Caffeine: Psychological Effects, Use and Abuse By: Sanford Bolton, Ph.D. and Gary Null, M.S.

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Jan102013

January 10, 2013

Caffeine: Psychological Effects, Use and Abuse

Sanford Bolton, Ph.D. and Gary Null, M.S.

Note: The information on this website is not a substitute for
diagnosis and treatment by a qualified, licensed professional.

ABSTRACT

Caffeine, probably the most widely used drug, affects the psychological state of those who consume it. Abuse results in symptoms of caffeinism which include agitation, disorientation and a syndrome which may be mistaken for anxiety/neurosis. It is a habit-forming drug in which tolerance develops. It affects sleep in a dose related manner which is dependent on the daily caffeine intake, i.e., high users have less effect. Its central nervous system stimulation can cause pleasant effects with improved attention and concentration at lower doses. At high doses, the reverse may occur. Used judiciously, it may be a useful therapy in the treatment of hyperkinetic children. These and other effects of caffeine are discussed in this review article.

INTRODUCTION

Caffeine is among the most widely used drugs because of its ubiquitous occurrence in commonly consumed beverages such as coffee, tea and cola. Many drugs contain caffeine and are readily accessible to the public in the form of OTC stimulants and combination analgesics. Clearly caffeine is an important drug-food substance in our society which deserves attention. According to an in depth 1999 article in Pharmacological Review which discusses the ways that caffeine affect our neural biology, on average, people drink between 70-76 mg of caffeine a day, between 210-238 mg in North America, and about double that in the Netherlands[i].

To begin to have a new consciousness about caffeine so that we can become aware of how this drug can affect our physiology and psychology is a problem. The reasons for this are certainly complicated, but we can start by considering a factor dominating all of our lives, our "habits." When we become aware of and take responsibility to change habits, we are taking a first step in the process of awakening. The result must be not only an improvement in the quality of our lives but the world itself will be changed for the better.

The use and abuse of caffeine is a major public "habit' and may be as important a factor as heredity and environment in the etiology of physiological and psychological disorders. To recognize this, we must know that we are creatures of habit. Most people are caffeine consumers because from birth this food-drug is set before us, if not offered directly, along with orange juice, cereal, dessert and cigarettes.

This paper reviews the literature relating to the psychological effects of caffeine. Caffeine is a potent central nervous system stimulant and much of its "psychological" activity may be related to this action of the drug. Its effects on the nervous system are obviously adverse at high doses. It may not be obvious that at lower doses when used in moderation, it may have beneficial effects. For example, its possible therapeutic use in hyperkinetic children certainly would seem advantageous when compared to the current treatment with more powerful stimulants which have concomitant adverse reactions. Also, with the intense day to day pressures imposed on and accepted by many of us, is there any harm in "relaxing" with a hot cup of coffee? On the other hand, caffeine is a drug which is subject to abuse. The fact that it is a drug with a potentially powerful physiological effect escapes most of us who think of coffee as a relatively harmless beverage. Recently published studies and reports of personal observations have shown without doubt that caffeine abuse (caffeinism) may result in a syndrome which resembles and may be confused or confounded with true psychotic states. This may lead to misdiagnosis and mistreatment. A question arises from the varied reports of caffeine consumption in psychiatric populations: Does caffeine stimulate psychosis or does psychosis stimulate caffeine consumption?

These are not trivial findings because of the ready availability of caffeine and the epidemic of psychological problems which we are experiencing in this era. This report reviews some of the knowledge of caffeine's effects with the hope that we will all be more educated and more careful in the use of this commonly ingested drug.

The physiological action of caffeine is briefly reviewed, as psychological and physiological effects must go hand-in-hand. In addition to its central nervous system effects, caffeine has significant effects on the cardiovascular system, gastric acid secretion and catecholamine (adrenaline) release. In large doses, it has been shown to be a mutagen in animals, plants and bacteria, and has been shown to exhibit teratogenic properties in various animal species.

PHYSIOLOGICAL AND PHARMACOLOGICAL EFFECTS

J. Murdoch Ritchie, in Goodman and Gilman's Pharmacology Text (Ritchie, 1975) described the pharmacological effects of caffeine. The largest sources of caffeine are from the plants used to make coffee, tea, cocoa and kola (the basis of cola beverages), although it is also found in Latin America as mate' and guarana. Caffeine particularly has a profound effect on the central nervous system, but it also affects, to a lesser degree the heart muscle, gastric secretion and diuresis. Interestingly, caffeine is ingested daily by a vast number of people and is unique in that it is a potent drug, considered to be part of our normal diet.

Caffeine stimulates the central nervous system first at the higher levels, the cortex and medulla, and finally the spinal cord at higher doses. Mild cortex stimulation appears to be beneficial resulting in more clear thinking and less fatigue. Caffeine has been shown to improve attention in a study which simulated night driving (Leinart, 1966). The onset of the effect of caffeine occurs within one hour and lasts for three to four hours (Baker, 1972).

The equivalent of one or two cups of coffee (150 to 250 mg of caffeine) is sufficient to induce adverse effects. The occurrence of hyperesthesia, an unpleasant sensory sensation, can be stimulated by large doses of caffeine.

The medullary, respiratory, vasomotor and vagal centers are stimulated by caffeine. This effect is due to an increased sensitization to carbon dioxide but needs large doses to elicit this effect, 150 to 250 mg, parenterally. The spinal cord is stimulated at higher doses and convulsions and death may result. More than 10 g are needed for such toxicity to occur in man (Ritchie, 1975).

Stimulation of the CNS is followed by depression (Klein and Salzman, 1975), although the effect is small at low doses e.g. a single cup of coffee. After two hours, Klein reported that males (but not females) showed a lower CNS stimulation compared to placebo. The post stimulation "let down" with caffeine results in fatigue and lethargy and the constant stimulation caused by chronic caffeine dosing could be disastrous (Abrams, 1977; Dowell, 1965).

Children, because of their smaller size, are more susceptible to caffeine. One report noted that hyperactivity and insomnia observed in children could be attributed to excess caffeine intake from cola drinks (Consumer Research, 1973). According to Dr. Page, "There is no doubt that children should be kept from using coffee and the popular caffeine containing soft drinks." (Abrams, 1977).

Caffeine's effect on the cardiovascular system predominates at very large doses with rapid heart rate and, eventually, irregular heart beats result. For example, a Middlesex, UK hospital discusses a 2007 case study of a person who had swelling of the heart muscle due to too much caffeine in the diet. The report noted that after half a year of abstaining from caffeine, the symptoms went away. The authors of the article mention that this case study could have relevance to the wider population, because in a portion of people who have irregular heart beat also have inflamed heart muscle that make beating of the heart difficult, which is caused by rapid beating of the heart. This has relevance to those who drink too much caffeine[ii]. Caffeine seems to have a non-discrimminatory effect on the cardiovascular system: in a 1983 study in the journal Psychosomatic Medicine, an experiment shoed that in young men, even non-extreme caffeine intake raised blood pressure both during periods of stillness and during times of bodily demand[iii].

Adenosine receptors may be the mechanism through which caffeine works in the heart. Adenosine receptors are found throughout the body, and tend to depress the function of that particular organ. For example, in the brain adenosine slows bodily functions by manipulating the speed at which various neurons fire. In the heart, adenosine works by slowing the heart-beat, by affecting the neural pathways that stimulate the pacemaker[iv].

This is one of the reasons for many of the recent studies on caffeine and its relevance to heart functioning--caffeine and various its immediate byproducts such as —theophilline – act against those adenosine receptors and, as a result speed up neuronal firing.

A 2002 rodent study confirmed the involvement of adenosine receptors in cardiac conditions --by the use of drugs which blocked specific receptor action—and showed that animals given caffeine laced water had a faster heart beat and elevated blood pressure as compared to non-caffeinated animals[v].

Recently, a whole field of science for Parkinson’s sufferers has opened up on the use of adenosine blockers—called ‘adenosine antagonists[vi].’[vii] Coffee, by action of its caffeine content, is an adenosine antagonist, and we will look at some of its effects:

Therapeutic effects have been suggested for caffeine because it inhibits the “freezing of gait” difficulties of advanced Parkinson’s sufferers for a short period of time. In one study however the patients regained a tolerance to caffeine, and the effect disappeared until the patient stopped the use of caffeine for a time[viii]. In fact, many studies have examined the link between low incidence of Parkinson’s and coffee drinking, and low incidence of Parkinson’s and cigarette smoking:

Neuroepidemiology. 2003 Sep-Oct;22(5):297-304. Links

A case-control study on cigarette, alcohol, and coffee consumption preceding Parkinson's disease. “results suggest an inverse association between coffee drinking, alcohol consumption and PD.”

Neurology. 2001 Apr 10;56(7):984-5.

Smoking, alcohol, and coffee consumption preceding Parkinson's disease: a case-control study. “These findings suggest an inverse association between coffee drinking and PD; however, this association does not imply that coffee has a direct protective effect against PD. Alternative explanations for the association should be considered”

Please note, however, that the authors of the article in Neurology above do not say that the inverse relationship found between the activity of coffee drinking and Parkinson’s disease means that the activity of coffee drinking or cigarette smoking prevents Parkinson’s. It says that further study of the relationship is warranted.

Although we know that caffeine is directly an adenosine antagonist, it also increases nerve cell firing.[ix]

1) “Caffeine acts as a competitive antagonist to the inhibitory effects of adenosine… One of these effects is to increase the release of the excitatory neurotransmitters serotonin and noradrenaline.” Journal of Physiology (2002), 545.2, pp. 671-679 Effect of caffeine on self-sustained firing in human motor units University, Toronto, ON, Canada

Caffeine increases paragigantocellularis neuronal firing rate and induces withdrawal signs in morphine-dependent rats

3) “caffeine increasedspontaneous firing of neurons between 12 and 80 min after treatment” Caffeine Regulates Neuronal Expression of the Dopamine 2 Receptor Gene The Neurosciences Institute, San Diego, California accepted August 19, 2003

Excess firing of neurons is suggestive of brain damage in human and animals as well:

1)“Caffeine has been used clinically to increase seizure length in electroconvulsive treatment (ECT)”Caffeine augmentation of electroconvulsive seizures Journal Psychopharmacology 8 December 1993 University, Toronto, ON, Canada

2) “Caffeine adversely affects outcome after concussive head injury, possibly as a result of blockade of adenosine receptors.” Caffeine Impairs Short-term Neurological Outcome after Concussive Head Injury in Rats. Neurosurgery. 53(3):704-712, September 2003.

3)Is Caffeine an Effective Pesticide Against Drosophila (fruit fly)?
Science project at PJAS Region 1B, first at PJAS States, second at Montgomery County Science Research Competition, and third at Delaware Valley Science Research Competition. “The overactive nervous system placed an extremely heavy emphasis on the gravitational stimuli, an emphasis so extreme that the flies suffocated themselves in the foam stoppers while responding to it.”

And, finally, in layman’s English:

“The average consumer may unwittingly consume excessive amounts of caffeine that may lead to adverse physiological side effects.”Is Caffeine Excess Part of Your Differential Diagnosis?. Nurse Practitioner. 29(4):39-44, April 2004.
Bridle, Leisa RN; Remick, June BSN, RN; Duffy, Evelyn MS, RN, CS

Caffeine studies on various areas of the body, including bone and sperm show that caffeine causes oxidative stress[x]. Caffeine has been shown to kill rodent brain cells in laboratory studies. Cell cultures of outer brain cells were killed at concentrations of 300 Molar of caffeine. Initial living animal studies have begun to show toxic effects of caffeine at very high doses. In newborn rodents, concentrations of 50 mg/kg of caffeine killed brain cells in assorted areas of the brain. This, of course, is a lot of caffeine. (For a person weighing 154 pounds, this comes out to 3500 mg of caffeine 3x per day)[xi]

Conversely, however, a study on the preventive use of caffeine on the blood vasculature is underwhelming: This experiment, published in the American Journal of Clinical Nutrition in 2007, showed that those who drank liquids containing caffeine, had a smaller likelihood of cardiovascular illness and death only if they did not have extreme levels of high blood pressure to begin with. Additionally this caffeine consumption did not protect those who were younger than 65, nor did it prevent death related to blood vessel disease in the brain[xii]. Since American caffeine consumption comes, for the most part, through drinking coffee, physician Joe Vinson suggests that it may be a causal factor in the development of high blood pressure to begin with.[xiii]

In addition to the conflicting information on the cardiovascular system and brain, seemingly condradictive data has been found between drinking coffee and diabetes. Apparently, studies since the year 2000 showed that caffeine increased blood glucose levels after eating. However, a large review showed that drinking coffee was related to a lower risk of developing diabetes type 2[xiv].

Bodily levels of magnesium may have something to do with the risk of developing diabetes[xv]: A 1999 Netherlands study notes the inclination of diabetes type 2 sufferers to be lacking in magnesium and that magnesium given supplementally increases the body’s ability to process blood glucose[xvi]. Data has also shown that coffee leaches magnesium from the body. A 1994 study entitled, "Effect of caffeine on circadian excretion of urinary calcium and magnesium," showed that the kidney was not able to overcompensate for mineral loss due to caffeine consumption early in the day, and that net losses of calcium and magnesium occurred by the evening.[xvii].

The clinical literature is also starting to show that we can create environmentally low levels of essential minerals in our bodies through what we consume: There are now numerous studies starting to show that caffeine consumption is related to the leaching essential minerals from the body. For example,

A 1993 Journal of Nutrition article states that the intake of caffeinated beverages raises the level of mineral elimination of the body for a minimum of one eighth of the day after caffeine intake. The article further notes that elderly females do not have enough dietary intake of minerals to compensate for the loss due to caffeine. [xviii].

A 2007 study on the effects of dietary caffeine on the risk of developing diabetes showed that blood magnesium levels were lower in those who consumed dietary caffeine, versus those who did not[xix].

Rapuri PB, Gallagher JC, Kinyamu HK, Ryschon KL. Caffeine intake increases the rate of bone loss in elderly women and interacts with vitamin D receptor genotypes. Am J Clin Nutr 2001;74; 694–700.

A study published in the Journal of the American College of Nutrition shows that caffeine consumption had a negative association with bone mineral density in women throughout the body when a person consumed 200-300 mg/day of caffeine[xx].

We also have examples from the literature examining the possible links between nutrient depletion and neurological illness:

Mechanisms of Action on the Nervous System in Magnesium Deficiency and Dementia Magnes Res. 1997 Dec;10(4):339-53.

Are age-related neurodegenerative diseases linked with various types of magnesium depletion?
Durlach J, Bac P, Durlach V, Durlach A, Bara M, Guiet-Bara A.

Caffeine also seems to have a direct effect independent of those we already mentioned) on certain tissues within the body:

An interesting 2007 animal study done at the University of Massachusetts Medical School shows that caffeine and its byproducts affect heart cells, independent of other mechanisms and that that irregular heart beat may be related to activation of a specific ion channel by caffeine and its biochemical products[xxi].

Although caffeine dilates blood vessels by a direct action, its central effect is one of constriction. At higher doses, the dilating effect is apparent (Peach, 1972; Poisner, 1973).

Similarly, because its direct and central effects are antagonistic, the resultant effect of caffeine on blood pressure is unpredictable. The net effect is usually of less than 10 mm of Hg in blood pressure (Ritchie et al., 1975). Caffeine's purported efficacy in hypertensive headaches may be due to a decrease in blood flow as a result of the increased cerebral resistance (Ritchie et al., 1975).

Caffeine also stimulates releases of catecholamines from the adrenal medulla and norepinephrine is released from nerve endings in the isolated heart (Bellett et al., 1971). .

It has been shown that prolonged augmentation of gastric 'secretion results from caffeine administration and that ulcer patients have sustained elevation of acid as opposed to normals (Ritchie et al., 1975).

Although a dose of approximately 10 g or more taken orally can be fatal, an oral (3.2 g IV) one gram dose will cause adverse effects (Gleason et al., 1969). The toxic effects are due to CNS and circulatory system stimulation and include some well recognized prominent symptoms in addition to those which can result at high doses or in hypersensitive persons: insomnia, restlessness, excitement, tinnitus, flashes of light, quivering muscles, tachycardia, extrasystoles, and even low grade fever and mild delirium have been observed.

Harrie (1970) described a patient whose constant headaches were due to excessive caffeine consumption. He states, "I suspect that the condition is much more common than supposed and could well be one of the more frequent causes of chronic recurrent headache." Headaches can also be precipitated by caffeine withdrawal especially by those who have the "habit".

Although caffeine is well absorbed when taken orally, its absorption may be erratic because of its low solubility and because it may cause gastric irritation. Caffeine is principally metabolized with only 10 percent excreted in the urine unchanged (Ritchie et al., 1975).

Caffeine has a physiological half-life of three and a half hours (Parsons and Neims, 1978) to six hours (Aranda et al., 1979). Its physiological effects are observed in less than one hour (Parsons and Neims, 1978). Infants do not metabolize caffeine as well as adults and thus have a half-life of about four days (Aranda et al., 1975). Certainly, continuous ingestion of caffeine by infants can be dangerous. If a cup of coffee is consumed by an adult six or seven times a day it would result in a high steady concentration of caffeine in the blood. As little as four cups a day can result in appreciable omnipresent amounts of caffeine in the body.

Caffeine can accumulate in severe liver disease (Stratland, 1976) when its half-life can increase to 96 hours. If these patients drink coffe(~ they should be closely monitored.

Caffeine is known to interact with other drugs resulting in a modified effect. For example, caffeine administered with nardil (an MAO inhibitor) caused headaches and high blood pressure (Pakes, 1979). This potentially dangerous interaction was first noted by Berkowitz et al., (1971) and implicated serotonin in the mechanism.

Caffeine and barbitol are antagonistic, with caffeine (in coffee) reducing the sleeping time induced by barbitol. Decaffeinated coffee had no effect (Aeschbacher et al., 1975). In another study, caffeine resulted in reduced sleeping time which was counteracted by pentobarbitol in hospitalized patients (Forrest et al., 1972).

PSYCHOLOGICAL EFFECTS OF CAFFEINE

Because of the wide spread use of caffeine and its known potent physiological effects, caffeine has been the subject of research in psychological related studies. This work has been stimulated by personal experiences and observations as well as by efforts to understand its action and mechanism.

Habituation and Tolerance: Caffeine ingestion and coffee drinking have been investigated with regard to the degree that this habit results in tolerance and withdrawal effects. These studies look beyond the obvious social implications and psychic dependence (Ritchie et al., 1975) of coffee consumption which may be related to the "first cup of coffee to wake me up" or "the coffee break" or to its association with smoking. In the latter case, it is of interest that coffee drinkers were shown to take more nicotine when deprived of coffee (Kozlowski, 1976).

Caffeine has not only been considered habit forming, but also addicting. Crothers considered morphinism and caffeinism to be similar, with caffeine causing loss of self-control, spells of agitation and depression as well as psychotic behavior (Stephenson, 1977). Ritchie mentions a report by Colton that tolerance can develop for the diuretic, salivary stimulation and sleep disturbance effects of caffeine.

Cola consumed in amounts of 48 to 111 ounces per day (144 to 333 mg of caffeine per day) was reported to have caused physical effects on withdrawal (Diamond and Pfifferling, 1974). The resultant effects were depression, nervousness, decreased alertness, sleeping difficulty, frequent mood changes, and various other behavioral difficulties which were attributed to caffeine withdrawal.

The dependence of coffee drinkers on caffeine was illustrated in a study by Kozlowski (1976) in which coffee drinkers drank more coffee if the caffeine content was lowered.

Abrams (1977) says "There is no doubt that a certain degree of psychic dependence, that is habituation, develops from the use of xanthine beverages".

A questionnaire completed by more than 200 young housewives showed that the perceived effects of caffeine depended on previous use (Goldstein et al., 1969). The heavy coffee drinkers had few sleep disturbances and less evidence of nervousness after their morning coffee as compared to nondrinkers. if the morning coffee was stopped, the habitual coffee drinkers experienced nervousness, headache and irritation. The non-coffee drinkers reacted negatively to coffee, experiencing effects opposite to the coffee drinkers. An experiment was devised to verify the results of the questionnaire involving 18 housewives, non-coffee drinkers, and 38 who drank five or more cups per day. The results confirmed those obtained from the questionnaire previously administered (Goldstein et al., 1969). This experiment was double-blind and placebo controlled and caffeine was administered in coffee at 0, 150 and 300 mg. Coffee drinkers showed a dose-response effect whereas non-coffee drinkers showed signs such as nervousness, jitters and upset stomachs at all doses of caffeine but not on placebo.

Ritchie (1975) says that tolerance and psychological dependence to caffeine beverages does occur to some extent but he feels that this does-not present a problem. He says that coffee or tea drinking are socially acceptable and are apparently not harmful when practiced in moderation.

However, it does appear that at least in some persons excess consumption of caffeine can result in severe phychological dependence and withdrawal effects and is a problem to be reckoned with.

Behavioral Effects: Caffeine's stimulating activity on the central nervous system as well as other body organs results in certain physiological effects which may be considered to be behavior oriented. Caffeine produces more rapid, clearer flow of thought, allays drowsiness and fatigue, increases the capability of a greater sustained intellectual effort and more perfect association of ideas. It also causes a keener appreciation of sensory stimuli, and reaction time is diminished. Motor activity is increased; typists, for example, work faster with fewer errors. Tasks requiring delicate muscular cobrdination and accurate timing may, however, be adversely affected. All of this occurs at doses of 150 to 250 mg of caffeine (approximately two cups of coffee) according to Ritchie (1975).

In 1912, Hollingsworth who was a psychologist reported caffeine's effect on mental and motor efficiency in a study sponsored by Coca-Cola. In nine double-blind tests, he found beneficial effects for both mental and motor performance at doses of 65 to 130 mg of caffeine. At a dose of 300 mg, caffeine caused tremors, poor motor performance and insomnia. These results have withstood the test of time (Stephenson, 1977).

Goldstein (1965) showed no effect of caffeine on objective measures of performance although most subjects "felt" more alert and physically active. However, some subjects felt nervous.

Mitchell, Ross and Hurst showed caffeine to prevent attention lapses in a visual monitoring test which simulated night driving. The effect persisted for the two to three hour experiment (Stephenson, 1977).

A 200 mg dose of caffeine resulted in decreased decision time scores and improved motor time scores in volunteers (Smith et al., 1977). Hand steadiness, however, was impaired. After a caffeine intake of 200 mg, introverts performed less well on a verbal ability test as compared to extroverts when time pressure was applied (Ritchie et al., 1975).

Wayner et al. (1976) reported on the effects of caffeine on schedule dependent'and schedule induced behavior in mice. Caffeine, (3.125, 6.25, 12.5, 25, 50 and 100 mg/kg) was tested on lever pressing, schedule induced licking and water consumption of mice. The effect on mice at 80 percent of body weight was different than when mice were allowed to recover the lost weight. At the lower weight, caffeine had little effect except at the highest dose (equivalent to 100 cups of coffee given at once). At their ordinary weight, the mice were more sensitive to caffeine, with all measures enhanced, even at the lowest dose (equivalent to approximately three cups of coffee). At high doses, all measures decreased; the mice became tolerant.

Castellano (1976) studied mice behavior under two sets of conditions. One involved a natural preference (swimming towards a light-"L" ) and the other involved an acquired behavior pattern (swimming toward the dark-"D"). A facilitation of learning and consolidation after caffeine dosing was noted in naive mice after the -D" procedure. Natural tendencies were also enhanced by caffeine as noted by improved performance in the "L" procedure. Animals pretrained in the "D" procedure exhibited behavioral disruption after treatment. Animals pretrained in the natural -U procedure needed very high doses to cause disruption. Caffeine decreases five HT turnover in rat brain. Amphetamines do not show the results as demonstrated in this paper, whereas other drugs such as hallucinogens show a similar effect. The implication is that the mechanism of caffeine's action may be similar to hallucinogenic drugs.

Effect on Sleep: Caffeine is known to cause insomnia because of its central nervous system stimulating activity. In fact, its major therapeutic use is to allay sleep and drowsiness, being the only OTC stimulant approved by the FDA. Several studies investigating this action in some detail have been published.

Karacan (1976) found that caffeine given half an hour before sleep adversely affected the sleeping process in normal sublects. The effect is dose related. Caffeine's effect simulates clinical insomnia and gave the same response as coffee containing an equivalent amount of caffeine. Decaffeinated coffee showed no effect on sleep.

Dorfman and Jarvick (1970) showed a dose-response effect of caffeine on the self estimation of sleep latency (which was increased) and quality (which was decreased). This was a double-blind study in which 0, 60, 120, and 250 mg of caffeine was administered one hour before bedtime.

Mikkelsen (1978) notes that caffeine seems to inhibit deeper stages of sleep as opposed to disturbances of the REM stage. Other studies show contradictory evidence, REM being affected by caffeine, leaving the situation to be resolved.

The tolerance developed to caffeine's effect on sleep by coffee drinkers has been documented by Colton (Stephenson, 1977). Non-coffee drinkers were more sensitive to coffee's insomnic effect whereas coffee drinkers were relatively insensitive in this regard. Non-coffee drinkers experienced disturbed sleep patterns and delayed onset of sleep.

Mueller-Limmroth (Stephenson, 1977) showed that the quality of the first three hours of sleep was impaired by the ingestion of coffee before retiring. This is approximately equal to the half-life of caffeine in the body.

Goldstein did extensive work on the effect of coffee and showed that coffee drinkers slept more soundly when they took placebo as opposed to caffeine in coffee. If 150 to 200 mg of caffeine was taken before bedtime, there was an increased sleep latency which was less pronounced in persons who were heavy ingestors of caffeine (Goldstein et al., 1965).

These studies show that caffeine has a profound effect on sleep. Heavy and continued use of caffeine results in tolerance so that heavy users have less sleep disturbance or need more to obtain its stimulating effect.

Treatment of Hyperkinetic Children: Hyperkinetic children have been shown to respond to central nervous system stimulants, resulting in improved attention, concentration, -and decreased activity. Side effects are usually disturbing with the more powerful drugs and include insomnia, anorexia, nervousness, weight loss and abdominal pain.

A study by Schnackenberg (1975) showed that 200 to 300 mg of caffeine was similar in effect to methylpheniclate in treating hyperkinetic impulse disorder secondary to minimal brain dysfunction syndrome. Some hyperkinetic children, he observed, drank coffee to calm down. Sixteen children who had shown improvement on methylphenidate but who had annoying side effects were given one cup of coffee at breakfast and lunch. Test scores showed a similar im-provement with coffee as compared to methylpheniclate and the annoying side effects disappeared when the children were on caffeine. Schnackenberg recommends 200 to 300 mg of caffeine in a time-release form.

In 1977, Reichard and Elder published an article on caffeine's effect on reaction time in hyperkinetic children. They tested the effect on a choice reaction time task and simple reaction time as compared to normal children. Caffeine increased the accuracy of stimulus identification and processing and decreased lapse of attention in the hyperkinetic group. This is what might be expected based on caffeine's known effects on such tasks in normals. Hyperkinetic children have a slower reaction time, are less able to maintain attention and have a lower rate of correct responses on a vigilance performance task as compared to normal children. In this study, six normal and six hyperkinetic children were compared in a double-blind design. Caffeine significantly raised the rate of correct responses on simple reaction time in the hyperkinetic group. The reaction time was reduced with caffeine but was not significantly less than the control period or placebo. Similar results were found with choice reaction time. The response is a function of the initial state of the children, i.e., the more severely afflicted had a larger response. The authors note that other studies have shown methylpheniclate was more effective than caffeine in controlling certain aspects of clinical behavior (impulsivity and hyperactivity). This result does not contradict those obtained in this study; they are compatible.

Garfinkel was unable to confirm the results of caffeine's effectiveness in controlling the behavior of children with minimal brain damage (Stephenson, 1977). Children responding to methylpheniclate did not necessarily respond to caffeine.

Firestone and associates in a study funded by the Ontario Mental Health Foundation (1978) showed a significant improvement with methylphenidate as rated by mothers and teachers on tests of impulsivity and motor control. No significant improvement was noted with caffeine although some children showed a slight improvement. Side effects with both drugs were minimal. Each of 21 hyperactive children received 500 mg of caffeine, 300 mg of caffeine, and 20 mg methylpheniclate. This was' a carefully controlled study consisting of 17 boys and four girls. In 1978, Firestone did a study comparing 300 mg of caffeine with placebo in a double-blind crossover design. In this study, subjective ratings by teachers and parents as well as a reaction time task showed caffeine to be better than placebo although the difference was not statistically significant. Firestone concludes on the basis of the most recent study that caffeine is not a meaningful alternative as a treatment for hyperkinetic children.

The use of caffeine in the treatment of hyperkinetic children remains unresolved at this time. Further work seems warranted to ensure that if caffeine is useful in this prevalent condition that it be available as a viable alternate treatment in lieu of more powerful CNS stimulants.

"Restless Legs, Anxiety and Caffeinism" (Lutz, 1978)

Restless legs is a syndrome which may be associated with anxious - depressed as well as other clinical states. Dr. Lutz, in an article titled as above, suggests that this syndrome is primarily caused by caffeine. Anxiety is not a causative factor. Caffeine stimulates the nervous system and has a direct contractile effect on striated muscle. This is reflected in anxiety, depression, insomnia: and the heightened proprioceptive awareness may result in restless legs. This manifestation consists of nervousness and movement of legs as a result of a distressing creeping sensation. Its symptoms are most obvious at night when the patient is trying to be still, and results in insomnia. Dr. Lutz describes cases of this disorder in detail and cites examples, all of which were alleviated when caffeine was removed from the diet. This condition has been attributed to many causes including psychiatric disturbances, e.g. restless legs is a frequent symptom of hysteria, anxiety, depression. In periods of stress, "normal" persons are also afflicted. All of these states are associated with high central nervous system arousal. Also, restless legs syndrome, was first described in England at the time when coffee and tea first were introduced in the country. Thus, diagnosis of the restless legs syndrome, as has also been observed in certain psychological disorders, may simply be the result of overdosage of ubiquitous caffeine.

Psychological Disorders: Dr. John Greden, a professor of psychiatry at the University of Michigan, says, “caffeinism can be found among those who have psychiatric problems". Symptoms of excessive caffeine consumption are similar to anxiety neurosis (Avery, 1980) and include nervousness, irritability, recurrent headache. twitching, and gastrointestinal disturbance among other symptoms (Greden, 1974). This is a known effect of caffeine and Greden adds "...all medications including caffeine have a potential for abuse and many individuals clearly ingest symptom-producing doses daily".

Other studies support the relationship indicated above. For example, a prisoner with severe anxiety symptoms admitted to drinking 50 cups of coffee per day (Niolde, 1975). The symptoms remitted after the coffee drinking stopped. Excess drinking of coffee by prisoners is not uncommon and may initiate a vicious cycle: a bored person drinking more coffee resulting in caffeinism which may result in more consumption.

The intake of caffeine (coffee, etc.) has been correlated with the degree of mental illness in psychiatric patients. It is not clear if the caffeine intake intensifies the psychiatric disorder or whether those with more severe problems tend to drink more coffee. In any event, in another study by Dr. Greden and associates (Greden, 1978) 83 hospitalized psychiatric patients were interviewed and showed an association of symptoms with high caffeine intake. This may provide an explanation of some problems which have been experienced in diagnosing out-patient disorders. Eighteen of the 83 patients (22 percent) were high caffeine consumers (7~0 mg or more). They scored significantlv higher on the State-Trait anxiety index and the Beck Depression Scale than lower caffeine consumers. The high consumers had more clinical symptoms: their physical health was worse; they used more sedatives, hypnotics, and minor tranquilizers. These patients showed a tolerance to sleep effects which could be due to a change in body kinetics or metabolism. Catecholamines contribute to the anxiety profile and patients may drink more coffee in response to stress, accentuating a neuro-transmitter response cycle. Since caffeine affects catecholamine levels and inhibits phosphodiesterase breakdown of C-AMP, sensitizing receptor sites, the association of caffeine with anxiety and depressive symptoms is indeed a possibility.

Dr. Greden considers caffeine to be a psychotropic drug and 25 percent of the population may take more than 500 mg per day, a large physiologically active dose. He describes three cases in which caffeinism may be misdiagnosed as an anxiety syndrome.

Dr. Greden concludes that caffeine is found among a fairly large percentage of hospitalized patients with psychiatric symptoms. Caffeine should not be used as part of psychiatric treatment routines, e.g., to reduce drowsiness from psychotropic medications as has been occasionally suggested.

Dr. John Neil and associates (1978) reported on the possible complication of caffeinism in diagnosing psychiatric patients. He suggests that self-medication may confound behaviors of patients. Caffeine has been considered the most popular "psychotropic" drug in North America and coffee and tea drinking are not usually in the records of psychiatric patients. In this experiment, hypersomnic patients with various diagnoses and caffeine consumption participated, The authors conclude that "self medication with large doses of caffeine is a likely response to the anergia and hypersomnia experienced during certain types of depression". This may lqad to diagnostic confusion and a complicated course of therapy. Mixed depressive states may be caused by excess caffeine consumption and they suggest, also, that unipolar 11 depressives may use more caffeine as they become depressed.

Caffeine, in these patients, provides only transitory relief as it is not a true antidepressant. Caffeine also may render anxiolytic and antipsychotic medications less effective.

Mikkelsen (1978) noted caffeine's involvement in schizophrenic-like states similar to that observed by Greden in anxiety/neurosis symptoms of patients who consumed large quantities of caffeine (coffee). One case cited was of a white male in a catatonic state who threatened his mother after having gone on a coffee jag over injustices caused to him by his mother. He developed paranoid delusions which he felt were, at least in part, due to the coffee. A 30 year old white single female exhibited paranoid and auditory hallucinations. An anxiety state had resulted in increased coffee consumption. in the hospital she noted the correlation of these strange feelings with coffee consumption. Other examples of psychotic behavior as noted in the literature are described in this paper. Forty years ago a case of psychosis was reported in which a 24 year old female took 60 gr (about four g) of caffeine. Manic symptoms developed. He theorizes that adenyl cyclase which is increased by caffeine may be a receptor for dopamine. If this system is abnormal in schizophrenics, caffeine may further sensitize the patient. Certainly, coffee should be considered as a factor in this disease.

Reimann (1967) noted that symptoms of a psychoneurotic woman disappeared when coffee was reduced. She presented with an irregular fever, insomnia, anorexia and irritability, having consumed large amounts of coffee.

Clearly, as recommended by Drs. Greden, Mikkelsen and Neil, caffeine intake should be considered as a factor in diagnosing and treating psychiatric patients.

CAFFEINE AND WOMEN

According to a 1999 study in Pharmacological Review, caffeine passes through the gut quickly and becomes almost entirely active in three quarters of an hour. Additionally, it is not prevented from going into the human brain or the fetus, by any biological mechanism, so, in effect, what you drink, is what you get[xxii].

Caffeine seems to have a deleterious effect upon women of childbearing years. A 2004 study showed that consuming caffeine while the fetus is in early gestation has been shown to increase its risk of being rejected from the mother’s body[xxiii].This study was supported by data that down’s syndrome fetuses were more likely to die than genetically normal fetuses when the mother consumed caffeinated beverages.[xxiv]

There does not seem to be a good time to drink coffee while pregnant: A Danish review of clinical data over the course of 8 years (from 1996-2002) indicated that drinking coffee was related to higher levels of mortality in the fetus, especially late in the second trimester[xxv].

Another study done in the same year at the University of Leeds showed that drinking greater than 300 milligrams of caffeine per day while pregnant increased the likelihood of miscarriage by 100%[xxvi]. Similarly, a Scandinavian study showed that more than 375 mg of caffeine per day increased likelihood of the loss of the fetus[xxvii].

One 2003 study showed that low birth weight was found to be a factor particularly for boy-babies born to mothers who drank more caffeine in the last three months of pregnancy[xxviii]. Additionally, a Johns Hopkins study showed that higher caffeine intake in the last 3 months of pregnancy especially along with smoking increases likelihood of having a small baby[xxix].

Even post birth, children born to caffeine consuming mothers are more likely to die of Crib-death[xxx].

Caffeine drinking in men may even deter conception. According to a 2002 Iranian study, caffeine caused DNA damage in human sperm, indicating that caffeine can negatively affect a man’s semen to fertilize an egg[xxxi].These changes were due to damage by oxidation.

Genetic susceptibility may play a role in the body’s sensitivity to caffeine.

Caffeine may mediate illness in the body through several genetic variations, having to do with processing of toxins and making them inactive in order to eliminate them from the body. Some of the initial by-products of these initial compounds --mediated by the particular gene (CYP1A1) have toxic and oxidative properties in the body, and several experiments have hypothesized whether caffeine intake and these genetic variants influence the risk of various cancers[xxxii].

For some women who the specific genotype:(CYP1B1 432 Val/Val), they were more likely to have a miscarriage during the first three months of their pregnancy, and caffeine was also shown to influence this risk.[xxxiii]

There is also a variant of gene called CYP1A1 that is related to higher probability of developing cancer of the ovary when a person drinks more than an average amount of caffeine.[xxxiv]

And even after child bearing years, caffeine may have deleterious effects upon the body. Drinks that have caffeine heighten the body’s process of getting rid of its stores of calcium, magnesium, zinc, and potassium, respectively[xxxv].

There is a relationship between the intake of caffeine and breaks in the hip bones of women in the age range of 45-65[xxxvi].

Additionally after menopause, intake of greater than 300 mg of caffeine increases the likelihood of losing bone matrix in the vertebral column [xxxvii].

Similarly, cola intake was shown to be related to lower bone mass in women[xxxviii]. According to a 2005 master’s degree thesis, oxidative stress due to caffeine consumption may be a reason for development of osteoporosis in women[xxxix]. The paper suggested that bone-culture cells initiated pre-programmed cell death pathways when treated with caffeine.

SUMMARY

A review of the literature reveals that caffeine is an important factor in modifying the psychological state of its consumers under the present condition of usage. Caffeine is probably the most widely used drug and those who drink coffee, tea, cola or take OTC caffeine containing drugs are all potential and susceptible candidates. Those of us who are "normal" can expect manifestations which may be subtle at low doses, overt at high doses, with the possibility of being the victims of a habit which results in tolerance and possible severe withdrawal symptoms. The pleasant stimulant feeling which often occurs at low doses may be replaced by psychological symptoms which resemble anxiety and depressive neuroses at high doses. Those with more severe psychological problems may have their symptoms exaggerated with excessive caffeine usage, or such symptoms can actually be caused by excess. Diagnosis of such conditions must take caffeine usage into account.

As a result of its potent physiological activity, caffeine can alter our behavior. it affects our sleeping habits generally resulting in insomnia and hyperactivity. Task oriented performance, attention, and concentrations may be modified by caffeine. At lower doses, these effects appear to be beneficial. At higher doses, we can expect the reverse, including toxic and rebound effects.

The common "Restless Legs Syndrome" which has often been related to psychological disturbances may, in fact, be primarily a symptom of caffeinism according to Lutz.

Caffeine has been investigated as a possible treatment for hyperkinetic children since central nervous system stimulants have been shown to be effective in this condition. Results of caffeine treatment are controversial, some studies showing a beneficial effect with little adverse reactions and other studies showing little or no benefit.

Caffeine's effect on our body, our nervous system, our mind, our psychology is no illusion. It is a potent drug. That it may cause symptoms of mental illness as recently published is no small concern. With these findings we see that caffeine abuse is more prevalent than we may imagine. These facts should be brought to the attention of the medical community as well as the public in order that we may have the opportunity of being aware of the possible interactions between ourselves and our environment.

References

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[i] Introduction - Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

Bertil B. Fredholm1, Karl Bättig2, Janet Holmén, Astrid Nehlig and Edwin E. Zvartau

[ii] Department of Cardiology, The Hillingdon Hospital, Middlesex UK

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Caffeine and cardiovascular responses to stress

[iv] http://en.wikipedia.org/wiki/Adenosine_receptor

[v] Vol. 65, No. 3, 2002 Chronic Caffeine Treatment Causes Changes in Cardiac Adenosine Receptor Function in Rats

P.J. White, T.T. Nguyen

Department of Pharmaceutical Biology and Pharmacology, Victorian College of Pharmacy, Monash University, Parkville, Vic., Australia

Pharmacology 2002;65:129-135

[vi]

ADENOSINE RECEPTORS AND PARKINSON'S DISEASE

To order this title, and for more information, click here

Edited By

Hiroshi Kase, Kyowa Hakko Kogyo Co., Ltd., Tokyo, Japan

Peter Richardson, University of Cambridge, U.K.

Peter Jenner, King's College, London, U.K.

[vii] E-MOVE reports from the 54th Annual Meeting of the American Academy of Neurology, April 13-20, in Denver Colorado. Poster numbers, session numbers, and pages are from Neurology 2002;58(supplement 7).

1. A novel adenosine antagonist (KW-6002) as a treatment for advanced Parkinson’s disease with motor complications
JP Hubble, R Hauser, Kyowa 6002-US-001 Study Group
S21.001; A162

The adenosine A2a antagonist KW-6002 can reduce off time in advanced PD, according to this study.

Brief Report

Effects of caffeine on the freezing of gait in Parkinson's disease

Mayumi Kitagawa, MD, PhD 1 *, Hideki Houzen, MD, PhD 2, Kunio Tashiro, MD, PhD 3

[ix] doi:10.1016/S0014-2999(01)00718-X
Copyright © 2001 Elsevier Science B.V. All rights reserved.

Caffeine increases paragigantocellularis neuronal firing rate and induces withdrawal signs in morphine-dependent rats

Mohsen Khalili^,^,^a^,^b, Saeed Semnanian^a^,^c and Yaghoub Fathollahi

[x] October 28, 2002, 13:15 > Caffeine-induced neuronal death... < Previous | Next >

ARTICLE LINKS:

Fulltext | PDF (400 K)

Caffeine-induced neuronal death in neonatal rat brain and cortical cell cultures.

Neuropharmacology And Neurotoxicology

Neuroreport. 13(15):1945-1950, October 28, 2002.

Kang, Sang Hwan 1 3; Ae Lee, Young 1 3; Won, Seok Joon 1 3; Rhee, Ki-Hyeong 4; Gwag, Byoung Joo 1 2 3 CA

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Department Chemistry, Chung Yuan Christian University

Year 2005

Semester 2

Degree Master

[xi] October 28, 2002, 13:15 > Caffeine-induced neuronal death... < Previous | Next >

ARTICLE LINKS:

Fulltext | PDF (400 K)

Caffeine-induced neuronal death in neonatal rat brain and cortical cell cultures.

Neuropharmacology And Neurotoxicology

Neuroreport. 13(15):1945-1950, October 28, 2002.

Kang, Sang Hwan 1 3; Ae Lee, Young 1 3; Won, Seok Joon 1 3; Rhee, Ki-Hyeong 4; Gwag, Byoung Joo 1 2 3 CA

[xii] American Journal of Clinical Nutrition, Vol. 85, No. 2, 392-398, February 2007

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ORIGINAL RESEARCH COMMUNICATION

Caffeinated beverage intake and the risk of heart disease mortality in the elderly: a prospective analysis1,2

James A Greenberg, Christopher C Dunbar, Roseanne Schnoll, Rodamanthos Kokolis, Spyro Kokolis and John Kassotis

1 From Brooklyn College of the City University of New York, New York, NY (JAG, CCD, and RS), and the Department of Cardiology, State University of New York Health Science Center at Brooklyn, Brooklyn, NY (RK, SK, and JK)

[xiii] JAMA

Vol. 295 No. 18, May 10, 2006

[xiv] References

1. Schaefer B. Coffee consumption and type 2 diabetes mellitus [letter]. Ann Intern Med. 2004;141:321

2. Caffeine-Induced Impairment of Insulin Action but not Insulin Signaling in Human Skeletal Muscle Is Reduced by Exercise, by F.S. Thong and Colleagues. Diabetes 51:583-590, 2002

3. Caffeine Impairs Glucose Metabolism in Type 2 Diabetes by Lane, J. Diabetes Care, August 2004; vol 27

4. Coffee Consumption and Risk of Type 2 Diabetes by Rob M. van Dam, PhD; Frank B. Hu, MD, PhD JAMA. 2005;294:97-104

5. Ceriello A, Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? the common soil hypothesis revisited. Arterioscler Thromb Vasc Biol. 2004;24:816-823.

6. de Valk HW. Magnesium in diabetes mellitus. Neth J Med. 1999;54:139-146

[xv] http://www.medopedia.com/caffeine-affects-glucose-level

[xvi] 1: Neth J Med. 1999 Apr;54(4):139-46. Links

Magnesium in diabetes mellitus.de Valk HW.

Department of Internal Medicine, Utrecht University Hospital, The Netherlands. h.w.devalk@digd.azu.nl

[xvii] Effect of caffeine on circadian excretion of urinary calcium and magnesium." J Am Coll Nutr 1994 Oct;13(5):467-72

[xviii] Journal of Nutrition Vol. 123 No. 9 September 1993, pp. 1611-1614

Caffeine, Urinary Calcium, Calcium Metabolism and Bone1,2,

Linda K. Massey3 and Susan J. Whiting*

Food Science and Human Nutrition, Washington State University, Spokane, WA 99204-0399 * Division of Nutrition and Dietetics, College of Pharmacy, University of Saskatchewan, Saskatoon, SA S7N 0W0, Canada

[xix] Association of serum caffeine concentrations with serum glucose levels in caffeine-drug users and non-users - results of German National Health Surveys.

Correspondence

Diabetes, Obesity & Metabolism. 9(5):756-758, September 2007.
Du, Y.; Melchert, H.-U.; Knopf, H.; Braemer-Hauth, M.; Pabel, E.

[xx] Journal of the American College of Nutrition, Vol. 21, No. 6, 536-544 (2002)
Published by the American College of Nutrition

To Drink or Not to Drink: How Are Alcohol, Caffeine and Past Smoking Related to Bone Mineral Density in Elderly Women?

Jasminka Z. Ilich, PhD, RD, FACN, Rhonda A. Brownbill, MS, RD, Lisa Tamborini, RD and Zeljka Crncevic-Orlic, MD

[xxi] Caffeine-activated large-conductance plasma membrane cation channels in cardiac myocytes: characteristics and significance

Yu-an Zhang,1 Richard A. Tuft,1,2 Lawrence M. Lifshitz,1,2 Kevin E. Fogarty,1,2 Joshua J. Singer,1 and Hui Zou1

1Department of Physiology and 2Biomedical Imaging Group, University of Massachusetts Medical School, Worcester, Massachusetts

Submitted 9 January 2007 ; accepted in final form 1 May 2007

[xxii] Introduction - Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

Actions of Caffeine in the Brain with Special Reference to Factors That Contribute to Its Widespread Use

Bertil B. Fredholm1, Karl Bättig2, Janet Holmén, Astrid Nehlig and Edwin E. Zvartau

[xxiii] : J Matern Fetal Neonatal Med. 2004 Jan;15(1):44-50.Links

Consequences of smoking and caffeine consumption during pregnancy in women with type 1 diabetes.Khoury JC, Miodovnik M

[xxiv] American Journal of Epidemiology Vol. 152, No. 12 : 1185-1191

[xxv] Coffee and Fetal Death: A Cohort Study with Prospective Data

Bodil Hammer Bech1, Ellen Aagaard Nohr1, Michael Vaeth2, Tine Brink Henriksen3 and Jørn Olsen1,4

[xxvi] Paediatric and Perinatal Epidemiology 17 (4) , 316–323 doi:10.1046/j.1365-3016.2003.00523.x

[xxvii] Acta Obstet Gynecol Scand. 2003 Feb;82(2):182-8. Links

Cigarette, alcohol, and caffeine consumption: risk factors for spontaneous abortion.Rasch V.

[xxviii] Paediatr Perinat Epidemiol. 2003 Oct;17(4):324-31. Links

High caffeine consumption in the third trimester of pregnancy: gender-specific effects on fetal growth.Vik T, Bakketeig LS

[xxix] American Journal of Epidemiology Vol. 155, No. 1 : 32-37

[xxx] Arch Dis Child 1998;78:9-13 ( January )

Heavy caffeine intake in pregnancy and sudden infant death syndrome

R P K Ford,a P J Schluter

The effect of antioxidants on Nicotine and Caffeine Induced Changes in Human Sperm—An in Vitro Study

Department ofd Biology, Shahrekord University, POB 115, Iran

Male Fertility and Lipid Metabolism

[xxxii] Clinical Pharmacology & Therapeutics (1996) 59, 624–635; doi:

The effect of liver disease on urine caffeine metabolite ratios*

Charles P. Denaro FRACP1,a, Margaret Wilson MA1, Peyton Jacob III PHD1 and Neal L. Benowitz MD1

[xxxiii] Association of cytochrome P450 1B1 polymorphism with first-trimester miscarriage . Fertility and Sterility , Volume 86 , Issue 5 , Pages 1498 - 1503 A . Karypidis , T . Söderström , A . Nordmark , F . Granath , S . Cnattingius , A . Rane

[xxxiv] Cancer Epidemiology Biomarkers & Prevention Vol. 12, 187-190, March 2003

Interaction between CYP1A1 Polymorphic Variants and Dietary Exposures Influencing Ovarian Cancer Risk

Kathryn L. Terry, Linda Titus-Ernstoff

[xxxv] Human Nutrition and Metabolism

Use of Oral Contraceptives Blunts the Calciuric Effect of Caffeine in Young Adult Women1

Mirna A. Ribeiro-Alves, Luiz C. Trugo and Carmen M. Donangelo2

Laboratório de Bioquímica Nutricional e de Alimentos, Departamento de Bioquímica, Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.

Caffeine, moderate alcohol intake, and risk of fractures of the hip and forearm in middle-aged women

M Hernandez-Avila, GA Colditz, MJ Stampfer, B Rosner, FE Speizer and WC Willett

Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA.

[xxxvii] American Journal of Clinical Nutrition, Vol. 74, No. 5, 694-700, November 2001

[xxxviii] American Journal of Clinical Nutrition, Vol. 84, No. 4, 936-942, October 2006

After menopause, intake of greater than 300 mg of caffeine increases the likelyhood of losing bone matrix in the spine[xxxviii].

--------------------------------------------------------------------------------

ORIGINAL RESEARCH COMMUNICATION

Colas, but not other carbonated beverages, are associated with low bone mineral density in older women: The Framingham Osteoporosis Study1,2,3

[xxxix] Statistics This thesis had been viewed 101 times, download 0 times

Department Chemistry, Chung Yuan Christian University

Year 2005

Semester 2

Degree Master

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