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    <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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