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Spilling the Beans on Coffee, Pt. 2

A recent study found that drinking coffee increases the resistance of low-density lipoprotein to oxidation, likely because of the incorporation of natural coffee antioxidants into LDL.


Studies show that coffee is the primary source of antioxidants for most Americans. A recent study found that drinking coffee increases the resistance of low-density lipoprotein to oxidation, likely because of the incorporation of natural coffee antioxidants into LDL.1 That’s significant because oxidized LDL is linked to cardiovascular disease. Coffee also contains soluble fiber, about 1.8 grams per cup, which is linked to lower blood lipid levels.2

High-strung, or type A, people are often considered at greater risk for cardiovascular disease. They’re said to secrete greater amounts of stress hormones, which stimulate cardiac risk factors such as high blood pressure. As coffee stimulates some of those same stress hormones, it would appear that people subject to extraordinary stress should avoid coffee.

A recent study, however, disputes that idea. For eight weeks one group of 21 subjects avoided all caffeine-containing substances. Another group of 43 subjects drank six cups of coffee a day. Researchers measured stress indices, such as heart rate and blood pressure, during mental and physical stress tests both before and after the eight-week test period. Avoiding caffeine made little or no difference in the subjects’ reaction to stress.

Caffeine increases the secretion of cortisol, a stress hormone that exerts catabolic effects in muscle. A study of caffeine intake examined what happens when men and women got 250 milligrams of caffeine three times a day and were subjected to either mental stress or exercise. The caffeine did increase cortisol release in the subjects exposed to mental stress. While exercise alone didn’t raise cortisol, taking caffeine prior to exercise did in both sexes.3

Ulcers are another disease associated with stress. Since the 1940s researchers have known that coffee stimulates acid flow in the stomach, and excess acid is associated with ulcers. Yet no clear-cut evidence proves that drinking coffee causes ulcers. Decaf also promotes increased acid flow, and most physicians advise patients who already have ulcers to avoid both coffee and decaf. It’s now known that ulcers are actually caused by the bacteria Helicobacter pylori.

In 1988, after reviewing the studies that associated coffee drinking with heart disease, the U.S. surgeon general concluded that evidence of a relationship between coffee and heart disease was too weak to recommend that Americans curb their coffee habit. The finding was echoed by the Institute of Food Technologists, a 23,000-member scientific society based in Chicago: “While common sense dictates that excessive consumption of stimulants such as caffeine is not particularly wise, there continues to be no evidence to suggest that moderate caffeine intake is a causative factor in cardiovascular disease.”

Whether caffeine increases the risk of cardiovascular disease may depend on your genes, according to a controversial recent study.4 It found that variations in a certain gene had either a slow- or rapid-metabolizing effect on caffeine. Those with the slow gene showed a 36 percent increased risk of heart attack when drinking two to three cups of coffee a day and a 64 percent increased risk with four or more cups daily. In contrast, those with the fast-metabolizing gene had a 22 percent decreased risk of heart disease with two to three cups and a 1 percent risk with four or more cups. Younger people showed a greater risk in that regard.

The Cancer Connection

Some coffee drinkers were terrified by a 1981 report that linked coffee with pancreatic cancer, an often fatal form of the disease.5 That study was severely flawed, however, and the authors reversed their findings five years later. Subsequent research found a definite connection between pancreatic cancer and tobacco and alcohol use but none with coffee.6 An evaluation of more than 16,000 men and women observed between 1967 and 1979 found no correlation between drinking coffee and any type of cancer.7 In 1984 the American Cancer Society issued a statement saying that coffee doesn’t increase the risk of cancer.

Coffee may even protect against cancer. A 1986 study conducted by researchers at Mount Sinai Medical Center in New York found that women who drank one to five cups of coffee a day showed increased cell differentiation, a process that slows tumor growth.8 Coffee also seems to inhibit cell replication in several other types of cancers.9,10 Caffeine itself is an antioxidant that scavenges free radicals, substances implicated in cancer activity, according to research emanating from West Virginia University.11

Another study reported that coffee may help prevent colon cancer by reducing the excretion of bile acids and cholesterol, both of which are linked to colon cancer. The authors of the study found that “recent coffee consumption is not related to an increased risk of large bowel cancer, and heavy coffee consumption may reduce the risk of colon cancer.”12 A meta-analysis, or compilation of previous studies, in this case 17, found that people who drink four or more cups of coffee daily had a 24 percent decreased risk of colorectal cancer over those who don’t drink it.13 Interestingly, the same compounds in coffee oils thought to promote heart disease may protect against cancer by stimulating phase-2 detoxifying enzymes in the liver and helping increase glutathione, one of the body’s natural antioxidant and detoxifying agents.14

The most recent study to examine the effects of coffee intake on cancer analyzed 13 prospective studies, involving 530,469 women and 244,483 men.15 The study compared the effects of drinking various fluids, such as coffee, tea, milk, soda and juice, on the incidence of renal, or kidney, cancer, which has increased steadily in recent years. The study found that drinking three or more cups of coffee, as opposed to drinking one cup a day, was consistent with a lower risk of getting renal cancer. Tea also showed protective effects, while none of the other fluids analyzed in the study had any effect, bad or good, on that type of cancer.

Another new study looked at the relationship between drinking coffee and nonmelanoma skin cancer, the most common type of skin cancer.16 When compared with women who abstained from daily coffee drinking, coffee-drinking women had a 10.8 percent lower incidence of nonmelanoma skin cancer. Drinking six or more cups daily produced a 36 percent reduction in that type of skin cancer. Decaffeinated coffee offered no such protection.

Women and Coffee

In 1979 reports linked coffee to fibrocystic breast disease, painful but benign lumps in women’s breasts. Further studies found no association.17

The United States Food and Drug Administration in 1980 advised women to limit caffeine intake during pregnancy. The advisory was based on animal studies showing skeletal defects in the offspring of rats that were force-fed caffeine. Turned out those rats were given amounts equivalent to what you’d get from drinking 87 cups of coffee a day. Even FDA officials admitted they didn’t know if the study had any validity for humans because rats metabolize caffeine differently from people.

A 1982 Harvard study of 12,205 women found no link between coffee intake and birth defects or fertility, although it did find an increased incidence of infertility in women who drank decaffeinated coffee.

Still, caffeine does cross the placenta, and fetuses can’t metabolize it—it may linger in fetal tissues for three to four days. In addition, pregnant women metabolize caffeine 40 percent more slowly than normal. So it’s a good idea for pregnant women to either limit or eliminate coffee—particularly during the first trimester of pregnancy, when organ formation occurs and birth defects are most likely to arise.

A recent study found that women over age 65 who drank more than three cups of coffee daily were 30 percent less likely to have a memory decline than women who drank one cup or less. The study, which involved more than 7,000 people, found that the figures rose to 70 percent over the age of 80. Drinking coffee, however, didn’t have any preventive effects against dementia and didn’t appear to preserve memory in male subjects.18

On the other hand, another recent study of 45,869 men over 40, which included 12 years of follow-up, found that drinking four cups a day or more of coffee decreases the risk of gout, characterized by the abnormal deposition of uric acid into joints.19 The more coffee drunk, the lower the risk. The researchers suspect that the preventive factor in coffee wasn’t caffeine but perhaps its antioxidants, such as chlorogenic acid.

Coffee and Exercise

Numerous studies over the years have shown that coffee appears to enhance fat burning and endurance. By enabling you to dip into fat stores faster than usual, it spares muscle glycogen, a stored form of complex carbohydrate and the primary energy source of muscular activity.20

Caffeine exerts its ergogenic effects through three mechanisms: 1) It increases the availability of calcium in muscle, which could produce stronger muscular contractions;21 2) it increases the amount of cyclic AMP, an intracellular messenger substance that raises blood sugar and stimulates free fatty acid release; 3) it blocks the effects of adenosine, a sedative chemical.22

The literature concerning the ergogenic effects of coffee and caffeine are contradictory. Design flaws complicate the results. For example, habitual coffee drinkers show few ergogenic effects when compared to what researchers call “coffee naive” subjects. To properly access the effects of coffee requires abstaining for at least four days.23

Another problem is that a high-carbohydrate diet or meal negates the fat-releasing effects of coffee. It releases insulin, which prevents free fatty acids from getting into the blood.24 Other studies suggest that pure caffeine is a more effective ergogenic agent than coffee.25

Still another problem is that subjects in most studies drink coffee one hour before being tested. Caffeine peaks in the blood after one hour. Peak fatty acid release, however, occurs three hours after intake.26 Since the increased release of fatty acids accounts for much of coffee’s positive effect on endurance, it’s easy to see why many studies found that caffeine and coffee had little or no effect.27

Using sedentary subjects to evaluate the merits of coffee as an athletic aid is likewise futile. They haven’t developed the physiological adaptations to exercise common in athletes and don’t react to coffee the way athletes do.

The ergogenic effects of coffee and caffeine remain controversial. Until fairly recently, the International Olympic Committee limited the use of high doses of caffeine in athletic competition. The illegal dosage of caffeine was 12 micrograms per milliliter of urine. That amount would result from drinking five to six cups of strong coffee over a one-to-two-hour period. Most world athletic governing organizations, such as WADA, have removed caffeine from their banned substances list.

Concerning the evidence of caffeine’s effects on endurance, the consensus is that caffeine and coffee enhance performance only in events lasting longer than 30 minutes. Some studies suggest that caffeine may have a harmful effect during sports conducted in hot weather because caffeine increases body temperature and has a minor diuretic action that could lead to dehydration.28 But other studies show that athletes become accustomed to those effects and have no problems when taking in caffeine before competition in hot weather.30 One found that caffeine intake resulted in a mild loss of water over a four-hour period, but exercise during that time blocked the water loss.29

Test tube studies show that caffeine theoretically increases muscular strength by releasing intramuscular calcium. The diffusion of additional calcium into muscle cells would increase muscular contraction strength. Most real-world studies, however, fail to support that.30 One study found increased thumb-muscle strength, but only under low-intensity conditions.31 A more recent study found that taking a supplement containing caffeine one hour prior to training did increase strength but only in the upper body.32 The supplement contained three natural sources of caffeine (yerba mate, guarana and black tea), for a total of 201 milligrams, the amount in two average cups of coffee. It didn’t affect lower-body strength or muscular endurance.

Many of the studies showing no effect of caffeine and coffee on strength and power were confounded by the use of sedentary subjects or insufficient doses. One study, however, examined whether caffeine increased strength and power in 20 football players who regularly lifted weights.33 The subjects took seven milligrams of caffeine per kilogram of bodyweight, and those who regularly drank more than a cup of coffee a day were excluded from the study, as were those with less than two years of weight-training experience. Compared to a placebo group, all the caffeine-using subjects showed increased strength and power.

Noting the dearth of studies that have examined the relationship between caffeine intake and strength, a new double-blind study looked at the effects of taking six milligrams per kilogram of bodyweight of caffeine (more than five cups of coffee) in 22 resistance-trained men.34 The subjects were tested for one-rep-maximum lifts on bench press and squat exercises. Some took caffeine, while others took a placebo. Caffeine intake had no effect on one-rep-maximum lifts, but there were 11 percent (bench press) and 12 percent (leg press) increases in the number of reps performed by the caffeine group when the weight was lowered to 60 percent of maximum and the exercise done to failure. While acknowledging the apparent increase in muscular endurance induced by caffeine, the study authors called it “insignificant,” noting that “the practical importance of the increased muscular endurance remains to be explored.”

Still another study found that drinking the equivalent of two cups of coffee prior to exercise reduced blood flow to the heart during exercise.35 While drinking coffee at rest didn’t affect coronary blood flow, doing it before exercise blunted the normal rise in heart blood flow during training. The effect was more pronounced when the exercise was done at high altitudes. The authors suggest that this may adversely affect exercise performance despite the well-known stimulant properties of caffeine.

Coffee for Fat Burning?

We’ve all seen people who seem able to eat anything without getting fat. Scientists explain that they divert excess calories into “futile energy cycles,” where calories convert into heat instead of being stored as fat. That process, called thermogenesis, is defective in obese people and may be one of the primary causes of obesity—besides overeating and underexercising.36

Caffeine can increase the metabolism of obese people by stimulating a thermogenic response. A Swiss study showed that giving 100 to 450 milligrams of caffeine to obese subjects caused fat burning to increase by 4 to 16 percent. Another study gave varying doses of caffeine and found that it increased thermogenesis in a dose-dependant fashion; that is, the higher the dose, the faster the metabolism. The response escalated as lactate and triglycerides increased in the blood.37

The metabolic effect of caffeine is enhanced when it’s combined with ephedrine.38 Ephedrine is found naturally in an herb called ma huang and was formerly used as an asthma medication because of its bronchodilating effects. Like caffeine, ephedrine is a mild stimulant. When combined with caffeine, it appears to have a potent thermogenic impact.39 One problem, however, is that ephedrine can raise blood pressure, just as caffeine does in people who don’t regularly drink coffee. Could that be dangerous?

In one study, six subjects took 20 milligrams of ephedrine and 200 milligrams of caffeine. They experienced a definite thermogenic effect without an excessive increase in either heart rate or blood pressure.40

Adding aspirin to the mixture may be even better.41 The mechanism works like this: Ephedrine enhances the release of norepinephrine, which stimulates brown adipose tissue, a specialized form of fat that has fat-burning properties. Recall that caffeine increases the cellular hormone messenger, cyclic AMP, which is involved in fat burning. Aspirin inhibits prostaglandins, body chemicals that shut down the norepinephrine effect. Ephedrine itself triggers the peripheral conversion of inactive to active thyroid hormone, which further stimulates metabolism.42 (By the way, the drug clenbuterol has a similar thermogenic effect.) Most experts still consider the combination of ephedrine and caffeine to be the best fat-burning supplement, though ephedrine was removed from the market by the FDA in 2005 for questionable reasons. While the fat-metabolizing effect of caffeine appears promising, further studies are needed to find long-term effectiveness or possible side effects.

A recent study looked at the fat-reducing effects of green coffee bean extract, which is sold in supplement form.43 It’s rich in both caffeine (10 percent) and chlorogenic acid (27 percent). The study, which used mice as subjects, found that giving the rodents the extract for two weeks led to a decrease in visceral fat and fat in the liver, both of which are associated with metabolic syndrome. Caffeine suppressed fat absorption, while the chlorogenic acid reduced the amount of fat in the liver. Chlorogenic acid inhibits an enzyme in the liver that promotes sugar release, which is a major problem in insulin resistance. Chlorogenic acid reduced liver fat by stimulating the enzyme that works with carnitine in fat oxidation.

Using caffeine with creatine may block the ergogenic effects of creatine, although creatine doesn’t affect caffeine. Not all experts, however, agree with that finding.

A recently published case study linked caffeine with muscle cramps.44 Another study found that drinking about two cups of coffee daily reduces delayed-onset muscle pain and loss of strength following intense training.45 That isn’t surprising considering the analgesic, or pain-relieving, effects of caffeine.46 Low doses are commonly added to various pain-relieving medications because it augments their painkilling impact and, by extension, may also permit more intense training.47

Is Caffeine Addictive?

An article in the New England Journal of Medicine reported the effects of a caffeine withdrawal syndrome. The subjective responses of the people in the study who went “cold turkey” in their coffee drinking included severe headaches, lethargy, depression and anxiety. The interesting aspect of the study was that the symptoms occurred in subjects who had drunk as little one to two cups of coffee a day.48

Most of the effects are attributable to caffeine’s ability to block adenosine receptors—recall that adenosine has a tranquilizing effect on the brain. The body senses, however, that receptor sites for the chemical are blocked and opens new ones. Sudden withdrawal of coffee causes new receptors to be flooded with adenosine, which tightens blood vessels in the head and causes headache.

The answer is to reduce caffeine gradually. That means not only coffee but tea and chocolate as well. In addition, more than 1,000 drugs contain caffeine because it amplifies the effects of pain relievers. Another method is to switch to instant coffee, which has two-thirds the caffeine of coffee. Avoid espresso, which has more-concentrated caffeine than regular coffee. You also might try drinking your coffee in a smaller cup.

According to Dr. Sanford Miller, an FDA official, the safe amount of caffeine is 10 milligrams per kilogram (2.2 pounds) of bodyweight, or up to seven cups of coffee a day for a 150-pound person. By comparison, the lethal dose is about 10 grams, or 100 cups, meaning 100 to 200 milligrams per kilogram of bodyweight. Adverse reactions to drinking too much coffee can include rapid heartbeat, insomnia, restlessness, nervousness, tremor, headache, abdominal pain, nausea, vomiting, diarrhea and excess urination.

French author and philosopher Voltaire lived to 84, despite his habit of drinking 50 cups of coffee a day. “It is a poison, certainly,” he remarked, “but a slow poison, for I have been drinking it these 84 years.”

 

Coffee: A Functional Food?

Although coffee has often been characterized as being bad for health, various studies dispute that notion. In fact, coffee is now considered a functional food because it provides many health benefits. It contains numerous nutritional elements that are believed to encourage good health, including flavonoids, caffeic acid, nicotinic acid (niacin) and trigonelline. During the roasting process, trigonelline is converted into the B-complex vitamin niacin, producing two to 80 milligrams per cup of coffee. Coffee also provides the minerals chromium and magnesium.

 

Here are a few more points to consider:

 

• Coffee may prevent viral infections, as well as exert antibacterial effects.

• Coffee is rich in antioxidants, such as caffeic and chlorogenic acids and polyphenols. The inner skin of the coffee bean produces a substance known as silverskin, which provides soluble fiber and antioxidant activity.

• Coffee may relieve asthma symptoms. Among the methylxanthines found in coffee is theophylline, a bronchodilator of the lungs that in drug form is used to treat asthma.

• Studies show that drinking coffee inhibits type 2 diabetes.49 A study done in the Netherlands found that those who drink seven or more cups a day were half as likely to develop type 2 diabetes as those who drank two cups or less daily. What’s curious is that caffeine decreases glucose tolerance and increases insulin resistance, both of which usually are harbingers of diabetes. The mechanism is an elevation of catecholamines by caffeine, which leads to increased fatty acids in the blood that interfere with glucose uptake into cells. On the other hand, substances in coffee, such as chlorogenic acid, are capable of lowering elevated blood glucose.

• Coffee offers liver protection. A recent study found that those who drank coffee had a 41 percent decreased risk of acquiring liver cancer.50 Coffee also lowers elevated liver enzymes.51 It inhibits both alcoholic and nonalcoholic liver cirrhosis. A study of 46,008 men, ages 40 to 75, found that drinking two to three cups of coffee a day lowered the risk of gallstones.52

• Recent studies show that drinking coffee offers protective effects against Parkinson’s disease, a degenerative brain disease.53 Other studies show protective effects against Alzheimer’s disease.54

• Recent studies show that the topical application of caffeine protects skin cells from damage caused by ultraviolet radiation.55 Another study found that caffeine may protect against skin cancer, an effect that was greatly amplified by combining caffeine intake with exercise.56 The mechanism in both studies involved an upgrade in apoptosis, or the self-destruction of damaged cells that would otherwise turn into cancer. A test tube study found that caffeine stimulates human hair growth and counteracts the baldness-producing effects induced by testosterone exposure.57

• While caffeine may induce acute anxiety in some people, exercise rapidly blocks that effect.58 Another study found that consuming a caffeine drink following intense exercise will improve brain function and reduce brain drain incurred by hard training.59

• One study shows a beneficial effect of coffee on male testosterone counts.60 —J.B.

 

References

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2 Saura-Calixto, F., et al. (2007). Dietary fiber in brewed coffee. J Agric Food Chem. 55:1999-2003.

3 Lovallo, W.R., et al. (2006). Cortisol responses to mental stress, exercise, and meals following caffeine intake in men and women. Pharm Biochem Behav. 83:441-447.

4 Cornelis, M.C., et al. (2006). Coffee, CYP1A2 genotype, and risk of myocardial infarction. JAMA. 295:1135-1141.

5 MacMahon, B., et al. (1981). Coffee and cancer of the pancreas. N Engl J Med. 304:630-33.

6 Olsen, G., et al. (1989). A case-control study of pancreatic cancer and cigarettes, alcohol, coffee and diet. Am J Public Health. 79:1016-1019.

7 Nomura, A., et al. (1986). Prospective Study of Coffee Consumption and the Risk of Cancer. JNCI. 76:587-90.

8 Pozner, J., et al. (1986). Association of tumor differentiation with caffeine and coffee intake in women with breast cancer. Surgery. 100:482-88.

9 Phelps, H.M., et al. (1988). Caffeine ingestion and breast cancer: A negative correlation. Cancer. 1051-1054.

10 Pozniak, P.C., et al. (1985). The carcinogenicity of caffeine and coffee: A review. J Am Diet Assoc. 85:1127-1133.

11 Jain, A.C., et al. (1991). Antioxidant behavior of caffeine: efficient scavenging of hydroxyl radicals. Food and Chem Toxicology. 29:1-6.

12 Rosenberg, L., et al. (1989). The risks of cancers of the colon and rectum in relation to coffee consumption. Amer J Epidm. 130: 895-903.

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16 Abel, E., et al. (2007). Daily coffee consumption and nonmelanoma skin cancer in Caucasian women. Eur J Cancer Prev. 16:446-450.

17 Levinson, W., et al. (1986). Nonassociation of caffeine and fibrocystic breast disease. Arch Int Med. 146:1773-1775.

18 Ritchie, K., et al. (2007). The neuroprotective effects of caffeine: A prospective population study (the Three City Study). Neurology. 69:536-45.

19 Choi, H.K., et al. (2007). Coffee consumption and risk of incident gout in men: a prospective study. Arthr Rheum. 56:2049-2055.

20 Costill, D.L., et al. (1978). Effects of caffeine ingestion on metabolism and exercise performance. Med Sci Sports Exer. 10:155-58.

21 Weber, A. (1968). The mechanism of the action of caffeine on sarcoplasmic reticulum. J Gen Physiol. 52:760-772.

22 Snyder, S.H., et al. (1984). Behavioral and molecular actions of caffeine: focus on adenosine. J Psychol Research. 18:91-106.

23 Fisher, S.M., et al. (1986). Influence of caffeine on exercise performance in habitual caffeine users. Int J Sports Med. 7:276-80.

24 Weir, J., et al. (1987). A high-carbohydrate diet negates the metabolic effects of caffeine during exercise. Med Sci Sports Exer. 19:100-105.

25 Graham, T.E., et al. (1998). The metabolic and exercise endurance effects of caffeine and coffee ingestion. J Appl Physiol. 85:883-889.

26 Bellet, S., et al. (1968). Response of free fatty acids to coffee and caffeine. Metabolism. 17:702-77.

27 Tarnopolsky, M.A., et al. (1989). Physiological responses to caffeine during endurance running in habitual caffeine users. Med Sci Sports Exer. 21:418-424.

28 Falk, B., et al. (1990). Effects of caffeine ingestion on body fluid balance and thermoregulation during exercise. Can J Physiol Pharmacol. 68:889-892.

29 Wemple, R.D., et al. (1997). Caffeine vs. caffeine-free sports drinks: Effects on urine production at rest and during prolonged exercise. Int J Sports Med. 18:40-46.

30 Williams, J.F., et al. (1988). Caffeine, maximal power output and fatigue. Brit J Sports Med. 22:132-34.

31 Lopes, J.M., et al. (1983). Effect of caffeine on skeletal muscle function before and after fatigue. J Applied Physiol. 54:1303-1305.

32 Beck, T.W., et al. (2006). The acute effects of a caffeine-containing supplement on strength, muscular endurance, and anaerobic capabilities. J Str Cond Res. 20:506-510.

33 Jacobson, B.H., et al. (1992). Effect of caffeine on maximal strength and power in elite male athletes. Br J Sport Med. 26:276-279.

34 Astorino, T.A., et al. (2008). Effect of caffeine ingestion on one-repetition maximum muscular strength. Eur J Appl Physiol. 102(2):127-132.

35 Namdar, M., et al. (2006). Caffeine decreases exercise-induced myocardial flow reserve. J Am Coll Cardiol. 47:405-410.

36 Proceedings of the Nutrition Society. (1984). 43:A29-A30.

37 Astrup, A., et al. (1990). Caffeine: A double-blind, placebo-controlled study of its thermogenic, metabolic, and cardiovascular effects on healthy volunteers. Am J Clin Nut. 52:759-767.

38 Dulloo, A., et al. (1987). Prevention of genetic fa/fa obesity with an ephedrine-methylxanthine thermogenic mixture. Am J Physiol. 252:R507-R513.

39 Dulloo, A., et al. (1985). The do-do pill: Potentiation of the thermogenic effects of ephedrine by methylxanthines. P Nutr Soc. 44:16A.

40 Astrup, A., et al. (1991). Thermogenic synergism between ephedrine and caffeine in healthy volunteers: A double-blind, placebo-controlled study. Metabolism. 40:323-329.

41 Dulloo, A., et al. (1987). Aspirin as a promotor of ephedrine-induced thermogenesis: potential use in the treatment of obesity. Am J Clin Nut. 45:564-569.

42 Dulloo, A., et al. (1989). Ephedrine, caffeine, and aspirin: Over-the-counter drugs that interact to stimulate thermogenesis in the obese. Nutrition. 5:7-9.

43 Shimoda, H., et al. (2006). Inhibitory effect of green coffee bean extract on fat accumulation and body weight gain in mice. BMC Comp Alt Med. 6:9.

44 Molema, M., et al. (2007). Caffeine and muscle cramps: a stimulating connection. Am J Med. 120:E1-E2.

45 Maridakis, V., et al. (2007). Caffeine attenuates delayed-onset muscle pain and force loss following eccentric exercise. J Pain. 8:237-243,

46 Sawynok, J., et al. (1993). Caffeine as an analgesic adjuvant review of pharmacology and mechanisms of action. Pharmacol Rev. 45:43- 85.

47 Graham, T.E. (2001). Caffeine and exercise. Sports Med. 31:785-807.

48 Griffiths, R.R., et al. (1992). Withdrawal syndrome after the double-blind cessation of caffeine consumption. New Engl J Med. 327:1109-14.

49 Salazar-Martinez, E., et al. (2004). Coffee consumption and risk for type-2 diabetes. Ann Intern Med.140:1-8.

50 Bravi, F., et al. (2007). Coffee drinking and hepatocellular carcinoma risk: A meta-analysis. Hepatology. 46:430-35.

51 Homan, D.J., et al. (2006). Coffee: good, bad, or just fun? A critical review of coffee’s effects on liver enzymes. Nutr Rev. 64:43-46.

52 Leitzmann, M.F., et al. (1999). A prospective study of coffee consumption and the risk of symptomatic gallstone disease in men. JAMA. 281:2106-2112.

53 Asherio, A., et al. (2001). Prospective study of caffeine consumption and risk of Parkinson’s disease in men and women. Ann Neurol. 50:56-63.

54 Dall’lgna, O.P., et al. (2003). Neuroprotection by caffeine and adenosine A(2A) receptor blockade of B-amyloid neurotoxicity. Brit J Pharmacol. 138:1207-1209.

55 Koo, S.W., et al. (2007). Protection from photodamage by topical application of caffeine after ultraviolet radiation. Brt J Dermatol. 156:957-64.

56 Ping-Lu, Y., et al. (2007). Voluntary exercise together with oral caffeine markedly stimulates UBV light-induced apoptosis and decreases tissue fat in SKH-1 mice.PNAS. 104:12936-12941.

57 Fischer, T.W., et al. (2007). Effect of caffeine and testosterone on the proliferation of human hair follicles in vitro. Int J Dermatol. 46:27-35.

58 Youngstedt, S.D., et al. (1998). Acute exercise reduces caffeine-induced anxiogenesis. Med Sci Sports Exer. 30:740-45.

59 Hogervost, E., et al. (1999). Caffeine improves cognitive performance after strenuous physical exercise. Int J Sports Med. 20:354-361.

60 Svartberg, J., et al. (2003). The associations of age, lifestyle factors, and chronic disease on testosterone levels in men: The Tromso study. Eur J Endocrinol. 149:145-52.  IM

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