The Psychopharmacology of Caffeine

A MEDLINE Search By, Ivan Goldberg, MD

J Clin Pharmacol 1997 Aug;37(8):693-703

[MEDLINE record in process]

Dose-dependent pharmacokinetics and psychomotor effects of caffeine in

Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Cotreau MM, Harmatz JS,
Shader RI

Department of Psychiatry and Human Behavior, Brown University, Providence,
Rhode Island.

Twelve healthy volunteers received oral placebo, 250 mg of caffeine, and
500 mg of caffeine in a randomized, double-blind, single-dose crossover
study. Caffeine kinetics were nonlinear, with clearance significantly
reduced and elimination half-life prolonged at the 500-mg compared to the
250-mg dose. The lower dose of caffeine produced more favorable subjective
effects than the higher dose (elation, peacefulness, pleasantness), whereas
unpleasant effects (tension, nervousness, anxiety, excitement,
irritability, nausea, palpitations, restlessness) following the 500-mg dose
exceeded those of the 250-mg dose. The lower dose of caffeine enhanced
performance on the digit symbol substitution test and a tapping speed test
compared to placebo; high-dose caffeine produced less performance
enhancement than the lower dose. The plasma concentration versus response
relationship revealed concentration-dependent increases in anxiety and
improvements in cognitive and motor performance at low to intermediate
concentrations. Both caffeine doses reduced electroencephalographic
amplitude over the 4 Hz to 30 Hz spectrum, as well as in the alpha (8-11
Hz) and beta (12-30 Hz) ranges; however, effects were not dose-dependent.
While favorable subjective and performance-enhancing stimulant effects
occur at low to intermediate caffeine doses, the unfavorable subjective and
somatic effects, as well as performance disruption, from high doses of
caffeine may intrinsically limit the doses of caffeine used in the general

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Brain Res 1997 Jan 30;747(1):78-84

Caffeine and light effects on nighttime melatonin and temperature levels in
sleep-deprived humans.

Wright KP Jr, Badia P, Myers BL, Plenzler SC, Hakel M

Department of Psychology, Bowling Green State University, OH, USA.

The effects of caffeine ingestion and exposure to bright light, both
separately and in combination, on salivary melatonin and tympanic
temperature were assessed in humans. Four treatments during a 45.5 h sleep
deprivation period were compared: Dim Light-Placebo, Dim Light-Caffeine,
Bright Light-Placebo and Bright-Light Caffeine. The Dim Light-Caffeine
condition (200 mg twice each night) relative to the Dim Light-Placebo
condition suppressed nighttime melatonin levels and attenuated the normal
decrease in temperature. Combining caffeine ingestion with bright light
exposure (> or = 2000 lux) suppressed melatonin and attenuated the normal
nighttime drop in temperature to a larger degree than either condition
alone; i.e. effects were additive. Circadian effects were also observed in
that the amplitude and phase of the temperature rhythm were altered during
treatment. These findings establish that the human melatonin system is
responsive to caffeine. Other evidence suggests that caffeine may influence
melatonin and temperature levels through antagonism of the neuromodulator

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Biol Psychiatry 1996 Dec 15;40(12):1218-1221

A study of the potential confounding effects of diet, caffeine, nicotine
and lorazepam on the stability of plasma and urinary homovanillic acid
levels in patients with schizophrenia.

Donnelly CL, McEvoy JP, Wilson WH, Narasimhachari N

Duke University Medical Center, Durham, NC, USA.

Ten men inpatients who met DSM-III-R criteria for schizophrenia
participated. On five occasions at least one week apart, each subject had
an intravenous line placed at 0730 after an overnight fast. On each
occasion blood samples were drawn at 0800 and hourly thereafter through
1200 noon for measurement of plasma homovanillic acid (HVA). Total
four-hour urine collections were obtained for measurement of urinary HVA.
Subjects received five experimental conditions, in randomized sequence: no
intervention, smoking one cigarette per hour, drinking one caffeinated cola
per hour, lorazepam 2 mg IV push, or a high monoamine meal. Baseline (0800)
plasma HVA measures showed only minor intrinsic variability. The average
standard deviation in baseline plasma HVA over five occasions of
measurement was low relative to the changes in HVA produced during
treatment with antipsychotic medications. The high monoamine meal
significantly elevated plasma HVA, with a similar trend for urinary HVA.
Neither caffeine, nicotine, nor lorazepam significantly affected plasma or
urinary HVA.

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Psychosomatics 1996 Nov;37(6):518-522

Consumption of alcohol, nicotine, and caffeine among depressed outpatients.
Relationship with response to treatment.

Worthington J, Fava M, Agustin C, Alpert J, Nierenberg AA, Pava JA,
Rosenbaum JF

Depression Research Program, Clinical Psychopharmacology Unit,
Massachusetts General Hospital, Boston 02114, USA.

The authors present findings from the first investigation of the use of
alcohol, nicotine, and caffeine in nonsubstance-abusing outpatients with
major depressive disorder. The patients (N = 94) were assessed for their
intake of alcohol, nicotine, and caffeine, and then treated openly for 8
weeks with 20 mg/day of fluoxetine. The degree of alcohol consumption at
baseline was a significant predictor of poorer response to the
antidepressant. This relationship remained significant even after adjusting
for severity of depression at baseline. Even moderate levels of alcohol
consumption appear to negatively affect pharmacologic treatment in
depressed outpatients.

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Psychol Rep 1996 Jun;78(3 Pt 1):915-923

Chronic psychiatric patients' use of caffeine: pharmacological effects and

Kruger A

University of British Columbia, Vancouver, Canada.

The uses and effects of caffeine as a psychoactive drug in chronic
psychiatric inpatient groups are described. Caffeine use and abuse is
linked etiologically to diverse psychiatric disorders; its mechanisms of
action are examined in relation to anxiety, anxiety neuroses, psychosis,
schizophrenia, and caffeine intoxication and dependence. It is postulated
that deleterious effects may result from the interaction of caffeine with
commonly prescribed psychotropic drugs. A possible model of caffeine abuse
is discussed. Increased public education about potential health problems
related to caffeine consumption is suggested, and further controls of
caffeine in psychiatric settings are recommended.

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Mil Med 1996 Apr;161(4):230-232

Is caffeine involved in the pathogenesis of combat-stress reaction?

Iancu I, Dolberg OT, Zohar J

Psychiatric Division, Sheba Medical Center, Tel Hashomer, Israel.

The role of caffeine in the pathogenesis of combat-stress reaction is
discussed in light of the expanding literature on caffeine's influence on
stress reactions in animals and in humans, and in regard to the two
clinical entities concerning caffeine: caffeinism and caffeine withdrawal.
It is proposed that caffeine is a contributing factor to the development of
combat-stress reaction and that the use of decaffeinated coffee in military
settings might reduce the prevalence of the various anxiety reactions,
including combat-stress reaction.

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Addiction 1996 Feb;91(2):269-273

The effect of caffeine on cue exposure responses in ex-smokers.

Hepple J, Robson P

Chilton Clinic, Warneford Hospital, Oxford, UK.

The responses of ex-smokers to an experimental cue exposure trial, and the
effect of caffeine on these responses, were compared with those of a
matched group of control subjects in a placebo controlled single-blind
cross-over design. In contrast to placebo, caffeine protected the
ex-smokers from a surge of anxiety and rise in blood pressure associated
with exposure to smoking-related cues. Caffeine had no significant effects
on the control group at this dose (equivalent to a single cup of strong
coffee). The results are discussed with reference to Stewart's conditioned
appetitive motivational model of addiction. It is suggested that further
work may identify caffeine as an adjunct to smoking relapse prevention

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Eur Arch Psychiatry Clin Neurosci 1996;246(2):83-92

Caffeine consumption in hospitalized psychiatric patients.

Rihs M, Muller C, Baumann P

Unite de biochimie et psychopharmacologie clinique, Departement
universitaire de psychiatrie adulte, Lausanne, Switzerland.

A total of 98 consecutively admitted psychiatric inpatients were asked for
their daily consumption of coffee, tea and other products containing
caffeine. Calculation of the corresponding daily caffeine intake was
performed using data from the literature and from caffeine measurements
carried out in different coffee and tea preparations in the hospital. Of
the patients 13% presented a high (> or = 750 mg daily) caffeine
consumption before hospitalization. The average caffeine consumption per
day decreased from 405 mg before to 332 mg during hospitalization (P <
0.04), but the before and during hospitalization caffeine consumptions were
highly correlated (rho = 0.651; P < 0.00001). The decrease in caffeine
consumption seems to be influenced by a lower availability of caffeine at
hospital. Among the diagnostic groups (DSM-III-R criteria), the caffeine
intake was highest in schizophrenia and lowest in anxiety and major
depression patients. Patients under a neuroleptic treatment before
admission presented a higher caffeine intake. At hospital the high caffeine
users showed the highest score on the factor depression (Hopkins Symptom
Checklist; HSCL-58). However, the influence of other factors, such as
weight and cigarette consumption, which correlated also with the caffeine
intake (rho = 0.359; P < 0.001; and rho = 0.83; P < 0.00001, respectively),
have also to be considered. Our data suggest that inquiry into caffeine
consumption should be included routinely for psychiatric patients, e.g. at
admission, because patients with a psychotic disorder undergo a higher risk
for an excessive caffeine consumption.

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J Clin Psychopharmacol 1995 Oct;15(5):376-377

Comments to "interaction between caffeine and clozapine".


Carrillo JA, Jerling M, Bertilsson L


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Psychopharmacology (Berl) 1995 Oct;121(4):494-502

Pharmacokinetic and pharmacodynamic responses to caffeine in poor and
normal sleepers.

Tiffin P, Ashton H, Marsh R, Kamali F

Department of Pharmacological Sciences, University of Newcastle upon Tyne,

Pharmacokinetic and pharmacodynamic responses to caffeine (2.5 mg/kg) were
compared between ten healthy self-rated poor sleepers and ten normal
sleepers. Sleep pattern assessed by the Pittsburgh Sleep Quality Index
(PSQI). There was no significant difference in mean estimated daily
caffeine consumption between the groups. The poor sleepers had
significantly higher scores for neuroticism on the Eysenck Personality
Questionnaire (EPQ) and anxiety on the Hospital Anxiety Depression (HAD)
scale, compared with normal sleepers. Caffeine pharmacokinetics were
assessed by measurement of saliva caffeine concentrations. Poor sleepers
showed significantly greater variability in caffeine Cmax, clearance had
half-life, compared to normal sleepers. Pharmacodynamic measures included
heart rate, blood pressure, visual analogue scales for concentration,
vigilance and relaxation, psychomotor performance [Digit Symbol
Substitution Test (DSST) and tapping rate (TR)] and EEG activity
[Contingent negative variation (CNV), auditory evoked potential and power
spectral analysis]. Prior to caffeine administration, poor sleepers
compared to normal sleepers had faster heart rates, lower ratings for
concentration and relaxation, poorer performance on the DSST, greater CNV
magnitude, faster peak alpha frequency and lower delta, theta and beta
power. These differences persisted after caffeine ingestion and overall
differences between the groups on these measures were significant (P <
0.01-.001). Post-dose, but not pre-dose, scores for vigilance and TR were
significantly lower overall in poor compared with normal sleepers. Despite
the baseline differences between poor and normal sleepers, the changes
following caffeine administration were similar in direction and magnitude
in both groups.

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Clin J Pain 1995 Sep;11(3):214-219

Caffeine and chronic low back pain.

Currie SR, Wilson KG, Gauthier ST

Department of Medicine, School of Psychology, University of Ottawa,
Ontario, Canada.

OBJECTIVE: Although caffeine apparently plays a role in the modulation of
pain perception in a variety of acute pain states, little is known about
its effects on the experience of chronic pain. This exploratory study
examined the relationship between dietary caffeine consumption and the
symptoms reported by patients with chronic low back pain. DESIGN AND
PATIENTS: A retrospective chart review was conducted of 131 patients with
chronic low back pain (64 men and 67 women; mean age = 42.1 years; mean
duration of pain = 6.1 years) referred to a multidisciplinary pain clinic
over a 2-year period. Patients were classified as low (less than 100 mg; n
= 34), moderate (100-400 mg; n = 68) or high (more than 400 mg; n = 29)
caffeine users based on their self-reports of daily coffee, tea, and cola
consumption. RESULTS: There were no significant differences among the low,
medium, and high caffeine consumer groups on any self-report measure of
pain severity, affective distress, anxiety-related symptoms, or sleeping
behavior. High caffeine users were more likely to be tobacco smokers than
low caffeine users (79% and 27%, respectively, p < 0.001). CONCLUSIONS: Our
findings indicate that dietary caffeine consumption is not related to the
global experience of pain and disability in patients with chronic low back
pain, although high caffeine use may be embedded in a context of other
unhealthy life-style behaviors.

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J Nerv Ment Dis 1995 Sep;183(9):559-565

Alcohol, cannabis, nicotine, and caffeine use and symptom distress in

Hamera E, Schneider JK, Deviney S

School of Nursing, University of Kansas Medical Center, Kansas City
66160-7700, USA.

The high prevalence of substance use, e.g., alcohol and illegal and
nonprescribed drugs, in schizophrenia is widely recognized. One explanation
for this high prevalence is that substance use may be a self-initiated
method for managing symptoms. To test whether the intake of four
substances--alcohol, cannabis, nicotine, and caffeine--would increase with
increases in symptom distress, daily self-reports of symptom distress and
substance intake over 12 weeks were analyzed with pooled time series
analyses. Compliance with neuroleptic medication was added to the analyses
to control for any changes in prescribed medication compliance while using
nonprescribed drugs or alcohol. Of the four substances studied, only
nicotine was significantly related to symptom distress. Higher distress
with prodromal symptoms was related to decreases in nicotine use. Analysis
of caffeine did not meet the criteria for significance but does provide
direction for further research. Higher distress, with neurotic symptoms,
was related to increases in caffeine use. Further research is needed to
clarify the relationship between nicotine and symptoms.

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BMJ 1995 Aug 26;311(7004):531-535

Preterm delivery: effects of socioeconomic factors, psychological stress,
smoking, alcohol, and caffeine.

Peacock JL, Bland JM, Anderson HR

Department of Public Health Sciences, St George's Hospital Medical School,

OBJECTIVE--To examine the relation between preterm birth and socioeconomic
and psychological factors, smoking, and alcohol, and caffeine consumption.
DESIGN--Prospective study of outcome of pregnancy. SETTING--District
general hospital in inner London. PARTICIPANTS--1860 consecutive white
women booking for delivery; 1513 women studied after exclusion because of
multiple pregnancy and diabetes, refusals, and loss to follow up.
MEASUREMENTS--Gestational age was determined from ultrasound and maternal
dates; preterm birth was defined as less than 37 completed weeks.
Independent variables included smoking, alcohol and caffeine consumption,
and a range of indicators of socioeconomic status and psychological stress.
MAIN RESULTS--Unifactorial analyses showed that lower social class, less
education, single marital status, low income, trouble with "nerves" and
depression, help from professional agencies, and little contact with
neighbours were all significantly associated with an increased risk of
preterm birth. There were no apparent effects of smoking, alcohol, or
caffeine on the length of gestation overall, although there was an
association between smoking and delivery before 32 weeks. Cluster analysis
indicated three subgroups of women delivering preterm: two predominantly of
low social status and a third of older women with higher social status who
did not smoke. Mean gestational age was highest in the third group.
CONCLUSIONS--Adverse social circumstances are associated with preterm birth
but smoking is not, apart from an association with very early births. This
runs counter to findings for fetal growth (birth weight for gestational
age) in this study, where a strong effect of smoking on fetal growth was
observed but there was no evidence for any association with psychosocial

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Physiol Behav 1995 Jun;57(6):1117-1125

Caffeine and time of day effects on a force discrimination task in humans.

Miller LS, Lombardo TW, Fowler SC

Department of Psychology, University of Georgia, Athens 30602-3013, USA.

The effects of caffeine (0 mg/kg, 1 mg/kg, 3 mg/kg) and time of day (TOD)
on human performance were studied using a multiple forceband discrimination
task (MFDT) and subjective ratings. Self-rated measures of energy level
were affected by TOD and caffeine, while mood was affected by TOD. Energy
level decreased throughout the day and was offset by caffeine which
increased energy level independent of TOD. Self-reported anxiety was not
affected by TOD or caffeine. Mood was affected by TOD in a complex cubic
trend with late morning and late evening peaks 12 h apart. MFDT performance
was affected by TOD, caffeine dosage, and their interaction. Trend analyses
showed varying patterns of TOD effects across peak force variability,
response latency, response duration, and correct responding. Results
support and extend previous findings of TOD influences on the MFDT and
support the utility of multicomponent proprioceptive tasks for examining
drug effects on performance.

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Behav Res Ther 1995 Jun;33(5):561-566

Alcohol and caffeine use by social phobics: an initial inquiry into
drinking patterns and behavior.

Holle C, Heimberg RG, Sweet RA, Holt CS

Department of Psychology, University at Albany, State University of New
York 12205, USA.

Social phobics are often fearful that their anxiety symptoms will cause
them embarrassment and lead to negative evaluation from others. Thus, it
was hypothesized that they might attempt to control the intake of
substances such as alcohol and caffeine that may affect their anxiety in
social situations. The current investigation sought to determine, via a
self-report questionnaire, whether the alcohol and caffeine consumption
patterns of social phobics differ from those of community controls in terms
of typical and greatest weekly quantities and how social phobics differ
from controls in alcohol and caffeine use in a variety of socially
threatening and nonthreatening situations. Social phobics reported less
typical weekly beverage consumption than community subjects. Specifically,
social phobics reported less consumption of wine and liqueur than community
subjects but did not differ from community subjects in typical weekly
consumption of caffeinated beverages. Further, social phobics reported a
significantly greater intent to drink alcohol while in social situations
involving strangers and significantly less intent to drink caffeinated
coffee in meetings than did community subjects. Finally, a number of gender
differences were found for both alcohol and caffeine consumption in
specific situations, and the implications of these findings are discussed.

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Psychophysiology 1995 Jan;32(1):19-27

Caffeine and smoking: subjective, performance, and psychophysiological

Pritchard WS, Robinson JH, deBethizy JD, Davis RA, Stiles MF

Psychophysiology Laboratory, Bowman Gray Technical Center, R.J. Reynolds
Tobacco Company, Winston-Salem, NC 27102.

The effects of caffeine and smoking on cognitive performance, subjective
variables, heart rate, and EEG were assessed in two sessions. In one
session, subjects received caffeine (2.5 mg/kg bodyweight), while in the
other they received placebo. In both sessions they smoked a cigarette (8
cued puffs) having a nicotine yield of 1.2 mg. Caffeine produced an
increase in self-reported muscular tension and tended to increase anxiety
and delta magnitude. Smoking facilitated performance of a paper-and-pencil
math task and increased heart rate. Smoking also appeared to produce
cortical activation as indexed by decreased right frontal delta, decreased
right centro-parietal theta, globally increased alpha, and increased
centro-occipital/decreased posterior-temporal beta 1. Smoking also
increased central/decreased posterior-temporal beta 2. Smoking and caffeine
did not interact for any measure, suggesting that the epidemiological link
between smoking and coffee drinking may have a non-pharmacological basis.

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Drugs 1995 Jan;49(1):37-50

Pharmacological rationale for the clinical use of caffeine.

Sawynok J

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia,

Caffeine is widely consumed in beverages to obtain mild CNS stimulant
effects. Long term use produces tolerance to some of the pharmacological
effects. Withdrawal of caffeine, even from moderate intake levels, can
produce symptoms such as headache, fatigue and anxiety. Caffeine is used
therapeutically in combination with ergotamine for migraine headaches and
in combination with nonsteroidal anti-inflammatory drugs in analgesic
formulations. Caffeine alone is used as a somnolytic, to treat various
headache conditions, respiratory depression in neonates, postprandial
hypotension and obesity, and to enhance seizure duration in
electroconvulsive therapy. In some headache and in pain paradigms, caffeine
may produce direct adjuvant analgesic properties, while in other headache
conditions (perioperative, postdural puncture) caffeine may be effective by
alleviating a manifestation of caffeine withdrawal. Other uses, such as to
promote wakefulness, for respiratory stimulation and seizure prolongation,
rely on central stimulant properties of caffeine. Effects of caffeine on
the vasculature may contribute to the relief of some headaches and in
postprandial hypotension. Blockade of methylxanthine-sensitive adenosine
receptors is the currently accepted mechanism of action of caffeine.

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Radiat Res 1994 Dec;140(3):393-400

Increased expression of cyclin B1 mRNA coincides with diminished G2-phase
arrest in irradiated HeLa cells treated with staurosporine or caffeine.

Bernhard EJ, Maity A, Muschel RJ, McKenna WG

Department of Radiation Oncology, University of Pennsylvania School of
Medicine, Philadelphia 19104.

The irradiation of cells results in delayed progression through the G2
phase of the cell cycle. Treatment of irradiated HeLa cells with caffeine
greatly reduces the G2-phase delay, while caffeine does not alter
progression of cells through the cell cycle in unirradiated cells. In this
report we demonstrate that treatment of HeLa cells with the kinase
inhibitor staurosporine, but not with the inhibitor H7, also results in a
reduction of the G2-phase arrest after irradiation. Cell cycle progression
in unirradiated cells is unaffected by 4.4 nM (2 ng/ml) staurosporine,
which releases the radiation-induced G2-phase arrest. In HeLa cells, the
G2-phase delay after irradiation in S phase is accompanied by decreased
expression of cyclin B1 mRNA. Coincident with the reduction in G2-phase
delay, we observed an increase in cyclin B1 mRNA accumulation in
irradiated, staurosporine-treated cells compared to cells treated with
irradiation alone. Caffeine treatment of irradiated HeLa cells also
resulted in an elevation in the levels of cyclin B1 message. These results
support the hypothesis that diminished cyclin B1 mRNA levels influence
G2-phase arrest to some degree. The findings that both staurosporine and
caffeine treatments reverse the depression in cyclin B1 expression suggest
that these two compounds may act on a common pathway of cell cycle control
in response to radiation injury.

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Br J Clin Pharmacol 1994 Dec;38(6):573-576

Inhibition of caffeine metabolism by ciprofloxacin in children with cystic
fibrosis as measured by the caffeine breath test.

Parker AC, Preston T, Heaf D, Kitteringham NR, Choonara I

Institute of Child Health, Alder Hey Children's Hospital, Liverpool.

The caffeine breath test was carried out in six children with cystic
fibrosis, before and during a course of ciprofloxacin. There was a
significant decrease in the 2 h cumulative labelled CO2 exhaled during
ciprofloxacin treatment, mean difference (s.d.) -5.2(3.3)%, P < 0.02. The
results suggest an inhibition of 3-N-demethylation of caffeine (CYP1A2
enzyme activity) by ciprofloxacin. Ciprofloxacin may cause significant drug
interactions in children with cystic fibrosis. The caffeine breath test can
be used to study drug interactions involving CYP1A2 in children.

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Neurotoxicol Teratol 1994 Nov;16(6):531-543

Potential teratogenic and neurodevelopmental consequences of coffee and
caffeine exposure: a review on human and animal data.

Nehlig A, Debry G

INSERM U 398, Universite de Nancy I, Faculte de Medecine, France.

The teratogenic effect of caffeine has been clearly demonstrated in
rodents. The sensitivity of different animals species is variable.
Malformations have been demonstrated in mice at 50-75 mg/kg of caffeine,
whereas the lowest dose usually needed to induce malformations is 80 mg/kg
in rats. However, when caffeine is administered in fractioned amounts
during the day, 330 mg/kg/day are necessary to reach teratogenicity in
rats. In rodents, the most frequently observed malformations are those of
the limbs and digits, ectrodactyly, craniofacial malformations (labial and
palatal clefts) and delays in ossification of limbs, jaw and sternum.
Nevertheless, even in rodents, caffeine can be considered as a weak
teratogenic agent, given the quite large quantities of caffeine necessary
to induce malformations and the small number of animals affected. In
humans, caffeine does not present any teratogenic risk. The increased risk
of the most common congenital malformations entailed by moderate
consumption of caffeine is very slight. However, caffeine potentiates the
teratogenic effect of other substances, such as tobacco, alcohol, and acts
synergistically with ergotamine and propranolol to induce materno-fetal
vasoconstrictions leading to malformations induced by ischemia. Therefore,
even though caffeine does not seem to be harmful to the human fetus when
intake is moderate and spread out over the day, some associations,
especially with alcohol, tobacco, and vasoconstrictive or anti-migraine
medications should be avoided. Maternal consumption of caffeine affects
brain composition, especially in case of a low-protein diet and also seems
to interfere with zinc fixation in brain. Maternal exposure to caffeine
induces also long-term consequences on sleep, locomotion, learning
abilities, emotivity, and anxiety in rat offspring, whereas in humans, more
studies are needed to ascertain long-term behavioral effects of caffeine
ingestion by pregnant mothers.

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Sports Med 1994 Aug;18(2):109-125

Caffeine and endurance performance.

Tarnopolsky MA

Department of Physical Medicine and Rehabilitation, Henderson General
Hospital, Hamilton, Ontario, Canada.

Caffeine is consumed in many beverages and foods throughout the world. It
is the most commonly used drug in North America and, probably, in many
other countries. The short term consumption of caffeine may result in
increased urination, gastrointestinal distress, tremors, decreased sleep,
and anxiety symptoms in certain individuals. The long term consumption of
caffeine at < 5 cups/day does not appear to increase the risk of cancer,
cardiovascular disease, peptic ulcer disease or cardiac arrhythmias. At the
cellular level, caffeine is a competitive antagonist of adenosine receptors
and probably acts directly on the ryanodine receptor (Ca++ release channel)
to potentiate Ca++ release from skeletal muscle sarcoplasmic reticulum. As
a result of these 2 cellular mechanisms of action, caffeine causes
increased lipolysis, a facilitation of central nervous system transmission,
a reduction in plasma potassium during exercise, an increased force of
muscle contraction at lower frequencies of stimulation, and a sparing of
muscle glycogen (partially or wholly due to an increase in free fatty acid
oxidation). These mechanisms of action would predict that caffeine should
be of ergogenic benefit during endurance exercise performance, especially
when glycogen depletion would be rate limiting to performance. A review of
the literature suggests that caffeine at doses of approximately 6 mg/kg is
not of ergogenic benefit to high intensity exercise performance, but
similar doses are ergogenic in endurance exercise performance. These doses
(approximately 6 mg/kg) would result in urinary caffeine concentrations
less than the current International Olympic Committee restricted level of
12 mg/L, and consideration should be given to lowering this level.

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J Clin Psychopharmacol 1994 Aug;14(4):284-285

Interaction between caffeine and clozapine.


Vainer JL, Chouinard G


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Addict Behav 1994 May;19(3):229-256

Caffeine and nicotine: a review of their joint use and possible interactive
effects in tobacco withdrawal.

Swanson JA, Lee JW, Hopp JW

School of Public Health, Loma Linda University, CA.

There is a strong, significant relationship between coffee consumption and
smoking. In six epidemiological studies reviewed and analyzed here, 86.4%
of smokers consumed coffee versus 77.2% of nonsmokers. Exsmokers use more
coffee than nonsmokers but somewhat less than smokers. Seventeen
experimental studies suggest that the pharmacologic effect of caffeine in
coffee may be partially but not totally responsible for the relationship.
Conditioning, a reciprocal interaction (caffeine intake increases
anxiety/arousal--nicotine decreases it), or joint effect of a third
variable (e.g., stress, alcohol) may account for the relationship. In
abstinent smokers, blood caffeine levels increase and remain elevated for
as long as 6 months. These higher caffeine plasma levels may be sufficient
to produce caffeine toxicity syndrome. A review of 86 studies of nicotine
withdrawal, caffeine withdrawal, and caffeine toxicity suggests that the
symptoms are similar enough to be confused, and that reported nicotine
withdrawal symptoms may be a mixture of nicotine withdrawal and caffeine

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Paediatr Perinat Epidemiol 1994 Apr;8(2):145-155

Symptoms and health problems in pregnancy: their association with social
factors, smoking, alcohol, caffeine and attitude to pregnancy.

Meyer LC, Peacock JL, Bland JM, Anderson HR

Department of Public Health Sciences, St George's Hospital Medical School,
London, UK.

This paper describes the prevalence and correlates of symptoms and health
problems in pregnancy using data from a prospective population study in
London. Data on the prevalence of 11 symptoms and 12 health problems were
obtained at three points in pregnancy from a consecutive sample of 1513
white women. Relationships were examined between these symptoms and a range
of psychosocial factors including social class, education, marital status,
income, smoking, alcohol, caffeine, attitude to pregnancy and whether the
pregnancy was planned. Most women reported nausea and breast tenderness in
early pregnancy. Heartburn, backache, constipation and headaches were also
common. The prevalence of symptoms tended to increase with gestation except
for nausea and vomiting. Women with manual occupations, minimum education,
low income, single marital status and unplanned pregnancy reported more of
most symptoms except nausea which was associated with higher social status.
A negative attitude to pregnancy was associated with more headaches but was
unrelated to nausea. Women who smoked reported more 'nerves and depression'
but less nausea. In general, nausea and vomiting showed a different pattern
of associations from all other symptoms.

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J Am Acad Child Adolesc Psychiatry 1994 Mar;33(3):407-415

Caffeine effects on learning, performance, and anxiety in normal school-age

Bernstein GA, Carroll ME, Crosby RD, Perwien AR, Go FS, Benowitz NL

Department of Psychiatry, University of Minnesota Medical School,
Minneapolis 55455.

OBJECTIVE: The purpose of this investigation was to study the acute effects
of caffeine on learning, performance, and anxiety in normal prepubertal
children. METHOD: Twenty-one children were evaluated in a double-blind,
placebo-controlled crossover design. Subjects were studied during four
sessions, 1 week apart, under the following conditions: baseline, placebo,
2.5 mg/kg caffeine, and 5.0 mg/kg caffeine. Subjects were randomized to
order of placebo and the two dosages of caffeine. Dependent measures
included tests of attention, manual dexterity, short-term memory, and
processing speed. Anxiety rating scales were also administered. Saliva
samples were analyzed for caffeine levels. RESULTS: Caffeine improved
performance on two of four measures of the Test of Variables of Attention
and on a test of manual dexterity in the dominant hand. There was a trend
toward increased current level of self-reported anxiety after caffeine on a
visual analogue measure of anxiety. Children reported feeling significantly
less "sluggish" after caffeine ingestion than after placebo ingestion.
CONCLUSIONS: In a small sample size, there was indication that caffeine
enhanced performance on a test of attention and on a motor task. Children
also reported feeling less "sluggish" but somewhat more anxious. Because
caffeine is so widely available and frequently consumed by children, these
results are important and need replication.

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Psychopharmacology (Berl) 1994 Mar;114(2):281-287

Acute dose-effect relationships of caffeine and mental performance, EEG,
cardiovascular and subjective parameters.

Hasenfratz M, Battig K

Comparative Physiology and Behavioral Biology Laboratory, Swiss Federal
Institute of Technology, ETH-Zentrum, Zurich.

The present study investigated the dose-effect relationship of caffeine on
mental performance using a caffeine-sensitive rapid information processing
task (RIP) in a pre/post cross-over design. Twenty female nonsmoking
regular coffee drinkers received 0, 1.5, 3 and 6 mg/kg caffeine in a
balanced order and the measurements were extended to cardiovascular, EEG
and mood parameters. Surprisingly, the dose-effect curves for the different
parameters were rather heterogeneous. Whereas increasing effects with
increasing caffeine doses were observed for alpha- and beta-EEG
frequencies, anxiety, wakefulness, and some coffee ratings, negative
dose-effect relationships were obtained for RIP processing rate and blood
pressure. No apparent dose-effect relationships were seen for reaction time
and motor activity. Thus, it was concluded that the dose-response
relationships are rather shallow and heterogeneous and that the different
parameters have different ranges in which they are sensitive to caffeine.
The caffeine doses which might have beneficial behavioral effects are at
the lower end of the tested dose range and comparable to those found in
caffeine-containing beverages.

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Anxiety 1994;1(4):161-168

Dose-response effects of intravenous caffeine in normal volunteers.

Nickell PV, Uhde TW

Department of Behavioral Medicine and Psychiatry, West Virginia University
School of Medicine, Morgantown, USA.

The administration of caffeine has been developed as a chemical model for
the study of anxiety. However, previous researchers investigating
caffeine-induced anxiety states in humans have administered oral caffeine.
In this dose-response study, we investigated the effects of blindly
administered intravenous caffeine (3, 5, and 7 mg/kg) versus placebo in
normal control subjects. We report the first series of subjects
experiencing olfactory hallucinations (10 of 10 subjects, 24 of 30
infusions) immediately following intravenous caffeine infusion. In
addition, consistent with our previous work with oral caffeine, we found
dose-related increases in ratings of anxiety and blood levels of cortisol
and lactate. One subject experienced a DSM-III-R panic attack. Further
questioning revealed that his mother suffers panic attacks. Our findings of
olfactory hallucinations are discussed within the context of localized
limbic system dysfunction, noting the phenomenologic and possible
neuroanatomic overlap between panic disorder and complex partial seizures.

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Anxiety 1994;1(3):138-140

Lactic acid response to caffeine in panic disorder: comparison with social
phobics and normal controls.

Tancer ME, Stein MB, Uhde TW

Section on Anxiety and Affective Disorders, National Institute of Mental
Health, Bethesda Maryland 20892, USA.

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J Gynecol Obstet Biol Reprod (Paris) 1994;23(3):241-256

Effects of coffee and caffeine on fertility, reproduction, lactation, and
development. Review of human and animal data.

[Article in French]

Nehlig A, Debry G

INSERM U 272, Universite de Nancy I.

In the present review, we have examined the effects of coffee ingestion on
fertility, reproduction, lactation and development. The potential effects
of coffee consumption on fertility, spontaneous abortion and prematurity
are not clearly established but appear to be quite limited. In rodents,
caffeine can induce malformations but this effect appears in general at
doses never encountered in humans. Indeed, as soon as the quantity of
caffeine is divided over the day, as is the case for human consumption, the
teratogenic effect of caffeine disappears in rodents. Coffee ingested
during gestation induces a dose-dependent decrease in birth weight, but
usually only when ingested amounts are high (i.e. more than 7 cups/day),
whereas coffee has no effect at moderate doses. Caffeine consumption during
gestation affects hematologic parameters of the new-born infant or rat. In
animals, caffeine induces long-term consequences on sleep, locomotion,
learning abilities, emotivity and anxiety, whereas, in children, the
effects of early exposure to coffee and caffeine on behavior are not
clearly established. The quantities of caffeine found in maternal milk vary
with authors, but it appears clearly that caffeine does not change maternal
milk composition and has a tendency to stimule milk production. In
conclusion to this review, it appears that maternal coffee or caffeine
consumption during gestation and/or lactation does not seem to have
measurable consequences on the fetus of the newborn, as long as ingested
quantities remain moderate. Therefore, pregnant mothers should be advised
to limit their coffee and caffeine intake to 300 mg caffeine/day (i.e. 2-3
cups of coffee or 2.5-3 l of coke) especially because of the increase of
caffeine half-life during the third trimester of pregnancy and in the

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Am J Psychiatry 1993 Dec;150(12):1897-1898

Olfactory hallucinations after the infusion of caffeine during sleep.


Koenigsberg HW, Pollak CP, Fine J


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Am J Gastroenterol 1993 Sep;88(9):1464

Caffeine withdrawal, metoclopramide, and depression.


Wenokur B, Lessem P


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Int J Neurosci 1993 Sep;72(1-2):1-14

Incidental information processing: effects of mood, sex and caffeine.

Turner J

Department of Psychology, Fylde College, University of Lancaster, U.K.

This experiment assessed the effects of various parameters on incidental
information processing. Participants from a nonclinical population were
asked to fill out mood and personality questionnaires before completing a
simple explicit and implicit memory task. It was predicted that
participants with more depressive symptoms would show lower implicit memory
scores. A number of sex differences were revealed: data from male
participants supported the prediction; however, female participants showed
a negative correlation between increasing depressive mood symptoms and
implicit memory; sex differences were also present along other cognitive
dimensions. Socioeconomic effects and hemispheric biases were factors
considered as possible explanations for these sex differences; hemispheric
bias could have resulted in differential female/male strategies being used;
these may have been responsible for the consistently higher female scores
found throughout the experiment. It is also suggested that implicit memory
might have a separate store; this may be influenced by the default/habitual
preference for a particular processing strategy (unique to the individual
participant and/or the presence of depressive symptoms).

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Br J Psychiatry 1993 Apr;162:543-545

Caffeine: use and effects in long-stay psychiatric patients.

Mayo KM, Falkowski W, Jones CA

Springfield Hospital, London.

In a double-blind crossover study of 26 long-stay schizophrenic patients,
no correlation was found between caffeine consumption and levels of anxiety
and depression. No significant changes in patients' behaviour or levels of
anxiety and depression occurred when the wards changed to decaffeinated
products. Serum caffeine levels confirmed compliance. No evidence was found
to support a removal of caffeinated products from this group of patients.

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Am J Psychiatry 1993 Feb;150(2):294-301

Depressive symptoms and the self-reported use of alcohol, caffeine, and
carbohydrates in normal volunteers and four groups of psychiatric

Leibenluft E, Fiero PL, Bartko JJ, Moul DE, Rosenthal NE

Clinical Psychobiology Branch, NIMH, Bethesda, MD 20892.

OBJECTIVE: The authors examined the relationship between depressive
symptoms and the self-reported use of alcohol, carbohydrates, and caffeine
in normal volunteers and four groups of psychiatric outpatients. METHOD:
Outpatients and normal volunteers were given a questionnaire asking about
their use of each of the three substances in response to each of the 14
depressive symptoms on the Hamilton Rating Scale for Depression. They also
rated how much each substance improved each symptom. Twenty-six normal
volunteers, 35 patients with major depression, 117 patients with seasonal
affective disorder, 16 patients with alcohol dependence, and 24 patients
with comorbid primary depression and secondary alcohol dependence completed
the questionnaire. Test-retest reliability was established. Analysis of
variance and stepwise multivariate discriminant function analyses were used
to determine if diagnostic groups differed in the reported use and effect
of each of the three substances. RESULTS: The responses concerning use and
effect of alcohol of patients with alcohol dependence with or without
depression were indistinguishable from each other. The responses of the
patient groups regarding caffeine and carbohydrate use did not differ from
each other, but all differed significantly from the responses of normal
volunteers. Discriminant function analysis distinguished alcoholics from
nonalcoholics in the relationship between drinking and the symptoms of
anger and anhedonia. CONCLUSIONS: The relationship between symptoms and
substance use varied depending on the substance. Alcoholics without
depression were as likely to report drinking in response to depressive
symptoms as were those who had had depression. Patients of all diagnostic
groups were more likely than normal volunteers to report using caffeine and
carbohydrates in response to depressive symptoms.

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Arch Gen Psychiatry 1992 Nov;49(11):867-869

Anxiogenic effects of caffeine in patients with anxiety disorders.

Bruce M, Scott N, Shine P, Lader M

Department of Psychiatry, Institute of Psychiatry, London, England.

The effects on measures of anxiety from two doses of oral caffeine (250 and
500 mg) and placebo were compared in 12 patients with generalized anxiety
disorder (GAD), 12 patients with panic disorder, and 12 normal subjects.
Caffeine produced significantly less decrease in electroencephalographic
alpha wave activity, greater decrease in N1-P2 auditory evoked potential
amplitude, and greater increased in skin conductance level, systolic and
diastolic blood pressure, critical fusion flicker frequency, and
self-ratings of anxiety and sweating in patients with GAD than in normal
patients. Patients with panic disorder showed different reactivity than
normal patients did with respect to electroencephalographic alpha waves, N2
latency, N2-P2 auditory evoked potential amplitude, and physical tiredness
but were less reactive than patients with GAD on several variables. It is
concluded that patients with GAD are abnormally sensitive to caffeine and
that the data support the view that panic disorder is a separable disorder
from GAD.

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N Engl J Med 1992 Oct 15;327(16):1109-1114

Withdrawal syndrome after the double-blind cessation of caffeine

Silverman K, Evans SM, Strain EC, Griffiths RR

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Baltimore, MD 21224.

BACKGROUND. People who stop consuming caffeine may have symptoms, but the
incidence and severity of caffeine withdrawal are not known. This study was
performed to determine the effects in the general population of ending
one's dietary intake of caffeine. METHODS. We studied 62 normal adults
whose intake of caffeine was low to moderate (mean amount, 235 mg--the
equivalent of 2.5 cups of coffee--per day). They completed questionnaires
about symptoms and tests of their mood and performance when consuming their
normal diets (base-line period) and at the end of each of two two-day
periods during which they consumed caffeine-free diets and under
double-blind conditions received capsules containing placebo (placebo
period) or caffeine (caffeine period) in amounts equal to their daily
caffeine consumption. RESULTS. More subjects had abnormally high Beck
Depression Inventory scores (11 percent), high scores on the trait scale of
the State-Trait Anxiety Inventory (8 percent), low vigor scores (11
percent) and high fatigue scores (8 percent) on the Profile of Mood States,
and moderate or severe headache (52 percent) during the placebo period than
during either the base-line period (2, 0, 0, 0, and 2 percent,
respectively; P less than 0.05) or the caffeine period (3, 2, 2, 0, and 6
percent; P less than 0.05). More subjects reported unauthorized use of
medications during the placebo period (13 percent) than during the caffeine
period (2 percent, P = 0.017). Performance of a tapping task was slower
during the placebo period than during the base-line and caffeine periods (P
less than 0.01). CONCLUSIONS. Persons who consume low or moderate amounts
of caffeine may have a withdrawal syndrome after their daily consumption of
caffeine ceases.

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Addict Behav 1992 Sep;17(5):447-457

The effects of caffeine and nicotine consumption on mood and somatic
variables in a penitentiary inmate population.

Hughes GV, Boland FJ

Psychology Department, Queen's University, Kingston, Ontario, Canada.

A sample of 144 inmates from a maximum security penitentiary responded to a
request for information regarding their average daily intake of nicotine
and caffeine. They also rated the quality of their appetite and sleep,
their level of concentration, their mood and specific feelings of anger,
anxiety, frustration, and irritability. Factor analysis generated a
two-factor solution of these variables, namely general mood state (mood,
anxiety, anger, frustration, and irritability) and a somatic state
(appetite, concentration, and sleep). Analysis of variance showed an
interaction between level of smoking (nonsmokers, low and high cigarette
smokers) and caffeine use (moderate vs. high) on the general mood factor.
Nonsmokers who consumed high levels of caffeine experienced poorer general
mood than any other group. There was a main effect of cigarette smoking
status on the somatic factor, such that greater dissatisfaction was
associated with greater consumption. Caffeine consumption was generally
high, averaging 800 mg of caffeine per day, per inmate, well above the
amount considered to be potentially damaging to health.

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Psychiatry Res 1992 Aug;45(2):105-113

Quantitative electroencephalographic effects of caffeine in panic disorder.

Newman F, Stein MB, Trettau JR, Coppola R, Uhde TW

Clinical Brain Disorders Branch, St. Elizabeths Hospital, National
Institute of Mental Health, Washington, DC.

It has been demonstrated that patients with panic disorder are more
sensitive than normal control subjects to the anxiogenic effects of
caffeine. The underlying physiologic basis for this difference is unclear.
We examined the electroencephalographic (EEG) activity of seven patients
with panic disorder and seven normal control subjects during the randomized
double-blind, placebo-controlled administration of oral caffeine (7 mg/kg).
EEG data were collected on-line from 28 electrodes; artifact-free epochs
were selected manually for off-line Fourier transformation. Caffeine was
associated with a significant increase in peak occipital alpha frequency
and significant decreases in occipital alpha amplitude, central beta
amplitude, and central theta amplitude. Despite the observation that
caffeine increased anxiety more in the patients with panic disorder than in
the normal control subjects, the two groups did not differ in their EEG
responses to caffeine.

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Psychophysiology 1992 May;29(3):272-282

Cardiovascular responses to the combination of caffeine and mental
arithmetic, cold pressor, and static exercise stressors.

France C, Ditto B

Department of Psychology, Ohio University, Athens 45701-2979.

The present study examined cardiovascular responses to the combination of
caffeine (250mg) and mental arithmetic, cold pressor, and static exercise
stressors in 48 healthy males. Subjects were tested in a within-subject,
placebo-controlled, double-blind design. Repeated measurements of heart
rate, finger temperature, respiratory sinus arrhythmia, forearm blood flow,
and blood pressure were obtained during a pre-drug resting baseline, a
post-drug resting baseline, the three stressor tasks, and a recovery
baseline. The primary analyses were 2(Drug) x 5(Period) x 6(Stress Order)
MANCOVAs using pre-drug baseline values as covariates. Significant period
main effects were observed for all measures. Significant drug main effects
were observed for blood pressure, finger temperature, respiratory sinus
arrhythmia, and forearm blood flow. The significant changes in blood
pressure and finger temperature produced by caffeine combined in an
additive fashion with the effects produced by the stressors. Significantly
greater increases in forearm blood flow and heart rate during mental
arithmetic on the caffeine day suggested a potentiation of sympathetic,
beta-adrenergic activity. Questionnaires administered during baseline
periods to assess psychological responses to stress and caffeine revealed a
potentiation of anxiety and anger responses to stress on the caffeine day.

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Brain Res Brain Res Rev 1992 May;17(2):139-170

Caffeine and the central nervous system: mechanisms of action, biochemical,
metabolic and psychostimulant effects.

Nehlig A, Daval JL, Debry G

INSERM U 272 Universite de Nancy I, France.

Caffeine is the most widely consumed central-nervous-system stimulant.
Three main mechanisms of action of caffeine on the central nervous system
have been described. Mobilization of intracellular calcium and inhibition
of specific phosphodiesterases only occur at high non-physiological
concentrations of caffeine. The only likely mechanism of action of the
methylxanthine is the antagonism at the level of adenosine receptors.
Caffeine increases energy metabolism throughout the brain but decreases at
the same time cerebral blood flow, inducing a relative brain hypoperfusion.
Caffeine activates noradrenaline neurons and seems to affect the local
release of dopamine. Many of the alerting effects of caffeine may be
related to the action of the methylxanthine on serotonin neurons. The
methylxanthine induces dose-response increases in locomotor activity in
animals. Its psychostimulant action on man is, however, often subtle and
not very easy to detect. The effects of caffeine on learning, memory,
performance and coordination are rather related to the methylxanthine
action on arousal, vigilance and fatigue. Caffeine exerts obvious effects
on anxiety and sleep which vary according to individual sensitivity to the
methylxanthine. However, children in general do not appear more sensitive
to methylxanthine effects than adults. The central nervous system does not
seem to develop a great tolerance to the effects of caffeine although
dependence and withdrawal symptoms are reported.

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Pharmacol Toxicol 1992 Apr;70(4):286-289

Caffeine moderately antagonizes the effects of triazolam and zopiclone on
the psychomotor performance of healthy subjects.

Mattila ME, Mattila MJ, Nuotto E

Department of Pharmacology and Toxicology, University of Helsinki, Finland.

To determine whether caffeine antagonizes the decremental effects of
triazolam and zopiclone on human performance, oral single doses of 0.250 mg
triazolam, 7.5 mg zopiclone, or respective placebos, with and without 300
mg caffeine, were given to parallel groups of student volunteers in two
double-blind studies. Objective tests and subjective visual analogue
ratings were done at baseline and 30 min. and 90 min. after the intake. In
Study I, triazolam produced drowsiness at 30 min. but did not differ from
the placebo in other tests. Caffeine induced alerting effects in various
tests and differed from triazolam in some (digit substitution, drowsiness,
calmness, mental slowness) but not all variables measured. Caffeine and
triazolam were interpreted as being antagonists. In Study II, zopiclone
impaired digit substitution and flicker fusion, produced exophoria and
lowered systolic blood pressure. Caffeine differed from zopiclone in
several test functions, but it also differed from caffeine + zopiclone
whereas zopiclone differed from caffeine + zopiclone only in two tests
(Maddox wing, systolic blood pressure). Thus, zopiclone counteracted the
effects of caffeine more easily than caffeine counteracted the decremental
effects of zopiclone. We conclude that triazolam may not differ importantly
from diazepam as regards their antagonism towards caffeine, whereas further
research on the antagonism between zopiclone and caffeine needs to be done.

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Neuropsychopharmacology 1992 Feb;6(2):101-118

Evidence for hypothalamo-growth hormone dysfunction in panic disorder:
profile of growth hormone (GH) responses to clonidine, yohimbine, caffeine,
glucose, GRF and TRH in panic disorder patients versus healthy volunteers.

Uhde TW, Tancer ME, Rubinow DR, Roscow DB, Boulenger JP, Vittone B, Gurguis
G, Geraci M, Black B, Post RM

Section on Anxiety and Affective Disorders, National Institute of Mental
Health, Bethesda, Maryland 20892.

Given the abrupt and time-limited nature of daytime-awake and
nocturnal-sleep panic attacks, several chemical and neuroendocrine
challenge tests have been employed to investigate the neurobiology of
"spontaneous" panic attacks. Previously we demonstrated that panic disorder
patients have blunted growth hormone (GH) responses to clonidine, an alpha
2-adrenergic agonist. However, the mechanism of this blunted response and
the role of hypothalamic-GH dysfunction, if any, remains unclear. To
further delineate the status of hypothalamic-GH function in panic disorder,
we review the literature and present original data on the GH responses to a
number of different chemical and neuroendocrine challenge paradigms.
Although stress-mediated increases in GH are thought to be a common
correlate of stress in humans, our findings indicate that panic disorder
patients have significantly blunted GH responses to clonidine, yohimbine,
growth-hormone releasing factor, and caffeine compared to normal control
subjects. A similar trend was noted in the delayed rise in GH after glucose
challenge. There was no difference in the rate of abnormal GH responses to
thyrotropin-releasing hormone in panic disorder compared to normal control
subjects. No drug or neuroendocrine challenge, even if associated with
marked increases in anxiety, produced a significantly enhanced GH response
compared to normal control subjects. These findings provide support for a
hyporesponsive hypothalamic-GH system in panic disorder. These
observations, combined with preliminary observations from our clinic of
short stature in several cases of prepubescent children with anxiety
disorders, also underscore the need for assessing early growth patterns in
individuals with panic disorder. Strategies for investigating the site(s)
of possible neurotransmitter or hypothalamic-GH-somatomedin dysfunction are

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Psychopharmacology (Berl) 1992;108(1-2):51-59

Caffeine tolerance and choice in humans.

Evans SM, Griffiths RR

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Behavioral Biology Research Center, Baltimore, MD

Thirty-two healthy subjects with histories of moderate caffeine consumption
abstained from dietary caffeine throughout the study. Subjects were
stratified into two groups based on several factors including caffeine
preference, which was assessed using a caffeine versus placebo choice
procedure. Subsequently, subjects received either caffeine (300 mg t.i.d.)
or placebo (placebo t.i.d.) for 18 consecutive days, and thereafter were
exposed again to a caffeine versus placebo choice procedure. The study
documented tolerance development to the subjective effects of caffeine:
after chronic dosing, administration of caffeine produced significant
subjective effects in the chronic placebo group but not in the chronic
caffeine group. The study also provided indirect evidence for tolerance
development: during chronic dosing, the chronic caffeine and placebo groups
did not differ meaningfully on ratings of mood and subjective effect. When
subjects were categorized into caffeine choosers or nonchoosers, caffeine
choosers tended to report positive subjective effects of caffeine and
negative subjective effects of placebo. Nonchoosers, in contrast, tended to
report negative subjective effects of caffeine. Chronic caffeine did not
alter the reinforcing effects of caffeine as assessed by caffeine versus
placebo choice, possibly because the relatively short duration of caffeine
abstinence in the placebo condition was not sufficient to result in maximal
withdrawal effects after termination of the relatively high caffeine dose.
This study provides the clearest evidence to date of complete tolerance
development to a CNS effect of caffeine in humans.

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Psychopharmacology (Berl) 1992;109(3):283-290

No psychophysiological interactions between caffeine and stress?

Hasenfratz M, Battig K

Comparative Physiology and Behavioral Biology Laboratory, Swiss Federal
Institute of Technology.

In earlier studies, the predominantly beta-adrenergic effects of mental
tasks and the alpha-adrenergic effects of caffeine on cardiovascular
functions were observed to be simply additive without interaction. In the
present study, annoying electrical shocks were superimposed on a mental
task affording either active coping, which specifically raises
beta-adrenergic activation, or passive coping, and the 40 female subjects
were preselected so as to differ in subjective stress susceptibility.
Caffeine as well as the type of coping and the considered personality
dimension produced significant effects, but almost no interactions were
obtained. The stress resistant subjects, who tended toward more
extraversion, emotional stability and more masculinity, had lower anxiety
scores, rated their performance higher and had a greater cardiac output
than the stress non-resistant subjects, who represented a rather normal
population according to the FPI personality dimensions. Caffeine increased
EEG alpha and beta frequency and delta power and decreased beta power,
raised blood pressure and enhanced stress reactions in respiration
amplitude and pre-ejection period. Active stress coping induced greater
stress reactions in heart rate (increase), left ventricular ejection time
(decrease) and ear pulse arrival time (decrease) than passive coping.

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Biol Psychiatry 1991 Nov 15;30(10):973-984

Anxiogenic effects of m-CPP in patients with panic disorder: comparison to
caffeine's anxiogenic effects.

Klein E, Zohar J, Geraci MF, Murphy DL, Uhde TW

Section of Anxiety and Affective Disorders, National Institute of Mental
Health, Bethesda, MD 20892.

The behavioral and neuroendocrine effects of meta-chlorophenylpiperazine
(m-CPP), a serotonergic agonist, were compared with the effects of
caffeine, an adenosine antagonist, in panic disorder patients. Patients
with panic disorder were given single oral doses of 0.5 mg/kg m-CPP, 480 mg
caffeine, and placebo on separate days under double-blind conditions. Both
m-CPP and caffeine had significantly greater anxiogenic and panic-inducing
effects than placebo, although caffeine produced nonsignificantly greater
increases on all anxiety rating scales than m-CPP. Both m-CPP and caffeine
produced significant equivalent increases in plasma cortisol
concentrations, but only m-CPP produced plasma prolactin increases. These
findings provide further evidence implicating both the serotonergic and
adenosinergic receptor systems in the neurobiology of panic disorder.

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DICP 1991 Oct;25(10):1079-1080

Caffeine in electroconvulsive therapy.

Cantu TG, Korek JS

Department of Pharmacy, Johns Hopkins Hospital, Baltimore, Maryland 21205.

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Med Hypotheses 1991 Oct;36(2):157-161

Exploring the role of an endogenous caffeine-like substance in the
pathogenesis of schizophrenia.

Missak SS

In a previous paper, I have proposed that the deficiency of an endogenous
caffeine-like substance is the underlying pathogenic mechanism in
schizophrenia (1). In the present paper, my new concept is used to explain
many of the clinical, biochemical, radiologic and pharmacologic facts about

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Clin Pharmacol Ther 1991 Aug;50(2):157-164

Effects of caffeine on tobacco withdrawal.

Oliveto AH, Hughes JR, Terry SY, Bickel WK, Higgins ST, Pepper SL, Fenwick

Department of Psychiatry, University of Vermont, Burlington 05401.

Smoking cessation increases caffeine blood levels, and this has been
hypothesized to cause some of the symptoms of tobacco withdrawal (e.g.,
anxiety and insomnia). To test this hypothesis, 10 coffee drinkers who
smoked cigarettes were entered into a completely within-subjects
experimental design in which the effects of caffeine dose (0, 50, and 100
mg/coffee serving) and smoking status (smoking versus abstinence) were
examined over a 4-day period. Self-reported and observed measures of
tobacco withdrawal, caffeine withdrawal, and intoxication, as well as
psychomotor tasks and vital signs, were completed daily; blood was drawn at
the end of each period. Temporary abstinence produced typical withdrawal
symptoms but did not significantly increase caffeine blood levels. Caffeine
did not increase the severity of symptoms but did decrease the severity of
withdrawal-induced hunger. These findings suggest that, in the absence of
increased blood levels, caffeine does not increase the severity of tobacco

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Hosp Community Psychiatry 1991 Mar;42(3):313-315

Caffeine consumption in patients with eating disorders.

Krahn DD, Hasse S, Ray A, Gosnell B, Drewnowski A

University of Michigan Medical Center, School of Public Health, Ann Arbor

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Biol Psychiatry 1991 Feb 15;29(4):391-396

Caffeine-induced anxiety and increase of kynurenine concentration in plasma
of healthy subjects: a pilot study.

Orlikov A, Ryzov I

Laboratory of Psychopharmacology, Leningrad V.M. Bekhterev
Psychoneurological Research Institute, USSR.

The concentration of kynurenine, a neuroactive tryptophan metabolite, in
blood plasma after pharmacologically induced anxiety was studied. Anxiety
was provoked in 15 healthy volunteers by an anxiogenic dose of caffeine.
Kynurenine concentration was markedly increased at the peak of anxiety and
returned to normal after anxiety had abated. Possible causes responsible
for this effect are discussed. There is a correlation between kynurenine
concentration in blood plasma and indices of state and trait anxiety
(Spielberger-Khanin scale) and anxiety (Hamilton scale) at baseline. The
correlation disappears at the peak of anxiety. It is suggested that
kynurenine is involved in caffeine-induced anxiety in humans. The absence
of correlation at the peak of caffeine-induced anxiety is discussed.

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J Gen Psychol 1991 Jan;118(1):5-12

Efficacy of caffeine versus expectancy in altering caffeine-related

Christensen L, Miller J, Johnson D

Department of Psychology, Texas A&M University, College Station 77843.

The study investigated the independent and interactive effects of caffeine
and expectancy on caffeine-related symptoms. High- and low-caffeine
consumers were randomly assigned to either an expectancy or nonexpectancy
instructional set and one of four caffeine doses. Subjects were
administered the State-Trait Anxiety Inventory, (Spielberger & Gorsuch,
1970) and a Symptom Questionnaire (Christensen, White, Krietsch, & Steele,
1990) prior to and 45 min following consumption of one of the four caffeine
doses. An analysis of covariance identified a significant main effect for
the State-Trait Anxiety Inventory scores and significant main and
interaction effects for four Symptom Questionnaire items. However, when the
alpha levels were corrected for the increased probability of Type I error,
using the Bonferroni procedure, these effects failed to achieve
significance. These results suggest that previous reports of subjective
caffeine effects are also suspect because of their failure to control for
the increased probability of Type I error.

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Psychophysiology 1991 Jan;28(1):65-71

Subjective and objective measures of sleepiness: effect of benzodiazepine
and caffeine on their relationship.

Johnson LC, Freeman CR, Spinweber CL, Gomez SA

Naval Health Research Center, San Diego, CA 92186-5122.

As part of a larger project on the effects of benzodiazepine and caffeine
on daytime sleepiness, performance and mood, this study examined the
relationship among the Multiple Sleep Latency Test, lapses during a tapping
task, a Visual Analog Scale, and the Stanford Sleepiness scale. Subjects
were 80 male, adult nonsmokers aged 20.3 +/- 2.7 years. The Multiple Sleep
Latency Test, Stanford Sleepiness Scale, and the Visual Analog Scale were
obtained at two-hour intervals beginning at 0700 h and ending at 1700 h.
The tapping task (lapses) was administered each day at 0600 h, 1000 h, and
1400 h. A lapse was a 3-s or greater pause between taps. Correlations
between the Multiple Sleep Latency Test and subjective (Visual Analog Scale
and the Stanford Sleepiness Scale) measures were significant at 0600 h, but
became nonsignificant as the day progressed. Correlations between lapses
and the two subjective measures were generally nonsignificant. The two
objective measures were significantly correlated in the total group but not
in all treatment groups. The subjective measures were significantly
correlated in the total sample and in each treatment group. This study
reaffirms the importance of time of day when measuring sleepiness, and
suggests that subjective and objective measures may measure different
aspects of sleepiness.

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Int J Psychophysiol 1990 Dec;10(2):171-179

The influence of user status and anxious disposition on the hypertensive
effects of caffeine.

James JE

Department of Psychology, Flinders University, Bedford Park, Australia.

The present study examined the influence of consumer status and anxious
disposition on the hypertensive effects of caffeine. A secondary aim of the
study was to investigate possible gender differences in response to
caffeine. Sixty normotensive subjects were assigned to 4 groups
representing high and low scorers on the variables of habitual caffeine
consumption and anxious disposition. A randomized double-blind crossover
design was used in which all subjects received a placebo (lactose) at one
of two 120-min laboratory sessions and caffeine (6 mg/kg) at the other.
Systolic and diastolic blood pressure, heart rate, hand steadiness, and EMG
were monitored before and after exposure to a psychological stressor.
Caffeine produced significant elevations in systolic and diastolic blood
pressure, and these effects were additive to the pressor effects of stress
and anxiety. While the general pattern of results was similar for both
sexes, reactions to caffeine were more pronounced in males than in females.
Notwithstanding the need for clarification of the chronic effects of
caffeine, present findings add further weight to current concerns about the
acute hypertensive effects of the drug.

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Arukoru Kenkyuto Yakubutsu Ison 1990 Dec;25(6):486-496

Caffeine consumption and anxiety and depressive symptomatology among
medical students.

Mino Y, Yasuda N, Fujimura T, Ohara H

Department of Public Health, Kochi Medical School.

Caffeine is one of the most widely consumed psychoactive substances in the
world and is ingested in a variety of favorites, such as coffee, tea, cola
and so on. Although it has been suggested that high dose caffeine users
have more anxiety and depressive symptoms than low users, this relationship
is not clear in Japan, where caffeine consumption is considered to be less
than in Western countries. A questionnaire survey was conducted among
medical students and 291 out of 423 initial subjects completed it. Among
males, caffeine consumption was significantly and positively correlated
with anxiety symptoms, when alcohol use and smoking habit were adjusted.
However, there was no relationship between caffeine consumption and
depressive symptoms. Among females, although there was no association
between caffeine consumption and anxiety symptoms, high dose caffeine users
showed less depressive symptoms than moderate and low users, when alcohol
use was adjusted. It is suggested that caffeine use is one of the important
factors, in researching psychological health among the general population.
We need further epidemiological studies to determine whether there is a
causal relationship between caffeine and psychological ill health or not.

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Acta Psychiatr Scand 1990 Jul;82(1):17-22

Behavioral and cerebrovascular effects of caffeine in patients with anxiety

Mathew RJ, Wilson WH

Department of Psychiatry, Duke University Medical Center, Durham, North
Carolina 27710.

Caffeine is believed to induce anxiety in normal people and anxiety
disorder patients and panic attacks in panic disorder patients. The drug is
also known to reduce cerebral blood flow (CBF). Findings suggesting an
anxiety-related cerebral vasoconstrictive factor have been reported. We
examined the relationship between changes in anxiety and CBF induced by
intravenously injecting 250 mg of caffeine (comparable to 2 cups of coffee)
in 8 patients with generalized anxiety disorder, 9 patients with panic
disorder and 9 normal controls. CBF measurements were also obtained before
and after an injection of normal saline in another group of 9 normal
volunteers. The anxiety disorder patients did not show any evidence of
increase in anxiety and panic after caffeine. Both patients and controls
who received caffeine but not normal controls who received saline showed
significant CBF decrease. The CBF changes were unrelated to changes in
mood, autonomic activity and carbon dioxide levels.

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Biol Psychiatry 1990 Jul 1;28(1):35-40

Effects of the acute administration of caffeine in patients with

Lucas PB, Pickar D, Kelsoe J, Rapaport M, Pato C, Hommer D

Section of Clinical Studies, National Institute of Mental Health, Bethesda,
Maryland 20892.

Caffeine, 10 mg/kg, was administered to 13 schizophrenic patients in a
double-blind placebo-controlled study of its behavioral effects. Some
measures of psychopathology were significantly increased: Brief Psychiatric
Rating Scale (BPRS) total, BPRS subscales thought disorder, unusual thought
content, and euphoria-activation, and several individual BPRS items.
Nurses' Bunney-Hamberg ratings of psychosis and mania, comparing the day
before with the day after pharmacological challenge, increased
significantly. Compared to placebo, caffeine also produced significant
increases of diastolic blood pressure and cortisol. Thus, these findings
indicate that caffeine increases arousal and has a psychotogenic effect
when administered to schizophrenic patients. The possible roles of various
neurotransmitters is discussed with special emphasis on caffeine's actions
on dopaminergic and adenosinergic systems.

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Postgrad Med J 1990;66 Suppl 2:S18-S24

The anxiogenic effects of caffeine.

Bruce MS

Unit of Clinical Psychopharmacology, Institute of Psychiatry, De Crespigny
Park, Denmark Hill, London, UK.

The contrast of attitudes to the psychiatric effects of caffeine between
North America and Britain is highlighted. A summary of the dietary sources,
pharmacology and effects on caffeine on normal subjects is given. The
emphasis in normal subjects is on the acute, chronic, toxic and withdrawal
effects. With this background information, a more specific evaluation of
the anxiogenic effects are discussed. In conclusion, the case is made for a
trial of caffeine abstention to become part of the management of anxious

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Int J Addict 1990 Jan;25(1):27-31

Expectancy effects in caffeine research.

Christensen L, White B, Krietsch K, Steele G

College of Liberal Arts, Texas A & M University, College Station

The impact of expectancy on the experience of caffeine-related symptoms was
investigated by randomly assigning subjects to an expectancy or
nonexpectancy instructional condition. Subjects were administered the
State-Trait Anxiety Inventory and a Symptom Questionnaire prior to and 45
minutes after receiving their designated instructional set and ingesting a
cellulose-filled gelatin capsule which ostensibly was filled with caffeine.
Results revealed that a significant expectancy effect existed on five
Symptom Questionnaire items.

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Life Sci 1990;47(13):1141-1146

Caffeine and human cerebral blood flow: a positron emission tomography

Cameron OG, Modell JG, Hariharan M

Department of Psychiatry, University of Michigan Medical Center, Ann Arbor

Positron emission tomography (PET) was used to quantify the effect of
caffeine on whole brain and regional cerebral blood flow (CBF) in humans. A
mean dose of 250 mg of caffeine produced approximately a 30% decrease in
whole brain CBF; regional differences in caffeine effect were not observed.
Pre-caffeine CBF strongly influenced the magnitude of the caffeine-induced
decrease. Caffeine decreased paCO2 and increased systolic blood pressure
significantly; the change in paCO2 did not account for the change in CBF.
Smaller increases in diastolic blood pressure, heart rate, plasma
epinephrine and norepinephrine, and subjectively reported anxiety were also

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Schizophr Bull 1990;16(3):371-372

Response to "Effects of caffeine on behavior of schizophrenic inpatients".

Hyde AP

Psychiatric Hospital, Columbia, SC 29203.

This article addresses itself to the apparent conflict between those
reports indicating that caffeine affects schizophrenic behavior and the
present study which failed to show substantial behavior or medication
changes with caffeine. It is suggested that there are important subgroups
of schizophrenic patients who are unusually sensitive to caffeine's
apparent psychotogenic actions as reported in case reports and data on
violence and destruction. It is also suggested that there are subgroups of
schizophrenia which seem to require increased medication doses to "cover"
caffeine effects.

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Psychopharmacology (Berl) 1990;101(2):160-167

Benzodiazepines and caffeine: effect on daytime sleepiness, performance,
and mood.

Johnson LC, Spinweber CL, Gomez SA

Naval Health Research Center, San Diego, CA 92138-9174.

In a double-blind parallel group design, 80 young adult males were divided
into eight treatment groups. Subjects received 15 or 30 mg flurazepam, 0.25
or 0.50 mg triazolam, or placebo at bedtime, and 250 mg caffeine or placebo
in the morning for 2 treatment days. Two objective (Multiple Sleep Latency
Test and lapses) and two subjective (Stanford Sleepiness Scale and Visual
Analog Scale) measures of sleepiness, five performance tests, and two mood
measures (Profile of Mood Scale and Visual Analog Mood Scale) were
administered repeatedly on both days. Significant treatment effects were
found for sleepiness but not for performance or mood. Early morning
caffeine significantly antagonized next day hypnotic-induced drowsiness and
enhanced alertness in the subjects who received bed-time placebo.
Flurazepam, 30 mg, subjects were more sleepy than all other groups.
Although not significantly different, the flurazepam, 30 mg, group
demonstrated a trend toward poorer performance and a more negative mood
than all other groups. Caffeine most improved performance of this group. In
all groups, sleepiness was greatest and performance and mood poorest in
early morning trials and caffeine was most effective at this time.

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Psychiatry Res 1989 Dec;30(3):231-242

Caffeine taste test for panic disorder: adenosine receptor

DeMet E, Stein MK, Tran C, Chicz-DeMet A, Sangdahl C, Nelson J

Department of Psychiatry and Human Behavior, University of California,
Irvine 92717.

The present study introduces a novel measure of adenosine receptor
sensitivity that is based on the action of specific receptor blockers
(e.g., caffeine) to potentiate the ability to detect threshold quinine
concentrations. The test is used to compare gustatory adenosinergic
responses to caffeine challenges in normal controls and patients with panic
disorder or posttraumatic stress disorder (PTSD). Panic disorder patients
had an exaggerated response to the caffeine challenge that was not found in
controls or PTSD patients, although the latter had higher anxiety scores on
psychometric tests. The results are related to a model in which
A1-adenosine receptors up-regulate in an attempt to modulate hyperactive
excitatory neuronal systems.

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Zh Vyssh Nerv Deiat 1989 Nov;39(6):1010-1013

Elevation of the blood kynurenine level in caffeine-induced anxiety.

[Article in Russian]

Orlikov AB, Ryzhov IV

Concentration of neuroactive tryptophane--kynurenine metabolite was studied
in healthy men volunteers in conditions of anxiety artificially elicited by
caffeine. At peak of the alarm the level of the kynurenine significantly
increased and came to norm after anxiety cessation. Possible causes of this
increase are discussed. High correlation has been obtained between the
kynurenine concentration and initial values of personal and reactive
anxiety. The conclusion is made about the participation of the kynurenine
in formation of personal and reactive anxiety in man.

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Biol Psychiatry 1989 Jul;26(3):315-320

Depersonalization disorder: effects of caffeine and response to

Stein MB, Uhde TW

Unit on Anxiety and Affective Disorders, National Institute of Mental
Health, Bethesda, MD 20892.

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Ann Intern Med 1989 Apr 15;110(8):593-598

The effect of caffeine on exercise tolerance and left ventricular function
in patients with coronary artery disease.

Hirsch AT, Gervino EV, Nakao S, Come PC, Silverman KJ, Grossman W

Charles A. Dana Research Institute, Boston, Massachusetts.

STUDY OBJECTIVE: To determine whether acute oral caffeine ingestion by
patients with coronary artery disease results in decreased treadmill
exercise performance or deterioration of echocardiographic measures of
systolic or diastolic left ventricular function. DESIGN: Randomized,
double-blind, placebo-controlled trial. SETTING: Referral-based
cardiovascular exercise laboratory at an urban teaching hospital. PATIENTS:
Thirteen volunteers with clinically stable coronary artery disease who had
exercise tests after a 2-week caffeine-free washout period. Patients
continued treatment with standard antianginal medications during the study
period. INTERVENTIONS: Maximal exercise treadmill testing and exercise
echocardiography were done at baseline, after acute ingestion of a placebo
beverage (97% caffeine-free coffee), or after drinking an identical
beverage containing 250 mg of caffeine sodium benzoate. MEASUREMENTS AND
MAIN RESULTS: Acute ingestion of caffeine produced a serum level of 4.50
+/- 0.16 micrograms/mL, but had no effect on resting supine heart rate,
blood pressure, left ventricular fractional shortening, posterior left
ventricular wall thinning or peak rates of increase in left ventricular
diastolic dimension. Despite a small increase in peak systolic blood
pressure during exercise (baseline, 153 +/- 8; placebo, 154 +/- 8;
caffeine, 161 +/- 7 mm Hg; P less than 0.05), exercise duration, time to
onset of angina, and time to 0.1 mV ST depression did not differ after
ingestion of placebo or caffeine. Rate-pressure product at onset of angina
and onset of 0.1 mV of ST depression were also unchanged. In response to
exercise, echocardiographic measures of left ventricular systolic and
diastolic function were unchanged after caffeine compared with placebo
ingestion. CONCLUSIONS: These data suggest that patients with
exercise-induced ischemia who are receiving appropriate antianginal therapy
tolerate the caffeine-equivalent of three cups of coffee without
detrimental effect on intensity of ischemia, myocardial function, or
exercise duration.

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BMJ 1989 Mar 25;298(6676):795-801

Effects on birth weight of smoking, alcohol, caffeine, socioeconomic
factors, and psychosocial stress.

Brooke OG, Anderson HR, Bland JM, Peacock JL, Stewart CM

Department of Child Health, St George's Hospital Medical School, London.

OBJECTIVE--To investigate the effects of smoking, alcohol, and caffeine
consumption and socio-economic factors and psychosocial stress on birth
weight. DESIGN--Prospective population study. SETTING--District general
hospital in inner London. PARTICIPANTS--A consecutive series of 1860 white
women booking for delivery were approached. 136 Refused and 211 failed to
complete the study for other reasons (moved, abortion, subsequent refusal),
leaving a sample of 1513. Women who spoke no English, booked after 24
weeks, had insulin dependent diabetes, or had a multiple pregnancy were
excluded. MEASUREMENTS--Data were obtained by research interviewers at
booking (general health questionnaire, modified Paykel's interview, and
Eysenck personality questionnaire) and at 17, 28, and 36 weeks' gestation
and from the structured antenatal and obstetric record. Variables assessed
included smoking, alcohol consumption, caffeine consumption, and over 40
indicators of socio-economic state and psychosocial stress, including
social class, tenure of accommodations, education, employment, income,
anxiety and depression, stressful life events, social stress, social
support, personality, and attitudes to pregnancy. Birth weight was
corrected for gestation and adjusted for maternal height, parity, and
baby's sex. MAIN RESULTS--Smoking was the most important single factor (5%
reduction in corrected birth weight). Passive smoking was not significant
(0.5% reduction). After smoking was controlled for, alcohol had an effect
only in smokers and the effects of caffeine became non-significant. Only
four of the socioeconomic and stress factors significantly reduced birth
weight and these effects became non-significant after smoking was
controlled for. CONCLUSIONS--Social and psychological factors have little
or no direct effect on birth weight corrected for gestational age (fetal
growth), and the main environmental cause of its variation in this
population was smoking.

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Psychol Med 1989 Feb;19(1):211-214

Caffeine abstention in the management of anxiety disorders.

Bruce MS, Lader M

Department of Psychiatry, Institute of Psychiatry, London.

Caffeine toxicity remains a rarely reported condition, which may mimic
anxiety disorders. Anxiety disorder patients do not consume toxic amounts
of caffeine. However, increased sensitivity to caffeine in these patients
has been suggested as contributing to their symptoms. Six cases of anxiety
disorder are presented who improved with only caffeine abstention, and
remained well for at least a six-month follow-up period.

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Schizophr Bull 1989;15(2):339-344

Effects of caffeine on behavior of schizophrenic inpatients.

Koczapski A, Paredes J, Kogan C, Ledwidge B, Higenbottam J

Dept. of Psychology, Riverview Hospital, Coquitlam, BC, Canada.

The present study replicates that of De Freitas and Schwartz (1979), using
more typical chronic patients (on open wards rather than locked wards), and
monitoring coffee intake with serum caffeine levels. The serum caffeine
levels observed indicate that caffeine can be effectively manipulated on an
open ward by switching the type of coffee served. Contrary to our
predictions, no significant improvements in patients' behavior occurred
when decaffeinated coffee was first introduced, nor was there any
deterioration when regular coffee was reinstated. Only after decaffeinated
coffee was introduced for the second time did any of the predicted changes
occur; however, the improvements were few in number and may be accounted
for by the considerable effect of time per se across all time periods.
Although the findings cannot be generalized to all psychiatric patients,
the results do not support recent calls for a switch to decaffeinated
coffee for this population of inpatients (i.e., chronic schizophrenic
patients on high doses of neuroleptics who drink large amounts of coffee).

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J R Nav Med Serv 1989;75(2):65-67

Caffeine and caffeinism.

Mackay DC, Rollins JW

Caffeine is a widely ingested and generally beneficial drug. However, when
taken in excess, anxiety related symptoms become increasingly apparent. A
case of caffeinism, which presented as a paranoid delusion, is reported as
an extreme example of this. A study of 60 hospital inpatients revealed that
about 40% of them consumed sufficient caffeine to produce symptoms of
caffeinism. It is thus recommended that all patients should be questioned
on their caffeine intake. Also, caffeinism should be considered as a
differential diagnosis of anxiety states.

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Psychopharmacol Bull 1989;25(3):473-478

Smooth pursuit eye movements in schizophrenia: effects of neuroleptic
treatment and caffeine.

Litman RE, Hommer DW, Clem T, Rapaport MH, Pato CN, Pickar D

Abnormal smooth pursuit eye movement (SPEM) has been proposed as a trait
marker in schizophrenia. We utilized high resolution infra-red oculography
to measure SPEM in 11 neuroleptic-treated schizophrenic patients, 10
drug-free schizophrenic patients, and 11 normals. The most characteristic
abnormality was a significant increase in saccadic intrusions during SPEM
in schizophrenic patients (p less than .001). SPEM gain was reduced in
schizophrenic patients (p less than .005). No significant effects of
neuroleptic treatment on SPEM were found, including analysis of seven
patients in whom paired data was available. We also measured SPEM prior to
and after caffeine ingestion (10 mg/kg) in 10 normals. We found reduced
saccadic interruptions as a result of caffeine ingestion compared with
placebo (p less than .05). As caffeine has been shown to selectively
increase dopaminergic neurotransmission in mesocortical neurons, further
study utilizing dopamine agonists during SPEM in schizophrenic patients is

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Encephale 1989 Jan;15 Spec No:177-180

Use of the methylxanthines, caffeine and theophylline, in the treatment of
extrapyramidal disorders caused by treatment with neuroleptics. Development
of a therapeutic hypothesis.

[Article in French]

Casas M, Torrens M, Duro P, Pinet C, Alvarez E, Udina C

Programa Sant Pau-CITRAN, Fundacio d'Investigacio Santa Creu i Sant Pau,
Hospital de la Santa Creu i Sant Pau, Barcelona, Espagne.

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Psychopharmacology (Berl) 1989;98(1):81-88

Reinforcing and subjective effects of caffeine in normal human volunteers.

Stern KN, Chait LD, Johanson CE

Department of Psychiatry, Pritzker School of Medicine, University of
Chicago, IL 60637.

The reinforcing and subjective effects of caffeine (100 and 300 mg, PO)
were determined in a group of 18 normal, healthy adults. Subjects (eight
females, ten males) were light to moderate users of caffeine, and had no
history of drug abuse. A discrete-trial choice procedure was used in which
subjects were allowed to choose between the self-administration of
color-coded capsules containing either placebo or caffeine. The number of
times caffeine was chosen over placebo was used as the primary index of
reinforcing efficacy. Subjective effects were measured before and several
times after capsule ingestion. The low dose of caffeine was chosen on 42.6%
of occasions, not significantly different from chance (50%). The high dose
of caffeine was chosen on 38.9% of occasions, significantly less than
expected by chance, indicating that this dose served as a punisher. Both
doses of caffeine produced stimulant-like subjective effects, with aversive
effects such as increased anxiety predominating after the high dose. When
subjects were divided into groups of caffeine-sensitive choosers and
nonchoosers, a consistent relationship emerged between caffeine choice and
subjective effects; nonchoosers reported primarily aversive effects after
caffeine (increased anxiety and dysphoria), whereas choosers reported
stimulant and "positive" mood effects. When compared with previous
findings, these results demonstrate that caffeine is less reinforcing than
amphetamine and related psychomotor stimulants.

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Br J Clin Psychol 1988 Sep;27( Pt 3):265-266

Caffeine reduction as an adjunct to anxiety management.

Smith GA

Department of Clinical Psychology, Seaford Court Lodge, Malvern Link,
Worcs, UK.

A reduction in tea and coffee drinking is popularly advocated for the
relief of tension and anxiety symptoms, and it was decided to collect
empirical data on this matter in the course of normal clinical practice. It
was found that patients who made substantial reductions in caffeine
drinking also made the greatest improvements in anxiety, irritability,
sleep disturbance, headaches and abdominal symptoms. The methodology leaves
an ambiguity in the interpretation of this result, but the data provide a
useful basis for the design of further studies.

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J Pharmacol Exp Ther 1988 Jul;246(1):21-29

Reinforcing effects of caffeine in humans.

Griffiths RR, Woodson PP

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Baltimore, Maryland.

The reinforcing and subjective effects of caffeine were studied under
double-blind conditions in 12 normal humans. After 2 forced exposure days
on which subjects received color-coded capsules containing either caffeine
(100, 200, 400 or 600 mg) or placebo, subjects had a choice day on which
they chose which one of the two types of color-coded capsules would be
ingested. Subjects were exposed to 10 experimentally independent choices
(i.e., involving exposure and choice between novel color-coded capsule
conditions) at each of several dose levels. All forced exposure and choice
opportunities occurred when subjects were overnight abstinent from their
normal dietary caffeine intake (mean, 116 mg/day). Significant caffeine
positive reinforcement was demonstrated in 5 of 12 subjects at one or more
doses. Percentage of selection of caffeine was inversely related to dose,
with four subjects showing significant caffeine avoidance at 400 and/or 600
mg. Choice behavior was correlated positively with feelings of
contentedness and was correlated negatively with prestudy trait anxiety
scores and with ratings of capsule disliking. Compared to placebo, caffeine
produced increases in subjective ratings indicating arousal while producing
decreases in headache and "craving" for caffeine-containing foods, even at
the lowest dose of 100 mg. At higher doses caffeine produced dysphoric
anxiety-like subjective effects. Overall, this study provides the first
demonstration in humans of the positive reinforcing effects of caffeine
alone (i.e., in capsules) and documents individual differences among normal
subjects in both caffeine positive reinforcement and caffeine avoidance.

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Int Clin Psychopharmacol 1988 Jul;3(3):215-229

Anxiogenic effect of yohimbine in healthy subjects: comparison with
caffeine and antagonism by clonidine and diazepam.

Mattila M, Seppala T, Mattila MJ

Department of Pharmacology and Toxicology, University of Helsinki, Finland.

Three placebo-controlled double-blind and crossover trials were carried out
to analyze the effects of oral yohimbine (YOH) 0.8 mg/kg on mood and
performance in 16 healthy students. Subjective assessments (visual analogue
scales, side-effects on questionnaire) and objective measurements (digit
symbols, flicker fusion, tapping, heterophoria) were done at baseline, and
post treatment. YOH shifted the healthy subjects' mood towards feeling
panicked, elevated systolic blood pressure and plasma prolactin
concentrations, reduced digit symbol substitution, and induced drowsiness
and passiveness. Caffeine (CAF) 10 mg/kg raised plasma cortisol and
rendered the subjects slightly panicked. Muzziness, clumsiness, tremor,
chills and nausea were common after both YOH and CAF. Diazepam (DZ) 0.3
mg/kg given at 60 min antagonized some effects of CAF but failed to
antagonize YOH. Clonidine (CLO) 100 micrograms counteracted YOH effects on
blood pressure but less the subjective and hormonal effects. CLO 200
micrograms partly antagonized the pressor, sedative but not the hormonal
responses of YOH. DZ counteracted YOH effects on plasma cortisol on panic
but not on other subjective measures or plasma prolactin. Since CLO did not
abolish YOH-induced prolactin increase, it is suggested that these effects
of YOH are mediated not only via adrenergic alpha 2-receptors; other
mechanisms made important contributions.

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Br J Addict 1988 Jun;83(6):689-694

The concurrent use of alcohol, cigarettes and caffeine in British
benzodiazepine users as measured by a general population survey.

Dunbar GC, Morgan DD, Perera KM


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Am J Psychiatry 1988 May;145(5):632-635

Anxiogenic effects of caffeine on panic and depressed patients.

Lee MA, Flegel P, Greden JF, Cameron OG

Department of Psychiatry, University of Michigan Medical School, Ann Arbor

Caffeine increases anxiety in people with anxiety disorders. To determine
whether caffeine exerts a similar effect in depression, the authors
compared retrospective reports of caffeine intake and symptoms produced by
caffeine ingestion in patients with panic disorder, patients with major
depression, and control subjects. Panic patients consumed less caffeine and
reported more symptoms than depressed or control subjects. Although
depressed patients did not differ from control subjects in caffeine intake
or most symptoms, more depressed patients reported that caffeine induced
anxiety. These data support prior reports that panic patients have
increased sensitivity to caffeine; some depressed patients may also have
increased sensitivity.

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Am Fam Physician 1988 May;37(5):167-172

Psychotropic effects of caffeine.

Clementz GL, Dailey JW

University of Illinois College of Medicine, Peoria.

Chronic, heavy caffeine ingestion may cause or exacerbate anxiety and may
be associated with depression and increased use of antianxiety drugs.
Caffeine may cause anxiety and panic in panic disorder patients and may
aggravate the symptoms of premenstrual syndrome. Chronic users who are
caffeine-sensitive may have symptoms of caffeinism at relatively low doses.
Individuals who regularly consume moderate to heavy amounts of caffeine may
develop caffeinism, or they may show signs of caffeine withdrawal syndrome
after abstaining from the drug.

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Psychiatry Res 1988 Apr;24(1):61-65

Chronic caffeine consumption and the dexamethasone suppression test in

Lee MA, Flegel P, Cameron OG, Greden JF

Department of Psychiatry, University of Michigan, Ann Arbor.

Acute caffeine administration increases cortisol and converts the
dexamethasone suppression test (DST) to nonsuppression in normal humans;
data concerning chronic administration as well as effects in depressed
patients are minimal. To determine whether caffeine intake influenced DST
results in depression, we retrospectively studied the relationship between
regular daily caffeine consumption and pretreatment DST status in major
depressives. Daily intake was not correlated with either post-DST cortisol
levels or symptom ratings. These data suggest that chronic caffeine use is
unlikely to be a major factor in dysregulation of the
hypothalamic-pituitary-adrenal axis in depression, perhaps because of the
development of tolerance.

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Psychopharmacology (Berl) 1988;94(4):437-451

Caffeine physical dependence: a review of human and laboratory animal

Griffiths RR, Woodson PP

Department of Psychiatry and Behavioral Sciences, Johns Hopkins University
School of Medicine, Baltimore, MD 21205.

Although caffeine is the most widely used behaviorally active drug in the
world, caffeine physical dependence has been poorly characterized in
laboratory animals and only moderately well characterized in humans. In
humans, a review of 37 clinical reports and experimental studies dating
back to 1833 shows that headache and fatigue are the most frequent
withdrawal symptoms, with a wide variety of other signs and symptoms
occurring at lower frequency (e.g. anxiety, impaired psychomotor
performance, nausea/vomiting and craving). When caffeine withdrawal occurs,
severity can vary from mild to extreme (i.e. incapacitating). The
withdrawal syndrome has an onset at 12-24 h, peak at 20-48 h, and duration
of about 1 week. The pharmacological specificity of caffeine withdrawal has
been established. The proportion of heavy caffeine users who will
experience withdrawal symptoms has been estimated from experimental studies
to range from 25% to 100%. Withdrawal symptoms have been documented after
relatively short-term exposure to high doses of caffeine (i.e. 6-15 days of
greater than or equal to 600 mg/day). Although animal and human studies
suggest that physical dependence may potentiate the reinforcing effects of
caffeine, human studies also demonstrate that a history of substantial
caffeine intake is not a necessary condition for caffeine to function as a
reinforcer. The similarities and differences between caffeine and classic
drugs of abuse are discussed.

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J Subst Abuse 1988;1(1):67-70

A survey of physician advice about caffeine.

Hughes JR, Amori G, Hatsukami DK

Department of Psychiatry, University of Vermont, Burlington 05401.

Six hundred and ninety-seven medical specialists were surveyed to determine
whether there is any consensus on the harmful effects of caffeine. More
than 75% of the specialists recommended reduction in caffeine in patients
with anxiety, arrhythmias, esophagitis/hiatal hernia, fibrocystic disease,
insomnia, palpitations, and tachycardia.

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J Clin Psychopharmacol 1987 Oct;7(5):315-320

The effects of caffeine and aspirin on mood and performance.

Lieberman HR, Wurtman RJ, Emde GG, Coviella IL

Department of Brain and Cognitive Sciences, Massachusetts Institute of
Technology, Cambridge 02139.

Caffeine, in addition to being a food constituent, is also a common
analgesic adjuvant that is used in combination with aspirin in certain
over-the-counter preparations. Caffeine has previously been shown to
significantly improve certain aspects of human performance, particularly
sustained vigilance, when administered in low and moderate doses (32 to 256
mg). We therefore attempted to determine whether caffeine, in the dose (64
mg) found in some over-the-counter drugs, retains this beneficial property
when combined with aspirin. We also measured self-reported mood state,
using various standardized questionnaires, since caffeine has been reported
to have both beneficial and adverse effects on alertness and anxiety. We
observed that caffeine (64 mg), when added to aspirin (800 mg),
significantly improves vigilance performance and increases self-reported
efficiency when compared with either placebo or aspirin alone. As
previously reported, this caffeine dose alone significantly increased
vigilance and decreased reaction time. No adverse effects of caffeine were
detected on any of the parameters that were assessed. This study therefore
demonstrated that the addition of caffeine to aspirin, in a dose commonly
employed in over-the-counter drugs, has significant beneficial consequences
with respect to mood and performance.

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Psychiatry Res 1987 Jul;21(3):247-255

Plasma adenosine levels: measurement in humans and relationship to the
anxiogenic effects of caffeine.

Boulenger JP, Salem N Jr, Marangos PJ, Uhde TW

The effects of caffeine on plasma adenosine were examined in eight healthy
normal volunteers. Subjects were randomly administered on 4 separate days,
in a double-blind fashion, either placebo or three different doses of
caffeine (240, 480, and 720 mg). Adenosine concentrations, measured by high
performance liquid chromatography, were in the micromolar range when
samples were drawn into tubes containing dipyridamole to prevent adenosine
reuptake by red blood cells. Plasma adenosine levels did not change after
caffeine administration. The effects of caffeine on anxiety were related to
changes in plasma caffeine but not plasma adenosine levels. The potential
interest of caffeine as a chemical model of anxiety is discussed.

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Acta Psychiatr Scand 1987 Jun;75(6):608-613

Dexamethasone suppression test in severe schizophrenic illness: effects of
plasma dexamethasone and caffeine levels.

Holsboer-Trachsler E, Buol C, Wiedemann K, Holsboer F

A dexamethasone suppression test (DST) was administered to 31 inpatients
with a severe acute schizophrenic exacerbation 4 or 5 days following
admission and repeated after 4 weeks or prior to discharge. We identified
15 patients (48%) who were nonsuppressors on the DST at the first test. To
exclude major confounders of DST results we monitored weight constancy and
plasma concentrations of dexamethasone. In a subgroup of patients also
plasma caffeine contents were determined. Our results indicate that DST
nonsuppression occurs frequently among patients with schizophrenic crisis.
Since caffeine plasma levels were indistinguishable between suppressors and
nonsuppressors we reject that excessive caffeine intake accounts for DST
nonsuppression among individuals with schizophrenia. Nonsuppressors had
lower plasma dexamethasone levels than suppressors and reversal of the DST
status from nonsuppression to suppression was associated with an increase
of plasma concentrations of the test drug.

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Int J Psychophysiol 1987 May;5(1):33-41

Autonomic nervous system effects of acute doses of caffeine in caffeine
users and abstainers.

Zahn TP, Rapoport JL

The effects of caffeine on autonomic nervous system (ANS) activity were
tested in 20 adult males who were either high or low consumers of caffeine.
Subjects received placebo, 3 mg/kg, and 10 mg/kg of caffeine in a
counterbalanced order (double-blind) before 3 test sessions 48 h apart.
Skin conductance (SC), heart rate, and skin temperature (ST) were recorded
during a rest period, a series of non-signal tones, and a simple reaction
time task. Caffeine increased resting electrodermal activity (EDA) and
increased the SC orienting response to the first non-signal tone, but
reduced the increase in tonic EDA due to task performance. ST was reduced
by caffeine in both rest and task periods. Increases in nervous/jittery
ratings occurred after caffeine ingestion, but task performance was not
affected. Low consumers of caffeine showed significantly more ANS
responsivity than high consumers under all conditions and did not differ in
ANS, behavioral, or subjective effects of caffeine. The acute physiological
changes are partly similar to those reported for patients with anxiety
disorders, suggesting a possible role of ANS activity in mediating the
anxiogenic effects of caffeine. Effects of user status may reflect a
predisposing trait, but an effect of chronic caffeine use on ANS
sensitivity cannot be ruled out.

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Psychopharmacology (Berl) 1987;92(3):308-312

The effects of low doses of caffeine on human performance and mood.

Lieberman HR, Wurtman RJ, Emde GG, Roberts C, Coviella IL

Caffeine is thought to have stimulant-like behavioral effects on mood and
performance. However few behavioral studies have examined this substance's
acute effects when administered in a range of doses that include the low
doses typically found in foods and over-the-counter drugs. We therefore
gave single doses of caffeine (32, 64, 128 and 256 mg) to 20 healthy male
subjects and assessed various aspects of performance and self-reported mood
states, as well as plasma caffeine concentration. As little as 32 mg (which
elevated plasma caffeine concentration to less than 1 microgram/ml),
typical of the dose found in a single serving of a cola beverage, and less
than that found in a single cup of coffee or a single dose of
over-the-counter drugs, significantly improved auditory vigilance and
visual reaction time. All other caffeine doses administered also
significantly improved performance on these tests. No adverse behavioral
effects, such as increased anxiety or impaired motor performance, were
noted even at the highest dose administered.

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Psychopharmacology (Berl) 1987;91(1):40-44

Acute autonomic nervous system effects of caffeine in prepubertal boys.

Zahn TP, Rapoport JL

The effects of caffeine on autonomic activity were tested in 19 normal
prepubertal boys. Subjects received placebo, 3 mg/kg, and 10 mg/kg caffeine
in a random order (double blind) before three test sessions 48 h apart.
Skin conductance (SC), heart rate (HR), and skin temperature (ST) were
recorded during a rest period, a series of nonsignal tones, and a simple
reaction time (RT) task. Caffeine increased the frequency of both
spontaneous and elicited SC responses (SCR) under all conditions. Resting
SC base level (SCL) was increased, and shorter SCR half recovery time also
occurred in some periods. In contrast, caffeine decreased HR and motor
activity at 3 mg/kg. Evidence of improved attention on caffeine was also
obtained. The physiological effects are partially similar to the effects
seen in clinical anxiety states, and they are also consistent with the
physiological concomitants of good sustained attention. The profile of
effects did not resemble those of dextroamphetamine in a similar

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Med J Aust 1986 Nov 17;145(10):518-521

Caffeine: a toxicological overview.

Abbott PJ

The health effects of caffeine have been examined in a review of its
toxicological and pharmacological properties together with its effect on
children. Caffeine commonly causes symptoms of an acute overdose and
withdrawal symptoms. These may be identified as anxiety in moderate
consumers and can lead to severe central nervous system effects in heavy
consumers. Pharmacological effects occur even at low doses but their
severity is influenced by wide individual variation and the development of
tolerance. Nevertheless, chronic consumption of caffeine is implicated in
various minor symptoms of ill health and is associated with elevated serum
cholesterol levels. At the doses that are consumed by humans, there is
little evidence at present to suggest effects on reproduction,
teratogenesis, tumour formation or the incidence of myocardial infarction.
A reduced consumption of caffeine is advocated for all age groups.

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J Clin Psychol 1986 Nov;42(6):860-863

Caffeine and memory performance on the AVLT.

Terry WS, Phifer B

The Auditory-Verbal Learning Test (AVLT) is a memory test that assesses
recall of lists of words on single and multiple trials. College students (N
= 33) were given the AVLT, either with or without a prior administration of
100 mg caffeine. Caffeine subjects recalled fewer words than did control
subjects, both after single presentations of lists and across repeated
trials. Caffeine subjects showed a greater deficit in recalling the
middle-to-end portions of the lists. Personality scores on the Maudsley
Personality Inventory showed a positive correlation of recall on a pretest
with Neuroticism, and no correlation with Introversion.

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Pharmacotherapy 1986 Sep;6(5):240-247

Analgesic effect of an aspirin-codeine-butalbital-caffeine combination and
an acetaminophen-codeine combination in postoperative oral surgery pain.

Forbes JA, Jones KF, Smith WK, Gongloff CM

The efficacy of an aspirin-caffeine-codeine-butalbital combination was
compared to an acetaminophen-codeine combination and placebo in outpatients
who had moderate or severe pain after the surgical removal of impacted
third molars. Using a self-rating record, patients rated their pain,
relief, anxiety and relaxation hourly for up to 6 hours after medicating.
Each active medication was significantly superior to placebo for measures
of analgesia and relaxation. Although the butalbital-containing combination
provided consistently greater analgesia, the differences between active
medications were not statistically significant. The acetaminophen-codeine
combination significantly reduced anxiety; however, the butalbital
containing combination did not. The results of this study suggest that
female patients may have greater efficacy than male patients. All adverse
effects were transitory and consistent with the known pharmacologic
profiles of the study medications or the backup analgesic.

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Psychol Rep 1986 Aug;59(1):83-86

Potentiation of performance-induced anxiety by caffeine in coffee.

Shanahan MP, Hughes RN


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Psychiatr J Univ Ott 1986 Jun;11(2):105-106

Hyponatremic coma and elevated serum creatine phosphokinase following
excessive caffeine intake.

Kirubakaran V


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Eur Arch Psychiatry Neurol Sci 1986;235(4):206-209

Caffeine-induced cerebral blood flow changes in schizophrenia.

Mathew RJ, Wilson WH, Tant S

Cerebral blood flow (CBF) measurements and mental status examinations were
performed before and 30 min after oral administration of 250 mg of caffeine
or a placebo given under double-blind conditions, in two groups of patients
with schizophrenia. Caffeine produced significant CBF reductions but no
changes in the patient's clinical condition.

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Servir 1986 Jan;34(1):34-38

Caffeine, stress and anxiety.

[Article in Portugese]

Boulenger JP


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Cardiovasc Res 1985 Dec;19(12):727-733

Electromechanical effects of caffeine in isolated human atrial fibres.

Lin CI, Chiu TH, Chiang BN, Cheng KK

Effects of caffeine on the action potential and contractile force of human
atrial fibres obtained at cardiac surgery were studied with standard
microelectrode technique. In 4 mmol . litre-1 [K]o, the only significant
action produced by 0.3 to 3 mmol . litre-1 caffeine on the
electro-mechanical activity of relatively normal atrial fibres was a slight
shortening of the action potential duration at 50% repolarisation. When the
fibres were depolarised in 27 mmol . litre-1 [K]o or in atrial fibres
showing slow responses in 4 mmol . litre-1 [K]o, however, caffeine could
increase the upstroke of slow response and the force. In 18% of atrial
fibres showing slow responses in 4 mmol . litre-1 [K]o, caffeine induced
spontaneous discharges and potentiated afterdepolarisations. The positive
inotropic and the arrhythmogenic effects of caffeine could be diminished by
pretreating the fibres with propranolol or Ca antagonists (diltiazem and
verapamil). In fibres beating spontaneously in normal [K]o, caffeine
accelerated spontaneous rhythms initially and then depressed them.
Propranolol potentiated the later depression but did not block the initial
acceleration. The results suggest that caffeine increases the transmembrane
Ca influx and enhances the release of Ca from the intracellular stores in
human atrial fibres. As a consequence, caffeine could induce arrhythmias in
atria from certain individuals.

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Psychol Rep 1985 Aug;57(1):39-42

Patterns of caffeine use and prescribed medications in psychiatric

Shisslak CM, Beutler LE, Scheiber S, Gaines JA, La Wall J, Crago M


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Arch Gen Psychiatry 1985 Jul;42(7):737-738

Caffeine-induced escape from dexamethasone suppression.


Uhde TW, Bierer LM, Post RM


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Psychiatry Res 1985 Jul;15(3):211-217

Anxiety and caffeine consumption in people with anxiety disorders.

Lee MA, Cameron OG, Greden JF

Forty-three anxiety disorder patients (DSM-III) who completed the Hopkins
Symptom Checklist (SCL-90-R) and a caffeine questionnaire were compared to
124 medical inpatients. Eighty-four percent of the anxious patients were
low caffeine consumers (0-249 mg/day) compared to 41% of medical
inpatients; 65% of anxiety patients consumed less than 100 mg/day. In
anxiety patients, there were no significant correlations between subscale
scores of the SCL-90-R and amount of caffeine consumption. Patients who
consumed less than 100 mg/day did not differ on anxiety subscale scores of
the SCL-90-R from those who consumed more. However, patients who reported
becoming anxious in response to drinking coffee had higher SCL-90-R anxiety
subscale scores than patients who did not, even though their daily
consumption was not different. It appears that anxiety disorder patients
have increased caffeine sensitivity which leads to decreased consumption.

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Arch Gen Psychiatry 1985 Mar;42(3):233-243

Increased anxiogenic effects of caffeine in panic disorders.

Charney DS, Heninger GR, Jatlow PI

The effects of oral administration of caffeine (10 mg/kg) on behavioral
ratings, somatic symptoms, blood pressure and plasma levels of
3-methoxy-4-hydroxyphenethyleneglycol (MHPG) and cortisol were determined
in 17 healthy subjects and 21 patients meeting DSM-III criteria for
agoraphobia with panic attacks or panic disorder. Caffeine produced
significantly greater increases in subject-rated anxiety, nervousness,
fear, nausea, palpitations, restlessness, and tremors in the patients
compared with healthy subjects. In the patients, but not the healthy
subjects, these symptoms were significantly correlated with plasma caffeine
levels. Seventy-one percent of the patients reported that the behavioral
effects of caffeine were similar to those experienced during panic attacks.
Caffeine did not alter plasma MHPG levels in either the healthy subjects or
patients. Caffeine increased plasma cortisol levels equally in the patient
and healthy groups. Because caffeine is an adenosine receptor antagonist,
these results suggest that some panic disorder patients may have
abnormalities in neuronal systems involving adenosine. Patients with
anxiety disorders may benefit by avoiding caffeine-containing foods and

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Psychopharmacology (Berl) 1985;87(3):344-350

Caffeine and diazepam: separate and combined effects on mood, memory, and
psychomotor performance.

Loke WH, Hinrichs JV, Ghoneim MM

The effects of caffeine and diazepam on several mood, cognitive, learning,
memory, and psychomotor tasks were investigated in a double-blind study of
108 young healthy adults who were randomly assigned to nine treatments;
oral administration of caffeine (0, 3 and 6 mg/kg), diazepam (0, 0.15, and
0.30 mg/kg) and their combinations. Subjects completed a battery of tasks
once before and twice after administration of the drugs. Caffeine alone
showed no effects on cognitive, learning, and memory performance, but
impaired fine motor coordination and increased anxiety and tenseness.
Diazepam alone produced sedation, lowered other ratings of subjective
moods, and impaired cognitive, learning, and memory performance. The two
drugs did not antagonize the effects of each other, except in the symbol
cancellation task.

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Arch Gen Psychiatry 1984 Nov;41(11):1073-1079

Behavioral effects of caffeine in children. Relationship between dietary
choice and effects of caffeine challenge.

Rapoport JL, Berg CJ, Ismond DR, Zahn TP, Neims A

From a survey of 24-hour caffeine intake of 798 grade-school children (mean
age, 10.3 years), 19 "high consumers" (reported intake of 500 mg/day or
more) and a matched group of 19 "low consumers" were recruited for a
double-blind, placebo-controlled, caffeine challenge study. Children
received 5 mg/kg of caffeine twice a day or placebo for two weeks each,
using a crossover design. While not receiving caffeine, high consumers had
higher scores on an anxiety questionnaire and tended to have lower
autonomic arousal (less frequent spontaneous skin conductance response and
lower skin conductance level). While receiving caffeine, low consumers were
perceived by their parents as more emotional, inattentive, and restless,
while high consumers were not rated as changed. These differences cannot be
attributed to tolerance, withdrawal, or subject selection, and suggest a
possible physiological basis in children for dietary caffeine preference.

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Arch Gen Psychiatry 1984 Nov;41(11):1067-1071

Increased sensitivity to caffeine in patients with panic disorders.
Preliminary evidence.

Boulenger JP, Uhde TW, Wolff EA 3d, Post RM

The results of a caffeine consumption inventory indicated that patients
with panic anxiety disorder, but not affectively ill patients or normal
controls, had levels of self-rated anxiety and depression that correlated
with their degree of caffeine consumption. In addition, this self-report
survey suggested that patients with panic disorder had an increased
sensitivity to the effects of one cup of coffee. This apparent sensitivity
to caffeine was also documented by the observation that more patients with
panic disorder reported the discontinuation of coffee intake due to
untoward side effects than controls. These results, based on self-reports,
suggest that the hypothesis that patients with panic disorder are more
reactive to caffeine should be directly tested using caffeine challenges
and that the mechanisms underlying caffeine's effects on anxiety should be
further explored.

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J Pediatr 1984 Sep;105(3):493-495

Caffeine toxicity as a cause of acute psychosis in anorexia nervosa.

Shaul PW, Farrell MK, Maloney MJ


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Life Sci 1984 Jul 9;35(2):135-144

The effects of caffeine on plasma MHPG, subjective anxiety, autonomic
symptoms and blood pressure in healthy humans.

Charney DS, Galloway MP, Heninger GR

The effects of oral administration of caffeine (10 mg/kg) on plasma free
3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) levels, behavioral ratings,
blood pressure, and autonomic symptoms was determined in eleven healthy
subjects. Caffeine produced robust increases in subject rated anxiety and
nervousness and small elevations in blood pressure and a decrease in heart
rate. Caffeine did not alter plasma MHPG in a consistent fashion and there
was no correlation between changes in plasma MHPG and changes in anxiety or
other ratings. Caffeine may produce symptoms of anxiety-nervousness without
increasing central norepinephrine turnover.

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J Abnorm Psychol 1984 Feb;93(1):120-122

Effects of caffeine on anxiety and depression.

Veleber DM, Templer DI


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Psychopharmacol Bull 1984;20(3):426-430

Caffeine: relationship to human anxiety, plasma MHPG and cortisol.

Uhde TW, Boulenger JP, Jimerson DC, Post RM


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J Psychiatr Res 1984;18(2):91-106

Behavioral and molecular actions of caffeine: focus on adenosine.

Snyder SH, Sklar P


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Br J Psychiatry 1983 Dec;143:604-608

Caffeine and cerebral blood flow.

Mathew RJ, Barr DL, Weinman ML

Two groups of normal volunteers had regional cerebral blood flow (rCBF)
measured, by the 133Xenon inhalation technique, before and 30 minutes after
250 mg or 500 mg caffeine given orally. rCBF was measured in a third group
of subjects, twice, at a similar interval under identical laboratory
conditions. Subjects who received caffeine showed significant decreases in
rCBF while the others showed no rCBF change from the first to the second
measurement. However, the two caffeine groups did not differ in degrees of
rCBF reduction. There were no regional variations in the post-caffeine
decrease in cerebral blood flow. The three groups did not show significant
changes in end-tidal carbon dioxide, pulse rate, blood pressure, forehead
skin temperature and respiratory rate.

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Clin Pharmacol Ther 1983 Nov;34(5):612-622

Effects of caffeine on cigarette smoking and subjective response.

Chait LD, Griffiths RR

We examined the effects of oral caffeine on cigarette smoking and
subjective response in a group of six smokers who smoked cigarettes ad
libitum in a naturalistic laboratory environment. A within-subject,
repeated-measures design was used, and each subject received placebo,
caffeine base (50 to 800 mg), or d-amphetamine sulfate (25 mg) on several
occasions before 90-min daily smoking sessions. There was no evidence of an
increase in the number of cigarettes smoked or the amount of smoke inhaled
per session after caffeine. Caffeine increased salivary caffeine
concentrations, arm tremor, and self-reported measures of mood and
subjective response. The major subjective effects of caffeine were
increases in tension-anxiety and dysphoric-somatic effects. In contrast,
d-amphetamine induced increases in the number of cigarettes smoked and in
the amount of smoke inhaled per session. The major subjective effects of 25
mg of d-amphetamine were increases in measures of well-being, euphoria, and
mental efficiency. Results demonstrate that caffeine and d-amphetamine have
different effects on cigarette-smoking behavior as well as on subjective
response and suggest that the positive correlation between cigarette
smoking and coffee drinking is not the result of a simple pharmacologic
effect of caffeine.

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Br J Addict 1983 Sep;78(3):251-258

Caffeine: a survey of some of the known and suspected deleterious effects
of habitual use.

James JE, Stirling KP


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Adv Alcohol Subst Abuse 1983;3(1-2):53-73

Caffeine: a potential drug of abuse.

Gilliland K, Bullock W

Recent investigations of caffeine abuse have questioned the indiscriminant
use of this commonly accepted drug. In some individuals, chronic excessive
caffeine consumption leads to the development of caffeinism, a syndrome
which includes increased anxiety, depression, frequency of
psychophysiological disorders, and possibly degraded performance. This
paper reviews research demonstrating the abuse potential of caffeine.
Special attention has been given those factors which mediate the wide
individual differences in consumption patterns, susceptibility to abuse,
and the varied psychological and physiological responses to this drug.
While the development of caffeine abuse is probably best viewed as an
idiosyncratic process, general guidelines for the recognition of potential
abuse, and caffeinism proper, are offered.

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J Behav Med 1982 Dec;5(4):415-439

Caffeine and human behavior: arousal, anxiety, and performance effects.

Sawyer DA, Julia HL, Turin AC

A review of the recent literature shows the role of caffeine in the
physiology, mood, and behavior of persons to be a complex one including
changes in arousal, anxiety, and performance. Questions are raised as to
what degree the physiological effects of caffeine are due to central
nervous system stimulation and/or result from the release of
catecholamines. Anxiety resulting from both high levels of caffeine
(caffeinism) and caffeine withdrawal plus an association between caffeine
and depression are discussed. Performance effects are mixed, with both
increases and decreases reported. Effects on mental tasks are related to
personality variables. The possible role of differences in initial
sensitivity, adaptation to caffeine, and/or interactions with nicotine and
alcohol is discussed. The present paper reviews these studies, discusses
their implications for both clinical and experimental work, summarizes the
major unresolved issues, and makes suggestions for new and continuing areas
of research.

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Lancet 1982 Oct 30;2(8305):985-986

Plasma caffeine concentration in outpatients.


Smith JM, Pearson S, Marks V


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Psychopharmacol Bull 1982 Oct;18(4):53-57

Caffeine consumption and anxiety: preliminary results of a survey comparing
patients with anxiety disorders and normal controls.

Boulenger JP, Uhde TW


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J Clin Psychopharmacol 1982 Apr;2(2):102-106

Interaction between effects of caffeine and lorazepam in performance tests
and self-ratings.

File SE, Bond AJ, Lister RG

In 18 normal volunteers, lorazepam (2.5 mg) compared with placebo
significantly impaired performance in a verbal learning task, in the
digit-symbol substitution test, and in symbol copying and number
cancellation tasks. These impairments were found equally in subjects with
high and low state anxiety and in subjects with high and low trait anxiety.
Caffeine citrate (125 to 500 mg) significantly improved performance on the
digit-symbol substitution test when given alone and reduced the lorazepam
impairment. In the symbol copying test caffeine counteracted the lorazepam
impairment. Lorazepam produced a significant loss of appetite and made the
subjects feel significantly more dizzy, physically and mentally tired,
withdrawn and tranquil, and significantly less anxious. Caffeine citrate
(500 mg) counteracted the lorazepam effect of reducing anxiety and making
the subjects feel more relaxed.

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Psychopharmacology (Berl) 1982;76(3):201-208

Model insomnia by methylphenidate and caffeine and use in the evaluation of

Okuma T, Matsuoka H, Matsue Y, Toyomura K

Experimental sleep disturbances (model insomnia) were produced by the
administration of methylphenidate (MPD) 10 mg and caffeine (CAF) 150 mg.
The effect of temazepam (TEM), 15 mg or 30 mg, on the model was
investigated. All-night polysomnography was performed on 8 normal young
male subjects under each of the following 9 conditions: baseline, MPD 10
mg, CAF 150 mg, TEM 15 mg, TEM 30 mg, MPD + TEM 15 mg, MPD + TEM 30 mg, CAF
+ TEM 15 mg, CAF + TEM 30 mg. A reduction in total sleep time and total
amount of stage REM (S-REM) sleep and an increase in the sleep latency and
wake time (S-W) were observed in both the MPD and CAF nights. The sleep
latency was significantly longer in the CAF night than in the MPD night.
Administration of TEM 15 mg or TEM 30 mg alone caused very few
modifications in the sleep parameters. These drugs in combination with MPD
or CAF resulted in almost complete recovery of the sleep disturbance
induced by MPD or CAF. The results indicate that CAF and MPD produced
similar models of insomnia except for a greater sleep latency for CAF than
for MPD. Both models were useful in the evaluation of hypnotic drugs such
as temazepam.

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Am J Psychiatry 1981 Apr;138(4):512-514

Ad lib caffeine consumption, symptoms of caffeinism, and academic

Gilliland K, Andress D

The authors explored the relationship between ad lib caffeine consumption
in college students and the incidence of caffeinism, characterized by
heightened anxiety, depression, and various psychophysiological reactions.
Students were randomly selected from four groups (abstainers from caffeine
and low, moderate, and high consumers). A survey battery assessed the
effects of caffeine, incidence of psychophysiological disorders,
state-trait anxiety, and depression. The moderate and high consumer groups
combined reported significantly higher trait anxiety and depression scores
when compared with abstainers. The high consumer group also reported
significantly higher levels of symptoms of caffeinism, higher frequency of
psychophysiological disorders, and lower academic performance.

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Mutat Res 1981 Mar;81(1):75-80

Inhibition of chromosome repair by caffeine or isonicotinic acid hydrazide
on chromosome damage induced by mitomycin C in human lymphocytes.

Okoyama S, Kitao Y


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Dev Pharmacol Ther 1981;3(2):74-82

Behavioral and autonomic effects of caffeine in normal boys.

Rapoport JL, Elkins R, Neims A, Zahn T, Berg CJ

Following a 1-week baseline, 19 normal boys (mean age 9.8 +1.8 years)
ingested either caffeine (5 mg/kg) or placebo twice a day for a 2-week
period per condition in a double-blind crossover study (total study
duration of 5 weeks) to study the behavioral, autonomic and side effects of
caffeine. Mothers of the whole sample and children who were low caffeine
users could distinguish between drug conditions by side effects. Caffeine
increased autonomic reactivity of low users only. Behavioral and autonomic
results were ambiguous for high users indicating possible caffeine
withdrawal symptoms. While 'caffeinism' may occur in children, either
self-selection and/or tolerance may prevent its occurrence in naturally
selected diets.

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Cancer Res 1980 Oct;40(10):3786-3791

Effects of caffeine on neocarzinostatin-induced inhibition of cell cycle
traverse in HeLa-S3 cells.

Iseki S, Ebina T, Ishida N

Caffeine was found to suppress the cell cycle effects of the cancer
chemotherapeutic agent neocarzinostatin (NCS). When caffeine was added
together with NCS to the culture of HeLa-S3 cells, NCS-induced inhibition
of DNA synthesis and of mitosis was markedly reduced in the presence of
caffeine. Theophylline was also effective, but N6, O2'-dibutyryl cyclic
adenosine 3':5'-monophosphate was not. The caffeine-caused reduction of
cell cycle effects was also observed in several other cancer
chemotherapeutic agents, including bleomycin and Adriamycin. In contrast,
the single-strand scission of cellular DNA and the final cell lethality
induced by NCS were not affected by caffeine. These results suggest that
the mechanism by which NCS inhibits the cell cycle traverse involves a kind
of cell damage which is repairable in a manner promoted by caffeine and
hence is different from single-strand scission of DNA. Such a mechanism
might be common to the cell cycle effects of X-irradiation and several
cancer chemotherapeutic agents including NCS.

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Science 1980 Sep 26;209(4464):1547-1548

Anxiety and muscle tension as consequences of caffeine withdrawal.

White BC, Lincoln CA, Pearce NW, Reeb R, Vaida C

Regular consumers of caffeine had higher muscle tension after three or more
hours of abstinence than low caffeine consumers. This difference was absent
after double-blind administration of caffeine citrate or placebo. In a
discriminative reaction time test, caffeine treatment improved performance.
Among subjects receiving placebo, anxiety was highly correlated with prior
caffeine use, suggesting that even a brief abstinence may produce anxiety
in the regular user.

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Links:  [205 medline neighbors]

Psychosomatics 1980 May;21(5):411-413

Caffeine-withdrawal headache: a clinical profile.

Greden JF, Victor BS, Fontaine P, Lubetsky M


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Links:  [140 medline neighbors]

Am J Dis Child 1980 May;134(5):495-498

Acute caffeine overdose in the neonate.

Banner W Jr, Czajka PA

To our knowledge, the clinical course of acute caffeine poisoning in
neonates has not been previously reported. Three full-term infants
manifested CNS irritability after the parenteral administration of large
doses of caffeine and benzoate sodium injection in the delivery room for
respiratory depression. The infants received caffeine in doses that ranged
from 36 to 136 mg/kg. On arrival in a regional newborn center, they
exhibited one or more of the following symptoms: tachypnea, fine tremor of
the extremities, opisthotonus, tonic-clonic movements, and nonpurposeful
jaw and lip movements. The overdose of caffeine produced a clinical picture
that suggested neonatal seizures and prompted therapy with anticonvulsants.
A fourth infant (premature) attained a high plasma caffeine concentration,
but this infant's symptoms were altered by intraventricular hemorrhage. The
combination of caffeine overdose and perinatal asphyxia may precipitate or
increase seizure activity in the neonate. Recognition of the potential
toxic effects of caffeine overdose should guide patient care and stimulate
further study to establish appropriate use of caffeine in the newborn

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J Mol Biol 1979 Dec 5;135(2):435-449

Accumulation of DNA growing points in caffeine-treated human lymphoblastoid

Tatsumi K, Strauss BS


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Links:  [132 medline neighbors]

Biull Eksp Biol Med 1979 Dec;88(12):685-688

Effect of phenamine and caffeine on the behavioral changes occurring after
the cessation of caudate nucleus electric stimulation in cats.

[Article in Russian]

Shishliannikova LV

Low doses of amphetamine (0.1-0.5 mg/kg), not influencing the spontaneous
behaviour of cats, prevent behavioral depression arising after repeated
low-frequency stimulation of the caudate nucleus. Activating phenomena,
observed after cessation of the stimulation, are considerably intensified
up to the stereotypy formation. Caffeine (10-80 mg/kg), when activating
spontaneous behaviour in cats, does not exclude a possibility of
caudate-induced depression.

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J Clin Psychiatry 1978 Sep;39(9):732-736

Caffeine and schizophrenia.

Mikkelsen EJ

Two cases are described in which markedly increased consumption of caffeine
led to an exacerbation of a schizophrenic process. The original description
of this phenomenon and the clinical and basic science literature regarding
the psychotropic effects of caffeine are reviewed. The cases are discussed
in light of the clinical and research implications.

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Links:  [128 medline neighbors]

Psychol Rep 1978 Jun;42(3 Pt 1):833-834

Anxiety and caffeine.

Hire JN


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Farmakol Toksikol 1975 Sep;38(5):540-543

Effect of caffeine and phenamin on caudate inhibition of aggressive
reactions in cats.

[Article in Russian]

Belozertsev IuA

In chronic experiments conducted on cats it was shown that caffeine (10--30
mg/kg) failed to change agressive reactions developing in stimulation of
the meso- or diencephalic structures. Phenamine (1--3 mg/kg) facilitated
the appearance of emotional manifestations and lowered the threshold of the
agressive response. Subliminal stimulation of the caudate nucleus in
control experiments caused motor tranquilization and depressed the
agressive behaviour to a lesser degree when practised against the
background of the caffeine action. At the same time, phenamine abolished
the influence not only of the threshold, but also of the subliminal
stimulation of the caudate nucleus on the spontaneous motor activity and
the rage behaviour.

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Clin Ter 1975 Mar 31;72(6):523-530

Interference of psychological stress and of bromazepam with the toxic and
electrocardiographic effects of caffeine in guinea pigs.

[Article in Italian]

Cuomo V, Cristallo E, Marino A


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Percept Mot Skills 1975 Feb;40(1):126

Paradoxical effects of caffeine.

Klein RH, Salzman LF


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Electroencephalogr Clin Neurophysiol 1974 Jul;37(1):59-71

The effect of caffeine, nitrazepam and cigarette smoking on the contingent
negative variation in man.

Ashton H, Millman JE, Telford R, Thompson JW


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Links:  [200 medline neighbors]

Andrologia 1974;6(1):53-58

Effects of caffeine on the motility and metabolism of human spermatozoa.

Johnsen O, Eliasson R, Kader MM


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Zh Nevropatol Psikhiatr 1973;73(5):759-761

Effect of caffeine on drug-induced parkinsonism and the caudal reaction of

[Article in Russian]

Arushanian EB, Stoliarov GV, Tolpyshev BA

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