insulin sensitivity reduction of 40% compared to decaffeinated coffee before the same meal. Caffeinated coffee prior to a low glycemic index meal led a 29% decrease in insulin sensitivity than the same meal eaten after consuming decaffeinated coffee. (22)

 

Coffee and glucose levels:

A study of 30 healthy nonsmoking individuals found that caffeine consumption can increase glucose concentrations. Participants went without coffee, tea, chocolate or coke for 4 weeks and were then given 200 mg oral caffeine or placebo (decaffeinated coffee) An 75g oral glucose tolerance test (OGTT) found similar blood insulin levels in both groups, but blood glucose levels were found to increase in the caffeine group at the 2nd, 3rd, and 4th hours compared to placebo. (23)

 

Caffeine and skin cancer:

Caffeine may reduce the risk of developing skin cancer, specifically basal cell carcinoma (BCC), according to a study of 112,897 participants (72,921 female nurses and 39,976 male health professionals). When participants were ranked according to caffeine consumption, with the highest consumption at the top and the lowest at the bottom, they found for women, the top 20% of caffeine consumers had an 18% lower risk of BCC than the bottom 20%. For men, the risk was lowered by 13%. The researchers also found that drinking 3 cups of caffeinated coffee was linked to a 21% lower risk of developing BCC in women and a 10% lower risk in men, compared to drinking less than 1 cup per month. And caffeine from other dietary sources (tea, cola, and chocolate) also had a similar effect: the higher the intake, the lower the risk of BCC. (24)

 

Osteoporosis and caffeine:

Osteoporosis patients should limit caffeine intake. Osteoporosis occurs due to a decrease of bone mass and quality of bone, which may lead to fracture. In addition to pharmacological options, individuals should also be counseled on the right intake of calcium and vitamin D, increasing weight-bearing exercise, limiting alcohol and caffeine, and avoiding smoking, all of which lessen the symptoms of osteoporosis. (25)

 

Caffeine adverse reactions and interactions:

As caffeine doses increases, reactions also increase:

As caffeine increased so did the reported risk of indigestion, palpitations, tremor, headache, and sleep difficulty in both men and women. A cross-sectional Australian study of 4558 participants revealed that as the intake of caffeine increased so did the reported risk of indigestion, palpitations, tremor, headache, and sleep difficulty in both men and women. Compared to non-coffee drinkers, men consuming 240 mg of caffeine (about 4-5 cups of coffee or tea) per day were more likely, by a factor of 1.6 times, to experience heart palpitations, 1.3 for tremor, 1.3 for headache and 1.4 for insomnia. In women, the corresponding results were 1.7, 1.5, 1.2, and 1.4. (26)

 

Caffeine and guarana:

Consumers should be aware that guarana has one of the highest concentrations of caffeine in any plant and intake of this herb supplement is not advised. The amount of caffeine in guarana may not be known, consistent or reliable in supplements. Authors report a case in which an individual taking two herbal supplements suffered from premature ventricular contractions (PVCs) believed to be an adverse effect of the supplements. Both supplements included a variety of herbs but both contained high doses of guarana. Guarana has one of the highest concentrations of caffeine in any plant and is found in many supplements sold in the US. (27)

 

Caffeine and hypokalemia:

Excessive caffeine intake can lead to severe hypokalemia (low serum potassium levels) due to the diuretic effect of caffeine. (28)

 

Caffeine and calcium:

Caffeine consumption increases calcium excretion in the urine and may increase the risk of kidney stones. A positive relationship between caffeine consumption and urine calcium levels in with and without kidney stones was found. The study examined 39 participants who had kidney stones but had normal levels of calcium in their body, and nine participants who had no stones and normal amounts of calcium. Consuming caffeine increased the amount of calcium in both group’s urine but not the amount of oxalate, molecule that can link up with calcium and crystallize causing stones. The researchers stated that the risk of getting calcium oxalate stones increased from 2.4 to 3.1 in those who had stones and from 1.7 to 2.5 in those who had no stones. (30)

 

Caffeine, hypertension, cardiovascular disease, and stroke:

Caffeine may increase risk of premature death in patients with hypertension, cardiovascular disease, and stroke. According to James J. E., caffeine through its daily consumption from a variety of sources (coffee, teas, soft drinks, chocolate and medicines), may have an impact on cardiovascular risk. This fact is related to the evidence found the scientific literature about the ability of caffeine to increase resting blood pressure (BP) in adults by about 4/2 mmHg. However, this increase in BP could be responsible for premature deaths of about 14% for coronary heart disease and 20% for stroke. (31)

Excessive caffeine in supplements may increase of stroke. A bodybuilder who appeared to be in good health and had no prior tobacco use or history of major medical problems suffered from an ischemic stroke (occurs when an artery to the brain is blocked). Prior to the stoke, the bodybuilder took one supplement (dose 2 capsules) containing MaHuang extract (20 mg ephedra alkaloids), 200 mg caffeine, 100 mg L-carnitine, and 200 μg chromium. A second supplement contained 6000 mg creatine monohydrate, 1000 mg taurine,100 mg inosine, and 5 mg coenzyme Q10 per scoop. Additionally, 40–60 mg ephedra alkaloids, 400–600 mg caffeine, and 6000 mg creatine monohydrate were taken daily for 6 weeks prior to having a stroke. (29)

 

Caffeine interactions:

Caffeine is classified as a methylxanthine and stimulant which should be avoided when taking medications including theophylline, aminophylline and pentoxyfylline which may potentiate the effects of these drugs. These are compounds which act as heart related stimulants, diuretics, and muscle relaxants. These substances have been reported to cause seizures in individuals without known epilepsy. The severity of seizures and damage to cells seen by methylxanthines use is related to timing, dose, and frequency of use (a few times vs long-term chronic use). (32)

 

Fibrocystic breast disease and caffeine:

The subject of caffeine and fibrocystic breasts is controversial. Research supports both that caffeine may increase breast pain in this condition and possibly affect hormone levels leading to the condition. Other studies have shown that decreasing caffeine intake does not result in improvement. In several studies, a positive link was found between consumption of methylxanthines such as caffeine, theophylline, aminophylline and pentoxyfylline and the level of painful, lumpy breasts (fibrocystic breast disease). The positive association of caffeine and total methylxanthines (from dietary and drug sources) to fibrocystic breast disease needs further research. (33)

 

Assessment and Plan: Caffeine

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

References:

 

1.American Academy of Pediatrics

 

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4.Brown et al. Occult caffeine as a source of sleep problems in an older population. J Am Geriatr Soc. 1995 Aug;43(8):860-4. http://www.ncbi.nlm.nih.gov/pubmed/7636092

 

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11.Maia L, de Mendonça A. Does caffeine intake protect from Alzheimer’s disease? Eur J Neurol. 2002 Jul;9(4):377-82. http://www.ncbi.nlm.nih.gov/pubmed/12099922

 

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16.Haskell CF, Kennedy DO, Milne AL, Wesnes KA, Scholey AB. The effects of L-theanine, caffeine and their combination on cognition and mood. Biol Psychol. 2008 Feb;77(2):113-22. Epub 2007 Sep 26. http://www.ncbi.nlm.nih.gov/pubmed?term=18006208

 

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18.Welsh EJ, Bara A, Barley E, Cates CJ. Caffeine for asthma. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD001112. http://www.ncbi.nlm.nih.gov/pubmed/20091514

 

19.Mineharu Y, Koizumi A, Wada Y, et al. Coffee, green tea, black tea and oolong tea consumption and risk of mortality from cardiovascular disease in Japanese men and women. J Epidemiol Community Health. 2011 Mar;65(3):230-40. Epub 2009 Dec 8. http://www.ncbi.nlm.nih.gov/pubmed/19996359

 

20.Cnattingius S, Signorello LB, Annerén G, et al. Caffeine intake and the risk of first-trimester spontaneous abortion. N Engl J Med. 2000 Dec 21;343(25):1839-45. http://www.ncbi.nlm.nih.gov/pubmed/11117975

 

21.Jarosz M, Wierzejska R, Siuba M. Maternal caffeine intake and its effect on pregnancy outcomes. Eur J Obstet Gynecol Reprod Biol. 2012 Feb;160(2):156-60. http://www.ncbi.nlm.nih.gov/pubmed/22142815

 

22.Moisey LL, Kacker S, Bickerton AC, Robinson LE, Graham TE. Caffeinated coffee consumption impairs blood glucose homeostasis in response to high and low glycemic index meals in healthy men. Am J Clin Nutr. 2008 May;87(5):1254-61. http://www.ncbi.nlm.nih.gov/pubmed/18469247

 

23.Pizziol A, Tikhonoff V, Paleari CD, et al. Effects of caffeine on glucose tolerance: a placebo-controlled study. Eur J Clin Nutr 1998 Nov;52(11):846-9. http://www.ncbi.nlm.nih.gov/pubmed/9846599

 

24.Song F, Qureshi AA, Han J. Increased caffeine intake is associated with reduced risk of basal cell carcinoma of the skin. Cancer Res. 2012 Jul 1;72(13):3282-9. http://www.ncbi.nlm.nih.gov/pubmed/22752299

 

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