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4 ,'l O ,•- ~ t ,, ·' · · · . . -. c.~ ~ ,., cr1l; ii?. n .Cincinnati, Ohio 45206-l 94 7,
UNION GRADUATE SCHOOL OF THE UNION INSTITUYE I 'BR~ r) '
1 COP'( - · \ . t\'r
A STUDY OF THE PSYCHOLOGICAL AND
PHYSIOLOGICAL EFFECTS OF
CAFFEINE ON HUMAN REALTH
PDE
Sub■itted to the Faculty of the
UNION GRADUATE SCHOOL
in partial fulfill a ent of the requirements for the degree of
DOCTOR OF PHILOSOPHY
in
HUMAN NUTRITION AND PUBLIC HEALTH SCIENCE
*
Gary Mull Cin c innati, Ohio
Prepared for a Graduation Co■aittee Meeting on May 29, 1989
--~
TABLE OF CONTENTS
Page
ABSTRACT • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • ii
ACD~ • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • V
CHAPTER 1.
CHAPTER 2.
IN'l'R.OOOCTION •• • ••••••• ••••• •••••••••••••• ••• •••••••••
REVIEW OF THE .BODY OF KNOWLEDGE ••••••••••••••••••••••
Physiological and Pharmacological Effects
Caffeinism .................................................. .......................................... Behavioral Effects
Effect on Sleep ............................................. The Caffeine Personality .................................... Smoking and Coffee ................................... -...... . Psychological Effects .......................................
1
7
7
13
15
17
19
20
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 ....................................... CHAPl'ER 3. RESEARCH HETHOOOLOGY OF THE SELECTED PROB!Df . ....... .
56
62
~eneral . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
Research Design••••···•••• • ••·•·••••·••••••·•••••••··•··•••• 63
xii
··~
TABLE OF CONTENTS (continued)
Research Methods ............................................ Subjects ....................................................
Page
64
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
CHAPTER 4. RESULTS AND DisaJSSION ..........................••... 71
Medical Examinations 73
Anabolic/Catabolic Index .................................... 94
Psychological Effects•••••••••••••••··•••••••••••·••••·•••·• .99
Mood ........................................................ 100
Sle ep ....................................................... 105
Physiological Effects ••••••••••••••.• ••••••• ~ ••••••••••••••• 110
xiii
· ···~ -., ..............
TABLE OF CONTENTS (continued)
CHAPTER 5. CONCLUSIONS AND REC01MENDATIONS . ••..•........•......• Page
114
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114
A.
B.
c.
D.
Adrenal Gland Function
Anabolic Effect •••••••• ••••••••••••• ••• •••••• •••••••
Psychological Effect
Physiological Effect
. ................ • .............. .
. .............................. . E. Comparison of Caffeine Group (C Group) to
Non-Caffeine (NC Group)
114
115
115
116
116
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117
Recommendations •••••• •.. • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • • 119
BIBLIOGRAPHY ..•.....•..•... •..•••..•....•.....•••••.....•••••..•• 121
APP:ENDICE'S ••••••••••••••••• · ••••••••••••••••••••••••••• ~ • • • • • • • • • • 145
A.
B.
c.
Consent for Caffeine Study•··•··•••••••••·•••·•••••••••••
Caffeine Study - Daily Diary
Caffeine Study Questionnaire
. ........................... . Plate I
Caffeine Study Questionnaire - Part II ................... D. Pearson Correlation Coefficients Between Blood Pressure
and Sodium S_ecretion for Pre, Week 1, and Week 2,
146
147
148
149
Caffeine Subjects··••••••••···•·••••••·•·••••••·••·•••••• 150
E. Pearson Correlation Coefficients Between Blood Pressure
F.
and Sodium Secretion for Pre, Week 1, and Week 2,
Non-Caffeine Subjects
(Title?) . ............................................... .
xiv
152
154
LIST OF TABLES
Table Page
1. Average Number of Cups Consumed, According to Caffeine
and Content . . . . . . . . . . . • . . . . . . . . . . . . . • . . . . • . . • . . . . . . . . . . . . . . . . 25
2. Caffeine Found in Various Sources ............................ 3. Subject Participation Information ............................ 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
36
71
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) ..............................................
7. Comparisons of Blood Pressures of Caffeine Users End of
Week 1 (Off Caffeine) versus End of Week 2 (Back on
78
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 .........................................
xv
84
- --~
LIST OF TABLES (Continued)
Table
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 ....................................................... 10. Anabolic/Catabolic Index of Caffeine and Non-Caffeine
Page
85
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) ....................... -..... 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 ............. 7. Mood, Psychological Effects via Questionnaire. Comparison
of End of Week 2 to End of Week 1 (Lighter Bars).
93
101
Caffeine Subjects·•••• • •••·•• • ·••·••···•·•·•••·•·•••••••·• • • 102
8. Mood, Psychological Effects via Questionnaire. Comparison
of End of Week 1 to "Pre" (Black Bar). Non-<:Affeine
Subjects ....................................................
xvii
104
--- ~ ···~
LIST OF FIGURFS
Figure
9. Mood, Psychological Effects via Questionnaire. Comparison
of End of Week 2 to End of Week 1 (Lighter Bar).
Page
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
---···~
CHAPTER I
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 .!!1flicrr public ~'habit" and may_ .~:- . . . ..... I. .. •..• ,•
-~_s imyortant 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 we are creatures of habit. Most people are caffeine consumers
because from birth this food-drug is set before us, if not offered
directly, along with orange juice, cereal, dessert, and cigarettes.
-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'red to 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.
3
.·•· .... "
I~ddi ;~<ln, .ti\~. ~~-•=1~~-!~.:~~us~--o_f _ ~e_s~_:e~s,..,~~-~~----_s.rnd1:p11:1e is .. be~~~v~d
to be due in some cases to caffeine. ~.,,,. ... -.. --·--,"'- _ ....... ,
The results of the small research study consists of three •kinds of
observations resulting _from consumption of caff~ine beverage during a
two-week period: (1) perceived psychological effects via administration
of a questionnaire; (2) effects on adrenal function de~ermined by a
medic~l examination; and (3) physical-chemical measurements of uri~e, an .r ,,..:,.:-.-- • - - - • - --- .____, -·• - ., ~~::::~~~~~ :,..•
indication _2;..,,S,~e .anabolic ~-f ~~~t ·o·f cafJ~i~~ u--~~~~~~i~g to ..... ~ .J.h~qr,y-2,f ,-;.~·,,...,_
Dr •. E· •. Revici.
The ·growing knowledge of the detrimental effects of caffeine and its
abuses have led to a plethora of articles attempting to raise the level
of awareness of the medical and scientific community in this regard. ; ......... .
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
'
6
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
REVIEW OF THE BODY 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
'
8
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 mm of 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
10
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.
vigilance test consisted of repetitive short length tones.
arithmetic test consisted of the calculation of simple sums.
The auditory
The
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
12
"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
13
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.
14
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
16
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.
17
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.
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18
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, REM being affected by
caffeine, leaving the situation to be resolved.
The tolerance developed to caffeine's effect on sleep by coffee
drinkers has been documented by Colton (Stephenson, 1977). Non-coffee
drinkers were more sensitive to coffee's insomnic effect, whereas coffee
drinkers were relatively insensitive in this regard. Non-coffee drinkers
experienced disturbed sleep patterns and delayed onset of sleep.
Mueller-Limmroth (Stephenson, 1977) showed that the quality of the
first three hours of sleep was impaired by the ingestion of coffee before
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
19
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.
20
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 21
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
, 22
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
, !
23
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,
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24
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
Table 1
Average Number of Cups Consumed, According to Caffeine and Content
Urn in university
School teachers
100 mg
4.2
2.6
Caffeine 50 mg
5.0
3.0
25 mg
4.5
3.1
25
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
1 I
'
--,
r I I
I
relieve the headache, and the caffeine habit continues and is
perpetuated.
26
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
1 ·1
l
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27
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
recommended treatment is to stop the cycle using intermittent withdrawal.
People do not really appreciate that all of this can be caused by
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
f ound 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
well documented, the effects of caffeine do not seem to be adaptive;
tolerance is not · obvious (Graham, 1978). That is, the physiological
j
' l l
1 ;
'
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.''
28
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
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 MHPG ever
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.
29
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
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.
30
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, cAMP is 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~
32
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).
l
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
33
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 cAMP phosphodiesterase inhibition.
Morphine withdrawal results in increased cAMP which 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
---~ ., ....
•
35
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
·- - - --- ~ ~~
caffeine tablets by habitual users. This technique resulted in both
decreased tea and coffee consumption.
36
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.
TABLE 2. CAFFEINE FOUND IN VARIOUS SOURCFS
Ground coffee 85 mg
Instant coffee 60 mg
Decaffeinated coffee
Instant tea
Cocoa
Cola (8 oz.)
Cold and allergy tablets
Headache tables
Sta y-awake tablets
3 mg
30 mg
6-42 mg
32 mg
15-30 mg/ tablet
32 mg/ tablet
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 McManamy and 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 s ymptoms 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.
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.
39
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 uncommon and 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 cAMP and 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
--~ -~
43
increased muscle tension. After coffee or placebo was taken, the EMG was
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.
1
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 REM occurred 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. who were
Winstead (1976) studied the caffeine habits and psychological
. particularly anxiety of psychiatric patients in a military traits,
setting. One hundred and thirty-five (135) patients were included in the
d and were given the State-Trait Anxiety Inventory Test and the stU Y
~nnesota Multiphasic Personality Inventory (MMPI) test. Thirty-four
(>4) patients drank five or more cups of coffee on each of two or more
days and 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 MP have yet
to be established.
This study was repeated, supposedly in a more rigid well-controlled
manner by Garfinkel et al. (1975), using MBD children 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 MBD who 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. Among the 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
-~
methylphenidate or dextroamphetamine. Caffeine showed cardiovascular
side effects and weight loss (Arnold, 1978).
53
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
that caffeine "filters out irrelevant material"; there are fewer
attention lapses.
54
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.
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
1 I I
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 ABO blood 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, SWR and 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-
induced and theophylline-induced stimulation of locomotor activity was
observed among progeny derived from backcrosses of Fl self-crosses.
60
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
founder effects and regional polymorphism. Several other instances of
ethnic differences in drug response were merely cited.
61
Interest has recently gr own in the possible ro l e of chromosomal
f ragile 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.
CHAPTER 3
RESEARCH METIIODOLOGY 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 .
62
------ ~
't_ I :• 'C', 1• !:_ , .. ,,' • • •• • ;f • a-('-, •• ;•. • • • • -...,.,,_, • • • -
63
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
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
66
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.
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 a l 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.
68
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.
-. ---~ ~
CHAPTER 4
RESULTS AND 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. ·
TABLE 3. SUBJECT PARTICIPANT INFORMATION
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
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.
72
. . ·... . • . ' .. i- • . . : - • ; . . (• .. -(- :-· . • ,:- . .. ' ~·
MEDICAL EXAMINATIONS
BLOOD PRESSURE, SODIUM SECRETION, AND ADRENAL STATUS
CAFFEINE CONSUMERS
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, BLOOD PRESSURE,
SODIUM SECRETION, AND ADRENAL STATUS OF CAFFEINE CONSUMERS 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.
73
~
TABLE 4. BLOOD PRESSURE, SODIUM SECRETION, AND ADRENAL STATIJS OF CAFFEINE CONSUMERS. WEEK. 1 THESE
SUBJECTS RECEIVED NO CAFFEINE, WHILE WEE( 2 TIIEY CX>NSUMED 5 ruPS OF CAFFEINATED TEA 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
CORRELATED T-TEST COMPARING THE MEANS OF BLOOD PRESSURE 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 s light impro vement in blood
pressure readings. This improvem~nt indicates better adrenal function.
Reintroducing caffeine after a week of abstinence improved adrenal
75
l
~
DOE 5. ClERlll.A1E> T-nsf <Dt>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
BP W<l -11.7273 11.884 3.583 11 -3.7273 10.t03 3.197 .457 .158 -1.17 10 .271 .136
BP \..K2 - 8.cx:ro 6.245 1.883
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<X> .0:fJ .59 10 .568 .284 ss \,,K2 36.4545 9.720 2.931
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 COMPARISONS OF BLOOD PRESSURES OF CAFFEINE USERS END OF WEEK 2 (BACK
ON CAFFEINE) VERSUS STATUS "PRE" (NORMAL CAFFEINE 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"
77
TABLE 6. C<MPARISONS OF BLOOD PRESSURF.S OF CAFFEINE USERS END OF WEEK 2 (BACI ON CAFFEINE) VERSUS STATUS "PRE" (NORMAL CAFFEINE STATE).
C- 2
C- 3
C-7
C-9
C-10
C-11
C-1
C-4
C-6
C- 5
C- 8
About the Same Week 2 versus "Pre"
Difference Pre Week 2 Week 2 vs. "Pre"
- 2 - 3 -1
- 4 +2 +6
-4 - 6 - 4
- 10 - 4 +6
-20 - 16 +4
-5 -2 +3
Improved Week 2 versus "Pre"
Difference Pre Week 2 Week 2 vs. "Pre"
- 30 -8 +22
-20 - 10 +t o
-22 - 10 +12
Adrenals Worse Week 2 versus "Pre"
Pre
-12
- 6
Week 2
- 19
-12
Differe nce Week 2 vs. "Pre"
-7
- 6
78
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 BLOOD PRESSURE OF CAFFEINE USERS END OF WEEK 1 (OFF CAFFEINE) VERSUS
END OF WEEK 2 (BACK ON 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
79
80
TABLE 7. C01PARISONS OF BLOOD PRESSURES OF CAFFEINE USERS END OF WEEK 1 (OFF CAFFEINE) VERSUS END OF WEE[ 2 (BACK ON 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
PRESSURE, SODIUM SECRETION, AND ADRENAL STATUS OF CAFFEINE CONSUMERS,
summarizes the presentation of all sodium secretion data. THE CORRELATED
T-TEST, shown in Table 5, COMPARING THE MEANS OF SODIUM SECRETION OF
CAFFEINE CONSUMERS 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, SODIUM SECRETION OF CAFFE~NE CONSUMERS, shows the bar
representation of data in Table 6.
81
- .. b --
VAL
7U
60
?
50 1} ./JI ;..#
'{j: --, I
40
llll.-.J~-.;I ~ I Ii PRE-TiliST
30
20 ·
10
" . C.l C.5 q; c:r
SODIUM [XC"ETlOff
ti
c.o
;~ .
"
C 'J
i ~ -
:lt.'. t: .
CJ0
I
,·-< i II I-IEE:!< _j
[ii I B IIEEK '2
~ 'i~' .. '
3J &-".· ~~,
rn~I i· ~ ,li::.j j!:
r:· :~,. .. ~-; ~L.
,illlm..:J~ C 11
FIGURE 1. SO0lllH SECRETION OV CAFFEINE CONSUHERS - DAR REPRESENTATION OF DATA LN TAIH.E 4.
().)
N
TABLE 8. BLOOD PRF.sSURE, SODIUM SECRETION, AND ADRF.NAL STATUS OF NON-CAFFEINE CONSUMERS. WEEK 1 TIIESE
SUBJECTS RECEIVED 5 CUPS OF CAFFEINATED TEA DAILY, WIITLE WEEK 2 THEY CONSUMED NO CAFFEINE.
Blood Pressure Standing Minus Supine
Subject Code
End of End of "Pre" Wk 1 Wk 2
NC-1 +14 0 -2
NC-2 0 +20 +20
NC-3 +10 +2 0
NC-4 -4 0 0
NC-5 -4 0 -10
NC-6 +10 0 +10
26 22 18
Mean - 4.33 3.66 3.00 ______ , T-Test
Sodium Secretion
"Pre"
23
26
20
33
20
21
143
23.83
End of Wk 1
28
22
26
29
28
26
159
26.5
· T-Test
End of Wk 2
29
25
27
30
32
22
165
27 . 5
Adrenal Status
End of End of "Pre" Wk 1 Wk 2
Normal Weakened Still Weakened
Normal Normal Normal
Normal Normal Normal
SL Weak Normal Normal
SL Weak Sl. Improved Regressed Sl. Weak
Normal Normal Normal
~
D11IE 9. CIERfJ.A1ED T-nsT CIWARIK; 1HE M7Nfi <F II.ill) ~ Ali> SlllJ.M SIDcEl1lfl <F ~ aJ6.HIR:i •~• WISE \HY. 19 •~
VFJS.6'-fff2.IRJI.EHIVHSEW-U:2.
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
BP W<2 3.a:m 10.488 4.282
BP W<l 3.fll57 8.C¼2 3.283 6 .fll57. 6.400 2.616 .7CJ2 .00) .25 5 .ro) .405
BPW<2 3.a:m 10.lffl 4.282
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<l 26.~ 2.510 1.025 6 -1.a:m 2.757 1.125 .649 .163 -.89 5 .415 .200 ss WK2 27.~ 3.619 1.478
VI
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
86
amount of sodium and chloride in the urine. NC-1 had normal adrenal
status in the pre-test condition.
Table 4, the CORRELATED T-TEST COMPARI NG THE MEANS OF SODIUM
SECRETION "PRE" VERSUS WEEK 1, "PRE" VERSUS WEEK 2, AND WEEK 1 VERSUS
WEEK 2 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 f or one week did affect adrenal function
if measured by sodium secretion. The wea kened adrenal function was
ac t ually more evident at the end of the second week. We have no
hypothesis as to why this occurred.
87
COMPARISON ACROSS SUBJECT GROUPS - CAFFEINE SUBJECTS 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, BLOOD PRESSURES 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
88
5
0 ~-~T'.J·q· . l"IIIJ~l,www.www... lw.uf..-,_j
-~ 1111 -10
IMIJW llft!IHN llliffllll~ ~• •lfWI I -: I Bl ~ 1 . -15 ~ID k..1:ffl~ lii~1:i:11 tmml 111 t~,
UAL IRI ~ leruJ IUR~~I U 1111
-Z0 -111 -tmffl lftil Ill -Ill mo trua
-25
- 30 ·
-35 ...
-40 Cl C2 CJ CJ1 <:.5 C6 C7 ~O C9 C 10 C 11
111,00D PHESSllHE A FIGURE 2. Ul.0011 PRESSURES OF CAFFl•:INI •: CONSUHl~RS - UAR REPRESENTATION OF DATA IN
TABLE 4.
f ■ PRE-TE~T I
l II UEEK 1 I t la 1-lEEK 2
00
'°
4 &JIM & HW&?tiiY
... (JI
J.rJ ~ N ... ' X ::r: ~ Ioli ~ = ~ Q,. :l :x
90
• ■ m
< :-< Q
:.a.. ~ 0
~ z 0 -:-< -z ::.: Cl) ::.= , .. ., Qi:: A
~ ~ Qi::
:II: < =
~ :r. t,;J :a::
"' - ~ - :r: c.J --'" ;,') -: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 ~ -
..J :a..
<: :>
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,
SODIUM SECRETION OF NON-CAFFEINE CONSUMERS, 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, MEDICAL INDEX, WEIGHTED COMBINATION OF BLOOD
PRESSURE AND 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
91
-~ · .... ._
4~
30 ,J..
VOL 20
10
0 NC. I l«..2 M: J
;. :i ::~ i l I: . I!
~~~;f;:~ i1,~ \~i~m. I: i~i{
,i.:: · .. ,q . ii1/ • • I ~-
'. :tj~• ,~!l_.F.'.
W.!l' 11\1; ,,,r.,. - ~!:!~~~~
~:j' .=:! l•F.··= i :i- 1A_; tif►•.L; '"' " . ., i! ,.; ;. j-r:f~ ~,·-.111 i:r1:1 .:..i-: , • .
J'tlit: .,_ t • ~I • , .. •1.1,
!!i'IRJt,C!I~~ \~Wi .;-;~111 , , t ·1-.:·
AA:. 'I
:,qd t.{/t
S 01• I Uti E>CCJU:T 1\)11
li-·i:1 I~ ·· • ';I' , ~:. ;ilf:r lr~i·
t.¼tr '~"1!; ~; , ~-r~f I i ... : ·
J~:. ~~r1 ~~·tW
I'~,~
~ ~}.I ~t :~
~?1 .lt-1:; iJt: ;I ; •
·f: w. ., ... -:.j1 ~.,;]
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~:r.;
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'it.i:1 '·.: '·I" . ~;~ ; .. . t::· I fil !pl.;:11 :{,;:11 =.·.C~:l 'l •! I :;, I: • • '·1 JI •• ~
4~/ !:, ':!.1: I!; :r.··-;:-1i.I/, rl.1::c::·1 .... , -· ;i:'L:J-i
FIGURE '•. SOil 1 IIM SECRET I ON OF NON-CA FF El NI•: CONSllHl~RS - BAR Rf.PRESENTATION OF DATA IN TAHI.E 8.
-- --
■ PRE--V-E~T
fl ~EEK
ri1 WEEK
'° N
1
2 _I
40
30
20 ----
I Jg ....... ..... ....,.
VAL 0 ::,-~,_:,_:••1-1 I~ r._ I ·r . 11 -10 + Ill II IDl IIJ
lffli
-20 -
- 30 (,- 1 2 J 4 ~ 6 7 u 9 i 0 11 tic.- I 1.. ~ 'I- 5 <o
HEI>. 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 (Bl.ACK UAKS) ANU P.ND Of' WP.F.K l COHPAKED TO END OF WF.El 2 (l,lGIITER BARS)
I■ ~EEK 1
I ■ WF.EI( 2
'° w
~f
-, 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/CATABOLIC INDEX
Introduction
The composite index of urine data is presented in Table 10,
ANABOLIC/ CATABOLIC INDEX OF CAFFEINE AND NON-CAFFEINE CONSUMERS "PRE,"
END OF WEEK 1 AND END OF WEEK 2. 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.
94
I
~
TABLE IO. ANA.BOLIC/CATABOLIC INDEX OF CAFFEINE AND NON-CAFFEINE CX>NSUMERS "PRE," END OF WEEK l, AND END 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 COLUMN TOTALS
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
I . I I I I
.~VERAG INDEX I (NC) I I_ 37.7 35.0 36.2 2.7 -1.2
CAFFEINE SUBJECTS
Results: The 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 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.
.,
TAIIE 11. CIH9.A1FD T-'IFSI' CDRRDC 'DE r£VE CF ANAllLIC/C\TAIU DtEC CF CAmillE 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
AC W<2 liO.<Xm 9.675 2.917
AC WCI 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-CAFFEINE SUBJECTS
The CORRELATED T-TEST COMPARING THE ANABOLIC/CATABOLIC INDEX "PRE"
VERSUS WEEK 11 "PRE" VERSUS WEEK 2 1 AND WEEK 1 VERSUS WEEK 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.
PSYCHOLOGICAL EFFECTS
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 MOOD INDEX included questions 1, 2, 4, 6, 9, and 10; and
the SLEEP INDEX included 7a, 7b, and 7c. The PSYCHOLOGICAL INDEX
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.E U. CimIAm> T-'IFSI' CIJl>ARDC 'DE NWDJC/OOAHLTC DIE( 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.<m 4.527 .500 .228 -.26 5 .007 .403
N:, W(2 36.1667 10.'H> 4.483
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 PHYSIOLOGICAL INDEX, 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.
100
- 4 .£
6
· VAL O -t--•-
-2
-4
_, C.-1 2 J •1
•
5 6 7· U CJ 10 11 NC- I Z. 3 f 5 ti, HOOD A
■ MEEJ< 1
II MEEI< 2
FIGURE 6. HOOD, PSYCHOLOGICAL EPl'ECTS VIA QUESTIONNAIRE. COMPARISON OP END OF WEEl 1 TO "PRR" (IlLACI HAR) AND RND OP WEE( 2 TO END OP WEE( l (LIGHTER DAR).
..... 0 .....
CAfl'RINE SUBJECTS.
I We analyzed Figure 7 by focusing upon the lighter bars which
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-CAFFEINE SUBJECTS
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
102
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2 ·1 ~~ RJ II I ffl~I II BHtJ faM I~ 111111
VAL 0 -l_all-fW.- 111,rt,_ U1111aaml,.. ~maall..f~l-t .r- t11111131 .. r ■ IJEEK 1 ,uwi,-., I 1r11r i 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
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 INDEX represents the three questions 7a, 7b, and 7c;
depicting insomnia, difficulty falling sleep, and difficulty staying
104
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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 s o that a positive response such as "less"
insomnia is depicted with a positive bar.
CAFFEINE SUBJECTS
Results: Three C subjects had sleep problems during Week 1 (C-1,
-4; C-4, -6; C-1 1, - 4). Two had improvement in s leep (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-CAFFEINE SUBJECTS
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
107
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1tma 1mma, t---1~--· r:GI
9 10 11 N::..-I SLEEP h.
2-'3~5(o
■ J.4£EK 1
■ J.4EEK 2
FIGURE 10. SI.RRP INDEX. SI.REP RFPRCTS VIA QUESTIONNAIRE. COHPARISON OF END OF WEE( I TO "PRE" (RLACI BAR) AND END OF WEEI 2 TO RND OF WEEI I (LIGIITER BAR).~ CAFFEINE SUBJECTS m
r i -1
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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.
PHYSIOLOGICAL EFFECTS
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).
CAFFEINE SUBJECTS
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) .
110
~
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2
1
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-3 .•.
-4 C-1 2 3 4 5 6 · 7 o 9 10 11 NC- I
l'IIVSIOLOGICnL /} 2.."3"" 5' ~
~--- - - -- - - -ll ~EEK 1
U MEE.K 2
,_. ,_.
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-
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-CAFFEINE SUBJECTS
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.
112
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ill;U~F. 13. PIIYSIOI.OGICAI. INDEX. PIIYSIOLOGIC .Al. F.1111F.CTS VIA QUF.STIONNAlRF.. COHPARISON OV F.ND 011 WF.F.l I TO."PRE" (RLACl UAR) AND END OF WEEl 2 TO END OV WF.F.l 1 (1.ICIITV.R UAR). NON!.CAl1fF.INF. SUBJECTS.
Conclusions
CHAPTER 5
CONCLUSIONS AND RECXlMMENDATIONS
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 B5
(Pantothenic Acid) in the range of 300-800 mg/ day
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. B2 (Ribofla~in) in the range of 1-3 mg/day
7. B3 (Niacin) in the range of 12-36 mg/day
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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-,-
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--~.------~ .. .:...:. ~ .- -oil""I',...-~
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- ------4
f I ' i
APPENDICF.S
1' • I
! !
145
' Name:
APPENDIX B CAFFEINE STUDY
Daily Diary
Day of Week ----- -----
147
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: Comments:
2. a) Concentra ti on:
b) Attention span: Comments:
3. a) Nervousness:
b) Depression:
c) Mood: Comments:
4. Irritability Comments:
S. Muscular strength: Comments:
6. Sense of well-being Comments:
7. Falling asleep: · Comments:
8. Endurance: Comments:
9. Headaches: Comments:
10. Appetite: Comments:
11. For smokers: ci garette use:
Comments:
/1 less II same
It poorer II same
It shorter II same
/1 less II same
It less II same
11 l ess II same
It less II same
It less II same
11 less LJ same
more 11 difficult II same
It less II same
;-r worse a same
It poorer It same
11 less II same
It more
It better
It longer
It more
It more
It more
O more
O more
It more
;-r easier
It more
It improved
It improved
It more
,, =.c • - --~
Name:
APPENDIX C CAFFEINE STUDY QUESTIONNAIRE
Plate I Sex:
To be answered prior_!:£ study
148
Age:
1. Approximately how many cups of CAFFEINATED coffee 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 CAFFEINATED tea do you drink per day ? (Note t hat 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 CAFFEINATED sodas 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?
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 approx imatel y how many cigarettes per day?
Never Occasionally Frequently
If you do smoke,
1 I
I
I
Name:
APPENDIX C CAFFEINE STIJDY QUFSTIONNAIRE
Plate I Sex: ---
To be answered prior !.2_ study
148
Age:
1. Approximately how many cups of CAFFEINATED coffee do you drink per day?
r-t 1 r-t 2 r-t 3-5 r-t more than 5
2. ARppoximately how many (Note that HERBAL teas
cups of CAFFEINATED tea do you drink are NOT CAFFEINATED)
per day?
r-t 1 r-t 2 r-t 3-5 r-t more than 5
3. How many ounces of CAFFEINATED sodas 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
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?
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 approximately how many cigarettes per day?
Never Occasionally Freque~tly
If you do smoke,
- - --- ----- ... _(1111.t-•,!LII
l Name:
CAFFEINE STUDY QUESTIONNAIRE
Part II
Week:
To be filled out AFTER Week One and Week Two of the study.
149
Answer the following according to how you usually felt during the previous week.
Less Same --
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. NONSMOKERS tmtY
13. For smokers only: Did you notice anything difterenh from usual? If yes,' explain.
14. For smokers only: Cigarette use per day:
r-t No r-t Yes
____ cigarettes
More --
--
--
--
------
--
----
--
--
1 Appendix D
PEARSON CORRELATION COEFFICIENTS BETWEEN BLOOD PR.FSSURE AND SODIOM S&::RE'IION FOR ''PRE~ WEEl I, AND WEEK 2.
CAFFEINE SOBJ7"S.
Introduction
150
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 NEGATIVE correlation 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, PEARSON CORRELATION COEFFICIENTS BETWEEN .BLOOD PRESSURE
AND SODIUM SECRETION FOR "PRE, 11 WEEK 1, AND WEEK 2, CAFFEINE SUBJECTS, 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).
l
1
\ I
dfEA&¥11&t SH&±+H
151
TABLE Dl. PEARSON CO~TION COEFFICIENTS BETWEEN BLOOD PRESSURE AND SODIUM SF.CRfil'ION FOR PRE," WEE[ 1, AND WEEI 2. CAFFEINE SUBJECTS.
BP "Pre"
BP "PRE" 1.0000 ( 0) p = •
BP WKl .5062 ( 11) p = .056
.4646 ( 11) p = .075
BP WK2
-. 8641 ( 11) p = .ooo
SS "PRE"
-.6802 ( 11) p = .011
SS WKl
-.5132 ( 11) p = .053
SS WK2
BP WK 1 BP WK2
1.0 000 ( ) p = •
.4568 ( 11) p = .079
1.0000 ( ) p = •
-.5708 ( 11) p = .033
-.6784 ( 11) p = .011
-.8515 -.5 810 ( 11) ( 11) p = .ooo p = .030
-.1899 -.7 908 ( 11) ( 11) p = .288 p = .002
SS "PRE" SS WK 1
1.0000 ( ) p :z •
• 8508 ( 11) p = .ooo
1.0000 ( ) p :::r •
• 7733 ( 11) p = .028
• 5904 ( 11) p = .028
SS WK2
1.0000 ( 0) p =
7 6 ;;ca,;
1 152
Appendix E
PEARSON CORRELAilON ~EFFICIENTS BETWEEN BLOOD PRFSSURE AND SODIUM SF.CRETION FOR 'PRE,' WEEK 1, AND WEEK 2. NON-CAFFEINE SUBJECI'S.
Appendix E, THE PEARSON CORRELATION COEFFICIENTS BETWEEN BLOOD PRESSURE
AND SODIUM SECRETION FOR "PRE," WEEK 1, AND WEEK 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
TABLE El. PEARSON CO~TIOH COEFFICIENTS BETWEEN BLOOD PRESSURE AND SODIUM SECRETION FOR PRE," WEEK 1, AND WEEK: 2. NOH-CAFFEINE SUBJECI'S.
BP "Pre" BP WK 1 BP WK2 SS "PRE" SS WK 1 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~ ( 6t ( 64 ( ) p = .1 7 pc: .3 9 p = .3 6 p = •
ss WK.1 -.0502 -.9017 -.8585 .1503 1.0000 ( 66 ( 66 ( 61 < 6a ( O) p = .4 2 p = .o 7 p = .o 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 = •
I !
154
APPENDIX F
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
Variable
BP "Pre"
C NC
SS "Pre"
C NC
Table Fl
Comparison of Caffein e and Non~ffeine Subjects at "Pre" Status
Number of Cases
11 6
11 6
Mean
-12.0909 4.3333
40.9091 23.8333
Standard Deviation
9.513 7.941
13. 736 5.037
Standard Error
2.868 3.242
4.142 2.056
T- Value
-3.59
2.90
Degrees of 2-Tail Freedom Probability
15 .003
15 .011
1-Tail Probability
.002
.006
t-J
Vl Vl
_....
Variable
Blood Press ure
C - Week 1 NC - Week 2
Sodi um Secretion
C - Week 1 NC - Week 2
Number of Cases
11 6
11 6
Table F2
Comparison of Caffeine Group End of Week One with Non-Caffeine Group End of Week Two
Mean
-1 1. 7273 3.0000
·38.4545 27.5000
Standard Deviation
11.884 10.488
13.779 3.619
Standard Error
3 . 584 4.282
4.155 1.478
Degrees of T-Value Freedom
- 2.54 15
1.80 15
2-Tail Probabili ty
,023
.079
1- Tail Probability
.012
.040
...... 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.
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