A Study of Psychological and Physiological Effects of Caffeine on Human Health

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UNION GRADUATESCHOOL 1 OF THE UNION INSTITUYE -I 'BR~· \ .t\'rr) ' COP'(

A STUDYOF THE PSYCHOLOGICALAND PHYSIOLOGICALEFFECTS OF CAFFEINE ON HUMANREALTH

PDE

Sub ■ itted to the Faculty of the UNION GRADUATESCHOOL

in partial fulfill a ent of the requirements for the degree of DOCTOROF PHILOSOPHY

in HUMANNUTRITION ANDPUBLIC HEALTHSCIENCE

Gary Mull Cin c innati, Ohio

Prepared for a Graduation Co ■a ittee Meeting on May 29, 1989

--~ TABLEOF CONTENTS

Page

ABSTRACT• • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • ii

ACD~ • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • V

CHAPTER1. IN'l'R.OOOCTION•• • ••••••• ••••• •••••••••••••• ••• ••••••••• 1

CHAPTER2. REVIEWOF THE .BODYOF KNOWLEDGE•••••••••••••••••••••• 7

Physiological and Pharmacological Effects 7 Caffeinism ...... 13 Behavioral Effects ...... 15 Effect on Sleep ...... 17 The Caffeine Personality ...... 19 Smoking and Coffee ...... -...... 20 Psychological Effects ...... 21 Habituation, Addiction, and Tolerance····•···········••••·•· 23 Anxiety and Caffeine ...... 37 Psychological Disorders and the Psychi a tric Population...... 44

Psychiatric Patients-Interaction with Drugs and Treatment ••• 48

Caffe ine's Effect in Attention Deficit Disorder (ADD) and

Hyperkinetic Children••••··••••••···•••·•••·•·••··•···••·• 49

Restless Legs, Anxiety, and Caffeinism •••••••••···•••• · •••·• 54 Caffeine and Genetics ...... 56

CHAPl'ER3. RESEARCHHETHOOOLOGY OF THE SELECTED PROB!Df ...... 62 ~eneral ...... 62

Research Design••••···•••• • ••·•·••••·••••••·•••••••··•··•••• 63

xii

··~ TABLEOF CONTENTS(continued)

Page Research Methods ...... 64 Subjects ...... 64 Adrenal Fune tion ...... 65

A Medical Evaluation Which Focused on Adrenal Gland Status 66

Ragland Postural Blood Pressure Test: Methods and

Physiological Basis (Burch and de Pasquale, 1962) 67

Koenigsburg Test for Urinary Sodium-Chloride Excretion (Brooks, 1925) ...... 68

Psychological Effects··•·•••••••••••·•••••••••••••••••••··•• 68 Urine Measurements (Revici Anabolic /Catabol ic Index) 69 CHAPTER4. RESULTSAND DisaJSSION ...... ••... 71 Medical Examinations 73 Anabolic/Catabolic Index ...... 94 Psychological Effects•••••••••••••••··•••••••••••·••••·•••·• .99 Mood ...... 100 Sle ep ...... 105

Physiological Effects ••••••••••••••.• ••••••• ~ ••••••••••••••• 110

xiii

· ···~ -., ...... TABLEOF CONTENTS(continued)

Page

CHAPTER5. CONCLUSIONSAND REC01MENDATIONS . ••..•...... •...... • 114

Conclusions ...... 114 A. Adrenal Gland Function 114 B. Anabolic Effect •••••••• ••••••••••••• ••• •••••• ••••••• 115 c. Psychological Effect ...... •...... 115 D. Physiological Effect ...... 116 E. Comparison of Caffeine Group (C Group) to

Non-Caffeine (NC Group) 116

Discussion ...... 117

Recommendations •••••• •.. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 119 BIBLIOGRAPHY..•.....•..•... •..•••..•....•.....•••••.....•••••..•• 121

APP:ENDICE'S••••••••••••••••• ·••••••••••••••••••••••••••• ~ • • • • • • • • • • 145

A. Consent for Caffeine Study•··•··•••••••••·•••·••••••••••• 146 B. Caffeine Study - Daily Diary ...... 147 c. Caffeine Study Questionnaire Plate I 148 Caffeine Study Questionnaire - Part II ...... 149 D. Pearson Correlation Coefficients Between Blood Pressure

and Sodium S_ecretion for Pre, Week 1, and Week 2,

Caffeine Subjects··••••••••···•·••••••·•·••••••·••·•••••• 150 E. Pearson Correlation Coefficients Between Blood Pressure

and Sodium Secretion for Pre, Week 1, and Week 2,

Non-Caffeine Subjects 152 F. (Title?) ...... 154

xiv LIST OF TABLES

Table Page 1. Average Number of Cups Consumed, According to Caffeine

and Content ...... • ...... • . . . . • . . • ...... 25

2. Caffeine Found in Various Sources ...... 36 3. Subject Participation Information ...... 71 4. Blood Pressure, Sodium Secretion, and Adrenal Status of

Caffeine Consumers. Week 1 these subjects received no

caffeine, while Week 2 they consumed 5 cups of

caffeinated tea daily~...... 74

5. Correlated T-Test Comparing the Means of Blood Pressure

and Sodium Secretion of Caffeine Consumers "Pre" versus

Week 1, "Pre" versus Week 2, and Week 1 versus Week 2 •••••••• 76

6. Comparisons of Blood Pressures of Caffeine Consumers End

of Week 2 (Back on Caffeine) versus Status "Pre" (usual . Caffeine State) ...... 78 7. Comparisons of Blood Pressures of Caffeine Users End of

Week 1 (Off Caffeine) versus End of Week 2 (Back on

Caffeine ...... • ...... • . • . . . . • ...... 79

8. Blood Pressure, Sodium Secretion, and Adrenal Status of

Non-Caffeine Consumers. Week 1 these subjects received

5 cups of caffeinated tea daily, while Week 2 they

consumed no caffeine ...... 84

- --~ LIST OF TABLES(Continued)

Table Page

9. Correlated T-Test Comparing the Means of Blood Pressure

and Sodium Secretion of Non-Caffeine Consumers "Pre"

versus Week 1, "Pre" versus Week 2, and Week 1 versus

Week 2 ...... 85 10. Anabolic/Catabolic Index of Caffeine and Non-Caffeine

Consumers "Pre," End of Week 1, and End of Week 2 ••••••• • •••• 95

11. Correlated T-Test Comparing the Means of Anabolic /

Catabolic Index of Caffeine Consumers "Pre" versus Week 1,

"Pre" versus Week 2, and Week 1 versus Week 2 •••••••••••••••• 96

12. Correlated T-Test Comparing the Anabolic/Catabolic Index

of Non-Caffeine Consumers "Pre" versus Week 1, "Pre"

versus Week 2, and Week 1 versus Week 2 •••••.•••••••••••••••• 98

Dl. Pearson Correlation Coefficients Between Blood Pressure and

Sodium Secretion for "Pre," Week 1, and Week 2 - Caffein e

Subjects ...... • ...... • . . • ...... 151

El. Pearson Correlation Coefficients Between Blood Pressure and Sodium Secretion for "Pre," Week 1, and Week 2 -

Non- Caffeine Subjects...... 153 Fl. Comparison of Caffeine and Non- Caffeine Subjects at

"Pre" Status ...... 155

F2. Comparison of Caffeine Group End Week One with Non-Caffeine

Group End of Week 2 ••••••••• • •••••••• •• •••••••••••••••••••••• 156

xvi LIST OF FIGURES

Figure Page 1. Sodium Secretion of Caffeine Consumers - Bar Representation of Data in Table 4 ...... 82 2. Blood Pressures of Caffeine Consumers - Bar Representation of Data in Table 4 ...... 88 3. Blood Pressures of Non-Caffeine Consumers - Bar

Representation of Data in Table 8 ••••••••••·••••••••·••••· • • 90 4. Sodium Secretion of Non-Caffeine Consumers - Bar

Representation of Data in Table 8 •••••••••••••• • ·••••••••••• 91 S. Medical Index, Weighted Combination of Blood Pressure and

Sodium Secretion Data. Bars Represent Comparison of "Pre"

to End of Week 1 (Black Bars) and End of Week 1 Compared to End of Week 2 (Lighter Bars) ...... -..... 93 6. Mood, Psychological Effects via Questionnaire. Comparison

of End of Week 1 to "Pre" (Black Bar) and End of Week 2 to End of Week 1 (Lighter Bar). Caffeine Subjects ...... 101 7. Mood, Psychological Effects via Questionnaire. Comparison

of End of Week 2 to End of Week 1 (Lighter Bars).

Caffeine Subjects·•••• • •••·•• • ·••·••···•·•·•••·•·•••••••·• • • 102 8. Mood, Psychological Effects via Questionnaire. Comparison

of End of Week 1 to "Pre" (Black Bar). Non-<:Affeine Subjects ...... 104

xvii

--- ~ ···~ LIST OF FIGURFS

Figure Page 9. Mood, Psychological Effects via Questionnaire. Comparison of End of Week 2 to End of Week 1 (Lighter Bar).

Non-Caffeine Subjects•••••••••••••••••••••·••••••••••••·•••• 106 10. Sleep Index. Sleep Effects via Questionnaire. Comparison of End of Week 1 to "Pre" (Black Bar) and End of Week 2 to

End of Week 1 (Lighter Bar). Caffeine Subjects••••••••••••• 107 11. Sleep Index. Sleep Effects via Questionnaire. Comparison of End of Week 1 to "Pre" (Black Bar) and End of Week 2 to

End of Week 1 (Lighter Bar). Non-Caffeine Subjects••••••••• 109 12. Physiological Index. Physiological Effects via Question naire. Comparison of End of Week 1 to "Pre" (Black Bar) and End of Week 2 to End of Week 1 (Lighter Bar).

Caffeine Subjects••••••••••••••••••••••••••••••••••••••••••• 111 13. Physiological Index. Physiological Effects via Question naire. Comparison of End of Week 1 to "Pre" (Black Bar) and End of Week 2 to End of Week 1 (Lighter Bar).

Non-Caffeine Subjects••••••••••••·•••••••••••••••••••••••••• 113

xviii

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CHAPTERI \ INTRODUCTION

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 our habits, we i are taking a first step in the process of awakening. The result must not only be an improvement in the quality of our lives, but the world itself will be changed for the better.

The _~~e__ a~d abuse of caffeine is a .!!1flicrrpublic ~'habit" and may_.~:- ...... I. ..•..• ,• -~_simyortant a factor as h~redity a:nd envi!.~!lDlent in the etiologr_.2£

. ,, ~siological and psychologi,ca~ disorders. To recogniz_e this, we must ------' '. ' .... _,. ~,----~-··~.. -•- know that weare 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. -The current liter_ature un~gu_~vocally demonstrates that caffeine not -· -····· ,,._ only affects our physiology, but has a ·profound'effect on our psychology ~swell. 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 ~oses. It may not be 9~!.i~~s th~t at lowe~ doses, when used in

moderation, it may have beneficial .. effecJ:s. • For example, its possible -----·•·~ .· . I • I

1 2 therapeutic use in hyperkinetic children certail]..1.·r.~uld seem advantageous when ~omp"a'redto the current treatment with more powerful stimulants which have concomitant adverse reactions, i.e., asthma, upper ,~· respiratory problems, colds, and flu~~ Also, with the intense day-to-day pressures imposed and accepted by many of us, is there any harm in

"relaxing" with a hot cup of tea or 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 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 a 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 psychological problems which we are experiencing in this era. This th_esis revi~ws __§.QtQ.e of the knowledge of caffeine's effects · with the ·hope that we wi.llAH be more educated and more careful in the __,...... - .. - use of this commonly ingested and a b_used 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 -: .•..- .... , ...... - ...·. •, :.· .. ,. ····· ••;;-:a,. .. •.•••--·

catecholamine (adrenaline) release. In large doses, caffeine has been shown to be a mutagen in animals, plants, and bacteria, and has been shown to exhibit teratogenic properties in various animal species. . ·•·.... " I~ddi ;~

; ...... In an editorial in Connecticut Medicine ( ~ 97.9) ,-~--the.._caffeine-hype is condemned. Four billion gallons of caffeine-containing soft drinks are produce_d each year~ ...using caffeine from decaffeinated coffee beverages. :.t:bus, ca£ feine is taken from the elderly and given to the young·:, The . - symptoms of caffeinism are evident at very low doses in some susceptible persons. The abuse of caffeine is now a public health problem in children. Agitation, restlessness, quality of sleep lessened, and hyperkinesis may result from overindulgence in cola and other

I~- -, ·. ·. caffeine-containing beverag~s. A recent study (Gross, 1975) in New Haven 4

on hyperkinetic children revealed a high consumption of caffeinated beverages among these afflicted children. The increasing sales of decaffeinated coffee suggests that the public is becoming more aware of the dangers of excess caffeine.

Dr. Reus, of the Langley-Porter Neuropsychiatric Institute, reports in Primary Care (1979) that the behavioral effects of caffeine are now well known. Doctors should be aware that many drugs can cause emotional and/or psychological changes which are difficult to differentiate from real stress-related psychological effects. Thus, incorrect diagnoses and treatments may often be incurred in such situations.

Dr. R. P. Grancher (1980), who is concerned with research on the physiological and psychological effects of caffeine, noted a publication by Defreitas in.which psychiatric patients had improved symptoms when decaffeinated·coffee replaced regular ~offee. Dr. Grancher considers this of "immediate clinical importan~e." He urges that the effects of caffeine in psychiatric patients (indeed, in all psychological disturbances) be clarified, as he puts it. He notes also the relationship of smoking and caffeine consumption. Smoking increases caffeine metabolism, thereby shorte~ing,and diminishing its effect. This may result in increased ingestion: Also, caffeine has been shown to

~nteract with anti-psychotic drugs, in vitro, a precipitate being formed.--•' Further investigation of these effects is also recommended. A very interesting editorial in the Journal of Clinical Toxicology (1978), addresses the problem of volatile disorders. The editor states

-~ 5

that caffeine is among those abused drugs (including narcotics,

sedatives, amphetamines) which are used to bring disorders upon ourselves with "volition." That is, some of us are willfully self destructive. This behavior is somewhat associated with a "defect" of the will. We must all become aware of the difficulties and severe problems of overcoming this behavior. Coffee is considered "the most innocent of beverages." As the author notes, a single cup of coffee (100 mg of caffeine) is usually thought of as harmless. However, some "sensitive" persons may develop "behavior toxicity indistinguishable from cocaine

amphetamine bummer." As is now well known, the psychological effects include sleeping problems, irritability (over-reacting to a stimulus),

nervousness, headache, and withdrawal symptoms characterized by headaches and shakiness.

In the same vein, Dr. James P. Henry, of U.S.C. School of Medicine, in an article in Aviation Space Medicine (1978), discusses the concept of self-imposed stress, what he calls the "noradrenaline addict." These types, typified by the James Bond model, must self induce an excitory state to enliven their existence. This is often accomplished by caffeine (in addition to smoking and drinking). Caffeine is a "drug of abuse." Five cups a day are sufficient to induce a habit. Caffeine results in adrenal stimulation or overstimulation (spurred on, stirred up, roused to action on a higher level). Withdrawal results in a depression of adrenal function, and the typical symptomatology of caffeine withdrawal, which I mention so often, headaches, irritability, and depression (dejection; ·a '

sinking of spirits). A study of Johns Hopkins graduates (by Thomas) showed that the graduates who showed depression, followed up in later life, were heavy caffeine and tobacco users. He suggested that increased awareness of nervousness, anger, and anxiety leads to more use of caffeine (cigarettes and alcohol) in an effort to alleviate these

feelings. CHAPl'ER2 REVIEWOF THEBODY OF INOWLEDGE

Physiological and Pharmacological Effects

J. Murdoch Ritchie, in Goodman and Gilman's text on pharmacology (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 leve?s, the cortex and medulla, and finally the spinal cord at higher doses. Mild cortex stimulation appears to be beneficial because it raises glucose, 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 coffee) is sufficient to induce adverse effects. The occurrence of

7 '

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 grams are needed for such toxicity to occur in man (Ritchie, 1975).

Stimulation of the central nervous system 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 central nervous system 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 small 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 is less profound than its central nervous system action. Its direct stimulatory effect on the heart may be neutralized by its central vagus stimulation. The direct

···-~ 9 effect predominates at very large doses with tachycardia and, eventually, with resulting arrhythmias. Caffeine has the ability to potentiate ionotropic responses to B-adrenergic agonists and glucogon (Ritchie et al., 1975).

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 mmof Hg in blood pressure (Ritchie et al., 1975). Caffeine's purported efficacy in hypertensive or migraine headaches may be due to a decrease in blood ~low 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). One of the many physiological effects of caffeine is an increase of the metabolic rate (Acheson, 1980). The increase is probably due to release of catecholamines (adrenaline). Dr. Bellett has shown that caffeine increases the free fatty acid content of the blood and increases t~e urinary secretion of catecholamines,although only at controlled times, post prandically and in absence of sugar. Dr. Acheson showed that free fatty acid levels doubled with 8 mg/kg of caffeine (equivalent to 5-6 cups of coffee). At half this dose (4 mg/kg), the same increase was

··--~ .. ·~ r

noted in both obese and normal persons. The increased metabolism is

thought to be due to the increase of the readily available fatty acids, a

source of energy. If caffeine was given with meals, the effect was

synergistic. Thus, the extra energy boost noted with caffeine is

probably related to the adrenal stimulation and increased free fatty acid

availability. The rise in free fatty acids items limited with food

intake, especially available carbohydrates.

Auditory reaction time was decreased and auditory vigilance

increased when caffeine was given to 12 volunteers at doses of 75 to 300

mg (Clubley, 1979). Subjects also felt more alert, but no differences in

short term memory or arithmetic performance were observed. The auditory

vigilance test consisted of repetitive short length tones. The

arithmetic test consisted of the calculation of simple sums. The

auditory reaction time was the total time required to press a switch.

Significant subject variabili~y was observed with regard to reaction

time. The effect of caffeine based on this test may be due to both

"peripheral (muscular work) and central stimulation."

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).

A dose of approximately 10 g or more taken orally can be fatal

(Gleason et al., 1969). The toxic effects are due to central nervous

system and circulatory system stimulation and include some well

recognized prominent symptoms in addition to those which can result at 11 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 stated, "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".

Caffeine's effects are more apparent in children than adults. A study by Dr. Judith Rappaport and colleagues (1981), of the National

Institutes of Mental Health, concerned the effect of caffeine in boys and male college students. The young boys were more affected by caffeine than the college men. These effects included increased "motor activity, speech rate, and decreased reaction time." Adverse effects of caffeine were more obvious in children and for those adults who habitually drank little caffeine.

The boys were approximately 11 years old and the men 22 years old on the average. The adults were either low (26 mg/day) or high (565 mg/day) caffeine users. The children averaged 125 mg a day. Side effects and psychological effects were measured using a questionnaire after consumption of a caffeine beverage or placebo beverage. Motor activity was measured electronically. Other measures of caffeine effects included r

"speech communication tasks," memory, reaction time, "sustained attention measure," and skin conductance.

This study confirmed previous investigations which showed that

performance measured in adults was not affected by caffeine very much.

Children, however, showed significant effects and also had more side

reactions. The effect of caffeine on "feeling nervous and jittery" was

clearly closely related in children. Children were less variable in

their response to caffeine than the adults in this study.

Low caffeine users had more severe subjective "psychological"

effects than high caffeine users. Even high users had the jitters and nervousness at high doses.

Kupiets and Winsberg (1977) used a test which showed discrimination

to psychostimulant drugs for children with reading difficulty. The

authors used a cross-over design with 10 boys, giving placebos and

caffeine. No effect of caffeine on "attentional" problems was found in this study.

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

physiologfcal effects are observed in less than one hour (Parsons and

Neims, 1978). Infants do not metabolize caffeine as well as adults and r

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 coffee, they should be closely monitored.

Caffeine is known to interact with other drugs, resulting in a modified effect. For example, caffeine administered with nardil (a 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).

CaffeiniSIII

Reimann (1967) describes the effects of caffeinism: insomnia, appetite loss, -weight loss, irritability, flushing, low fever, and chilliness. Those most susceptible are night people, people whose jobs

·-~,--..~ ···-~ '

keep them up at night, such as truck drivers, waitresses, and theater people.

Caffeine beverages are said to give a "vigorous, energetic feeling," working for 2-3 hours after ingestion. It has been shown to prevent "attention lapses" and to improve the speed at which physical tasks can be performed. However, intellectual performance seems not to be affected (Graham, 1978).

Other symptoms attributed to the habitual excessive ingestion of caffeine are such disturbing effects as agitation, restlessness, and anxiety, sometimes misdiagnosed as anxiety neurosis (Greden, 1974). Caffeinism has been considered by some medical authorities to be a real public health problem. Children are particularly susceptible and the "hyperkinetic" syndrome observed in many children may be at least

partially due to habitual caffeine use. Children who consume only cola drinks may be taking in an amount of caffeine equivalent to 8 cups of coffee a day, if their lower weight is taken into account. Particularly, children should not be given caffeine-containing beverages and if symptoms resembling those attributable to caffeine overdosage occur, excess caffeine consumption should certainly be considered as a possible cause. Gilliland and Andress of the University of Oklahoma (1981) investigated caffeinism in college students. Caffeinism is expressed by anxiety, depression, and other psychophysiological factors. Through a survey, they identified abstainers, low, moderate, and high caffeine ------··········

15 consumers. They then compared caffeine consumption to performance. High consumption of coffee was 5 or more cups per day. (The average of the high consumer group was 8 cups/day.) The high user group showed more evidence of anxiety and depression. Men seemed less affected than women. Academic scores were also adversely affected in the high user group. The moderate and high consumer group showed similar traits, which were significantly different from the caffeine abstainers.

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 behaviorally-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 i~eas. 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 coordination 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

·---r.~ r

and motor performance at doses of 65 to 130 mg of caffeine. At a dose of 300 mg of caffeine, the results were 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, SO, 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 lower dose (equivalent

.c-.,.,,.~ ,

to approximately three cups of coffee). At high doses, all measures decreased: the mice became tolerant.

Castellano (1976) studied the behavior of mice 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 "L" procedure needed very high doses to cause

disruption. Amphetamines do not show the results as demonstrated in this

paper, whereas other drugs, such as hallucinogens, do 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 (over-the-counter) stimulant approved by the FDA (Federal Food and Drug Administration).

Several studies investigating this action in some detail have been published. r

Karacan (1976) found that caffeine given half an hour before sleep adversely affected the sleeping patterns in normal subjects. 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 on caffeine on the self estimation of sleep latency (which was increased) and quality (which was decreased). This was a double-blind study in which 60, 120, and 250 mgs. 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(Rapid Eye Movement) stage. Other studies show contradictory evidence, REMbeing 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 re~iring. 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 placebos, as opposed to r

caffeine in coffee. If 150 to 200 mgs. of caffeine were 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.

'lbe Caffeine Personality

Several studies have been designed to see if an association between a "personality" type and caffeine consumption exists, i.e., "what kind of person drinks coffee?" Also, how do various "types" respond to caffeine. One hundred ninety-nine (199) females from a non-coed college were given a personality test, self-rated, and no significant differences were found between coffee and non-coffee drinkers (Primavera, 1975). (There were differences between smokers and non-smokers, however.) People considered to be "low impulsives" performed less well and "high impulsives" were aided by morning coffee; but the opposite occurred

when coffee was taken at night (Revelle et al., 1975). The authors of this study suggest that the effect could be due to the different circadian rhythms of extroverts and introverts with regard to impulsivity and caffeine's stimulant effect. The decreased performance is considered to be a consequence of "overarousal." Caffeine has been said to have effects on arousal and anxiety. It was shown that stress is also a ·---. r

factor affecting the observed activity of caffeine, with reduced performance and effectiveness when stress is increased. Eysenck and Folkard (1980) disagree with the above findings, pointing out discrepancies and incorrect assumptions. For example, the times at which the coffee and tests were administered did not coincide with the circadian rhythms of introverts and extroverts as observed in the authors' experience and published studies. Also the analysis was unidimensional, based on an impulsive component only. This seems to be an oversimplif.ication. The cross-over design also may have introduced complications caused by a carry over effect. Caffeine is known to induce anxiety and has arousal effects. These are related to measures of neurosis and, perhaps, should not have been neglected in Revelle's analysis •

. Smoking and Coffee

It has been established that coffee consumption and cigarette smoking are correlated; they go hand-in-hand. Marshall performed a test where smokers were given 0, 1, 2, or 3 cups of coffee while working on a crossword puzzle (Marshall, 1980). The more coffee they drank, the more they smoked. The experiment was repeated, testing "no beverage, water, postum, decaffeinated, and regular coffee." Drinking coffee, both caffeinated and decaffeinated, was associated with increased cigarette consumption. When no beverage or water was given, smoking was less. Kozlowski, in 1976, showed that more nicotine was taken with the r

caffeinated coffee and was not related to the caffeine concentration.

Therefore, smoking seems to be related directly to caffeine and not to

the liquid consumption. The author suggests that coffee consumption be

reduced for those who wish to stop smoking .

Marshall thought that the association of smoking and coffee

consumption could be explained on the basis of physiological rather than

psychological effects. He reasoned that change in urine acidity caused

by coffee could affect the excretion of nicotine and caffeine might

affect the metabolism of nicotine. Coffee makes the urine acid and

nicotine is excreted more rapidly under these conditions. Smokers were

given water, coffee, coffee plus sodium bicarbonate (an alkalizing agent)

and .coffee plus ascorbic acid. The urine acidity had no effect on

cigarette use. There was increased smoking with both bicarbonate and

ascorbic acid. This author suggests that smoking with coffee is a

conditioned reflex.

Psychological Effects

Caffeine in excess has been reported to induce hallucinatory and

psychotic states in high doses in some people (Mullin, 1978). The case

of a man who hallucinated after taking in 1000 mgs. of caffeine in a

short time internally during a dog sled race has been reported. She

tells of a 31 year old truck driver who said he was being attacked by

bright shiny bugs and flies which were trying to bite him. He worked in

a cola factory and drank 120 ounces a day (10 cans). The day before the ,

attack, he had consumed 20-25 cans, equivalent to more than 1000 mgs. of caffeine. This man recovered from his hallucinatory, psychotic attack in 2 days. Similar reports of caffeine's effect at high doses have been reported previously. As early as 1914, Orendorff reported a case of excess cola consumption in which an individual showed eccentric and stubborn behavior with periods of exhilaration and depression. In 1936, a psychosis which included symptoms of delirium, confusion, and manic-depressive character was reported as a result of an overdose of caffeine. As pointed out by Rippere in the British journal, The Lancet, coffee can "cause and exacerbate pre-existing psychological states. Nevertheless, coffee is still given to psychiatric patients and little

effort is made to give decaffeinated coffee." Reimann (1967) noted that symptoms of a psychoneurotic woman disappeared when coffee intake was reduced. She presented with an irregular fever, insomnia, anorexia, and irritability, having consumed large amounts of coffee. Mikkelsen (1978) noted caffeine's involvement in schizophrenic like states similar to those 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 felt that the patient developed paranoid delusions which 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 report. Forty years ago a case of psychosis was reported in which a 24-year old female took 60 gr. (about 4 g.) of caffeine. Manic symptoms developed. Mikkelsen theorizes that adrenal 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.

Habituation, Addiction, and Tolerance

Caffeine and.coffee consumption 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. Coffee, milk, sugar, cigarettes, and sugar with chemicals certainly poison the body and brain and create toxicity. In the latter case, it is of interest that coffee drinkers were shown to take more nicotine when deprived of coffee; a substitution of one toxic allergen for the other (Kozlowski, 1976). Caffeine has not only been considered habit forming, but also addicting. Crothers considered morphinism and caffeinism to be similar, r

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 consumption in amounts of 48 to 111 ounces per day (144 to 333

mgs. of caffeine per day) was reported to have caused physical effects on

withdrawal (Diamond and Pfiffering, 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.

In an oft-quoted study, Kozlowski observed that habitual coffee

drinkers will drink more coffee if it contains less caffeine. He

supplied coffee containing either 25, 40, or 100 mgs. of caffeine to

experimental subjects, keeping at least some caffeine in the coffee to

prevent possible severe withdrawal symptoms which include, according to

Kozlowski, headache, fatigue, and irritability. The test took place in

two settings: a university dining room, where an urn was supplied, and

in an area where school teachers had their coffee breaks. The average

number of cups consumed, according to caffeine content, is shown in the table below: I r 1 I

25 ' Table 1

Average Number of Cups Consumed, According to Caffeine and Content

Caffeine 100 mg 50 mg 25 mg

Urn in university 4.2 5.0 4.5

School teachers 2.6 3.0 3.1

The subjects also reported feeling better as more coffee was consumed.

This study suggests that the taximolecular levels of caffeine dropped, so

craving for the "fix" and withdrawal syndrome symptoms arose.

One of the most frequently observed symptoms of caffeine withdrawal

from regular users is headache. This effect is paradoxical in that

caffeine is also used to ameliorate headache pain (British Medical

Journal, 1977).

Greden (1980) reported that approximately 11% of psychiatric

patients experienced headaches when caffeine was withdrawn. The

headaches usually start about 18 hours after the last caffeine dose and

are characterized by painful throbbing with the worst pain 3-6 hours

later. These headaches, according to Greden, can last for a day or more,

often occurring on weekends, because of the changes in habits which occur

at these times, for these patients. This is how a vicious cycle can

begin with caffeine. Thus, coffee or caffeine-containing drugs can

--, r 1·1

I I l

relieve the headache, and the caffeine habit continues and is perpetuated.

Indeed, headache is one of the chief symptoms observed as a result of caffeine withdrawal in those who ingest relatively large quantities of caffeine on a regular basis. Dr. Greden has done considerable research in this area (1980). He tested people who experienced caffeine withdrawal headache and found that they showed more anxiety and depression, as evidenced by psychological tests. These people also feel less healthy and take more caffeine and anti-anxiety drugs compared to persons who do not experience the withdrawal headache. Dr. Greden notes that a large caffeine intake results in a certain tolerance to caffeine's effects. He also points out that 22% of psychiatric patients ingest 750 mgs. or more of caffeine daily. In this report, 28% of 152 persons tested had caffeine withdrawal headaches. This group considered their health not as good as others and scored worse on State-Trait An~iety Index scores. They also fared worse on the Beck Depression scores, particularly with regard to sadness, guilt, pessimism, failure, and expectation of punishment. The persons who experienced the withdrawal headaches took in more caffeine, an average greater than 600 mg/day. They perceived that the caffeine gave them energy and cleared their thoughts, although they agreed that it could have deleterious effects. Thirty-eight (38) percent of those with caffeine withdrawal headaches thought that caffeine helped their headache, as compared to 7% in the group who did not experience the

------~ r'

headaches. A case history of a 32-year old housewife was presented. She

reduced her caffeine intake because the headaches she experienced were relieved with a caffeine-containing pill, creating the cycle. The j recommended treatment is to stop the cycle using intermittent withdrawal.

People do not really appreciate that all of this can be caused by l l caffeine intake and thus are reluctant to stop their caffeine intake. ' Once the cycle is interrupted, any problems, such as headaches, can be treated symptomatically.

Harrie reported a case of a patient who experienced constant

headaches for a period of time exceeding two years. When a psychiatrist

found that tension was not the cause, the medical diagnosis was too much

"serenity." This woman was so psychologically habituated to caffeine

that she even suffered after having coffee passed off as decaffeinated.

Thus, paradoxically, the caffeine headache can occur in some from

drinking coffee as well as in others during the withdrawal.

The 24-hour fasting during Jewish high holidays (Yom Kippur) often

results in headaches. Other symptoms include a ·lethargy in the morning,

nausea, and occasional vomiting (Shorofsky, 1977). These symptoms were

found to be relieved by caffeine or salicylates, suggesting that the

adverse effects of fasting might be due to withdrawal.

Although the occurrence of headaches when caffeine is withdrawn is 1; ' well documented, the effects of caffeine do not seem to be adaptive;

tolerance is not · obvious (Graham, 1978). That is, the physiological 28 effects of caffeine are evident in heavy caffeine users as well as abstainers.

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 non-drinkers. If the morning coffee was stopped, the habitual coffee drinkers experience 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 O, 150, and 300 mg. Coffee drinkers showed a dose-response effect, whereas non-coffee drinkers showed signs such as nervousness, ji~ters, and upset stomachs at all doses of caffeine, but not on placebo. An interesting case of caffeine withdrawal was reported by Dr. C. Gibson of M.I.T. in the New England Journal of Medicine (1981). According to Dr. Gibson, the amount of MHPG,a norepinephrine metabolite,

.A 29 is "used to classify patients with affective disorders and to predict therapeutic response to antidepressant drugs ••• " A patient who drank

10-15 cups of coffee per day showed the highest levels of MHPGever observed by the author, after elimination of coffee (3 to 4 times that observed in normals). The patient also had withdrawal symptoms which

"included headache and anxiety." This increase probably is a result of

"sympathetic activation," perhaps a rebound effect or compensatory action. Ritchie (1975) says that tolerance and physiological dependence on 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 physiological dependence and withdrawal effects and is a problem to be reckoned with.

The addiction liability of caffeine and its relation to the mechanism of addiction has been studied in quite some detail in both human and animal models. This interest in caffeine stems not only because of its wide use but because of its profound pharmacological activity.

Caffeine is a phosphodiesterase inhibitor and induces a

morphine-like withdrawal syndrome in "opiate-naive" rats as shown in a

study by Butt and co-workers (1979). This ·effect is related to

caffeine's ability to inhibit cyclic AMP(cAMP) phosphodiesterase in rat 30 brain homogenates. (The activity is not related to CGMP phosphodiesterase.) Naloxone, a narcotic antagonist, results in withdrawal symptoms when given to narcotic (morphine) addicts. Similar symptoms occur when naloxone is given to chronic caffeine users

(methylxanthines, in general). In fact, withdrawal symptoms caused by naloxone in addicts are greatly increased in the pre~ence of caffeine.

The methylxanthines appear to act by inhibiting the hydrolysis of phosphodiesterase of cyclic AMP. Caffeine was given subcutaneously to opiate-naive rats one hour before naloxone was given. The animals were observed for 15 minutes after the naloxone, with particular emphasis on behavioral excitation effects. Opiate dependence is characterized by increased cAMP activity, which is related to the abstinence syndrome.

Collier and co-workers (1981) have been active in research elucidating the mechanism of addiction. They hypothesize that opiate dependence is due to a "hypertrophy of a neuronal cAMP in compensation for the inhibition by the opiate of an adenylate cyclase." They show that there is a relationship between caffeine consumption and opiate addiction. Also, opiates may be used as an antidote for theophylline and caffeine poisoning. The withdrawal symptoms from caffeine are very much like that of morphine. They cannot be differentiated in opiate-naive animals. The typical experiment is to give the narcotic antagonist, naloxone, after administration of the "addicting" drug. With some caffeine derivatives, the time for withdrawal symptoms to occur after administration of naloxone is much &horter than that observed with

- ~- -~ 31 morphine. They have tested this theory of opium dependence and the hypertrophy of neuronal cAMP, which is inhibited by opiates. If this is true, phosphodiesterase inhibitors, such as caffeine, in conjunction with opiates, should increase withdrawal symptoms. Opiates are stronger than caffeine and, if given together, opiates predominate. However, if the caffeine is administered to opiate dependent animals, the withdrawal effects caused by naloxone are increased.

If rats are left on their own, they seek more morphine when given methylxanthines. The methylxanthines counteract the effects of opiates but synergize the dependence. The authors of this report state that the relationship of methylxanthines to opiates is intimate and paradoxical.

The inhibition by caffeine of phosphodiesterase increases cAMP which antagonizes the opiates and synergizes antagonists such as naloxone.

They postulate the increased cAMP causes the release of andogenous opiates which inhibit andenylate cyclase. Therefore, phosphodiesterase inhibitors (which increases cAMP) enhance the opiate dependence. When opiate dependent rats are withdrawn, cAMPis increased. The inhibition of neuronal adenylate cyclase by opiates results in hypertrophy of cAMP.

Caffeine increases the induction of opiate dependence. In relation to caffeine's role in opiate addiction, the authors state, "Since caffeine is arguably the most widely taken drug in the world, we believe these possibilities demand serious study.''

Dr. E. M. Boyd -(1965), in an article in the Canadian Journal of

Physiology and Pharmacology, observed the effects caused by the caffeine~ l

Dr. Boyd noted withdrawal symptoms which lasted one week. These included decreased locomotor activity (1/2), proteinuria, glycosuria, and lowered body temperature.

Deneau and co-workers (1969) used a test where monkeys were able to self-administrate drugs to demonstrate drug dependence. If a dependency occurs, the monkey voluntarily takes more drug. A drug which is "psychotoxic" is considered addictive with abuse potential. In this report, caffeine (in addition to the usual narcotics such as morphine) was shown to produce a "psychological dependence." However, caffeine did not produce psychotoxic effects •. The monkey has been shown to be a very good model for humans for such drugs. Most of the drugs which cause physiological dependence are central nervous system depressants, although some stimulants also fall into this class. The authors define physiological dependence as the "voluntary initiation and maintenance of self-administration of drugs." If the drug is desired, the monkey can press a lever (in this experimental set-up) and the drug is delivered through an intravenous indwelling catheter. A second lever did not deliver the drug. With caffeine, self-administration was sporadic but was increased by automatically injected priming doses. No toxicity was observed during the experiment or after withdrawal. It should be noted that the monkeys make their own decisions and that these animals had not been pre-treated to induce dependence (in marked contrast to parallel types of studies with cocaine). 33

Vitiello and Woods (1977) describe an experiment in which rats received caffeine injections for 12 consecutive days. The rats then avoided a solution which they had associated with the absence of caffeine. The authors call this a "physiological withdrawal." Similar behavior had been previously demonstrated in morphine addicted rats. In the present experiment, rats were given various doses of caffeine and saline controls by injection. After 12 days, the saline group was divided into two groups, half being given saline and the others given caffeine. The rats on caffeine were also divided into two groups, one group given saline and the other the same dose of caffeine they had been given on the previous 12 days. Then, on the 13th day, the rats were given water with saccharine rather than their usual plain water. The rats which (1) were on saline during the 12 days and saline on the 13th day or (2) on caffeine during the 12 days and caffeine during the 13th day consumed the saccharine water in preference to the plain water. They had not been changed and preferred the sweeter water. Those which were switched from saline to caffeine or caffeine to saline on the 13th day avoided the saccharine water according to the caffeine dosage, i.e., the lar ger the dose, the greater the avoidance . This aversion showed that caffeine can cause a dependence. A change in caffeine dose in one day was sufficient to cause an aversion to the associated drink in this conditioning experiment (taste acuity change, catecholamines, hypot_halamic effects).

- ~ 34

The effect of nalox~ne of precipitating withdrawal symptoms in morphine addicted monkeys was duplicated by caffeine in a study by Aceto et al. (1978). The addicted monkeys were more severely affected by the typical, usual effects of caffeine than non-addicted animals. This result is again theorized to be due to cAMPphosphodiesterase inhibition. Morphine withdrawal results in increased cAMPwhich can be inactivated by phosphodiesterase. The symptoms, which were intensified by caffeine, include "avoiding contact, vocalizing, crawling or rolling, restlessness, tremors, wretching, vomiting, and coughing.

Although many people become dependent on caffeine and exhibit symptoms of caffeinism at low doses (8 cups or more a day is considered to be very harmful), a certain tolerance has been observed, after constant use, to diuretic and salivation effects (Foxx and Rubincoff, 1979). Also, drinkers of coffee have less sleep disturbance reactions. It has been also reported that ~offee consumption is increased in time to compensate for the diminished effects due to tolerance. Foxx and Rubincoff (1979) applied a method for the gradual withdrawal of caffeine which had previously been used for coffee. Three persons were chosen for the study on the basis of a questionnaire describing previous habits with regard to caffeine consumption. These persons drank eight or more brewed cups of coffee, had symptoms associated with coffee drinking, and wanted to cut down consumption. During a baseline period, an assessment of ·caffeine intake was made. The objective of the experiment was to decrease the consumption gradually to

---~ ., .... •

a specified target value in four phases. A small monetary incentive was

included as part of the program.

The subjects recorded daily consumption, including activities

associated with drinking the beverage. Graphs were made each day of

total consumption. These were handed in at the end of each phase.

Follow-up contacts were made at the end of the study . to check consumption

following the withdrawal regimen. During the study, subjects were

monitored by people who agreed to check on the veracity of the subjects.

These monitors ~ere contacted by the authors to see if, indeed, habits

had changed and to verify the reports. Each subject showed a significant

decrease in caffeine consumption, which was maintained or decreased over

almost a one-year period. Subject one consumed 1000 mgs. of caffeine at

the start, which was decreased to 300 mgs. after the withdrawal regimen .

The second subject showed similar results, whereas the third subject did

less well. Subject three decreased his caffeine intake from almost 2200

to 300 mg, but went up to 500 mgs. during the follow-up. All subjects reported lessened psychological ·effects, i.e., lessened

irritability, tenseness, and "h yper" feeling. Thus, this approach can be

considered as a possibly useful approach in reducing the intake of

caffeine among habitual users.

Among other methods to break the coffee habit is a relaxation

technique reported by Hyner (1979), in which he used reinforcement cards.

This resulted in decreased tachycardia and eventual discontinuance of

·------~ ~~ 36 caffeine tablets by habitual users. This technique resulted in both decreased tea and coffee consumption.

Just how much is too much coffee? That depends upon the individual, but obvious physiological effects are considered to occur after one or two cups of coffee, and certainly after intake of 250 mgs. of caffeine.

Table 2 (Graham, 1988) shows the amount of caffeine typically found in various beverages and OTC (over-the-counter) drugs. The moderately high intake of 650 mgs. per day taken by 1/ 4 of the adult population is certainly enough to elicit ad verse physiological and psychological effects.

TABLE2. CAFFEINEFOUND IN VARIOUSSOURCFS

Ground coffee 85 mg

Instant coffee 60 mg

Decaffeinated coffee 3 mg

Instant tea 30 mg

Cocoa 6-42 mg

Cola (8 oz.) 32 mg

Cold and allergy tablets 15-30 mg/ tablet

Headache tables 32 mg/ tablet

Sta y-awake tablets 100-200 mg 37

Anxiety and Caffeine

A particularly disturbing symptom of caffeinism has recently been observed to be more prevalent than previously supposed in the development of psychotic symptoms, indistinguishable from anxiety neurosis, according to Dr. John Greden of the University of Michigan. That caffeine can produce an effect of this sort was reported in the literature as early as

1936 by McManamyand Schube (Navin, 1980; Stephenson, 1977). They described the psychotic state of a woman who had just ingested 10 cups of coffee, _equivalent to about 1 gm (1000 mg) of caffeine, over the course of several hours. Pierce also had reported delirium and tremulousness in adults when large amounts of caffeine were taken (Stephenson, 1977). It is known that, even in smaller amounts, "dangerous sensory and motor disturbances" can occur.

Dr. Greden reported several case studies of patients in whom symptoms which were "indistinguishable from anxiety neurosis" were caused from excessive doses of caffeine (1974, 1976). According to this researcher, these symptoms included "nervousness, irritability, tremulousness, occasional muscle twitching, insomnia, sensory disturbances, tachypnea, palpitations, flushing, arrhythmias, diuresis, and GI disturbances." He also noted that when caffeine was withdrawn, symptoms s11ch as anxiety and headaches occurred. He made a special point to note that psychiatrists should be aware of this syndrome and consider caffeine intake when diagnosing psychiat~ic patients. Thus, if a diagnosis of anxiety neurosis is made, caffeine intake should be 38 carefully monitored to eliminate caffeine as a possible instigating factor. Although 1 billion kg (more than 2 billion pounds) of coffee are consumed annually in this country, caffeine intake has not been a usual part of the information on the patient's record. According to Greden, as little as 50-200 mgs. of caffeine can induce the effect in susceptible persons. Withdrawal symptoms have been documented in other studies. Greden notes the study by Goldstein (previously noted) in which withdrawal symptoms of heavy coffee drinkers who were deprived of their daily morning coffee included irritability, less efficiency on the job, nervousness, lethargy, restlessness, and headache. Three cases were described by Dr. Greden. One case involved a nurse who drank 10-12 cups of coffee a day and reported headaches, breathlessness," PVC/s, and lightheadedn~ss. Examination revealed no overt illness; she was normal except for these symptoms, which disappeared 36 hours after withdrawal of coffee. A 37-year old army lieutenant colonel had suffered for two years with anxiety, dizziness, tremulousness, apprehension, restlessness, and diarrhea, having chronic difficulty in falling asleep. He drank 8-14 cups of coffee each day, blaming the habit and his symptoms on the p~essure put on him by a very demanding boss. His total caffeine intake was 1200 mg/day, including cola and cocoa drinks. The symptoms were relieved when his caffeine intake was reduced. 39

Another army officer who drank 10-15 cups of coffee a day in addition to tea and cola as well as consuming caffeine-containing analgesics (1500 mgs. of caffeine per day) had severe tension headaches which disappeared after his caffeine intake was reduced.

These symptoms of excess caffeine usage are not new. The previous literature had reported anxiety, vertigo, instability, agitation, weakness, and headaches, as well as psychotic episodes as a result of caffeine abuse. Dr. Greden points out that if patients do not respond to psychopharmacological or hypnotic agents, then caffeine abuse may be the cause of these symptoms. Particularly, this should be considered in the diagnosis of "hyperkinetic" children.

The effects described by Greden have since been corroborated and verified in various reports in the literature. Molde (1975) tells of a prisoner who drank 50 cups of coffee a day! He showed "severe anxiety symptoms" which did not remit-when drugs such as tranquilizers and other antipsychotic agents were administered. Reduction in caffeine intake caused the symptoms to disappear. Excess drinking of coffee by prisoners is not uncommonand may initiate a vicious cycle: a bored person drinking more coffee resulting in caffeinism which may result in more consumption. MacCullum (1979) reported the case of a young 28-year old housewife from a professional family who drank more than 20 cups of coffee each day. She had "palpitations, persistent anxiety, attacks of cold sweat, shortness of breath, and tingling of extremities," and was in a state of

=9_,_ 40 panic. In an unsuccessful effort to relieve these symptoms, she was put on a regimen of benzodiazepines for more than six weeks. The symptoms only disappeared three weeks after coffee was eliminated. Again, as Dr.

Greden also has recommended, Dr. MacCullum suggests inquiries about caffeine habits with the answer coming by "simply asking a few questions."

An article by Hire (1978) showed a strong correlation between coffee drinking and anxiety, although no correlation of tea or cola consumption and anxiety was noted.

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 (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 outpatient disorders. Eighteen of the 83 patients (22 percent) were high caffeine consumers (750 mgs. or more).

These high caffeine users had higher scores on various psychiatric tests which measure anxiety and depression compared to those whose caffeine intake was lower. The high users also had more clinical symptoms, used more drugs such as sedatives, hypnotics and tranquilizers, and reported that their general health was less good than the low users. 41

Three groups of caffeine users were identified in this population, categorized as low, intermediate and high users. The low users took in between 0 and 249 mg/day, the intermediate users 250-749 mg/day, and the high users 750 mgs. or more per day. There were no special differences between the groups based on demographic information such as age, sex, race, marital status, and religion. In addition to the increased anxiety and depression in the high user group (1/2 of these showed severe depression), they also reported feeling more tired, blue, and tense. They were less rested, happy, and content. As reported in other studies, the high caffeine users had less trouble sleeping when taking caffeine. Greden feels this is due to a tolerance or, perhaps, a difference in the metabolic handling of caffeine .by these patients. The high users group also smoked more and drank more alcohol. (Many alcoholics substitute coffee for alcohol in Alcoholics Anonymous.) The exaggerated symptoms described above are the same as thpse of caffeinism, although the depressive effect is unexpected. Caffeine is used to counter depression due to its stimulating effect. In an attempt to explain the above effects, Greden notes that caffeine "modifies catecholamine levels, inhibits phosphodiesterase breakdown of cAMPand sensitizes catecholamine receptor sites." He notes the work of Cobb in which a group of unemployed workers who had a greater norepinephrine (a catecholamine) release when stressed than when not under stress, and. he concludes that these biochemical effects may be involved in the induction of anxiety/depression by caffeine. Dr. Greden 42 considers caffeine to be a psychotropic drug and 25 percent of the

population may take more than 500 mgs. per day , a large physiologically active dose. He describes three cases in which caffeinism may be misdiagnosed as an anxiet y 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. A case of delirium induced by caffeine under stress was reported by

Stillner (1978). A man involved in an Alaskan dog sled race went 48

hours without sleep in an effort to win the race. He took 1000 mgs. of

caffeine within three hours, after which he hallucinated, became

tremulous, had buzzing his ears, and experienced dizziness. These

symptoms disappeared with time and he reported his experience after the

race. This corroborates other reports of the effects of excessive use of

caffeine. Caffeine withdrawal can also cause anxiety symptoms. White and

co-workers (1980) reported in Science that muscle tension and anxiety

were evident among college students (who were regular coffee drinkers)

when the y abstained from caffeine. This was a double blind study in

which grapefruit juice, with and without caffeine, was administered after

3-7 hours abstinence from caffeine. Electromyographic (EMG) readings in

high coffee drinkers before caffeine was to be given was higher, showing

--~ -~ 1

43 increased muscle tension. After coffee or placebo was taken, the EMGwas not increased. Psychological tests were administered and no difference in anxiety was observed between high and low caffeine users or between the placebo and treatment group. However, there was a strong correlation between coffee consumption history and anxiety scores. The authors conclude that caffeine withdrawal symptoms include increased anxiety and muscle tension to go along with reports of headache, drowsiness, lethargy, and irritability.

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 lead to diagnostic confusion and a complicated course of therapy. Mixed depressive states may be caused by excess caffeine consumption and Dr. Neil et al. suggest, also, that unipolar II depressives may use more caffeine as they become depressed.

Caffeine, in these patients, provides only transitory relief as it is no·t a true antidepressant. Caffeine also may render anxiolytic and antipsychotic medications less effective. 44

Psychological Disorders and the Psychiatric Population

Dr. Greden 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."

According to a survey, one of four Canadian adults took more than

250 mgs. of caffeine/day, enough to bring on severe caffeine effects.

Psychiatric patients are particularly susceptible to caffeine according

to Bezchlibnyle and Jeffries (1981). Coffee drinkers show anxiety and

·get higher depression scores on psychological tests. Schizophrenia is

worsened with caffeine. · Hostility, suspiciousness, anxiety, and

irritability were reduced in schizophrenics as shown by DeFrietas and

Schwartz (1979). Coffee drinking and use of tranquilizers are highly

correlated. They recommend that coffee and tea not be served to

psychiatric patients. Identification of drugs which may interact with

caffeine should be routine. The authors feel that to institute such

changes may be difficult and considerable education is necessary to

effect changes in the coffee "habit" among patients, physicians, and

administrators of psychiatric institutions.

• p; - 9 ~ 45

Rodby and Mallory of Sonoma State Hospital in California (1977) reported a study involving 15 aggressive females. ages 18 to 30. in their institution. They attacked others and caused disturbances. in general.

They drank 4 to 15 cups of coffee a day. an average of 7.1 cups.

Decaffeinated coffee was substituted for the regular coffee. After eight weeks. the average coffee consumption was reduced to two cups a day. The number of disturbing episodes was reduced from 15 to 6.3 per day during the last two weeks. Decaffeinated coffee was continued after the study was completed.

As previously noted. one of the most well known effects . of caffeine. indeed marketed for this effect. is its ability to ward off sleep. to help one stay awake. Of interest is the fact that a common symptom of psychiatric patients is sleep disturbance" ••• and. psychiatric patients drink lots of coffee" (Navin and Wilson. 1980). This unfortunate occurrence results in a certain amount of confusion when diagnosing and treating psychiatric patients. According to Navin and Wilson. the time patients spend in hospitals is increased because of such unrecognized effects and that. in fact. patients may be given medication to counteract

the caffeine-induced sleep disturbances. resulting in unnecessary overmedication.

Brezenova. in 1974. published results of a study on 82 psychiatric

patients. comparing the effects on sleep patterns of coffee and

decaffeinated coffee. He noted previous studies in which 300 mgs. of 46 caffeine resulted in less sleep, longer latency (time to fall asleep) and easier arousal once asleep, in a group of volunteers.

Karacan (1976) had showed that REMoccurred earlier than usual in the sleep cycle, and that deeper stages of sleep, stages III and IV, occurred later in the night compared to normal sleep patterns. The effects were dose related; the more caffeine, the stronger the sleep disturbance. Tolerance can develop with habitual caffeine use, heavy coffee drinkers having been shown to have less caffeine induced adverse effects on sleep than those who took smaller amounts. When these heavy users were deprived, the caffeine effects were similar to non-users. In his study, Brezenova tested 82 patients in a small facility. Most of the patients were schizophrenic or depressives. The study was blinded; the coffee served by the kitchen staff was either caffeinated or decaffeinated, unknown to the p~tient and floor-staff population. Paradoxically, when regular coffee was served, there was a gr_eater tendency to sleep quietly; and patients had more trouble sleeping or returning to sleep once awakened when taking decaffeinated coffee. Also, when decaffeinated coffee was served, there was an increase in the dispensing of medication within the institution. In fact, there was less nervousness when coffee was served. A possible clue to this result was that more decaffeinated coffee was consumed than caffeinated coffee, suggesting that the need for caffeine was involved; the patients were looking for more caffeine. The results could be explained by "withdrawal syndrome symptoms." The increased restlessness and difficulty in

24£111 47

could be due to the withdrawal of caffeine from these patients sleeping used to having their caffeinated coffee. whowere Winstead (1976) studied the caffeine habits and psychological

. particularly anxiety of psychiatric patients in a military traits, One hundred and thirty-five (135) patients were included in the setting. and were given the State-Trait Anxiety Inventory Test and the stU dY ~nnesota Multiphasic Personality Inventory (MMPI) test. Thirty-four (>4) patients drank five or more cups of coffee on each of two or more daysand were considered high coffee users . The high users tended to be older, single, divorced, or separated. The high users had more incidence of psychosis, depression, and neurosis. There was significantly higher anxiety among these high users, but none was diagnosed as having anxiety-neurosis. There was a tendency towards anxiety symptoms upon caffeine withdrawal in the high user group. According to Winstead, it is not clear which is "cause and effect" with regard to these findings. Is caffeine causing the effects or is increased caffeine consumption a result of the disease? In any event, schizophrenic and psychotic

?atients should not be given any coffee. It increases anxiety, can neutralize the effect of sedatives, and interfere with the action of other anti-psychotic drugs.

The effects of caffeine in chronic psychiatric patients were

described by Defreitas. Fourteen (14) males, ages 22-56 years, of whom

11 were schizophrenic, were included in the study. They were first given

decaffeinated coffee for three weeks," followed by regular coffee. Two 48 psychiatric rating scales, Nurses Observation Scale for In-Patient Evaluation (NOSIE) and Pupil Behavior Rating Scale (PBRS), were used to evaluate the patients. Overall, the patients improved when on decaffeinated coffee. Anxiety and tension were reduced when patients who chronically drank coffee were given decaffeinated coffee, although a temporary worsening was sometimes seen at first. Some of the factors and scale items which were improved with decaffeinated coffee were suspiciousness, anxiety, tension, hostility, excitement, and somatic concern on the BPRS scale and patient's assets, social competence, personal neatness, irritability, manifest psychosis, and retardation factors on the NOSIE scale. That psychiatric patients drink more coffee has been repeatedly documented. Granacher (1980) concurs that such patients drink huge amounts of coffee. He also notes that ~moking is correlated with coffee consumption. Metabolizing enzymes are induced by these substances which would increase the metabolism of other substances, including drugs; this is a factor to be seriously considered for such patients.

Psychiatric Patients-Interaction with Drugs and Treatment

Kulhanek et al. (1978) has reported that coffee drinking by psychiatric patients can have effects other than those directly induced pharmacologically. Caffeine can physically interact with and affect the action of some antipsychotic drugs. Caffeine is used therapeutically in schizophrenic patients, e.g. based on its central nervous·system action. 49

Mikkelson (1978) told of two schizophrenics whose symptoms were lessened on coffee or tea. When drugs such as phenothiazines, fluphenazine, and butyrophenone drops are mixed with caffeine-containing beverages such as coffee or tea, a precipitation reaction occurs. This reaction occurs with pure caffeine benzoate or caffeine salicylate but not caffeine HCl, as reported by Kulhanek (1978). In an article by Hirsch (1981), this precipitation was noted with elixir of CPZ, haloperidol, fluphenazine, dropnidol, promethazine, promazine, and prochlorperazine. Trifuoperazine and propranol did not form precipitates. In a recent article in The Lancet, Bowen (19 ) notes that in addition to the above effects, caffeine may act as a pharmacological antagonist to some psychotropic drugs as well as enhancing their metabolism. He tested blood levels of various drugs in patients who did and did not take coffee and found no difference as a result of caffeine intake. Apparently, these interactions are not evident in ..!!Y.Q.,i.e., in the body.

Caffeine's Effect in Attention Deficit Disorder (ADD) and Byperki.Detic Children

Hyperkinetic (hyperactive) children have been shown to respond to central nervous system stimulants resulting in improved attention, concentration, and decreased activity. S~de effects are usually disturbing with the more powerful drugs (i.e., .methylphenidate) and include insomnia, anorexia, nervousness, weight loss, and abdominal pain. 50

Sympathomimetic drugs, for example, have a positive effect in many

Attention Deficit Disorder (ADD) hyperkinetic children. Side effects are observed in about one of eight children so treated and included anorexia, nervousness, irritability, insomnia, and stomachache or abdominal pain. Schnackenberg (1973) reported in the American Journal of Psychiatry that positive effects were seen when two cups of coffee were taken rather than the usual drugs, dextroamphetamine and methylphenidate (MP). The children said that the coffee made them feel better; it "calms me down." Both teachers and parents evaluated the children; the teachers not knowing when children were off treatment. A rating scale for hyperkinesis devised by Davids was used. The score, when the children were on MP, was 17.2; when children were off the drug without coffee, the score was 25.9; and the score was 16.87 when coffee was used ·without

drug. The children were on the coffee regimen for an average of 6.2

months. No side effects were observed and 200-300 mgs. of caffeine

appeared to work well (2-3 cups of coffee). The conclusion was that caffeine, considered a safer alternative, works as well as MP with less side effects and less cost. Also, the long term effects of MPhave yet

to be established. This study was repeated, supposedly in a more rigid well-controlled manner by Garfinkel et al. (1975), using MBDchildren as the subjects. Garfinkel's study was double blind, comparing the effects of MP, caffeine, and a placebo on the behavior of the children. Eighteen 51 children with MBDwho had the following characteristics were tested: hyperactive, short attention span, impulsive, affective disturbance, and poor school performance. They were all boys with an IQ greater than or equal to 90. The first two weeks of the study no medication was given; then six weeks of medication was given (except _weekends); then there was a week of no medication. All drugs (160 mgs. caffeine, MP, and placebo) were added to decaffeinated coffee taken twice a day. The Connors

Teacher Rating Scale was used to evaluate the children's behavior. This measures five factors: aggressiveness, inattentiveness, anxiety, sociability, and hyperactivity. MP did better than caffeine on all of these factors. Also, MP was better on a matching test, the Kazan

Matching Familiar Figures Test. MP was particularly better on the aggressiveness and hyperactive factors. Caffeine, however, showed no side effects at the dose of 160 mg.

These children were more aggressive than hyperactive. The condition has been considered to be due in part to catecholamine "deficits in dopaminergic pathways," chemical mediators of nervous activity. The

author of the article notes that caffeine does not exert its

physiological effect in this matter and this fact may account for its

lack of effect in his study. Finally, it is of interest that this study,

which showed caffeine ineffective in this condition, was sponsored by

General Foods, the largest coffee marketer in this country.

Firestone and associates (1978), in a study funded by the Ontario

Mental Health Foundation, showed a significant improvement with 52 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 mgs. of caffeine, and 20 mgs. of methylphenidate. This was a carefully controlled study consisting of 17 boys and four girls. In 1978, Firestone did a study comparing 300 mgs. 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. Gross (1975) published an article on this subject in the journal, Psychosomatics. He compared placebo, caffeine, Ritalin (MP), dextroamphetamine, and imipramine (an antidepressant drug). This study was not double blind and the experimental design was deficient; drugs were given to the children in one order. Gross reported that caffeine actually made the children worse rather than better. Amongthe 25 children in the study, none were improved on the caffeine and more were "wound up, noisy, loud, jumpy, and silly." The other drugs showed some improvement based on observations of mothers and teachers. Caffeine did not show activity in 26 minimal brain dysfunction children based on six psychological ratings compared to placebo and

-~ 53 methylphenidate or dextroamphetamine. Caffeine showed cardiovascular

side effects and weight loss (Arnold, 1978).

In another report on hyperkinetic children, coffee was found to be

slightly less effective than thioridazine and obviously less effective

than dextroamphetamine. In 1977, Reichard and Elder published an article on caffeine's

effect on reaction time in hyperkinetic children. It is noted that some

of the other drugs used in this condition may inhibit growth and it was

concluded that caffeine has potential use in the treatment of these

children. Although the stimulants which are used, paradoxically, seem to

slow down the children, it may actually be working by increasing their

attention span. David's Hyperkinetic Scale was used on the children.

They also tested simple reaction time and choice reaction time •

. Initially, no drug was given (a fruit drink), followed by a drink with

about 165 mgs. of caffeine.

Caffeine increased the accuracy of stimulus identification and

processing of 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. Many hyperkinetic, in general, 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. The worse the condition of the children, the more

improvement as a result of caffeine was seen. Thus, it worked better for

the hyperkinetic children than for the normals. The authors hypothesized 54 that caffeine "filters out irrelevant material"; there are fewer attention lapses.

At higher doses of caffeine, about 300 mgs. or more, side effects were noted such as "hand tremors and unsteadiness." This result was seen in both hyperkinetic and normal children. MP was given to three children after the completion of this test and they showed faster reaction time than controls, but the results were not more accurate. The author suggests that caffeine may be a potentially valuable therapy in the treatment of hyperkinetic children.

The authors note that other studies have shown methylphenidate was more effective than caffeine in controlling certain aspects of clinical behavior (impulsivity and hyperactivity). This result does not contradict those obtained in the study; they are compatible.

The use of caffeine in the treatment of hyperkinetic children remains unresolved at this time.

Restless Legs, Anxiety, and Caffeinism

Restless legs is a syndrome which may be associated with anxious-depressed as well as other clinical states. Dr. Lutz (1978), in an article, 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 55 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. But, there were many changes and other introductions at that same time. 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.

Recent studies have shown that IgE mediated immune mechanisms do not explain many food reactions (American Academy of Allergy, 1980; Kniker and Rodriguez, 1985).

Another area of harmful caffeine effect are those related to early pregnancy. Hughes and Goldstein indicated that there are possible adverse fetal effects of exposure to caffeine during the first 4 months of pregnancy. At birth the infant showed evidence of early arrested cerebral maturation and paraplegia. 56

Caffeine and Genetics

Propanolol and caffeine are known to cross the placental barrier and

will produce pharmacological effects in the fetus. In general, caffeine

is a smooth muscle relaxant and vasodilator. However, it appears to

exert a constrictor effect on human cerebral vasculature. Thus, it is

reasonable to speculate that the synergistic effect of caffeine and

ergotamine could result in a more pronounced vasoconstriction of the

cerebral vessels. The present case suggests the need for caution in the

use of combined vasoconstrictive agents for the treatment of migraines

·during pregnancy. Therapy with ergotomine combined with caffeine or beta

blocker agents increased risk for malformation with a vaso-occlusive

aetiology.

Case Study. A caucasian female , product of a first pregnancy,

unremarkable family history, however, mother treated for migraines during

pregnancy with ergotamine and caffeine. Infant was breech, clinically

microencephalic, paraplegic, sensation absent in knees and thighs, etc.

Spinal cord lesion.

The co-occurence of the brain abnormality and cord lesion could be

accounted for by a vascular disruptive mechanism. It is significant that

the infant was exposed to ergotamine, caffeine, and propanolol during the

first 14-20 weeks of gestation.

With a review of the literature, we see the wide effects of caffeine

on humans and animals. Now it is necessary to choose specific problems

and to select appropriate research methodology. 1

II 57

Bronchogenic carcinoma is closely associated with cigarette smoking although additional environmental or individual factors might regulate a person's susceptibility to that disease. To further define such risk factors, the prevalence of the genetic debrisoquine 4-hydroxylation deficiency was determined before therapeutic intervention in 270 lung cancer patients. Nineteen homozygous carriers of this defect (poor metabolizers) were found (7.0%, 95% confidence limits 4.3%-1 0 .8 %), a number being lower than 30 out of 270 reference patients (11.1%, 95% confidence limits 7.8%-15.5%). The odds ratio of 0.81 was of marginal statistical significance (P = 0.067). Subdividing the collective according to histology revealed a trend towards underrepresentation of poor metabolizers especially among patients with adenocarcinoma (1 out of

37, P = 0.086) and among young patients not older than 50 years (none out of. 32, P = 0.028). All poor metabolizers (PMs) in the cancer gro up were smokers. In 18 patients the phenotype assignment was confirmed _ by a second test several weeks after surgical or other treatment. In 220 of the lung cancer patients the N-acetyltransferase · polymorphism was evaluated by means of the molar ratio of 5-acetylamino-6-formylami no- 3- methyluracil and 1-methyixanthine in urine after ingestion of caffeine

(coffee). There were 111 (50.5%) slow acetylators and 109 (49.5%) fast acetylator s. A statistically significant clustering of either phenotype after stratification according to histology, or debrisoquine hydroxilator status was lacking. Moreover, there was no difference in the ratio of

both phenotypes as compared to the reference collective of 245 patients 58

(53.5% slow and 46.5% fast acetylators). As a third genetic host factor the ABO blood group frequencies were evaluated in 283 lung cancer patients. The frequency ratio of A/0 was sign ificantl y higher as compared to 41,423 blood donors (odds ratio 1.37, 95% confidence limits

1.02-1.84, Pless than 0.05). A/0 tended to be especially high in young patients not older than 50 years. The ratio B/0 in bronchial cancer was significantly higher than expected. The results sugges t that the debrisoquine hydroxilator status might have an impact on an individual's susceptibility to lung cancer. This association is either a weak one and/or is restricted to certain histological cancer types or to patients with certain characteristics. The acetylator phenotype could not be established as a risk factor, whereas ABOblood groups weem to influence lung cancer susceptibility.

SOS-ind ucing activity of UV or chemical mutagens (AF-2, 4NQO, and

MNNG)was strongly suppressed by instant coffee in Salmone lla typhimurium

(TA1535/pSK1002). As decaffeinated instant coffee showed a similarly strong suppressive effect, it would seem that caffeine, a known inhibitor of SOS responses, is not responsible for the effect observed. The suppression was also shown by freshly brewed coffee extracts. However, the suppression was absent in green coffee-bean extracts. These results suggest that coffee contains some substance(s) which, apart from caffeine, suppresses SOS-inducing activity of UV or chemical mutagens and that the suppressive substance(s) are produced by roasting coffee beans. 59

The intent of this study was to investigate the role of inheritance in the determination of susceptibility to methylxanthine-induced behavioral changes. Two strains of inbred mice, SWRand CBA, which differ significantly in their response to caffeine- and theophylline induced stimulation of locomotor activity, were used in classical genetic crosses to produce reciprocal Fl hybrids, reciprocal backcross progeny F2 progeny. Theophylline dose response curves in the reciprocal Fl hybrid strains were identical to each other and to their methyixanthine responsive (CBA) parent. These results indicated that theophylline responsiveness behaved as a simple autosomai dominant trait. Behavioral responses of these Fl hybrid strains to caffeine showed the same maximal enhancement of locomotor activity as their CBA progenitor at a dose 10 mg/kg IP, but locomotor activity stimulation also occurred at 32 mg/kg

IP, a dose which inhibited their CBA parent. These data suggest that the genes specifying caffeine responsiveness differ from those encoding theophylline responsiveness. For both caffeine and theophylline, behavioral phenotypes and their expected frequencies of occurrence among backcross and F2 progeny differed significantly from the segregation ratios expected for a trait determined by a single gene. These non

Mendelian segregation ratios suggest that locomotor activity stimulation by both of these methyixanthines is polygenically determined. It was anticipated that the same genetically encoded neurochemical mechanism would underlie the difference in behavioral response to the two methylxanthines. However, no significant correlation between caffeine- 60 induced and theophylline-induced stimulation of locomotor activity was observed among progeny derived from backcrosses of Fl self-crosses.

I have presented some diverse papers which illustrated several problems with caffeine use. A study of caffeine metabolites revealed two kinds of interethnic variation, one pertaining to the wel l-known acetylation polymorphism affecting the secondary metabolism of the parent drug; the other consisted of a difference in paraxanthine excretion which might indicate an ethnic difference in renal function. Older data on the pharmacokinetics of the antihistaminic drug diphenhydramine also suggested interethnic variables in the fate of the drug w~ic h do not necessarily involve metaboiizing capacity. In short, pharmacokinetic factors other than metabolism may make additional contributions to ethnic differences in drug response. Studies of taste and smell are not only models of receptor variability but they may be used to reveal underlying biochemical differences. Furthermore, a polymorphism in . tasting ability constit uted an epidemiological risk factor for thyroid disease which was greate d enhanced in the presence of an appropriate human leukocyte antigen (HLA, histocompatibility gene). It is clear that the HLA complex will have to be increasingly considered in relation to pharmacological responses. Variabilities of superoxide dismutase and of various enzymes involved in heme production were described briefly because of their inherent or historical interest. In each case, however, the occurrence of variants was confined to small population groups as an expression of 61 founder effects and regional polymorphism. Several other instances of ethnic differences in drug response were merely cited.

Interest has recently gr own in the possible ro l e of chromosomal fragile sites as factors predisposing to chromosome rearrangements characteristic of specific human cancers. Data from two series of experiments relating to this hypothesis are presented. First, the effects of caffeine and theophylline on expression of the fragile X and common fragile sites was studied in lymphocytes from three subjects.

Caffeine and theophylline did not enhance fragile X expression under the conditions employed, but did greatly enhance expression of the common fragile sites. Second, three patients with acute nonlymphocytic leukemia-M4 and inv(l6)(p13q22) in leukemic cells were tested for the presence of fra(16)(q22) in normal cells. The fragile site was not seen in any of the patients in this study. CHAPTER3 RESEARCHMETIIODOLOGY OF THE SELECTED PROBLEM

General

Caffeine is probably the most widely used drug in the world. Its ubiquitous use is accepted because caffeine is usually thought of as benign or at least exhilarating. In fact, caffeine is not innocuous. It is a potent drug, and excessive or sustained use can lead to adverse physiological and psychological effects. Studies of these effects have been reported in the medical and scientific literature for many years as presented in Chapter 2 of this study. Some of these reports are anecdotal. More recently, many scientific, controlled studies have been published. As the potential for the adverse effects of caffeine become more apparent, more effort is being devoted to document its activity.

Perceived psychological effects are difficult to quantify or calculate. Goldstein (1969) has published several studies in which reactions to caffeinated and decaffeinated coffee were assessed in both caffeine and non-caffeine users via extensive · questionnaires. The reactions depended on previous caffeine habituation and use. Heavy users had less effects on sleep, irritability, and nervousness.

Caffeine ingestion stimulates many bodily responses, some of which are opposite in direction. For example, after ingesting caffeine, the heart rate is initially decreased, and then increased about an hour after intake .

------~ 't_ I :• 'C', 1• !:_ ,.. ,,' • • •• • ;f • a-('-, •• ;•. • • • • -...,.,,_, • • • -

In some persons, the drug may also promote increases in serum lipids and glucose, probably through catecholamine mediation. However, in individuals disposed to . hypoglycemia, a rapid elevation in blood glucose prompts an insulin response, which may then lower the blood glucose to comfortable levels about two or three hours following intake of caffeine. (Ritchie, 1975)

Subjects with high levels of caffeine ingestion may, in part, enjoy

the effects of the drug which is stimulating their otherwise

under-functioning adrenal glands.

Previous experimental work has shown that caffeine increases the

output of epinephrine and norepinephrine from the adrenal glands

(Ritchie, 1975). In the present study, this effect of caffeine was measured by physical examination and urine sodium levels in the

experimental subjects.

Another objective of the study was to verify the effects of caffeine as an anabolic agent. According to Dr •. Emanuel Revici, certain

physical-chemical properties of urine are indicators of the anabolic or catabolic effect of drugs and nutrients.

Research Design

Caffeine is a potent pharmacologic and psychotropic agent. Many studies in both animals and humans have been performed in order to qliantify and characterize its physiological and psychological effects.

The research presented in this dissertation consists of two kinds of observations resulting from consumption of a caffeine beverage during a second week: (1) effects on adrenal function determined by a medical ••• • • • •,... -. •. ,, ,; •, -•r .. ,' •..: ."• \. • , •

64 examination; and (2) physical-chemical measurements of urine, an indication of the anabolic effect of caffeine according to a theory proposed by Dr. E. Revici. In addition, perceived psychological effects of caffeine were studied by means of a questionnaire and daily diary.

Research Methods

Subjects

A. One group of subject volunteers had been drinking the equivalent of at least three cups of coffee per day (approximately 150 mg. of caffeine from all sources, including tea, caffeinated soda, and chocolate). This level of caffeine consumption was for at least one year. Eleven such subjects completed both the first week of decaffeinated tea and the second week of return to the caffeinated tea beverage. Six other chronic caffeine users who started the study dropped out during the first week. Th~ policy was to advise these subjects who were uncomfortable that they, in fact, were drinking decaffeinated tea.

Those who dropped out returned to their usual caffeinated beverages.

These subjects ranged in age from 25 to 75 years.

B. A second group of subject volunteers who had a history of no caffeine consumption, ingested no caffeine. Six such subjects completed both the first week of caffeinated tea and the second week of decaffeinated tea. Five other non-caffeine subjects who started the study dropped out during the first week. They stopped because they were uncomfortable. These subjects ranged in age from 25-65 years. 65

The tea bags given to all subjects were identical in appearance and flavor. Tetley tea manufactures a standard caffeinated tea and a decaffeinated with the same appearance and flavor. The subjects were never informed as to which tea they were issued.

The subjects were instructed to steep the tea by placing the bag in a cup and pouring boiling water over the tea bag, filling the cup. The tea bag was to be removed after three minutes.

Two separate studies were conducted:

In Study ·A, eleven (11) chronic caffeine users brewed and drank five cups of decaffeinated tea per day for one week. They returned at the end of Week 1 and were re-examined via the Ragland Postural Blood Pressure

Test (Burch and de Pasquale, 1962) and had their urine analyzed via the

Koenigsburg Test (Brooks, 1925) for Urinar y Sodium-Chloride Excretion and the Revici Anabolic/Catabolic Index (1961). They were then given thirt y-five tea bags from which to brew fi ve cups of caffeinated tea per day for a second week. At the end of this week, the blood pressure and urine measurements were recorded.

In Study B, six (6) non-caffeine users brewed and drank five cups per day of caffeinated tea during the first week and were switched to decaffeinated tea during the second week.

Adrenal Function

In addition to the data supplied by the diary, subjects were given a physical-medical examination to as~eS$ adrenal function prior to and after each week of the study. According to Goodman and Gilman, caffeine 66 stimulates "the release of catecholamines from the adrenal medulla."

Caffeine also releases catecholamines due to a central action and by affecting C-AMP.

Adrenal function was tested via the:

1. Ragland Blood Pressure Test

2. Koenigsburg Urinary Sodium and Chloride Excretion

Various responses were observed for 17 subjects during a two week period. Each subject participated in one week of caffeine intake (150 mg daily) from tea and one week of consumption of an otherwise identical non-caffeinated tea.

A Medical Evaluation Which Focused on Adrenal Gland Status

The tests for adrenal function included the following:

1. Ragland Blood Pressure

2. Koenigsburg Test for Urinary Sodium-Chloride Excretion.

Ragland Postural Blood Pressure Test: Method and Physiologic Basis (Burch and de Pasquale, 1962):

This test is a means of evaluating adrenal activity. It detects

diminished adrenal function. Method: The difference of the systolic blood pressure measured with

the patient in the supine position and in the erect, or standing,

position, · is an -indication of adrenal function. The patient lies supine

for four minutes. The blood pressure is taken in this position and

immedia_tely after the patient stands up. 67

Upon arising from the supine position and standing erect, the normal subject has a rise, or elevation, of the systolic blood pressure. The systolic pressure usually rises approximately 5-10 mm mercury, since the cardiovascular system must pump blood to the head against the force of gravity, higher blood pressure is required .

When diminished adrenal function is present, the systolic blood pressure taken in the erect, or standing, position may actually fall.

The degree of lowering of the erect blood pressure gives some indication of the magnitude of diminished adrenal function.

Adrenal glands have a major role in controlling the tone of the splanchnic veins. These veins do not have valves and are dependent upon nerve function.

Ioenigsburg Test for Urinary Sodium-Chloride Excretion (Brooks, 1925):

The adrenal gland produces aldosterone, which instructs the kidneys to retain sodium. If adrenal gland function is diminished, aldosterone production is decreased and salt is spilled into the urine.

Method: The Koenigsburg Test is a titration procedure. Ten drops

of urine are placed in a test tube. One drop of 10 percent potassium

chromate solution is added to the urine. 0.74 percent silver nitrate

solution is added dropwise until the color of the solution turns brick

red. The number of drops required for subjects with normal adrenal

function is about 25. Excessive sodium and chloride in the urine will

require more silver nitrate reagent to turn the solution brick red. 68

Psychologi cal Effects

In addit i on to keep i ng a daily diary, subjects were requested to answer a questionnaire prior to, and after each week of the s t udy, as fo ll ows:*

1. Did you fee l stimulated?

2. Did you feel tired?

3. Did you drink more coffee, tea, or cola tha n usual? 4. Did you fee l al ert? s. Did you have headaches? 6. Were you nervous or anxious?

7. Did you have:

a. insomnia?

b. -difficulty falling asleep?

c. Diff i culty staying asleep?

8. Did you have stomachaches? 9. Did you feel depressed? 10. Did you feel "good" (a feeling of well-being?) 11. How was your appetite?

12. Did you notice anything different from usual? (Non-smokers only). If "yes," explain. 13. Did you notice anythi ng different from usual? (Smokers only)

If "yes," explain. 14. For smokers only: Cigarette use per day - __ cigarettes.

* See Appendix for the actual form used. 69

Urine Measurements (Revici Anabolic/Catabolic Index)

Urine samples were analyzed prior to the study and after each of the

two study weeks to determine specific gravity, surface tension* and pH.

These results were combined to form an index to describe the

catabolic/anabolic effect of the drug.

According to Dr. E. Revici, the best indication of catabolic/ anabolic effect is measured by a composite index of the urine measurements as follows:

Index= 1 = 2(74 - s.t.) +pH+ last t..u digits of s.g .

pH = aJ.ka.lire = 5

pH = neutral = 10

pH= acid= a:)

For example, if s.t. = 70, pH= acid and s.g. = 1.016, the index is

2(74-70) + 20 + 16 = 44 (see Discussion) .

Having outlined the research methodology, it is now necessary to review the results and discuss the projects.

Statistical Methods

Three statistical procedures are used in this experiment--correlated

t-tests, t-tests for independent groups, and Pearson Correlation

Coefficients:

*Revici urotensiometer. 70

1. Correlated t-tests are used when the same subjects are compared on two occasions, e.g., "Pre" test status and then at the end of week 1.

The t-ratio comparing the two means is used as a measure of significance based on a pre-determined significance level.

2. The t-tests for independent groups are utilized when two independent groups are compared, i.e., caffeine group versus no-caffeine group. The t-ratio indicates whether the two means are statistically different.

3. The P~arson correlation coefficient indicates the amount of linear relationship between two variables, with the coefficient ranging between +1.0 and -1.0 with O indicating no relationship between the two variables. For example, this coefficient was used to indicate the degree of relationship between BP and sodium secretion.

The level of significance in behavioral research is usually set at

.OS. A one-time test is presented to indicate possible trends.

-. ---~ ~ CHAPTER4

RESULTSAND DISCUSSION

Previous experimental work has shown that caffeine increases the output of epinephrine and norepinephrine from the adrenal glands (Goodman and Gilman, 1975). In the present study, this effect of caffeine was measured by physical examination and urine sodium levels in the experimental subjects.

Various responses were observed for 17 subjects during a two-week period. Most subjects participated in a week of caffeine intake (175 mg daily) from a caffeine tea, and a week of consumption of an otherwise identical non-caffeinated tea. ·

TABLE3. SUBJECT PARTICIPANTINFORMATION

Non-caffeine participants 7, 8, 9, 10, and 11 dropped out, as follows:

Subject Age Sex Days in Study Reason for Withdrawal

7 27 F 6 Irritable 8 32 M 7 Stomach upset 9· 37 M 6 Overstimulated 10 29 F 7 Irritable 11 41 M · 7 Headache

71 72

These five subjects dropped out since they were uncomfortable. Even though we explained to them that the caffeine week was nearing its end and that the next week would be the converse; namely, the decaffeinated tea, they were still reluctant. Some were fearful that they might continue to receive some caffeine despite our explanation. It is of interest that the desire to avoid caffeine was so strong in these subjects.

Each participant in the caffeine experiment completed daily diary

sheets which are represented in Appendix B. Dr. Feldman and I were very

specific and exacting in our instructions for patient compliance. An

example was that each patient was interviewed on a nearly daily basis by

phone and once a week in the office. We would ask them, "Have you

complied exactly?" Six non-caffeine users and eleven (11) caffeine users

maintained the strict research protocols to the end. All of the N.C.'s

from all sources of caffeine, including chocolate, beverages, and

medicines. There were at least 13 of the caffeine-consuming participants

(chronic caffeine users) were disqualified during the experiment because

of non-compliance. Of the non-caffeine participants, five withdrew by

day six or seven (the later stages of the experiment) and eleven by the

third day. Comparisons of the amount of sodium and chloride in the urine serve

as an indirect reflection of aldosterone level and thus, indirectly,

adrenal function. . . ·... . • . ' .. i- • . . : - • ; . . (• .. -(- :-· . • ,:- . .. ' ~·

MEDICALEXAMINATIONS

BLOODPRESSURE, SODIUM SECRETION, AND ADRENAL STATUS

CAFFEINECONSUMERS

Blood Pressure

Introduction

During the pre-test examination, C-1 had a supine blood pressure of

110/70, which fell to 80/50 when rapidly standing erect. The important data is the change between the systolic blood pressure (the upper-higher number) when standing versus lying down (supine). Since in the normal subject the systolic pressure should rise when standing erect, the usual difference between standing minus supine is a positive number. Since C-1 had a drop of systolic reading from 110 to 80, we generate a -30, which is the mathematical data placed in Table 4. This table, BLOODPRESSURE,

SODIUMSECRETION, ANDADRENAL STATUS OF CAFFEINECONSUMERS AFTER WEEK 1,

summarizes the presentation of all blood pressure data.

Since we compared the blood pressure when standing erect with that

of the supine position, a negative value reflects a fallen blood pressure

upon standing. The more negative the number, the greater the drop in

blood pressure and thus the greater abnormal or weakened adrenal

function. TABLE 4. BLOODPRESSURE, SODIUM SECRETION, AND ADRENALSTATIJS OF CAFFEINE CONSUMERS. WEEK.1 THESE SUBJECTSRECEIVED NO CAFFEINE, WHILE WEE( 2 TIIEYCX>NSUMED 5 ruPS OF CAFFEINATEDTEA DAILY.

Blood Pressure Standing minus Supine Sodium Secretion Adrenal Status SubJect Coe End of End of End of End of End of End of "Pre" Wk 1 Wk 2 "Pre" Wk 1 Wk 2 "Pre" Wk 1 Wk 2

C-1 -30 -14 -8 60 52 48 Severely lml_)roved; Weakened but Low Still Low better than pre C-2 -2 -0 -3 2_8 26 31 Normal About same Almost same C-3 -4 -9 +2 27 32 25 Mildly Slightly About same Low Worse C-4 -20 -40 -10 58 65 34 Severely Mildly Better than Low Worse Pre C-5 -12 -25 -19 48 56 51 Mildly Slightly About same Low Worse as Pre C-6 -22 -16 -10 41 35 29 Severely Slightly About same Low Better C-7 -2 -5 -6 29 31 32 Slightly Almost same About same Low C-8 -6 -9 -12 35 27 37 Slightly About same About same Low C-9 -10 - 6 -4 30 26 28 Slightly About same About same Low C-10 -20 -5 -16 62 45 53 Severely Improved Back to Pre Low Status C-11 -5 0 -2 32 28 33 Mildly Improved Mildly Low Low

-132. 99 -1 29.0 0 -88.00 450.00 422.95 400.99 ...._, Mean - -12.09 - 11. 72 -8.01 I 4o.9o 38.45 36.45 1 ~

T-Test T-Test ~ ' .... ~;...... :':: _,.,. . -~ ~ '~ .. '......

Comparison of Means

Results: Each individual's score was· added to produce a sum divided by the number of subjects, producing a mean value. The comparison of these means for the "Pre," End of Week 1 and End of Week 2 are shown in

Table 5. The statistical analysis is illustrated in detail as the

CORRELATEDT-TEST COMPARINGTHE MEANSOF BLOODPRESSURE OF CAFFEINE

CONSUMERS(Table 5).

Two findings which were of interest although not statistically significant at the .OS level were: 1) the difference between the blood pressure End of Week 2 versus the "Pre" blood pressure and 2) the blood pressure Week 2 versus the blood pressure End of Week 1.

The mean for the blood pressure "Pre" was -12.09 with a standard deviation of 9.51. The mean for blood pressure after Week 2 was -8.00 with a standard deviation of 6,245. The mean difference score was -4.09 with a T-ratio of -1.57, thus the probability was equal to .147 for a

2-tail test of significance. Similarly, the mean for blood pressure End of Week 1 was -11.72 while at the End of Week 2, it was 8.00. The mean difference score was -3.72 with a T-ratio of -1.17, thus the probability was equal to .271 for a 2-tail test of significance or . 136 for a 1-tail test of significance.

Co11111ent: Since the blood pressure means at End of Week 1 versus End of Week 2 were less negative, this reflects a slight impro vement in blood pressure readings. This improvem~nt indicates better adrenal function.

Reintroducing caffeine after a week of abstinence improved adrenal DOE 5. ClERlll.A1E>T-nsf

ARD(; 1JE flW6 CF RilD ~ At1>™1t ~ CF CAFFEll£ CllfDE5 "Pl~' VFISE \IIH. 1. ~• VBSE YH:2. Nl)lifB l VEJB.6\HX 2.

Nunrer Standard Standard (Difference) Standard Standard 2-Tail T Legrees of 2-Tail 1--Tail Variable of Cases ~ ~viatioo &ror ~ ~viatioo &ror C.orr. Prob. Value Freedan Prob. Prob.

BP''Pre" -12.<1.m 9.513 2.868 11 - .3@6 10.828 3.265 •.'.n> .112 - .11 10 .914 .457 BP\..Kl -11.7273 11.884 3.583

BP' 'Pre" -12.<1.m 9.513 2.868 11 -4.c:n:E 8.619 2.5"1 .465 .1.50 -1.57 10 .147 .074 BP\..K2 - 8.CXXX)6.245 1.883

BPW

SS ''Pre" 40.so:Jl 13.736 4.142 11 2.4545 7.515 2.266 .851 .001 1.08 10 -~ .152 ss wa. 38.4545 13.779 4.155

SS ''Pre" . --40.so:Jl 13.736 4.142 11 4.4545 8.7:fJ 2.640 .773 .005 -1.59 10 .122 .CX>l ss \,,K2 -36.4545 9.720 2.931

SS \..Kl 38.4545 13.779 4.155 11 2.cx:ro 11.234 3.387 .5 .0:fJ .59 10 .568 .284 ss \,,K2 36.4545 9.720 2.931

l ~ 77

function. Also when comparing adrenal status End of Week 2 with the ad renal status "Pre," there was a slight but not significant improvement.

Since caffeine abstinence seemed to improve adrenal function slightly, one could hypothesize that the adrenals had a rest period. The striking improvement after caffeine is reintroduced evidently shows that caffeine has the ability to strengthen the adrenal function . Since the subjects had weakened adrenal function in the "Pre" state, we can only conjecture that after more than one week back on the caffeine, they might in time return to the pre-adrenal ("Pre") state. See Table 6 depicting

THE COMPARISONSOF BLOODPRESSURES OF CAFFEINEUSERS END OF WEEK2 (BACK

ON CAFFEINE) VERSUSSTATUS "PRE" (NORMALCAFFEINE STATE).

Comparison of Subjects to Themselves

Results: Each subject's blood pressure "Pre " versus End of Week 2 was tabulated and the difference computed · as s_een in Table 6.

When comparing each person's data across time as computed to averaging all subjects, we noted that six subjects had differences of -4 to +6 where an improvement would generate a positive number (C-2, C-3,

C-7, C-9, C-10, C-11). Three subjects had improved readings of +10 to

+22 (C-1, C-4, C-6). Two sub j ects had numbers of -6 or -7, which was a worsened adrenal state.

Comments: Those subjects that improved the most (C-1, C-4, C-6) showed the most aberrant negative blood pressure readings in the "Pre" 78 TABLE6. C

About the Same Week 2 versus "Pre"

Difference Pre Week 2 Week 2 vs. "Pre" C- 2 - 2 - 3 -1 C- 3 - 4 +2 +6 C-7 -4 - 6 - 4 C-9 - 10 - 4 +6

C-10 -20 - 16 +4

C-11 -5 -2 +3

Improved Week 2 versus "Pre" Difference Pre Week 2 Week 2 vs. "Pre"

C-1 - 30 -8 +22 C-4 -20 - 10 +t o C-6 -22 - 10 +12 Adrenals Worse Week 2 versus "Pre" Differe nce Pre Week 2 Week 2 vs. "Pre" C- 5 -12 - 19 -7 C- 8 - 6 -12 - 6 79

state. The two subjects (C-5, C-8) who were worse had no specific profile in the "Pre" state.

Each subject's blood pressure was also analyzed as THE COMPARISONS

OF BLOODPRESSURE OF CAFFEINEUSERS ENDOF WEEK1 (OFF CAFFEINE) VERSUS ENDOF WEEK2 (BACKON CAFFEINE) (Table 7).

Results: Similar results to Table 6 were found when comparing End of Week 1 versus End of Week 2. Eight subjects (C-1, C-2, C-5, C-6, C-7,

C-8, C-9, C-11) had a difference of -3 to +6. Two had improved from +11 to +30 (C-3, C-4). One subj~ct worsened (C-10) with a difference of -11.

Comments: Thus, reintroduction of caffeine in chronic caffeine users, in general, showed very little change. Eight subjects were about the same, three were improved, and one was worse. Thus, the chronic caffeine group showed little change via the reintroduction of caffeine.

Sodium Secretion

Introduction

During the pre-test examination, C-1 required 60 drops of 0.74 silver nitrate solution added drop-wise until the color of the solution turned brick red. The number of drops required is proportional to the quantity of sodium and chloride in the urine. The same method of drop titration was used on each urine sample so that the number of drops is proportional to the sodium and chloride of all subject titrations.

Please note that 60 drops is a very high reading and represents a high amount of spillage of sodium and chloride into the urine. Table 4, BLOOD 80 TABLE7. C01PARISONSOF BLOODPRESSURES OF CAFFEINEUSERS END OF WEEK1 (OFF CAFFEINE)VERSUS END OF WEE[ 2 (BACKON CAFFEINE).

About the Same End of Week 1 versus End of Week 2

End of End of Difference Week 1 Week 2 End Week 2 vs. End Week 1

C-1 -14 -8 46 C-2 -0 -3 -3

C-5 -25 -19 +6 C-6 -16 -10 +6

C-7 -5 -6 -1

C-8 -9 -12 -3

C-9 -6 -4 +2

C-11 0 -2 -2

Improved End of Week 1 versus End of Week 2 End of End of Difference Week 1 Week 2 End Week 2 vs. End Week 1

C-3 -9 +2 +11

C-4 -40 -10 +30 Work End of Week 1 versus End of Week 2 End of End of Difference Week 1 Week 2 End Week 2 vs. End Week 1

C-10 -5 -16 -11 81

PRESSURE,SODIUM SECRETION, AND ADRENAL STATUS OF CAFFEINECONSUMERS, summarizes the presentation of all sodium secretion data. THE CORRELATED

T-TEST, shown in Table 5, COMPARINGTHE MEANSOF SODIUMSECRETION OF

CAFFEINECONSUMERS is a statistical evaluation of significance of the results.

Results: The only significant correlated T-test numbers were sodium secretions End of Week 2 versus the "Pre" test. End of Week 2 had fewer drops of solution and thus, less sodium secretion. The mean "Pre" was

40.90 with a standard deviation of 13.73. The mean End of Week 2 was

36.45 with a standard deviation of 9.72. The mean difference score was

4.45 with a T-ratio of 1.59. The probability was equal to .122 for a

2-tail test of significance of .061 for a 1-tail test of significance.

Comments: Thus the analysis of adrenal function via sodium secretion yielded results very similar to the blood pressure data.

Figure 1, SODIUMSECRETION OF CAFFE~NECONSUMERS, shows the bar representation of data in Table 6.

- .. b -- 7U

50 1} .;..#/JI

llll.-.J~-.;I'{j: --, I 40 I Ii PRE-TiliST ~ I VAL ;~ . i ~ - " :lt:t..'. ,·-< i II I-IEE:!< _j 30 B IIEEK '2 ti [ii I 'i~..' 20 · 3J &-".· ~~,

rn~Ii· 10 ,li:~:.j j!: :..r:~~,.·- ; ~L. " . ,illlm..:J~ C.l C.5 q; c:r c.o C 'J CJ0 C 11 SODIUM [XC"ETlOff

FIGURE 1. SO0lllH SECRETION OV CAFFEINE CONSUHERS- DAR REPRESENTATIONOF DATA LN TAIH.E 4.

().) N TABLE8. BLOODPRF.sSURE, SODIUM SECRETION, AND ADRF.NAL STATUS OF NON-CAFFEINECONSUMERS. WEEK 1 TIIESE

SUBJECTSRECEIVED 5 CUPSOF CAFFEINATEDTEA DAILY, WIITLE WEEK 2 THEYCONSUMED NO CAFFEINE.

Blood Pressure Standing Minus Supine Sodium Secretion Adrenal Status Subject Code End of End of End of End of End of End of "Pre" Wk 1 Wk 2 "Pre" Wk 1 Wk 2 "Pre" Wk 1 Wk 2

NC-1 +14 0 -2 23 28 29 Normal Weakened Still Weakened

NC-2 0 +20 +20 26 22 25 Normal Normal Normal

NC-3 +10 +2 0 20 26 27 Normal Normal Normal

NC-4 -4 0 0 33 29 30 SL Weak Normal Normal

NC-5 -4 0 -10 20 28 32 SL Weak Sl. Improved Regressed Sl. Weak

NC-6 +10 0 +10 21 26 22 Normal Normal Normal

26 22 18 143 159 165 Mean -______4.33 3.66 3.00 , 23.83 26.5 27 . 5 T-Test · T-Test •~ D11IE 9. CIERfJ.A1EDT-nsT CIWARIK; 1HE M7Nfi SlllJ.M SIDcEl1lfl

Nunber Standard Standard (Difference) Standard Standard 2-Tail T fugrees of 2-Tail 1-!'fail Variable of Cases t1:!an fuviatioo Frror ~ fuviatioo Prror Corr. Prob. Value Freedan Prob. Prob.

BP "Pre" 4.3133 7. 941 3.242 6 .fll57 12.565 5.129 - .236 .653 .13 5 .451 BP~ 3.fll57 8.C¼2 3.283 -~

BP ''Pre" 4.1333 7.941 3.242 6 1.3313 12.628 5.155 .002 .878 .26 5 .oos .Lim BPW<2 3.a:m 10.488 4.282

BPW

SS ''Pre" 23.8133 5.037 2.056 6 -2.fll57 5.279 2.155 .1.50 .776 - 1.24 5 .271 .136 ss~ 26.~ 2.510 1.025

SS ''Pre" 23.8133 5.037 2.056 6 -3.fll57 5.645 2• .Il5 .181 .731 - 1.59 5 .172 .006 ss WK2 27.~ 3.619 1.478

SS W

VI ~ 86

While the mean for the "Pre" blood pressure was 4.33 with a standard deviation of 7.94 after Week 1, it was 3.66 with a standard deviation of 8.04. The mean difference score was .66 with a T-ratio of .13 based on s degrees of freedom. The probability was equal to .902 for a 2-tail test of significance or .457 for a 1-tail test of significance. Thus, there was not a significant difference between these two means. Similarly, the mean difference score comparing "Pre" to Week 2 and Week 1 to Week 2 showed no significant difference.

Comments: Evidently, the introduction and the subsequent cessation of caffeine did not affect the blood pressure of the non-caffeine subjects in any statistically significant manner. It is also apparent that the levels of caffeine present to the non-caffeine consumer for the one week of time did not significantly affect the Ragland blood pressure findings at the end of that week.

Sodium Secretion

Introduction During the pre-test examination, NC-1 required 23 drops of 0.74 silver nitrate solution added drop-wise until the color of the solution turned brick red. The number of drops required is proportional to the quantity of sodium and chloride in the urine. The same method of drop titration was used on each urine sample so that the number of drops is proportional to the sodium and chloride of all subject titrations. Please note that 23 drops is a very low reading and represents a normal 87

amount of sodium and chloride in the urine. NC-1 had normal adrenal status in the pre-test condition.

Table 4, the CORRELATEDT-TE ST COMPARI NG THE MEANSO F SODIUM

SECRETION"PRE" VERSUSWEEK 1, "PRE" VERSUSWEE K 2, AND WEEK1 VERSUS

WEEK2 is a statistical evaluation of significa~ce.

Results: The onl y significant statistical dfrference was the comparison of sodium secretion End of Week 2 when compared to "Pre . "

The "Pre" mean was 23.83 with a standard deviation of 5.02. The mean End of Week 2 was 27.30. The mean difference score was -3.66 wit h a

T-ratio of 1.59; probability was equal to .172 for a 2-tail test of significance of .086 for a 1-tail test of significance.

Sodium secretion of the NC group showed higher values (greater sodium secretion) at the End of Week 1 and Week 2 alth ough the "Pre" to

Week 2 period had greater statistical meaning. Thus, the caffeine during

Week 1 weakened adrenal function but at the End of Week· 2, it was even worse. The five cups of tea a day for one week did affect adrenal function if measured by sodium secretion. The weakened adrenal function was ac t ually more evident at the end of the second week. We have no

hypothesis as to why this occurred. 88

COMPARISONACROSS SUBJECT GROUPS - CAFFEINESUBJECTS VERSUS NON-CAFFEINE SUBJECTS

Blood Pressure

The number representing the difference between standing minus supine systolic pressure as numerically listed in Table 4 is put into a bar chart, Figure 2, with three test numbers for each subject, namely "Pre" test, Week 1, and Week 2. For example, C-1, who had a -30 standing minus supine on a "Pre" test condition has a black bar down to the -30 on the vertical scale in this bar chart. The blood pressure reading at the End of Week 1 was a -14 and is shown by the less black second bar which declines down to the -14 on the scale. The End of Week 2 blood pressure of -8 is likewise depicted by the third downward bar.

Comment: This graphic bar display shows that most of the caffeine

suojects had negative bars. Thus, the caffeine group tends to have weakened ad renal function.

In the NC group, five out of seven had positive numbers during the

"Pre" test (NC-1, +14; NC-3, +10; NC- 6, +10; and NC-2, a zero reading).

Two subjects had negative numbers but only slightly so (NC-4, -4; and

NC- 5, -4). The most negative number in the NC group was NC-5, with -10

at the end of the second week. Figure 3, BLOODPRESSURES OF NON-CAFFEINE

CONSUMERS- BAR REPRESENTATION,illu~trates this data in graphic form.

The .most striking data for the non-caffeinated subjects are the

blood pressure status in the "Pre" state , whereby the most negative 5

. l"IIIJ~l,www.www... lw.uf..-,_j 0 ~-~T'.J·q· -~1111 -10 IMIJW llft!IHN llliffllll~ ~• •lfWI I -: I. Bl ~ 1

f ■PRE-TE~T -15 ~ID k..1:ffl~ lii~1:i:11tmml 111 t~, I UAL IRI ~ leruJ IUR~~I U 1111 l II UEEK 1 I -Z0 -111 -tmffl lftil Ill - t la 1-lEEK 2 Ill mo trua -25

- 30 ·

-35 ...

-40 Cl C2 CJ CJ1 <:.5 C6 C7 ~O C9 C 10 C 11 111,00D PHESSllHE A 00 FIGURE 2. Ul.0011 PRESSURES OF CAFFl•:INI •: CONSUHl~RS - UAR REPRESENTATION OF DATA IN TABLE 4. '° 4 &JIM & HW&?tiiY ... (JI ...J.rJ ~ N X ::r: ~' Ioli ~ ~ 90 =Q,. :l :x • ■ m < :- < Q :.a.. ~ 0 z ~ 0 -:- < -z ::.: Cl) ::.= Qi:: ,..., A ~ ~ Qi:: :II: =<

~ :r. t,;J :a:: ~ c.J - :r: "' ;,') - :r.- c.') z '" ~ 0 - c.,; -'- ::.: c::::a z 0 ::.: 0 :.:.. t"') .. ::.. -- < - :..:i ~ I z ._,,_ z :.:.. 0 :r. N :..: c.J :a:: c:: :r. . :r. a: :.:.: :i::~ A = C<,_ ._, :-. 0 ~ ..:.z <.J =- z. ~ :a: ::ii:: II' :, I =~ I ~ -:a.. ..J <: :> 91

reading was -4 (NC-4, NC-5). The mean "Pre" blood pressure was 4 .33 ' compared to -12 for the caffeine-consumer group.

Sodium Secretion

The sodium secretion by many of the non-caffeine subjects at the

"Pre" level was much lower than for the chronic caffeine users. The highest value of the NC group was 33; of the C group, none had sodium secretion less than 27, and 6 had a number of 35 or higher. Figure 4,

SODIUMSECRETION OF NON-CAFFEINECONSUMERS, graphically shows the sodium secretion levels of this group.

A Combined Adrenal Score Integrating Blood Pressure and Sodium Secretion Data

Introduction

The bars in Figure 5, MEDICALINDEX, WEIGHTEDCOMBINATION OF BLOOD PRESSUREAND SODIUM SECRETION DATA, represents a comparison of "Pre" to

End of Week 1 (black bars) and End of Week 1 compared to End of Week 2

(lighter bars). Caffeine subjects C-1 through C-11 and non-caffeine subjects NC-1 t hrough NC-6 are displayed on the same sheet. Note the NC data is to the far right. In order to combiPe the Ragland Postural Blood Pressure data with the Koenigsburg Urinary Sodium Excretion for each subject at each test sampling, the Ragland · value was mathematically weighted as 3 and the Koenigsburg Urinary Sodium Excretion as 1. This was an arbitrary

-~· ....._ 4~

30 ,J.. li-·i:1 ;. :i ::~ I~ ·· • ';I' , ~:. i l I:. I! ;ilf:r lr~i· i1,~~~~;f;:~\~i~m. '~"1!;t.¼tr -- -- I: i~i{ ~-~; , ·,i.::.. ,q . r~f ■ PRE--V-E~T ii1/ Ii ...: · •• I ~- VOL 20 '.:tj~• J~:. fl ~EEK 1 ,~!l_.F.'. ~~r1~·tW W.!l' 11\1;,,,r.,. ~'~,~ ri1 WEEK 2 -~!:!~~~~ _I ~:j' .=:! ~ :_~ii- . l•F.··=i ~}.I :i- 1A_; I tif►•.L; '"'.,i! ,.;" ;.. ~t :~ j-r:f~ 'it.i:1·.: '·I" . '~;~;.. 10 .t::· I fil ~,·-.111 .lt-1:;~?1 !pl.;:11 iJt: ;I ; • i:r1:1.:..i-: , •. :{,;:11 -:.j1~ .,;] ·f: 'l•! I :;, J'tlit:.,_t • ~I • =.·.C~:lI: w..,... JI •• ~ , ..•1.1, ~.·· • • • '·1 · •ii I 4~/ !:, ~ 1;~:_ !!i'IRJt,C!I~~\~Wi 1iM. I •!W.: ► ':!.1:I!; .;-;~111 t:r.; :r.··-;:- ,, t ·1-.:· ".fffim. - :.~.; . 1i.I/, .,r~, 1 :,qd ~ rl.1::c::· t.{/t ·I'~· .· ...., - · 0 :~ - ;i:'L:J-i NC.I l«..2 M: J AA:.'I NC r:. A/C..,. S 01• I Uti E>CCJU:T1\)11

'°N FIGURE '•. SOil 1 IIM SECRET I ON OF NON-CA FF El NI•: CONSllHl~RS - BAR Rf.PRESENTATION OF DATA IN TAHI.E 8. ~f 40

20 ----

Jg ...... ,. lffli I ■~EEK 1 VAL I

■ WF.EI( 2 0::,-~,_:,_:••1-1 I~ I I . 11 ·r r._ -10 + Ill II IDl IIJ

-20 -

- 30 (,- 1 2 J 4 ~ 6 7 u 9 i 0 11 tic.- I 1.. ~ 'I- 5 . INDEX~

FIGURE 5. HIWICAI. INDP.I, WP.IGIITP.D COHUINAT(ON OF 81.00D PRESSUKE AND SODIUH SP.CKlffATION DATA. HAKS RRl'KESP.NT COHPARISON OF "PKE"TO END OF WP.EK l '°w (Bl.ACK UAKS) ANU P.ND Of' WP.F.Kl COHPAKED TO END OF WF.El 2 (l,lGIITER BARS)

~ -, l

formula. This bar graph (Figure 5) visually compares the "Pre" condition

to Week 1 and Week 1 with Week 2.

The mathematical combining of these indicators gave a positive bar

graph of approximately 19. In other words, C-1 had an improvement in

adrenal function from the "Pre" to the End of Week 1. The second bar for

C-1 with a value of 7 reflects an End of Week 2 blood pressure of -8 with

a sodium secretion of 48 . The -8 was 6 better than -14 and the 48 was 4

better than the 52.

Comparison Across Subject Groups - Medical Index Adrenal Score - Caffeine Subjects versus Non~feine Subjects

When comparing the medical index changes, "Pre" to Week 1 and Week 1

to Week 2 of the C group versus the NC group, there was less change of

the NC's from week to week as compared with the C's.

ANABOLIC/CATABOLICINDEX

Introduction The composite index of urine data is presented in Table 10,

ANABOLIC/ CATABOLICINDEX OF CAFFEINEAND NON- CAFFEINE CONSUMERS"PRE,"

ENDOF WEEK1 ANDEND OF WEEK2. This reflects the body's status with

re gard to its anabolic or catabolic mode. A decline in the index number

re f lects movement in the anabol i c direct i on. Conversely, an increase in

the index is a movement in the catabolic direction. TABLEIO. ANA.BOLIC/CATABOLICINDEX OF CAFFEINEAND NON-CAFFEINE CX>NSUMERS "PRE," END OF WEEKl, ANDEND OF WEE( 2.

S=Alk. Surface Tension pH lO=Neut. SEecific Grav. AC/Index (2-(74-ST)) 20=Acid ( ast 2 Digits) 2x74 - ST+ pH+ SG -- Index Index C 0 L u M N s COLUMNTOTALS

SubJect 1 2 3 4 5 6 7 8 9 "Pre" to "Pre" to Coe "Pre" Wk 1 Wk 2 "Pre " Wk 1 Wk 2 "Pre" Wk 1 Wk 2 1+4+7 2+5+8 3+6+9 Wk 1 Wk 2 -- C-1 16 10 20 10 10· 5 22 26 19 48 46 44 2 2 C- 2 14 8 12 10 20 10 5 10 7 29 28 29 1 - 1 C-3 12 26 14 10 20 5 17 21 20 39 67 39 - 28 28 C- 4 8 6 12 5 20 5 13 16 10 26 42 27 -16 15 C-5 20 10 22 5 10 5 33 14 29 58 34 56 24 -22 C-6 12 10 14 5 10 5 14 10 9 31 30 28 1 2 C-7 14 12 16 10 20 5 18 23 19 42 55 40 -13 15 C-8 14 8 14 20 20 10 13 19 14 47 47 38 0 9 C- 9 . 8 12 12 20 20 10 21 9 16 49 41 38 8 3 C-10 18 16 20 10 20 10 26 20 21 54 56 51 - 2 5 C-11 20 18 22 10 20 5 24 19 23 54 57 so -3 7 1VERAG~ INDEX (C) 43.4 45.7 40.0 -2.4 5. 7 NC-1 -2 4 0 20 5 20 15 12 17 33 21 37 12 -16 NC-2 6 10 8 10 5 10 29 25 30 45 40 48 5 - 8 NC-3 8 14 6 20 5 5 11 6 12 39 25 23 14 2 NC- 4 12 20 14 5 10 10 25 27 24 42 57 48 - 15 9 NC-5 4 6 2 20 5 20 18 19 15 42 30 37 12 -7 NC-6 -2 10 0 5 10 5 22 17 19 25 37 24 -12 13 . .~VERAGINDEX I(NC) I 37.7 35.0 36.2 2.7 -1.2 I I I I I I_

I ~ CAFFEINESUBJECTS

Results: The CORRELATEDT-TEST COMPARINGTHE ANABOLIC/CATABOLIC

INDEXOF NON-CAFFEINECONSUMERS "PRE" VERSUSWEEK 1, "PRE" VERSUSWEEK 2,

ANDWEEK 1 VERSUSWEEK 2 data, Table 11, showed significant differences

between Week 1 compared to Week 2 and Week 2 comp~red to "Pre."

The mean anabolic/catabolic index for the End of Week 2 was 40 with

a standard deviation of 5.72. The mean anabolic/catabolic index at the

End of Week 1 was 45.7 with a standard deviation of 12.28. The

difference between the means was 5.72 with a T-ratio of 1.54; 2-tail

probability was .156 and ·I-tail probability was .078. This significantly

different fall is in the anabolic direction, which would be expected by

the reintroduction of caffeine. It is also of interest that the index

was significantly less at the end of Week 2 as compared to the

precondition. The mean "Pre" was 43.4 with a standard deviation of

10.90. The difference between the means was -3.36 with a T-ratio value

of 3.02. The probability was equal to .013 for a 2-tail test of

significance or .007 for a 1-tail test of significance.\

ColllDellts: Evidently, the abstinence from coffee during Week 1

increased the anabolic/catabolic index but not by a statistically

significant amount. However, reintroduction of the coffee did

significantly lower the index reflecting a true anabolic effect.

., TAIIE11. CIH9.A1FDT -'IFSI'CDRRDC 'DE r£VE CFANAllLIC/C\TAIU DtEC CFCAmillE CIJBHRS ''PRE''VOOE 1i1B: 1, ''PRE''VHBE 111B 2, AND \DI l VflSE \DI 2.

Ntmber Standard Standard (Di.f fereoce) Standard Standard 2-Tail T ~ of 2-Tail 1--Tail Variab le of Cases ~ ~viatioo Error ~ ~viatioo Error C.Orr . Prob. Value Freedan Prob. Prob.

AC''Pre" 43.36l:> 10.~ 3.287 11 -2.36l:> 13.441 4.053 .332 .318 - .58 10 .573 .287 ACWCl 45.7273 12.281 3.703

AC' 'Pre" 43.36)) 10.<.Xl2 3.287 11 3.36)) 3.695 1.114 .942 .cm 3.02 10 .013 .007 ACW<2 liO.

ACWCI 45.7273 12.281 3.703 11 5.7273 12.370 3.7'XJ .385 .243 1.54 10 .156 .078 AC\..Kl liO.OlX) 9.675 2.917 98

NON-CAFFEINESUBJECTS

The CORRELATEDT-TEST COMPARINGTHE ANABOLIC/CATABOLICINDEX "PRE"

VERSUSWEEK 1 1 "PRE" VERSUSWEEK 2 1 ANDWEEK 1 VERSUSWEEK 2 (Table 12) compared statistical evaluation of significance.

Comments: Although the Revici Anabolic/Catabolic Index moved in the expected direction for the caffeine subjects, the data was inconclusive for the non-caffeine group. This area requires further investigation.

PSYCHOLOGICALEFFECTS

Introduction

Each subject was requested to answer a questionnaire prior to the study, after Week 1 and after Week 2. A sample of Plate II follows.

The focus was upon changes from the "Pre" condition to Week 1 mode and from the Week 1 mode to the Week 2 mode. The caffeine subjects had

five bags per day of decaffeinated tea for Week 1 and upon re-examination

at the end of Week 1, they were then given five caffeinated tea bags per

day for seven days.

The responses to the questions 1-11 were grouped into three

categories. The MOODINDEX included questions 1, 2, 4, 6, 9, and 10; and

the SLEEP INDEXincluded 7a, 7b, and 7c. The PSYCHOLOGICALINDEX

included questions 5, 8, and 11. Since some questions were negative parameters, such as "Did you feel

tired," the responses to such a -question were reversed in sign in the TAII.EU. CimIAm> T-'IFSI'CIJl>ARDC 'DE NWDJC/OOAHLTCDIE( CF tlX-CAmIDE CIHDe5 ~ VFJSE WB: 1. ''Am''VFJSE WB: 2. Ni> WK. 1 VFlSE liiB: 2.

rbnrer Standard Standard (Differeoce) Standard Standard 2-Tail T ~ees of 2-Tail 1-Tail Variable of Cases t1:an Lev:i.atioo Frror t1:an Lev:i.atioo Frror Corr. Prob. Value Freeian Prob. Prob.

N:, ''Pre" 37.fHJ7 7.421 3.029 6 2.fHJ7 12.925 5.277 .2.86 .583 .51 5 .635 .317 N:, WCl 35.a:ro 12.915 5.273

N:, ''Pre" 37.fHJ7 7.421 3.029 6 l.:ro) 8.118 3.314 .673 .143 .45 5 .670 .335 N:, W(2 36.1667 10.'H> 4.483

N:, W(l 35.a:ro 12.915 5.273 6 -1.1667 11. 4.483 100

tabu lations. For example, "Did you feel tired?" the subjects responds,

"less." This "less tired" is actually a double negative or more energetic. The inversions of sign were also required for question 6,

"Were you nervous or anxious?" and question 9, "Did you feel depressed?"

For the PHYSIOLOGICALINDEX, question 5, "Did you have headaches?" was reversed and "Did you have stomach aches?" was reversed. Improvements which were toward better health or better feelings were depicted with a

rising bar.

MOOD

We began the analysis of Figure 6 by focusing upon the heavy black

bars for each subject which represents the comparison (or difference)

betwee n the End of Week 1 and the "Pre" state.

During the week when the chronic caffeine subjects were given

decaffeinated tea (Week 1), there was no clear-cut pattern of mood

change . Whereas four reported negative or "worse" mood responses (C-1,

-5; C-4, -4; C-6, -1; C-10, -4), four reported positive or improved mood

changes (C-3, +2; C-7, +2; C-8, +l; C-9, +2). The other three had no

alteration of mood (C-2, C-5, C-11).

Comment: Evidently the mood-related reactions to caffeine

abstinence show no single directional pattern.

- 4 .£ 6

■ MEEJ< 1

· VAL O -t--•- II MEEI< 2

-2

-4 _, • 7· U CJ 10 11 NC- I Z. 3 f 5 ti, C.-1 2 J •1 5 6 HOOD A FIGURE 6. HOOD, PSYCHOLOGICALEPl'ECTS VIA QUESTIONNAIRE. COMPARISONOP END OF WEEl 1 ..... TO "PRR" (IlLACI HAR) AND RND OP WEE( 2 TO END OP WEE( l (LIGHTER DAR)...... 0 CAfl'RINE SUBJECTS. 102

We analyzed Figure 7 by focusing upon the lighter bars which I represent the comparison (or difference) between the End of Week 2 and the End of Week 1. In the chronic caffeine group, caffeine was reintroduced during Week

2. For most subjects (eight subjects) this reintroduction did move them

toward "more" stimulated, "less" tired, "more" alert, and "less"

depressed. Keep in mind that this was compared to a prior point in time,

namely, the week the subjects received decaffeinated tea and this does

not necessarily reflect a better state of health. The mood data, as

shown by the lighter bars, revealed (C-1, +5; C-2, +4; C-4, +6; C-5, +6; C-6, +3; C-7, +3; C-9, +4; C-10, +6). On the other hand, two subjects

had negative mood changes (C-3, -5; C-8, -3); C-11 had no change.

CoDJDent: Although the mood effects of one week of abstinence were

~oth negative and positive, the reintroduction of caffeine did move mood

changes in the positive direction. This is not to conclude that caffeine

is a healthy or desirable mood elevator, but rather relates to the short

term effect of a one-week abstinence . What might be an interesting

future study would be analyzing three weeks of caffeine abstinence and

the effect on mood.

NON-CAFFEINESUBJECTS

Each non-caffeine subject answered a questionnaire in the same

manner as the caffeine consumer subjects. The NC subjects were given

five tea bags of caffeinated tea per day during Week 1. Upon (j

2 ·1 ~~RJ II I ffl~I II BHtJ faMI~ 111111

■IJEEK 1 1111113 ,uwi,-.,.. rI VAL 0 -l_all-fW.- 111,rt,_ U1111aaml,.. ~maall..f~l-t .r- t 1 1r11ri ii IJEEK 2

-2

-4

..!

-6 C.-1 2 3 '1 5 6 7 u 9 10 Jl NC.- I 2-- °3 J/ 5 (p HOOD /i

~ FIGURE 7. HOOO, PSYCIIOI.OGICAt RFFECTS VIA QUP.STIONNAIRE. COHPARISON OF END OF WEE( 2~ TO RND OF WHl!l 1 (1.IGll'fEK OAKS). CAFFEINE SUBJECTS 104

re-examination at the End of Week 1, they were then given five tea bags per day for seven days of decaffeinated tea. Focusing upon the comparison of End of Week 1 to "Pre" depicted by the heavy black bars in

Figure 8 showed that the introduction of caffeine to the non-caffeine user created both positive and negative mood changes without a clear pattern.

Comment: Thus, the caffeine must interact with each person's biochemistry in a unique way. When correlating adrenal status with mood change, it was of interest to note that the three NC group subjects with improved mood all had normal adrenal function. Perhaps, caffeine can stimulate the normal adrenal function. Perhaps, caffeine can stimulate the normal adrenal to produce positive mood in the short-run (in this study for one week).

Analysis of the comparison of End of Week 2 to End of Week 1

(lighter bars) (Fig~re 9) showed that return to the caffeine-free state in Week 2 resulted in negative mood changes for four subjects (NC-3, -1; Nc-4, -2; NC-5, -2; NC-6, -2).

Coument: Even though the caffeine had been ingested for one week (Week 1), it began to affect mood.

SLEEP

Introduction

The SLEEP INDEXrepresents the three questions 7a, 7b, and 7c;

depicting insomnia, difficulty falling sleep, and difficulty staying N

105 ...

1111111 c:&: ca: > Cl. 0 Q z ca: Cl. 0 z 0 ::n ~ CIC < Q,. z: 0 -- u I • • ~ tr.I ~ QC ... ~u <:a.:l z-, z= o= <= ...~ tr.I Q ::n c:&: 0 :a.:iz 0 ::, ~ J: O' ca: ~ c::a. .... < > ~ I = er. z i-0 uz ca: Cl,, Cl. • ei:;i- :ii: ..: C cc: u...... c., u 5~ 0 = u=- >- = tr. ~ ~ :ii: 4 -·=- o·-00 N :c =-

.... C0 ca: 0 CIC .,. \,G \,G ~ N ~ N I I I c.,= """' ~ ca. C: ~

-~ ~ N ::.: ::.: ..1'••. w wJ wJ :% :x 106 ml ■ --

~ 0

z w= c.. 0 :.t.l !- z :.; ._,..... ::zJ ct:! -, ...:::: C1' :::, < :.I.I c:.. X ::iJ C z u ..... ::J A% - ~ I .t::.. ~ < ~ ::a::u I -< z z 0 z z .....0 e- ti: ...... -...; ::.:~ :. - :.:.. ~ - ::,,,,: ...; ::.: < ·-· c..; :a .. :. ·-·-·a---:=:--~==.=---:::-:.~~.~~--:·~ ...... ···-- ·-· - ....-···~ ·:--..~.r.--·~ -~:r. ---···-...... :::: t z u ::: >- ti: ...... :- •N =C ::,,,,: 0 :.:.: X :.:: :a

a,. ::; :x :::, t.,..... c..

- --- -, 107

asleep. The bar graph (Figure 10) represents the change s between the End of Week 1 and "Pre" and the End of Week 2 and the End of Week 1. The numerical sign is inverted so that a positive response such as "less" insomnia is depicted with a positive bar.

CAFFEINESUBJECTS

Results: Three C subjects had sleep problems during Week 1 (C-1,

-4; C-4, -6; C-1 1, - 4). Two had improvement in sleep (C-7, +2; and C-8,

+6). Six had no sleep changes (C-2, C-3, C-5, C-6, C-9, C-10). In Week 2, two had worse sleep · ( C-2, -2; and C-8, -2). Two had better sleep (C-4, +6 ; and C-11, +6). Seven others had no change (C-2,

C-3, C-5, C-6, C-7, C-9, C-10).

Comnent: The sleep effects showed no clear pattern at the End of Week 1 compared to "Pre." It was of interest that many subject s had no alteration of sleep function. Also, there was relatively little effect on sleep when the caffeine was reintroduced.

NON-CAFFEINESUBJECTS

The comparison of End of Week 1 to "Pre" (black bars) and also End of Week 2 to End of Week 1 (lighter bars) is shown in Figure 11. Four subjects had no change in sleep status comparing End of Week 1 to "Pre"

(NC-1, NC-2, NC- 5, and NC-6). Two had sleep problems during Week 1

compared to "Pre" (NC-3, -2; and NC-4, -6). In the comparison of Week 2 6 .

'I .

2 ....

■ J.4£EK 1 UAL 0 1111l~--f tP'Pl'l..t!Bl!S I 1tma 1mma,t---1~--· r:GI ■ J.4EEK 2

-2

- 6 C-1 2 3 '1 5 (, 1 0 9 10 11 N::..-I 2-'3~5(o SLEEP h.

FIGURE 10. SI.RRP INDEX. SI.REP RFPRCTS VIA QUESTIONNAIRE. COHPARISONOF END OF WEE( I TO "PRE" (RLACI BAR) AND END OF WEEI 2 TO RND OF WEEI I (LIGIITER BAR).~ CAFFEINE SUBJECTS m 109

w Cl:I • ca:i >C.: < :a. C: 0 Qt! Q::a.: z E :a.:i C.,:)= :s.,.. 0~ z o- ,..~ w c:a::::sJ Q..><:a.:i :c r ora. uo Q • z: i -I :a: :r,; - Cl: ,..0 ~ < E 1 z ZN mas:e@@,¥lfflitf1i¥di.tt2:@:f,;;h 0 -w ... Aft- ► "- :a: en:a: :a: > == I O' CII., 0 - < ; >-= z: :rJ ~ E- Q e--ra--a-·&-w.... ------it#ie$&erm:w &$#@¥iii@· - uz :a.:i< .,. CII.,

::.Jer.. -Cl: ~ EM pg~ < E Q.. ::c u :a: :a:: :a: ... -, ~ u C: ~< == i ..: :n C: • -1:1: .,,,c z I- !:LI=es.:~ I: - z ~ :s. - :Q.. :a.< =- u :a.:I O I :a: E- z ~ 0 r ~-z N -

:sl N ~ I I "'I 110 to Week 1, three subjects had sleep problems (NC-3, -2; NC-4, -6; NC-5,

-2 ) and three subjects had no change (NC-1, NC-2, and NC-6).

The NC group had group had caffeine during Week 1 and decaffeinated tea during Week 2.

Comment: For the most part, caffeine produced little change in the sleep function in the NC group. It is of interest that one subject

(NC-4), __who had the most sleep problems, started the study with somewhat weakened adrenal function.

PHYSIOLOGICALEFFECTS

Introduction

Questions 5, 8, and 11 comprise the components of this index.

Please note that questions 5 and 8 were plotted in the positive direction

such that having "less" headache or "less" stomach ache would actually be a positive, healthful sign and therefore is depicted with a bar in the

positive direction. As with Figure 7 (Mood), this represents the

comparison of the End of Week 1 to the "Pre" status and the End of Week 2

status with the End of Week 1 status (Figure 12).

CAFFEINESUBJECTS

Results: Five of the eleven had improvements in their physiological

indicators of +2 at the End of Week 1 (C-3, C-6, C-7, C-8, and C-9).

Four had no change (C-i, C-2, C-5, C-10) and two had physiological

changes in the negative direction (C-4, -2; and C-11, -4) . 4

1 ~------ll ~EEK 1 UAL 0 -1~-i U MEE.K 2

-1

-2 ....

-3 .•.

-4 C-1 2 3 4 5 6 · 7 o 9 10 11 NC- I 2.."3"" 5' ~ l'IIVSIOLOGICnL /}

,_. ,_. FIGURE 12. PHYS 101.0GICAI. I NORI. PHYS IOI.OGICAL EFFECTS VIA QUESTIONNA I RF.. COMPARISON ,_. 011 P.ND OF WP.EK I 1'0. "PRP." (RI.AC[ DAR) AND END 01' WERl 2 TO END OF WEEl 1 ~ {I.IGll'ff.R DAI). CAFt'IHNF. SUDJF.CTS I- I-

112

At the End of Week 2, two had worse of negative physiological changes (C-8, C-1O) of -2 each. One had a marked positive C-4, +4. All of the others had no change (C-1, C-2, C-3, C-5, C-7, c~9, C-11). Comment: Many of the C group subjects had improvement in physiological indicators during Week-1 without caffeine. Such symptoms as stomach aches and headaches were diminished or improved on the schedule which included decaffeinated tea. For most subjects, the reintroduction of caffeine seemed to produce little change as compared to their prior status.

NON-CAFFEINESUBJECTS

Analysis of the End of Week 1 to "Pre" (black bar) (Figure 13) revealed: four had negative physiological changes (NC-1, -2; NC-2, -2; NC~3, -4; NC-4, -4). Two had no change (NC-5 and NC-6). Comparing End of Week 2 status with End of Week 1 status (lighter bar) (Figure 13): four had negative physiological changes (NC-1, -4; NC-4, -2; NC-5, -2; NC-6, -2). One had positive physiological changes (NC-3, +2).

Comment: The NC group tended to respond to caffeine with headache or stomach ache. The NC group had physiological reactions both to the caffeine mode and to the non-caffeine mode.

__,.____ a 4 --

3 -

2 III

1 ....

K ~EEK 1 Imm 1...... -..--; UAL 0 -lllllll.1111111 Ii UEEJ< 2

- 1

-2 -•-

-3 -··

-4 8

Conclusions

A. Adrenal Gland Function

1. Chronic caffeine users tended to have diminished adrenal gland function. 2. Caffeine may be taken to stimulate underactive (or even normal) adrenal glands in order to raise the blood sugar level. 3. The temporary energy improvement tends to weaken the adrenal glands so that a higher dose of caffeine is needed to achieve the same energy effect. 4. a) After months of caffeine stimulation to the adrenals, their function becomes suboptimal. The majority of.caffeine users in this sample presented with weakened adrenals as shown by the abnormal readings of the Ragland Postural Blood Pressure and the Koenigsburg Urinary Sodium Excretion. b) Conversely, the majority of the NC group subjects presented with normal adrenal function. S. Adrenal status was determined by Ragland Postural Blood Pressure and Koenigsburg Urinary Sodium Excretion. The results of these two tests were consistent and in agreement. These two indicators correlated closely, where diminished standing blood

114

-·---~ -_,..-____ 115

pressure was seen, there was a higher spillage of sodium into the urine. These two indicators serve as a mathematical indicator of adrenal strength or weakness. 6. In chronic caffeine subjects, abstinence and reintroduction seemed to improve adrenal function.

B. Anabolic Effect*

7. In chronic caffeine subjects, the reintroduction of caffeine after one week abstinence significantly lowered the Anabolic/ Catabolic Index at the End of Week 2. This index change was in

the negative direction which ~eflects an anabolic process.

C. Psychological Effects

8. Mood Effects -- In the chronic caffeine-user group, one week of abstinence produced both positive and negative mood changes. There was no discernible pattern, however, reintroduction of caffeine did lead to mood changes in the "positive direction." Introduction of caffeine to non-caffeine subjects was also associated with both positive and negative mood alterations. Although there was no consistent pattern, the three NC subjects with normal adrenals all showed positive mood changes.

*This theory is still the subject of debate and has not yet gained wide scientific support.) For literature review, see Dr. E. Revici, 1961. 116

Cessation of caffeine after one week by the NC subjects was followed by a preponderance of mood changes in the "negative direction." 9. Sleep Effects -- The chronic caffeine users had no clear pattern of sleep alteration during Week 1 or Week 2. Also, most of the NC group showed little sleep changes. ·

D. Physiological Effects

10. In the C group, the preponderant response to abstinence of caffeine was an improvement in the physiologic.al indicators. Reintroduction.produced little change by the end of Week 2.

There was a strong tendency for the NC group to respond to caffeine with physiological changes such as headache and stomachache.

E. Comparison of Caffeine Group (C Group) to Non-Caffeine (NC Group)

11. NC Group -- The introduction of caffeine to the non-user produced varied reactions although subjects with normal adrenals had positive mood changes. Cessation led to negative mood changes in the majority of NC subjects. There was little change in sleep pattern during either week. Physiological changes such as headaches or stomachaches occurred during the caffeine-use week. The majority also had physiological changes during Week l•

---~ 117

12. C Group -- The most consistent effects of caffeine abstinence

were diminished stomachache and/or headache. This was

quantified via numerical changes toward higher numbers which

reflected healthful or positive changes. Abstinence showed no

overall pattern of mood change. Reintroduction of caffeine was

associated with mood changes in the positive direction. Neither

Week 1 nor Week 2 produced a clear pattern of sleep changes;

there was oniy very slight effect on sleep during Week 2.

However, a week may not be adequate time for complete withdrawal

from caffeine's stimulatory effects. No situations were found

in the literature to corroborate these observations.

Discussion

One of caffeine's major effects is to stimulate the adrenal glands to secrete epinephrine and norepinephrine, resulting in an immediate boost of energy. However, in time, the adrenals may become exhausted.

In our society, the stress of day-to-day living has a tendency to

"wear out'' our adrenal glands. This diminished activity results in fatigue. In order to revive adrenal function, many people ingest moderate to high quantities of caffeine. This is an external stimulant.

In time, this stimulation wears out the glands, thus the immediate benefit is at the cost of eventual exhaustion .

In day-to-day clinical practice, many patients come to the doctor's office complaining of fatigue. The degree of this symptom varies from "mild" to "severe." An example of "severe" fatigue is a feeling of being tired and drained of energy, even upon awakening from a restful sleep.

At the other end of the spectrum is a diminished ability to work efficiently at the end of the day.

Occasionally, the fatigue is a result of anemia, depression, malabsorption, a toxic state, or a hypothyroid condition. However, it is our observation that most of the time fatigue is a result of diminished adrenal function or adrenal exhaustion. The level of adrenal function can be ascertained by appropriate physical examination and laboratory testing.

In this study, the results of the physical examination and urine sodium excretion evaluation showed that chronic users of caffeine can be differentiated from non-users based on tests which reflected changes in adrenal function during the two test weeks.

In the active nutritional practice of Dr. Martin Feldman, _ who has served as the scientific monitor, a recent review of medical records showed that more than 65 percent of new patients complaining of fatigue as a major medical symptom were drinking three or more cups of coffee or tea daily. Many patients reported increased intake of coffee and tea as their day-to-day fatigue became more severe. Upon interview they reported the necessity of coffee, tea, chocolate, or certain soft drink bever ages to "boost" their energy. It is very likely that caffeine's ability to stimulate adrenal gland activity accounts for the popularity of caffeine beverages in our society.

•. 119

However, the daily use of caffeine over a period of months leads to diminished adrenal function. The caffeine does, in fact, increase energy but at a price. Also, most patients report the need to drink more caffeine for a similar effect as time passes.

Reconnendations

The main point of this study is to educate the public at-large as to

the physiology of why they like their caffeinated beverages so much and

the long-term damage to their body which results. For the great

majority, it is to obtain more energy by stimulating their underactive

adrenals.

Fortunately, there are available non-drug nutritional programs which

have the ability to repair or rebalance weakening adrenal glands toward

normal. Such a program consists of lifestyle changes, the avoidance of

adrenal stimulants (caffeine in any form) and the consumption of specific

nutrients.

1. Vitamin B (Pantothenic Acid) in the range of 300-800 mg/ day 5 2. Vitamin C (Ascorbic Acid) in the range of 2000-10,000 mg/day

3. Herbal Licorice Root in the ran ge of 50-150 mg/ day

4. Bovine Adrenal Gland processed to remove any hormonal activity

and purified to remove possible toxins

5. L-Arginine in the range of 500-1,000 mg/day

6. B (Ribofla~in) in the range of 1-3 mg/day 2 7. B (Niacin) in the range of 12-36 mg/day 3 120

8. B6 HCl (Pyridoxine Hydrochloride) in the range of 10-50 mg/day.

The lifestyle changes should include diminishing stressors and learning strategies which might diminish anxiety. Some of the many avenues would include meditation, biofeedback, yoga, subliminal stress reduction tapes, excessive stress management counseling.

It is my hope that a larger and more sophisticated experiment will evolve from this work. That experiment should be done in a prison or in an experiment with people's whose diet, behavior, and lifestyle can be controlled and carefully monitored. With proper funding and research facilities, a more comprehensive analysis can be made available to the scientific community and to the public.

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145

f I i'

APPENDICF.S ' 147 APPENDIXB CAFFEINESTUDY Daily Diary Name: Day ----- of Week ----- At the end of each day, check off on the following chart any chan ges between this week and last week that you are experiencing in energy, sleep, etc. Add any comments. 1. Energy: /1 less II same It more Comments:

2. a) Concentra ti on: It poorer II same It better b) Attention span: It shorter II same It longer Comments:

3. a) Nervousness: /1 less II same It more b) Depression: It less II same It more c) Mood: 11 l ess II same It more Comments:

4. Irritability It less II same O more Comments:

S. Muscular strength: It less II same O more Comments:

6. Sense of well-being 11 less LJ same It more Comments: more 7. Falling asleep: · 11 difficult II same ;-r easier Comments:

8. Endurance: It less II same It more Comments:

9. Headaches: ;-r worse a same It improved Comments:

10. Appetite: It poorer It same It improved Comments: 11. For smokers: ci garette use: 11 less II same It more Comments:

,, -=.c--~ • 148

APPENDIXC CAFFEINESTUDY QUESTIONNAIRE Plate I Name: Sex: Age: To be answered prior_!:£ study 1. Approximately how many cups of CAFFEINATEDcoffee do you drink per day? r-t 1 r-t 2 r-t 3-5 r-t more than 5 2. ARppoximately how many cups of CAFFEINATEDtea do you drink per day ? (Note t hat HERBALteas are NOT CAFFEINATED) r-t 1 r-t 2 r-t 3-5 r-t more than 5 3. How many ounces of CAFFEINATEDsodas do you drink per day? (Include beverages containing cola) __ _ 4. Do you have trouble falling asleep? r-t No r-t Yes 5. Once you fall asleep, do you sleep soundly? r-t No r-t Yes 6. Do you have headaches? r-t Never H Seldom r-t About once a month /1 About once a week r-t Almost every day 7. Do you feel irritable? r-t Never .Ct Seldom .Ct Occasionally /1 Fr equen tly 8. Do you take over-the-counter analgesics (pain-killers)? r-t _No .t::f Yes If "Yes," what brand?

Never Occasionally Frequently

9. Do you feel nervous?

10. Do you feel tired?

11. Do you feel overstimulated (hyper)?

12. Do you have heart palpitations ?

13. Do you have stomach upsets ?

14. Do you smoke cigarettes? r-t No H Yes If you do smoke, approx imatel y how many cigarettes per day? 1 I 148

APPENDIXC I CAFFEINESTIJDY QUFSTIONNAIRE Plate I Name: Sex: --- Age: To be answered prior !.2_ study 1. Approximately how many cups of CAFFEINATEDcoffee do you drink per day? r-t 1 r-t 2 r-t 3-5 r-t more than 5 2. ARppoximately how many cups of CAFFEINATEDtea do you drink per day? (Note that HERBAL teas are NOT CAFFEINATED) r-t 1 r-t 2 r-t 3-5 r-t more than 5 3. How many ounces of CAFFEINATEDsodas do you drink per day? (Include beverages containing cola) __ _ 4. Do you have trouble falling asleep? r-t No rt Yes 5. Once you fall asleep, do you sleep soundly? rt No rt Yes 6. Do you have headaches? rt Never rt Seldom J::t About once a month /1 About once a week r-t Almost every day I 7. Do you feel irritable? rt Never rt Seldom J::t Occasionally /1 Frequently I 8. Do you take over-the-counter analgesics (pain-killers)? rt No J::t Yes If "Yes," what brand?

Never Occasionally Freque~tly

9. Do you feel nervous?

10. Do you feel tired?

11. Do you feel overstimulated (hyper)?

12. Do you have heart palpitations?

13. Do you have stomach upsets?

14. Do you smoke cigarettes? r-t No rt Yes If you do smoke, approximately how many cigarettes per day?

------..._(1111. t-•,!LII l 149

CAFFEINESTUDY QUESTIONNAIRE Part II

Name: Week: To be filled out AFTERWeek One and Week Two of the study. Answer the following according to how you usually felt during the previous week.

Less Same More -- -- 1. Did you feel stimulated? -- -- 2. Did you feel tired? -- -- 3. Did you dr.ink more coffee, tea, or cola than usual? -- 4. Did you feel alert? . -- s. Did you have headaches? -- -- 6. Were you nervous or anxious? -- -- 7. Did you have a) insomnia? b) difficulty falling asleep? c) difficulty staying asleep? ------8. Did you have stomachaches? -- 9. Did you feel depressed? -- -- 10. Did you feel "good" (a feeling of well-being)? -- -- 11. How was your appetite? -- -- 12. Did you notice anything different from usual? r-t No It Yes If yes, explain. NONSMOKERStmtY

13. For smokers only: Did you notice anything difterenh from usual? r-t No r-t Yes If yes,' explain.

14. For smokers only: Cigarette use per day: ____ cigarettes 1 150

Appendix D PEARSONCORRELATION COEFFICIENTS BETWEEN BLOOD PR.FSSURE AND SODIOMS&::RE'IION FOR ''PRE~ WEEl I, AND WEEK2. CAFFEINESOBJ7"S.

Introduction

The Pearson Correlation shows the degree of linear relationship between two variables. A POSITIVE correlation would indicate that the two sets of scores varied together, while a NEGATIVEcorrelation signifies an inverse relationship. Of the 15 non-redundant Pearson Correlation coefficients, 14 of the 15 correlations are significant (.10 or less). There are positive correlations between blood pressure at "Pre, 11 Week 1 and Week 2 and between sodium secretion at "Pre," Week 1 and Week 2. There are negative correlations between blood pressure and sodium secretion, the only exception being the correlation between sodium secretion at Week 2 and blood pressure at Week l; this correlation is negative, but does not reach the desired level of significance. Using the .10 level for a I-tail test for the three-measure blood press_ure and sodium secretion taken at the "Pre, 11 Week 1 and Week 2 periods shows from Appendix D, PEARSONCORRELATION COEFFICIENTS BETWEEN .BLOOD PRESSURE ANDSODIUM SECRETION FOR "PRE, 11 WEEK1, ANDWEEK 2, CAFFEINESUBJECTS, the following specific data: For the chronic caffeine subjects, a POSITIVE correlation between blood pressure "Pre" and blood pressure Week 1 (.506, p=.056). This correlation indicates the values tended to vary together, i.e., subjects who had high scores at "Pre" tended to have high scores at Week 1 and low scores were paired with low scores. There was a significant BLOOD PRESSURE"Pre" and Sodium Secretion "Pre" (-.864, p=.001), i.e., high scorers on blood pressure "Pre" were paired with low scorers on Sodium secretion "Pre" and vice versa.

Comment: The most striking correlation was the very linear negative correlation between each caffeine subject's blood pressure and sodium secretion. In other words, as the blood pressure became less negative (more positive), the sodium secretion values diminished (less sodium was spilled). dfEA&¥11&t SH&±+H 7 6 ;;ca,; l 151

TABLEDl. PEARSONCO~TION COEFFICIENTSBETWEEN BLOOD PRESSURE AND SODIUM SF.CRfil'IONFOR PRE," WEE[ 1, ANDWEEI 2. CAFFEINESUBJECTS.

BP "Pre" BP WK1 BP WK2 SS "PRE" SS WK1 SS WK2 BP "PRE" 1.0000 ( 0) p = • BP WKl .5062 1.0 000 ( 11) ( ) p = .056 p = • BP WK2 .4646 .4568 1.0000 ( 11) ( 11) ( ) p = .075 p = .079 p = • SS "PRE" -. 8641 -.5708 -.6784 1.0000 ( 11) ( 11) ( 11) ( ) p = .ooo p = .033 p = .011 p :z • SS WKl -.6802 -.8515 -.5 810 • 8508 1.0000 ( 11) ( 11) ( 11) ( 11) ( ) p = .011 p = .ooo p = .030 p = .ooo p :::r • SS WK2 -.5132 -.1899 -.7 908 • 7733 • 5904 1.0000 ( 11) ( 11) ( 11) ( 11) ( 11) ( 0) p = .053 p = .288 p = .002 p = .028 p = .028 p =

\ I 1

152

Appendix E PEARSONCORRELAilON ~EFFICIENTS BETWEEN BLOOD PRFSSURE AND SODIUM SF.CRETION FOR'PRE,' WEEK1, ANDWEEK 2. NON-CAFFEINESUBJECI'S.

Appendix E, THE PEARSONCORRELATION CO EFFICIENTS BETWEENBLOOD PRESSURE AND SODIUMSECRETION FOR "PRE," WEEK1, ANDWEEK 2 for non-caffeine user subjects, displays 15 non-redundant Pearson Correlation coefficients and of the 15 correlations, five are significant at the .10 level or less. These include positive correlations between blood pressure at Week 1 and Week 2 and sodium secretion at Week 1 and Week 2, and negative correlations between blood pressure at Week 1 and sodium secretion at Week l; blood pressure at Week 2, and sodium secretion at Week 2 . The significant Pearson Correlation coefficients for the NC group relates blood pressure inversely to sodium secretion as illustrated in Appendix E.

Cooment: One of the major findings of this entire experiment is the high degree of correlation or agreement when measuring adrenal gland status via both blood pressure and sodium secretion. Although the numbers move-in opposite directions, nevertheless they are measuring the identical physiological s_trength or weakness. 153 TABLEEl. PEARSONCO~TIOH COEFFICIENTSBETWEEN BLOOD PRESSURE AND SODIUM SECRETIONFOR PRE,"WEEK 1, ANDWEEK: 2. NOH-CAFFEINESUBJECI'S.

BP "Pre" BP WK1 BP WK2 SS "PRE" SS WK1 SS WK2 BP "PRE" 1.0000 ( 0) p = • BP WKl .2359 1.0000 ( 6~ ( ) p = .3 6 p == • BP WK2 .0816 .7920 1.0000 ( 63 ( 63 ( ) p = .4 9 p = .o 0 p = • SS "PRE" -.4984 .1761 .2084 1.0000 ( 6~ ( 64 ( ) p = .1 7 pc:( .36t 9 p = .3 6 p = • ss WK.1 -.0502 -.9017 -.8585 .1503 1.0000 ( 66 ( 66 < 6a ( O) p = .4 2 p = .o 7 p( = .o61 4 PC e3 8 p = • SS WK2 -.4662 -.3504 -.8061 .1810 .6495 1.0000 ( 63 ( 64 ( 6~ ( 66 ( 6~ ( 0) p = .1 6 p = .2 8 p = .o 6 p = .3 6 p = .o 1 p = • 154

APPENDIXF

Table Fl shows at-test for independent groups, comparing caffeine and

non-caffeine subjects at "Pre" status. For blood pressure (BP) at "Pre"

status, the caffeine groups have a mean of -12.0909, which is significantly

lower (t-ratio = -3.59) than the non-caffeine group (4.3333). For sodium

secretion, the caffeine group had a mean of 40.9091, which is a significantly

higher t-ratio (2.90) than the non-caffeine group (23 .8 333).

The mean of the BP of the caffeine group at -12.00 reflects an average

drop in BP from supine to erect, which indicates a diminished adrenal

function. The NC subject group, with a BP mean of 4.3, reflected much better

adrenal function. This difference had a 2-tail probability of .003.

Similarly, the sodium secret _ion (SS) mean for the C subjects "Pre" (40.91)

versus 23.83 for the NC subjects. The higher mean reflects sodium secretion

which indicates diminished adrenal function.

The mood effects in the caffeine subjects during week one were re1ated to

the abstinence from caffeine. In the non-caffein~ subject group during week 1

the mood effects were from the introduction of caffeine. Comparing mood data

of caffeine subjects versus non-caffeine subjects was difficult since the

experimental design actually had two separate independent sub-studies.

Table F2 displays at-test for independent groups, comparing the caffeine

group at week one with the non-caffeine group at week two, as previously

explained. For BP, the caffeine group had a mean equal to -11.7273, which is

significantly lower43 than the non-caffeine group (3.0000, t-ratio equal to

I! _....

Table Fl

Comparison of Caffein e and Non~ffeine Subjects at "Pre" Status

Number Standard Standard Degrees of 2-Tail 1-Tail Variable of Cases Mean Deviation Error T- Value Freedom Probability Probability

BP "Pre"

C 11 -12.0909 9.513 2.868 15 .003 .002 NC 6 4.3333 7.941 3.242 -3.59

SS "Pre"

C 11 40.9091 13. 736 4.142 2.90 15 .011 .006 NC 6 23.8333 5.037 2.056

t-J Vl Vl Table F2

Comparison of Caffeine Group End of Week One with Non-Caffeine Group End of Week Two

Number Standard Standard Degrees of 2-Tail 1- Tail Variable of Cases Mean Deviation Error T-Value Freedom Probabili ty Probability

Blood Press ure

C - Week 1 11 -1 1. 7273 11.884 3 . 584 - 2.54 15 ,023 .012 NC - Week 2 6 3.0000 10.488 4.282

Sodi um Secretion

C - Week 1 11 ·38.4545 13.779 4.155 1.80 15 .079 .040 NC - Week 2 6 27.5000 3.619 1.478

...... Vl • 0-- -,

157

-2.54). For SS, the caffeine group had a mean which was significantly higher

than the non-caffeine group, but only for a 1-tail test. When the caffeine subjects were deprived of caffeine items, their BP at

the end of week 1 was -11.72, which reflected adrenal under-activity; whereas

the non-caffeine subjects at the end of week 2 (their abstinence week) had BP

mean of 3.00. This difference was significant at the .023 level. The sodium

secretion caffeine subjects at the end of week 1 was 30.45 as compared with

the non-caffeine subjects at the end of week 2 with a mean of 27.50. This was not significant since the probability level was .019 for a 2-tail tests.

Since the caffeine subjects were removed from caffeine during week 1 and . - -".... the non-caffeine subjects were taken off their one week of caffeine after week

1 (no caffeine during week 2), it is of interest to compare caffeine subjects

during week 1 (stopped caffeine) with non-caffeine subjects du~ing week 2 (stopped caffeine).

Another aspect comparing the caffeine subjects to non-caffeine. subjects

was the comparison of their BP and sodium secretion data in the "Pre" test.

These two indications reflect adrenal status prior to the experimental condition.

- --=--•~,::::Z&:;:m.:_QQ:iik4J_~~~Q=""'....::.,141D.,.=i[::::::~~~~:=------.'.'.l.-)'.l,••Zlral·· ...•-. ./.' =... 24 4 ;; I' ··~-~~~;>/));'~',J