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<html>
<head><title>Caffeine: A vitamin-like nutrient, or adaptogen</title></head>
<body>
<h1>
Caffeine: A vitamin-like nutrient, or adaptogen
</h1>
<p>
<strong>
Questions about tea and coffee, cancer and other degenerative diseases, and the hormones.</strong>
</p>
<p></p>
<p>
There is a popular health-culture that circulates mistaken ideas about nutrition, and coffee drinking has
been a perennial target of this culture. It is commonly said that coffee is a drug, not a food, and that its
drug action is harmful, and that this harm is not compensated by any nutritional benefit. Most physicians
subscribe to most of these "common sense" ideas about coffee, and form an authoritative barrier against the
assimilation of scientific information about coffee.
</p>
<p>
I think it would be good to reconsider coffee"s place in the diet and in health care.
</p>
<p>
<strong>Coffee drinkers have a lower incidence of thyroid disease, including cancer,
thannon-drinkers.</strong>
</p>
<p>
<strong>Caffeine protects the liver from alcohol and acetaminophen (Tylenol) and other toxins, and coffee
drinkers are less likely than people who don"t use coffee to have elevated serum enzymes and other
indications of liver damage.</strong>
</p>
<p>
<strong>Caffeine protects against cancer caused by radiation, chemical carcinogens, viruses, and
estrogens.</strong>
</p>
<p>
<strong>Caffeine synergizes with progesterone, and increases its concentration in blood and tissues.</strong
>
</p>
<p>
<strong>Cystic breast disease is not caused by caffeine, in fact caffeine"s effects are likely to be
protective; a variety of studies show that coffee, tea, and caffeine are protective against breast
cancer.</strong>
</p>
<p>
<strong>Coffee provides very significant quantities of magnesium, as well as other nutrients including
vitamin B1.</strong>
</p>
<p><strong>Caffeine "improves efficiency of fuel use" and performance: JC Wagner 1989.</strong></p>
<p><strong>Coffee drinkers have a low incidence of suicide.</strong></p>
<p><strong>Caffeine supports serotonin uptake in nerves, and inhibits blood platelet aggregation.</strong></p>
<p>
<strong>Coffee drinkers have been found to have lower cadmium in tissues; coffee making removes heavy metals
from water.</strong>
</p>
<p><strong>Coffee inhibits iron absorption if taken with meals, helping to prevent iron overload.</strong></p>
<p>
<strong>Caffeine, like niacin, inhibits apoptosis, protecting against stress-induced cell death, without
interfering with normal cell turnover.</strong>
</p>
<p><strong>Caffeine can prevent nerve cell death.</strong></p>
<p><strong>Coffee (or caffeine) prevents Parkinson"s Disease (Ross, et al., 2000).</strong></p>
<p>
<strong>The prenatal growth retardation that can be caused by feeding large amounts of caffeine is prevented
by supplementing the diet with sugar.</strong>
</p>
<p>
<strong>Caffeine stops production of free radicals by inhibiting xanthine oxidase, an important factor in
tissue stress.
</strong>
</p>
<p>
<strong>Caffeine lowers serum potassium following exercise; stabilizes platelets, reducing thromboxane
production.</strong>
</p>
<p>
One definition of a vitamin is that it is an organic chemical found in foods, the lack of which <strong><em
>causes</em></strong> a specific <strong><em>disease,</em></strong>
or group of diseases. A variety of substances that have been proposed to be vitamins haven"t been recognized
as being essential, and some substances that aren"t essential are sometimes called vitamins. Sometimes these
issues haven"t had enough scientific investigation, but often nonscientific forces regulate nutritional
ideas.
</p>
<p>
The definition of "a disease" isn"t as clear as text-book writers have implied, and "causality" in biology
is always more complex than we like to believe.
</p>
<p>
Nutrition is one of the most important sciences, and should certainly be as prestigious and well financed as
astrophysics and nuclear physics, but while people say "it doesn"t take a brain surgeon to figure that out,"
no one says "it doesn"t take a nutritionist to understand that." Partly, that"s because medicine treated
scientific nutrition as an illegitimate step-child, and refused throughout the 20th century to recognize
that it is a central part of scientific health care. In the 1970s, physicians and dietitians were still
ridiculing the idea that vitamin E could prevent or cure diseases of the circulatory system, and babies as
well as older people were given "total intravenous nutrition" which lacked nutrients that are essential to
life, growth, immunity, and healing. Medicine and science are powerfully institutionalized, but no
institution or profession has existed for the purpose of encouraging people to act reasonably.
</p>
<p>
In this environment, most people have felt that subtleties of definition, logic and evidence weren"t
important for nutrition, and a great amount of energy has gone into deciding whether there were "four food
groups" or "seven food groups" or a "nutritional pyramid." The motives behind governmental and
quasi-governmental nutrition policies usually represent something besides a simple scientific concern for
good health, as when health care institutions say that Mexican babies should begin eating beans when they
reach the age of six months, or that non-whites don"t need milk after they are weaned. In a culture that
discourages prolonged breast feeding, the effects of these doctrines can be serious.
</p>
<p>
After a century of scientific nutrition, public nutritional policies are doing approximately as much harm as
good, and they are getting worse faster than they are getting better..
</p>
<p>
In this culture, what we desperately need is a recognition of the complexity of life, and of the
political-ecological situation we find ourselves in. Any thinking which isn"t "system thinking" should be
treated with caution, and most contemporary thinking about health neglects to consider relevant parts of the
problem-system. "Official" recommendations about salt, cholesterol, iron, unsaturated and saturated fats,
and soybeans have generally been inappropriate, unscientific, and strongly motivated by business interests
rather than by biological knowledge.
</p>
<p>
Definitions have rarely distinguished clearly between nutrients and drugs, and new commercial motives are
helping to further blur the distinctions.
</p>
<p>
<strong>Essential nutrients, defensive (detoxifying, antistress) nutrients, hormone-modulating nutrients,
self-actualization nutrients, growth regulating nutrients, structure modifiers, life extension agents,
transgenerationally active (imprinting)</strong>
<strong>nutrients--</strong>the line between nutrients and biological modifiers often depends on the
situation. Vitamins D and A clearly have hormone-like properties, and vitamin E"s effects, and those of many
terpenoids and steroids and bioflavonoids found in foods, include hormone-like actions as well as
antioxidant and pro-oxidant functions. The concept of "adaptogen" can include things that act like both
drugs and nutrients.
</p>
<p>
Some studies have suggested that trace amounts of nutrients could be passed on for a few generations, but
the evidence now indicates that these transgenerational effects are caused by phenomena such as
"imprinting." But the hereditary effects of nutrients are so complex that their recognition would force
nutrition to be recognized as one of the most complex sciences, interwoven with the complexities of growth
and development.
</p>
<p>
The idea that poor nutrition stunts growth has led to the idea that good nutrition can be defined in terms
of the rate of growth and the size ultimately reached. In medicine, it is common to refer to an obese
specimen as "well nourished," as if quantity of food and quantity of tissue were necessarily good things.
But poisons can stimulate growth ("hormesis"), and food restriction can extend longevity. <strong>We still
have to determine basic things such as the optimal rate of growth, and the optimal size.</strong>
</p>
<p>
Nutrition textbooks flatly describe caffeine as a drug, not a nutrient, as if it were obvious that nutrients
can"t be drugs. Any of the essential nutrients, if used in isolation, can be used as a drug, for a specific
effect on the organism that it wouldn"t normally have when eaten as a component of ordinary food. And
natural foods contain thousands of chemicals, other than the essential nutrients. Many of these are called
nonessential nutrients, but their importance is being recognized increasingly. The truth is that we aren"t
sure what they "aren"t essential" for. Until we have more definite knowledge about the organism I don"t
think we should categorize things so absolutely as drugs or nutrients.
</p>
<p>
The bad effects ascribed to coffee usually involve administering large doses in a short period of time.
While caffeine is commonly said to raise blood pressure, this effect is slight, and may not occur during the
normal use of coffee. Experimenters typically ignore essential factors. Drinking plain water can cause an
extreme rise in blood pressure, especially in old people, and eating a meal (containing carbohydrate) lowers
blood pressure. The increased metabolic rate caffeine produces increases the cellular consumption of
glucose, so experiments that study the effects of coffee taken on an empty stomach are measuring the effects
of increased temperature and metabolic rate, combined with increased adrenaline (resulting from the decrease
of glucose), and so confuse the issue of caffeine"s intrinsic effects.
</p>
<p>
In one study (Krasil"nikov, 1975), the drugs were introduced directly into the carotid artery to study the
effects on the blood vessels in the brain. Caffeine increased the blood volume in the brain, while
decreasing the resistance of the vessels, and this effect is what would be expected from its stimulation of
brain metabolism and the consequent increase in carbon dioxide, which dilates blood vessels.
</p>
<p>
In the whole body, increased carbon dioxide also decreases vascular resistance, and this allows circulation
to increase, while the heart"s work is decreased, relative to the amount of blood pumped. But when the whole
body"s metabolism is increased, adequate nutrition is crucial.
</p>
<p>
In animal experiments that have been used to argue that pregnant women shouldn"t drink coffee, large doses
of caffeine given to pregnant animals retarded the growth of the fetuses. But simply giving more sucrose
prevented the growth retardation. Since caffeine tends to correct some of the metabolic problems that could
interfere with pregnancy, it is possible that rationally constructed experiments could show benefits to the
fetus from the mother"s use of coffee, for example by lowering bilirubin and serotonin, preventing
hypoglycemia, increasing uterine perfusion and progesterone synthesis, synergizing with thyroid and cortisol
to promote lung maturation, and providing additional nutrients.
</p>
<p>
One of the most popular misconceptions about caffeine is that it causes fibrocystic breast disease. Several
groups demonstrated pretty clearly that it doesn"t, but there was no reason that they should have had to
bother, except for an amazingly incompetent, but highly publicized, series of articles--classics of their
kind--by J. P. Minton, of Ohio State University. Minton neglected to notice that the healthy breast contains
a high percentage of fat, and that the inflamed and diseased breast has an increased proportion of glandular
material Fat cells have a low level of cyclic AMP, a regulatory substance that is associated with normal
cellular differentiation and function, and is involved in mediating caffeine"s ability to inhibit cancer
cell multiplication. Minton argued that cAMP increases progressively with the degree of breast disease, up
to cancer, and that cAMP is increased by caffeine. A variety of substances other than caffeine that inhibit
the growth of cancer cells (as well as normal breast cells) act by <em>increasing</em> the amount of cyclic
AMP, while estrogen lowers the amount of cAMP and increases cell growth. Minton"s argument should have been
to use more caffeine, in proportion to the degree of breast disease, if he were arguing logically from his
evidence. Caffeine"s effect on the breast resembles that of progesterone, opposing estrogen"s effects.
</p>
<p>
Many studies over the last 30 years have shown caffeine to be highly protective against all kinds of
carcinogenesis, including estrogen"s carcinogenic effects on the breast. Caffeine is now being used along
with some of the standard cancer treatments, to improve their effects or to reduce their side effects. There
are substances in the coffee berry besides caffeine that protect against mutations and cancer, and that have
shown strong therapeutic effects against cancer. Although many plant substances are protective against
mutations and cancer, I don"t know of any that is as free of side effects as coffee.
</p>
<p>
To talk about caffeine, it"s necessary to talk about uric acid. <strong>
Uric acid, synthesized in the body, is both a stimulant and a very important antioxidant, and its
structure is very similar to that of caffeine.
</strong>
A deficiency of uric acid is a serious problem. Caffeine and uric acid are in the group of chemicals called
purines.
</p>
<p>
Purines (along with pyrimidines) are components of the nucleic acids, DNA and RNA, but they have many other
functions. In general, substances related to purines are stimulants, and substances related to pyrimidines
are sedatives.
</p>
<p>
When the basic purine structure is oxidized, it becomes in turn hypoxanthine, xanthine, and uric acid, by
the addition of oxygen atoms. When methyl groups (CH<sub>3</sub>) are added to nitrogens in the purine ring,
the molecule becomes less water soluble. Xanthine (an intermediate in purine metabolism) has two oxygen
atoms, and when three methyl groups are added, it becomes trimethyl xanthine, or caffeine. With two methyl
groups, it is theophylline, which is named for its presence in tea. We have enzyme systems which can add and
subtract methyl groups<strong>;</strong> for example, when babies are given theophylline, they can convert
it into caffeine.
</p>
<p>
We have enzymes that can modify all of the methyl groups and oxygen atoms of caffeine and the other purine
derivatives. Caffeine is usually excreted in a modified form, for example as a methylated uric acid.
</p>
<p>
One of the ways in which uric acid functions as an "antioxidant" is by modifying the activity of the enzyme
xanthine oxidase, which in stress can become a dangerous source of free radicals. Caffeine also restrains
this enzyme. There are several other ways in which uric acid and caffeine (and a variety of intermediate
xanthines) protect against oxidative damage. Coffee drinkers, for example, have been found to have lower
levels of cadmium in their kidneys than people who don"t use coffee, and coffee is known to inhibit the
absorption of iron by the intestine, helping to prevent iron overload.
</p>
<p>
Toxins and stressors often kill cells, for example in the brain, liver, and immune system, by causing the
cells to expend energy faster than it can be replaced. There is an enzyme system that repairs genetic
damage, called "PARP." The activation of this enzyme is a major energy drain, and substances that inhibit it
can prevent the death of the cell. Niacin and caffeine can inhibit this enzyme sufficiently to prevent this
characteristic kind of cell death, without preventing the normal cellular turnover<strong>;</strong> that
is, they don"t produce tumors by preventing the death of cells that aren"t needed.
</p>
<p>
The purines are important in a great variety of regulatory processes, and caffeine fits into this complex
system in other ways that are often protective against stress. For example, it has been proposed that tea
can protect against circulatory disease by preventing abnormal clotting, and the mechanism seems to be that
caffeine (or theophylline) tends to restrain stress-induced platelet aggregaton.
</p>
<p>
When platelets clump, they release various factors that contribute to the development of a clot. Serotonin
is one of these, and is released by other kinds of cell, including mast cells and basophils and nerve cells.
Serotonin produces vascular spasms and increased blood pressure, blood vessel leakiness and inflammation,
and the release of many other stress mediators. Caffeine, besides inhibiting the platelet aggregation, also
tends to inhibit the release of serotonin, or to promote its uptake and binding.
</p>
<p>
J. W. Davis, et al., 1996, found that high uric acid levels seem to protect against the development of
Parkinson"s disease. They ascribed this effect to uric acid"s antioxidant function. Coffee drinking, which
<em>lowers</em> uric acid levels, nevertheless appeared to be much more strongly protective against
Parkinson"s disease than uric acid.
</p>
<p>
Possibly more important than coffee"s ability to protect the health is the way it does it. The studies that
have tried to gather evidence to show that coffee is harmful, and found the opposite, have provided insight
into several diseases. For example, coffee"s effects on serotonin are very similar to carbon dioxide"s, and
the thyroid hormone"s. Noticing that coffee drinking is associated with a low incidence of Parkinson"s
disease could focus attention on the ways that thyroid and carbon dioxide and serotonin, estrogen, mast
cells, histamine and blood clotting interact to produce nerve cell death.
</p>
<p>
Thinking about how caffeine can be beneficial across such a broad spectrum of problems can give us a
perspective on the similarities of their underlying physiology and biochemistry, expanding the implications
of stress, biological energy, and adaptability.
</p>
<p>
The observation that coffee drinkers have a low incidence of suicide, for example, might be physiologically
related to the large increase in suicide rate among people who use the newer antidepressants called
"serotonin reuptake inhibitors." Serotonin excess causes several of the features of depression, such as
learned helplessness and reduced metabolic rate, while coffee stimulates the <em>uptake</em> (inactivation
or storage) of serotonin, increases metabolic energy, and tends to improve mood. In animal studies, it
reverses the state of helplessness or despair, often more effectively than so-called antidepressants.
</p>
<p>
The research on caffeine"s effects on blood pressure, and on the use of fuel by the more actively
metabolizing cells, hasn"t clarified its effects on respiration and nutrition, but some of these experiments
confirm things that coffee drinkers usually learn for themselves.
</p>
<p>
Often, a woman who thinks that she has symptoms of hypoglycemia says that drinking even the smallest amount
of coffee makes her anxious and shaky. Sometimes, I have suggested that they try drinking about two ounces
of coffee with cream or milk along with a meal. It"s common for them to find that this reduces their
symptoms of hypoglycemia, and allows them to be symptom-free between meals. Although we don"t know exactly
why caffeine improves an athlete"s endurance, I think the same processes are involved when coffee increases
a person"s "endurance" in ordinary activities.
</p>
<p>
Caffeine has remarkable parallels to thyroid and progesterone, and the use of coffee or tea can help to
maintain their production, or compensate for their deficiency. Women spontaneously drink more coffee
premenstrually, and since caffeine is known to increase the concentration of progesterone in the blood and
in the brain, this is obviously a spontaneous and rational form of self-medication, though medical editors
like to see things causally reversed, and blame the coffee drinking for the symptoms it is actually
alleviating. Some women have noticed that the effect of a progesterone supplement is stronger when they take
it with coffee. This is similar to the synergy between thyroid and progesterone, which is probably involved,
since caffeine tends to <em>locally</em> activate thyroid secretion by a variety of mechanisms, increasing
cyclic AMP and decreasing serotonin in thyroid cells, for example, and also by lowering the systemic stress
mediators.
</p>
<p>
Medical editors like to publish articles that reinforce important prejudices, even if, scientifically, they
are trash. The momentum of a bad idea can probably be measured by the tons of glossy paper that have gone
into its development. Just for the sake of the environment, it would be nice if editors would try to think
in terms of evidence and biological mechanisms, rather than stereotypes.
</p>
<p>
<strong><h3>REFERENCES</h3></strong>
</p>
<p>
Fiziol Zh SSSR Im I M Sechenova 1975 Oct;61(10):1531-8. <strong>[Changes in the resistance and capacity of
the cerebral vascular bed under the influence of vasoactive substances].</strong> [Article in Russian]
Krasil'nikov, V.G. Effects of intracarotid injections of vasoactive agents on cerebrovascular resistance
(CVR) and cerebral blood volume (CBV) were studied in hemodynamically isolated brain of cats. Perfusion
pressure shifts at a constant blood volume perfusion reflected CVR changes, and changes of venous outflow -
CBV alterations. Administration of adrenaline, serotonin, and angiotensine was followed mainly by an
increase of CVR and a decrease of CBV. The <strong>CVR</strong>
<strong>
could be reduced by isopropilnoradrenaline, acetylcholine, histamine, and caffeine.</strong>
<strong>CBV was decreased after isopropilnoradrenaline, acetycholine, histamine injections and increased by
caffeine.
</strong>The possible role of the active changes of cerebral capacitance vessels in the transcapillary fluid
exchange is discussed. Capacitance vessels active responses are supposed to entail wrong results when using
certain techniques for measurement of cerebral blood flow and metabolism.
</p>
<p>
Proc Soc Exp Biol Med 1999 Apr;220(4):244-8. <strong>The prevention of lung cancer induced by a
tobacco-specific carcinogen in rodents by green and black Tea.</strong> Chung FL "The oxidation products
found in black tea, thearubigins and theaflavins, also possess antioxidant activity, suggesting that black
tea may also inhibit NNK-induced lung tumorigenesis. Indeed, bioassays in A/J mice have shown that black tea
given as drinking water retarded the development of lung cancer caused by NNK." "We conducted a 2-year
lifetime bioassay in F344 rats to determine <strong>whether black tea and caffeine are protective against
lung tumorigenesis induced by NNK. Our studies in both mice and rats have generated important new data
that support green and black tea and</strong>
<strong>
caffeine as potential preventive agents against lung cancer, suggesting that a closer examination of the
roles of tea and caffeine on lung cancer</strong>
in smokers may be warranted."
</p>
<p>
Pharmacol Biochem Behav 2000 May;66(1):39-45. <strong>Caffeine-induced increases in the brain and plasma
concentrations of neuroactive steroids in the rat.</strong> Concas A, Porcu P, Sogliano C, Serra M,
Purdy RH, Biggio G. "A single intraperitoneal injection of caffeine induced dose- and time-dependent
increases in the concentrations of pregnenolone, progesterone, and 3alpha-hydroxy-5alpha-pregnan-20-one
(allopregnanolone) in the cerebral cortex." "Caffeine also increased the plasma<strong>
concentrations of pregnenolone and progesterone with a dose-response relation similar to that observed
in the brain . . ."
</strong>
"Moreover, the brain and plasma concentrations of pregnenolone, progesterone, and allopregnanolone were not
affected by caffeine in adrenalectomized-orchiectomized rats."
</p>
<p>
Cancer Res 1998 Sep 15;58(18):4096-101. <strong>Inhibition of</strong>
<strong>lung carcinogenesis by black tea in Fischer rats treated with a tobacco-specific carcinogen:
caffeine as an important constituent.</strong> Chung FL, Wang M, Rivenson A, Iatropoulos MJ, Reinhardt
JC, Pittman B, Ho CT, Amin SG. "The NNK-treated group, given 2% black tea, showed a significant reduction of
the <strong>total lung tumor (adenomas, adenocarcinomas, and adenosquamous carcinomas) incidence from 47% to
19%, whereas the group given 1% and 0.5% black tea showed no change. The 2% tea also reduced liver tumor
incidence</strong> induced by NNK from 34% in the group given only deionized water to 12%." <strong>"The
most unexpected finding was the remarkable reduction of the lung tumor incidence, from 47% to 10%, in
the group treated with 680 ppm caffeine, a concentration equivalent to that found in the 2% tea. This
incidence is comparable to background</strong> levels seen in the control group. This study demonstrated
for the first time in a 2-year lifetime bioassay that black tea protects against lung tumorigenesis in F344
rats, <strong>and this effect appears to be attributed, to a significant extent, to caffeine as an active
ingredient of tea."</strong>
</p>
<p>
Cancer Lett 1991 Mar;56(3):245-50.<strong>
Inhibition by caffeine of ovarian hormone-induced mammary gland tumorigenesis in female GR mice.</strong
> VanderPloeg LC, Welsch CW. "Hormone treatment induced mammary tumors in 95-100% of the mice. Caffeine
treatment significantly (P less than 0.05) reduced the mean number of mammary tumors per mouse and
significantly (P less than 0.05) increased the mean latency period of mammary tumor appearance."
</p>
<p>
Breast Cancer Res Treat 1991 Nov;19(3):269-75.<strong>
Caffeine inhibits development of benign mammary gland tumors in carcinogen-treated female Sprague-Dawley
rats.</strong> Wolfrom DM, Rao AR, Welsch CW.
</p>
<p>
Cancer 1985 Oct 15;56(8):1977-81.<strong>
The inhibitory effect of caffeine on hormone-induced rat breast cancer.</strong> Petrek JA, Sandberg WA,
Cole MN, Silberman MS, Collins DC. "The current investigation examines the effect of two caffeine doses in
ACI rats with and without diethylstilbestrol (DES). Without DES, cancer did not develop in any of the rats
receiving either of the two caffeine dosages. With DES, increasing caffeine dosage lengthened the time to
first cancer, decreased the number of rats that developed cancers, and decreased the number of cancers
overall." "In conclusion, chronic caffeine ingestion inhibits rat breast cancer, neither by interfering with
the high prolactin levels--a necessary step in murine tumor development--nor by causing hypocaloric intake."
</p>
<p>
Nutr Cancer 1998;30(1):21-4.<strong>
Association of coffee, green tea, and caffeine intakes with serum concentrations of estradiol and sex
hormone-binding globulin in premenopausal Japanese women.</strong> Nagata C, Kabuto M, Shimizu H.
"Although the <strong>effect of caffeine cannot be distinguished from effects of coffee and green tea,
consumption of caffeine-containing beverages appeared to favorably alter hormone levels associated with
the risk of developing breast cancer."</strong>
</p>
<p>
J Environ Pathol Toxicol Oncol 1992; 11(3):177-89.<strong>
Caffeine, theophylline, theobromine, and developmental growth of the mouse mammary gland.</strong>
VanderPloeg LC, Wolfrom DM, Rao AR, Braselton WE, Welsch CW. <strong>"These data demonstrate that certain
methylxanthines (e.g., caffeine and theophylline) but not others (e.g., theobromine) can significantly
enhance mammotrophic hormone-induced mammary lobulo-alveolar differentiation
</strong>
in female Balb/c mice, an effect that appears not to be manifested via a direct action of the
methylxanthines on the mammary gland."
</p>
<p>
J Environ Pathol Toxicol Oncol 1994;13(2):81-8.<strong>
Enhancement by caffeine of mammary gland lobulo-alveolar development in mice: a function of increased
corticosterone.</strong> Welsch CW, VanderPloeg LC. Previously we have reported that the stimulatory
effect of caffeine on<strong>
lobulo-alveolar development
</strong>in the mammary glands of female Balb/c mice is not due to a direct action of the drug on the
mammary gland but appears to be due to a caffeine-induced alteration of a yet to be defined systemic
physiological process (VanderPloeg et al., J Environ Pathol Toxicol Oncol 11:177-189, 1992). "In the present
study, we administered caffeine (via the drinking water, 500 mg/L) to ovariectomized, estrogen- and
progesterone-treated Balb/c mice. After 30 days of caffeine treatment, a significant (p &lt; 0.001)
enhancement of lobulo-alveolar development in the mammary glands of the hormone-treated mice, compared with
hormone treated control mice, was observed."
</p>
<p>
Am J Clin Nutr 1997 Jun;65(6):1826-30. <strong>Dietary caffeine intake and bone status of postmenopausal
women.</strong> Lloyd T, Rollings N, Eggli DF, Kieselhorst K, Chinchilli VM.
</p>
<p>
Eur J Epidemiol 1993 May;9(3):293-7. <strong>Unexpected effects of coffee consumption on liver
enzymes.</strong> Casiglia E, Spolaore P, Ginocchio G, Ambrosio GB. Istituto di Medicina Clinica,
Universita di Padova, Italy. The effects of regular daily coffee consumption on liver enzymes were studied
in a large number of subjects from the general population. In coffee drinkers, liver enzymes (gamma-glutamyl
transferase, alanine-amino transferase, and alkaline phosphatase) and serum bilirubin were lower than in
non-coffee-drinking subjects or in those consuming less than 3 cups daily. The hypothesis proposed is that
liver enzymes are a target for caffeine contained in coffee.
</p>
<p>
Anticancer Res 1996 Jan-Feb;16(1):151-3<strong>
Suppression by coffee cherry of the growth of spontaneous mammary tumours in SHN mice.</strong> Nagasawa
H, Yasuda M, Sakamoto S, Inatomi H Experimental Animal Research Laboratory, Meiji University, Kanagawa,
Japan. We previously found that coffee cherry (CC), residue after removal of coffee beans, significantly
suppressed the development of spontaneous mammary tumours of mice. In this paper, the effects of CC on the
growth of the palpable size of this type of tumour was examined. Free access as drinking<strong>
water of 0.5% solution of the hot water extract of CC for 10 days resulted in a marked inhibition of the
tumour growth: The percent changes of tumour sizes were 53.8 +/- 11.7% and 13.8 +/- 10.9% in the
</strong>
control and the experimental groups, respectively. Associated with this, thymidylate synthetase activity in
the mammary tumours was significantly lower in the experimental group than in the control. Normal and
preneoplastic mammary gland growth, body weight change and weights and structures of endocrine organs were
only slightly affected by the treatment. The findings indicate that CC is promising as an antitumour agent.
</p>
<p>
Yakugaku Zasshi 1997 Jul;117(7):448-54. <strong>[Effect of tea extracts, catechin and caffeine against
type-I allergic reaction].</strong> [Article in Japanese] Shiozaki T, Sugiyama K, Nakazato K, Takeo
T.<strong>
"Caffeine also showed a inhibitory effect on the PCA reaction. These results indicate that tea could
provide a significant protection against the type-I allergic reaction. These findings also suggest that
tea catechins and caffeine play an important role in having an inhibitory effect on the type-I allergic
reaction."
</strong>
</p>
<p>
Acta Chir Scand 1989 Jun-Jul;155(6-7):317-20. <strong>Does coffee consumption protect against thyroid
disease?</strong> Linos A, Linos DA, Vgotza N, Souvatzoglou A, Koutras DA
</p>
<p>
Br J Nutr 1999 Aug;82(2):125-30.<strong>
Inverse association between coffee drinking and serum uric acid concentrations in middle-aged Japanese
males.</strong> Kiyohara C, Kono S, Honjo S, Todoroki I, Sakurai Y, Nishiwaki M, Hamada H, Nishikawa H,
Koga H, Ogawa S, Nakagawa K
</p>
<p>
Cancer Res 1997 Jul 1;57(13):2623-9. <strong>Effects of tea, decaffeinated tea, and caffeine on UVB
light-induced complete carcinogenesis in SKH-1 mice: demonstration of caffeine as a biologically
important constituent of tea</strong>. Huang MT, Xie JG, Wang ZY, Ho CT, Lou YR, Wang CX, Hard GC,
Conney A.H.
</p>
<p>
Mutat Res 1981 Jun;89(2):161-77. <strong>Non-mutagenicity of urine from coffee drinkers compared with that
from cigarette smokers.</strong> Aeschbacher HU, Chappuis C.
</p>
<p>
Biol Neonate 1981;40(3-4):196-8. <strong>The effects of maternal carbohydrate (sucrose) supplementation on
the growth of offspring of pregnancies with habitual caffeine consumption.</strong> Dunlop M, Court JM,
Larkins RG. "When maternal caffeine (10 mg/kg/day) was consumed together with supplementary sucrose (7
g/kg/day) the expected offspring growth reduction attributed to caffeine did not occur."
</p>
<p>
Biochim Biophys Acta 1992 Dec 15;1175(1):114-22. <strong>Caffeine promotes survival of cultured sympathetic
neurons deprived of nerve growth factor through a cAMP-dependent mechanism.</strong> Tanaka S, Koike T.
</p>
<p>
JAMA 2000 May 24-31;283(20):2674-9. <strong>Association of coffee and caffeine intake with the risk of
Parkinson disease.</strong> Ross GW, Abbott RD, Petrovitch H, Morens DM, Grandinetti A, Tung KH, Tanner
CM, Masaki KH, Blanchette PL, Curb JD, Popper JS, White LR.
</p>
<p>
Farmakol Toksikol 1983 Sep-Oct;46(5):107-11 <strong>[Use of the swimming test for demonstrating
antidepressive activity of drugs during single and repeated administration].</strong> [Article in
Russian] Rusakov DIu, Val'dman AV. <strong>
"The use of the "swimming test" made it possible to identify the activity of tricyclic (desipramine,
chlorimipramine, amitryptyline) and atypical antidepressants (befuralin, zimelidine, trazodon), that of
pyrazidol (type A MAO inhibitor) and of a number</strong> of new compounds--derivatives of benzofuran
and morpholine upon single and chronic administration. To define the method specificity, use was made of the
neuroleptic haloperidol, the tranquilizer diazepam, and of nembutal, which did not exhibit any activity in
the test in question.<strong>
Psychostimulants (amphetamine, caffeine) dramatically increased the time of active swimming. The effect
lasted throughout all the 30 minutes of testing, which is not characteristic for
antidepressants."</strong>
</p>
<p>
Gen Pharmacol 1996 Jan;27(1):167-70 <strong>The influence of antagonists of poly(ADP-ribose) metabolism on
acetaminophen hepatotoxicity.</strong> Kroger H, Ehrlich W, Klewer M, Gratz R, Dietrich A, Miesel R.
</p>
<p>
Ann Clin Lab Sci 1977 Jan-Feb;7(1):68-72. <strong>Effects of drugs on platelet function.</strong> Morse EE.
</p>
<p>
Thromb Haemost 1982 Apr 30;47(2):90-5. <strong>Effect of cAMP phosphodiesterase inhibitors on ADP-induced
shape change, cAMP and nucleoside diphosphokinase activity of rabbit platelets.
</strong>
Lam SC, Guccione MA, Packham MA, Mustard JF.
</p>
<p>
Carcinogenesis 1998 Aug;19(8):1369-75.<strong>
The coffee-specific diterpenes cafestol and kahweol protect against aflatoxin B1-induced genotoxicity
through a dual mechanism.</strong> Cavin C, Holzhauser D, Constable A, Huggett AC, Schilter B.
</p>
<p>
Am J Epidemiol 1994 Apr 1;139(7):723-7.<strong>
Coffee and serum gamma-glutamyltransferase: a study of self-defense officials in Japan.</strong>
Kono S, Shinchi K, Imanishi K, Todoroki I, Hatsuse K.
</p>
<p>
Carcinogenesis 1996 Nov;17(11):2377-84<strong>
Placental glutathione S-transferase (GST-P) induction as a potential mechanism for the anti-carcinogenic
effect of the coffee-specific components cafestol and kahweol</strong>. Schilter B, Perrin I, Cavin C,
Huggett AC
</p>
<p>
J Nutr 1999 Jul;129(7):1361-7.<strong>
Teas and other beverages suppress D-galactosamine-induced liver injury in rats.</strong> Sugiyama K, He
P, Wada S, Saeki S
</p>
<p>
Nutr Cancer 1999;33(2):146-53.<strong>
Effects of oral administration of tea,</strong>
<strong>decaffeinated tea, and caffeine on the formation and growth of tumors in high-risk SKH-1 mice
previously treated</strong> with ultraviolet B light. Lou YR, Lu YP, Xie JG, Huang MT, Conney AH.
</p>
<p>
Ind Health 2000 Jan;38(1):99-102. <strong>Effects of coffee consumption against the development of liver
dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers.
</strong>Nakanishi N, Nakamura K, Suzuki K, Tatara K.
</p>
<p>
Ind Health 2000 Jan;38(1):99-102. <strong>Effects of coffee consumption against the development of liver
dysfunction: a 4-year follow-up study of middle-aged Japanese male office workers.
</strong>Nakanishi N, Nakamura K, Suzuki K, Tatara K. .
</p>
<p>
Biochim Biophys Acta 1992 Dec 15; 1175(1):114-22. <strong>Caffeine promotes survival of cultured sympathetic
neurons deprived of nerve growth factor through a cAMP-dependent mechanism.</strong> Tanaka S, Koike T.
</p>
<p>
Int J Epidemiol 1998 Jun;27(3):438-43. <strong>Coffee consumption and decreased serum
gamma-glutamyltransferase and aminotransferase activities among male alcohol drinkers.</strong> Tanaka
K, Tokunaga S, Kono S, Tokudome S, Akamatsu T, Moriyama T, Zakouji H. <strong>
". . . recent epidemiological studies have suggested unexpected, possibly beneficial effects of coffee
against the occurrence of alcoholic liver cirrhosis</strong> and upon serum liver enzyme levels."
"Increased coffee consumption was strongly and independently associated with decreased GGT activity among
males (P trend &lt; 0.0001); the inverse association between coffee and serum GGT was more evident among
heavier alcohol consumers (P &lt; 0.0001), and was absent among non-alcohol drinkers." "Similar inverse
associations with coffee and interactions between coffee and alcohol intake were observed for serum
aspartate aminotransferase and alanine aminotransferase. Intake of green tea, another popular source of
caffeine in Japan, did not materially influence the liver enzyme levels. CONCLUSIONS: Our results suggest
that coffee may inhibit the induction of GGT in the liver by alcohol consumption, and may possibly protect
against liver cell damage due to alcohol."
</p>
<p>
Am J Hosp Pharm 1989 Oct;46(10):2059-67. <strong>Abuse of drugs used to enhance athletic performance.
</strong>Wagner JC.
</p>
<p>
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