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Psychopharmacology (2004) 176: 1–29DOI 10.1007/s00213-004-2000-x
REVIEW
Laura M. Juliano . Roland R. Griffiths
A critical review of caffeine withdrawal: empirical validation
of symptoms and signs, incidence, severity, and associated
features
Received: 9 March 2004 / Accepted: 24 July 2004 / Published online: 21 September 2004# Springer-Verlag 2004
Abstract Rationale: Although reports of caffeine with-drawal in the medical literature date back more than170 years, the most rigorous experimental investigationsof the phenomenon have been conducted only recently.Objectives: The purpose of this paper is to provide acomprehensive review and analysis of the literatureregarding human caffeine withdrawal to empiricallyvalidate specific symptoms and signs, and to appraiseimportant features of the syndrome. Methods: A litera-ture search identified 57 experimental and 9 survey studieson caffeine withdrawal that met inclusion criteria. Themethodological features of each study were examined toassess the validity of the effects. Results: Of 49 symp-tom categories identified, the following 10 fulfilledvalidity criteria: headache, fatigue, decreased energy/activeness, decreased alertness, drowsiness, decreasedcontentedness, depressed mood, difficulty concentrating,irritability, and foggy/not clearheaded. In addition, flu-likesymptoms, nausea/vomiting, and muscle pain/stiffnesswere judged likely to represent valid symptom categories.In experimental studies, the incidence of headache was50% and the incidence of clinically significant distress orfunctional impairment was 13%. Typically, onset ofsymptoms occurred 12–24 h after abstinence, with peakintensity at 20–51 h, and for a duration of 2–9 days. Ingeneral, the incidence or severity of symptoms increasedwith increases in daily dose; abstinence from doses as lowas 100 mg/day produced symptoms. Research is reviewed
indicating that expectancies are not a prime determinant ofcaffeine withdrawal and that avoidance of withdrawalsymptoms plays a central role in habitual caffeineconsumption. Conclusions: The caffeine-withdrawalsyndrome has been well characterized and there issufficient empirical evidence to warrant inclusion ofcaffeine withdrawal as a disorder in the DSM and revisionof diagnostic criteria in the ICD.
Keywords Caffeine . Abstinence . Cessation .Deprivation . Withdrawal . Headache . Physicaldependence . DSM . ICD . Humans
Introduction
Caffeine is the most widely used behaviorally active drugin the world (Gilbert 1984). In North America, 80–90% ofadults report regular use of caffeine (Gilbert 1984; Hughesand Oliveto 1997). Mean daily intake of caffeine amongcaffeine consumers in the United States is about 280 mg,with higher intakes estimated in some European countries(Gilbert 1984; Barone and Roberts 1996). In the UnitedStates, coffee and soft drinks are the most commonsources of caffeine, with almost half of caffeine consumersingesting caffeine from multiple sources, including tea(Hughes and Oliveto 1997).
After oral ingestion, caffeine is rapidly and completelyabsorbed, with peak blood levels generally reached in 30–45 min (Denaro and Benowitz 1991; Mumford et al. 1996;Liguori et al. 1997a), and is quickly eliminated, with atypical half-life of 4–6 h (Denaro and Benowitz 1991).The primary mechanism of action of caffeine is compe-titive antagonism at A1 and A2A adenosine receptors(Fredholm et al. 1999). Caffeine produces a variety ofphysiological effects, including effects on the cerebralvascular system, blood pressure, respiratory functioning,gastric and colonic activity, urine volume, and exerciseperformance (James 1997). Low to moderate doses ofcaffeine (20–200 mg) produce reports of increased well-being, happiness, energy, alertness, and sociability,
L. M. JulianoDepartment of Psychology, American University,4400 Massachusetts Avenue,Washington, DC, 20016, USA
R. R. Griffiths (*)Department of Psychiatry and Behavioral Sciences, Departmentof Neuroscience, Johns Hopkins University School ofMedicine,5510 Nathan Shock Drive,Baltimore, MD, 21224-6823, USAe-mail: [email protected].: +1-410-5500034Fax: +1-410-5500030
whereas higher doses are more likely to produce reports ofanxiety, jitteriness, and upset stomach (Griffiths et al.2003). Chronic administration of caffeine results intolerance to a number of its physiological, subjective,and behavioral effects (Griffiths and Mumford 1996).Caffeine has been shown to function as a reinforcer inhumans (e.g. Hughes et al. 1991; Evans et al. 1994), andsome individuals become clinically dependent on caffeineas indicated by being unable to quit and continuing usedespite having medical problems made worse by caffeine(Strain et al. 1994; Hughes et al. 1998).
Regular use of caffeine also produces physical depen-dence, evidenced as time-limited withdrawal symptomsupon the termination or reduction of one’s usual caffeinedose. Physical dependence on caffeine has been docu-mented in both pre-clinical and clinical research, and thebiological basis has been hypothesized to be increasedfunctional sensitivity to endogenous adenosine (Griffithsand Mumford 1996). Symptoms of caffeine withdrawalhave been described in the medical literature for more than170 years. In 1988, the first comprehensive review ofclinical reports and experimental studies on caffeinewithdrawal was published (Griffiths and Woodson1988), which provided evidence for caffeine withdrawalas a discrete clinical syndrome. Since that time, theresearch literature on caffeine withdrawal has increasedsubstantially. For example, of 48 blind caffeine-withdraw-al studies identified for this review, only five werepublished before 1988.
The present review was inspired by this emergentresearch literature, which has not been comprehensivelyreviewed, as well as by the practical need to developempirically based diagnostic criteria for caffeine with-drawal. In 1994, a tentative research diagnosis of caffeinewithdrawal was proposed in the Diagnostic and StatisticalManual of Mental Disorders (DSM-IV) to encourageresearch on diagnostic criteria and the utility of thediagnosis (American Psychiatric Association 1994). Onlyone-quarter of the blind studies identified for this reviewwere available to the DSM-IV Work Group (Hughes1994). The review also addresses the previous suggestions(Rubin and Smith 1999; Dews et al. 2002) that caffeinewithdrawal is not clinically significant and is primarilydetermined by expectancies.
Methods for searching and categorizing the literature
Search strategy and inclusion criteria
The following strategies were used to identify possiblestudies for this review: (1) PubMed (1950–2004) andPsycInfo (1872–2004) searches were conducted with thekeywords “caffeine” in conjunction with “withdrawal,”“dependence,” “deprivation,” or “abstinence”; (2) theauthors searched their personal journal article collectionson caffeine withdrawal; and (3) relevant references cited inpapers obtained through the first two strategies and majorreviews of caffeine and caffeine withdrawal (Griffiths and
Woodson 1988; Fredholm et al. 1999; Nehlig 1999;Griffiths et al. 2003) were examined to identify additionalrelevant papers. To be included, experimental studies hadto require a caffeine abstinence period of 12 h or greaterbecause withdrawal onset generally occurs after 12 h ofabstinence (Griffiths and Woodson 1988).
Excluded studies
Although possibly relevant to caffeine withdrawal, severaltypes of studies were excluded from detailed summariza-tion and analysis (Tables 1, 2, 3, 4): (1) several studieswere excluded because they were not clearly interpretable(Horst et al. 1934; Mackenzie et al. 1981; Ammon et al.1983; Smith 1996; Reeves et al. 1999; Watson et al. 2000);(2) a series of carefully conducted studies comparingplacebo and caffeine conditions after overnight abstinencewere not presented in a way that was clearly interpretableas caffeine-withdrawal effects (Yeomans et al. 2000a,b,2001); (3) several studies that purported to demonstratecaffeine effects after a period of abstinence (e.g., Lieber-man et al. 1987; Brice and Smith 2002) were excluded,although some of these studies acknowledged that theeffects may represent a reversal of caffeine withdrawal(e.g., Bruce et al. 1986; Hindmarch et al. 1998; Kenemanset al. 1999; Smit and Rogers 2000); (4) studies exploringcaffeine-withdrawal headache following surgical anesthe-sia were excluded because of the possible confoundingeffects of anesthesia (Galletly et al. 1989; Fennelly et al.1991; Weber et al. 1993; Nikolajsen et al. 1994; Hampl etal. 1995); (5) case studies of neonatal caffeine withdrawalwere excluded (McGowan et al. 1988; Thomas 1988); and(6) a survey study purporting to assess the prevalence ofcaffeine-withdrawal headache was excluded because themethods were ambiguous and it was not clear whether thesubjects ever experienced periods of caffeine abstinence(Sjaastad and Bakketeig 2004).
Categorization of withdrawal studies
The inclusion strategy resulted in the identification of 42double-blind experiments (Table 1), 15 non-blind andsingle-blind experiments (Table 2), and 9 survey studies(Table 3). Table 4 provides a summary of the individualwithdrawal symptoms that are documented in Tables 1, 2,and 3 (for completeness, Appendix A shows which of theexperimental studies in Tables 1 and 2 failed to documenteach of the evaluated symptoms and signs). In construct-ing Table 4, all symptoms documented in Tables 1, 2, and3 were first catalogued, and then phenomenologicallysimilar descriptors were combined (e.g., drowsiness,sleepy, drowsy/sleepy/tired, sedated, feel half awake, anddecreased wakefulness were combined in a single categorycalled “drowsiness/sleepiness”). Categories and descrip-tors for each category are presented below. It is recognizedthat the resulting 49 symptom categories may not representfully independent constructs. In the absence of empirical
2
Tab
le1
Sum
maryof
doub
le-blin
dexperimentalstud
iesof
caffeine
with
draw
ala
Reference
Design
With
draw
alsig
nsandsymptom
sb,c
1.Goldstein
(1964)
[experim
entscandd]
N=approxim
ately16
heavycoffe
edrinkers(5
ormorecups/day),25
moderatedrinkers(2–4
cups/day),and37
light
drinkers
(0–1
cups/day);with
in-subjectsd
esign;
subjectsabsta
ined
from
coffe
eafterlunch
andreceived
150-mgcaffe
ineor
placeboin
decaffe
inated
coffe
eat
bedtim
eover
four
consecutivenights,
with
both
treatmentsgiventwice;
abstinencenotb
iologically
verified
Inheavycoffe
edrinkers
morning
headache
occurre
dsig
nific
antly
morefre
quently
afterp
lacebo
(25%
oftrials)
than
after
caffe
ine(3%
oftrials);inmoderatedrinkers
thefre
quency
ofheadache
was
non-sig
nific
antly
higher
afterp
lacebo
(12%
oftrials)
than
afterc
affeine(7%
oftrials);inlig
htdrinkersthefre
quency
ofheadache
was
<1%
afterb
othcaffe
ineandplacebo
2.Goldstein
etal.(1969)
N=38
femaledaily
coffe
edrinkers
(5or
morecups/day)a
nd18
femalecoffe
eabsta
iners;with
insubjectsandacross
group
desig
n;subjectsabsta
ined
from
caffe
ineafterd
innera
ndreceived
placebo,150-mgor
300-mgcaffe
inein
decaffe
inated
coffe
ethefollo
wingmorning
(about
0900
hours);treatmentswererepeated
threetim
es;a
bstin
ence
notb
iologically
verified
Comparedwith
coffe
eabsta
iners,coffe
euserswereless
alert,activ
e/energetic,a
ndcontent,andmoresle
epy,
irritable,
and
nervousa
fterc
affeineabstinence;am
ongcoffe
eusersplaceboproduced
increasedratin
gsof
headache,lazy/slu
ggish
,irritable,
sleepy,
anddecreasedratin
gsof
talkative,
contentedness,andenergy/activecomparedwith
caffe
ine;
caffe
inegenerally
produced
adose-re
latedsuppressionof
with
draw
alsymptom
sin
thecoffe
eusers
3.Ro
bertson
etal.(1981)
N=18
adultswho
werenoth
abitu
alcaffe
inec
onsumersw
erecaffe
ineabstinent
for3
weeks
precedingthes
tudy;w
ithin
subjects
andacross
groupdesig
n;approxim
atelyhalfthesubjectsreceived
750mgcaffe
ine/dayin
flavoreddrinks
for7
days,followed
bysubstitutionof
placebofla
voreddrinks
for4
days;a
bstin
ence
was
biologically
verified
Substitutionof
placebodidnotresultindetectable
effectson
bloodpressure,u
rinarynorepinephrin
e,or
urinaryepinephrine
4.Griffiths
etal.(1986)
N=7males
who
wereheavycoffe
edrinkers
(mean12
cups/day);with
in-subjectsdesig
n;aftera
pproximately10
consecutive
days
ofad
libitu
mcoffe
econsum
ption(m
ean1.25-g/day
caffe
ineforthe
last5days),subjectsweresw
itchedto
decaffe
inated
coffe
efora
tleast10
days;a
bstin
ence
notb
iologically
verifiedbutstudy
was
conductedin
aresid
entiallaboratory
Comparedwith
caffe
inated
coffe
econsum
ption,
decaffe
inated
coffe
esubstitutionresultedin
increasedsubjectratings
ofheadache,sleepy,lazy,fatigue
(POMS)
anddecreasedalert,activ
e,vigor(PO
MS),and
friendliness(POMS);o
bservatio
nof
subjects’
behavior
also
show
edsig
nific
antw
ithdraw
albasedon
acompositewith
draw
alscore;
cigarette
smokingdecreased
durin
gdecaffe
inated
coffe
econsum
ption;
100%
ofsubjectsreporte
dwith
draw
alheadache
5.Griffiths
etal.(1990)[Ph
ase1]
N=7investigator-s
ubjectswith
histo
riesof
regularc
affeineconsum
ption;
with
in-subjectsdesig
n;subjectsgivencapsules
containing
100mgcaffe
ine/dayfor9
–14days,thenplacebocapsules
for1
2days,a
ndthen
capsules
containing
100mg
caffe
ine/dayfor7
–12days;a
bstin
ence
was
biologically
verified
Comparedwith
caffe
inemaintenance,p
lacebo
substitutionresultedin
increasedheadache,c
erebralfullness,irritable/cross/
grum
py,d
epression,
musclepain/stiffness,lethargy/fatig
ue/tired/slu
ggish
,craving,and
flu-like
feelings,a
nddecreasedalert/
attentive/observant,well-b
eing,sociald
isposition,m
otivationforw
ork,
concentra
tion,
energy/active,
urge
todo
tasks/w
ork,
content/satisfied,
andself-confidence;these
with
draw
alsymptom
speakedon
days
1or
2andprogressivelydecreasedtoward
pre-with
draw
allevelsover
abouta
week
6.Griffiths
etal.(1990)[Ph
ase2]
N=7investigator-s
ubjectswith
histo
riesof
regularc
affeineconsum
ption;
with
in-subjectsdesig
n;subjectsgivencapsules
containing
100mgcaffe
ine/dayfor6
weeks;o
nfiv
eoccasio
nsplacebocapsules
weresubstituted
forc
affeinefor1
day
(separated
byan
averageof
9days);abstinencewas
biologically
verified
Comparedwith
caffe
inedays,intermittentp
lacebo
resultedin
increasedfatig
ue(POMS)
d ,confusion–bewild
erment(PO
MS),
andtotalm
ooddistu
rbance
(POMS),a
nddecreasedvigor(PO
MS)
andfriendliness(POMS);inadditio
n,comparedwith
caffe
inedays,intermittentp
lacebo
resultedin
allo
fthe
with
draw
alsymptom
sobserved
inphase1(see
above)
aswella
sincreasedmuzzy,d
rowsy/sleepy,y
awning,b
lurre
dvisio
n,lig
htheaded/dizzy,impaire
dwork/thoughtrelated
activ
ities
and
impaire
dverbal
ability;a
llof
thesewith
draw
alsymptom
splus
decreasedanxious/n
ervous
werealso
signific
antw
hen
interm
ittentp
lacebo
was
comparedwith
achronicplaceboperio
d(days8–
12of
placebofro
mphase1)
[exceptio
ns:
lightheaded/dizzy,impaire
dverbal
ability,u
rgeto
dotasks/w
orkandmotivationforw
orkwerenotsignific
ant];
with
in-
subjectsanalysisof
both
interm
ittentp
lacebo
versus
caffe
ineandof
interm
ittentp
lacebo
versus
chronicplacebodemonstrated
thatmorethan
57%
ofsubjectsshow
edincreasedheadache,m
uzzy,d
rowsy/sleepy,impaire
dwork/thoughtrelated
activ
ities,
anddecreasedsocial
disposition,c
oncentratio
n,andself-confidence.
7.vanDusseldorpandKatan
(1990)
N=45
daily
coffe
edrinkers
(4–6
cups/day);with
in-subjectsdesig
n;subjectsreceived
5-cups/day
caffe
inated
coffe
e(435
mg
caffe
ine/day)
ordecaffe
inated
coffe
e,each
for6
weeks;a
bstin
ence
notb
iologically
verified
Headachewas
signific
antly
morelik
elyto
occurd
uringthefirstweekof
thedecaffe
inated
coffe
eperio
d;42%
ofsubjects
reporte
dheadache;h
eadaches
starte
don
the1sto
r2nd
dayof
abstinenceandlaste
d1–6days
(mean2.3days)
8.Bruceet
al.(1991)
N=21
habitual
caffe
ineusers(m
ean389mg/day);w
ithin
subjectsandacross
groupdesig
n;subjectsin
onegroupabsta
ined
from
caffe
inefor2
4-hpriortothreesessions
conductedatweeklyintervals;subjectsin
anotherg
roup
absta
ined
from
caffe
ine
for7
days
before
aswella
sbetweenthreesessions
conductedat
48-h
intervals;subjectsin
both
groups
received
capsules
containing
placebo,
250-mgor
500-mgcaffe
inein
random
order;abstinencewas
biologically
verified
Afte
rplacebo,subjectsinthe24-h
abstinencegroupreporte
dincreasedheadache
andtiredness
andshow
edmorepsychomotor
perfo
rmance
tiringthan
the7-dayabstinencegroup;
inthe24-h
abstinencegroup,
comparedwith
either
dose
ofcaffe
ine,
placeboincreasedheadache
andtiredness
onunipolar
scales,a
ndincreasedlethargy
anddrow
sinesson
bipolars
cales
(lethargic–energetic;d
rowsy–alert)
9.Silverman
etal.(1992)
N=62
daily
caffe
ineconsum
ers(m
ean235mg/day);w
ithin-subjectsdesig
n;subjectswereassessed
while
consum
ingtheir
norm
alcaffe
ineintake
(baseline)
andaftertwo2-dayperio
dsdurin
gwhich
they
consum
edcaffe
ine-fre
edietsandwere
administered
capsules
containing
caffe
ine(m
atched
totheiru
sual
intake)o
rplacebo;a
bstin
ence
was
biologically
verified
Comparedwith
both
baselin
eandcaffe
ine,placeboincreasedirritable/cross/g
rumpy,b
lurre
dvisio
n,drow
sy/sleepy,y
awning,
lethargy/fa
tigued/tired/sluggish,m
uzzy/fo
ggy/notclearheaded,headache,flu
-like
feelings,heavy
feelingin
armsa
ndlegs,hot
andcold
spells,
Beck
DepressionInventoryscores,som
atization(SCL
-90-R),state
andtra
itscales
ofState-TraitA
nxiety
Inventory,
fatig
ue(POMS),c
onfusio
n–bewild
erment(PO
MS),total
mooddistu
rbance
(POMS),a
nddecreasedwell-b
eing,
desireto
socialize,
talkativeness,urge
todo
tasks/w
ork-relatedactiv
ities,e
nergy/activ
e,content/satisfied,
self-confidence,
vigor(PO
MS),frie
ndlin
ess(PO
MS),p
sychom
otor
perfo
rmance
(tappingspeed);com
paredwith
baselin
eandcaffe
ine,durin
gtheplaceboperio
dmoresubjectsreporte
dmoderateor
severe
headache
(52%
),used
analgesic
sdespite
discouragement
(13%
),andshow
edabnorm
alscores
ontra
it-anxiety(8%),vigor(11%),andfatig
ue(8%),andtheBe
ckDepressionInventory
(11%
)10.E
vans
andGriffiths
(1992)
N=32
daily
caffe
ineconsum
ers(m
ean343mg/day);w
ithin
subjectsandacross
groupdesig
n;subjectsreceived
capsules
throughout
thestu
dy;subjectsin
thechronicplacebocondition
(N=1
6)received
placebofor1
8days,followed
bya3-day
caffe
ineversus
placebochoice
phase,
follo
wed
byanother7
days
ofplacebo;
subjectsin
thechroniccaffe
inecondition
(N=1
6)received
caffe
inefor1
8days
(thedose
progressed
from
100-mgt.i.d.to300-mgt.i.d.);
follo
wed
bya3-daycaffe
ine
versus
placebochoice
phase;follo
wed
by2days
ofprogressivelylower
doseso
fcaffeine(approximately183-mgt.i.d.o
nthe
2ndday),followed
by5days
ofplacebo;
abstinencewas
biologically
verified
Comparedwith
subjectsin
thechronicplacebocondition,subjectsinthechroniccaffe
inecondition
reporte
dhigher
ratin
gsof
headache
andlower
ratin
gsof
talkativenessin
thefin
alwith
draw
alperio
d;with
inthecaffe
inegroup,
noeffectsoccurre
dbetweentheplaceboandcaffe
inechallengedays
which
was
interpretedas
indicatin
gthat24
hof
abstinencewas
insufficient
toproducewith
draw
alsymptom
supon
term
inationof
very
high
caffe
inedoses(i.e.,9
00mg/day)
3
Reference
Design
With
draw
alsig
nsandsymptom
sb,c
11.H
ughese
tal.(1993)
[sum
marizes
results
from
Hughese
tal.(1991,1992);Oliv
etoet
al.(1992a,b)]
N=37
daily
coffe
edrinkers
(mean552mg/day)
who
reporte
dusingcoffe
eforc
affeineeffectsor
show
edwith
draw
alor
preference
forc
affeinein
ascreeningtest;
with
in-subjectsd
esign;
sixtrialsa
tweeklyintervals;on
oned
aysubjectsconsum
eddecaffe
inated
coffe
eandon
anotherd
ayconsum
edcaffe
inated
coffe
e(100
mg/serving);assessm
ento
ccurredaftera
bout
24-h
abstinence;
abstinencenotb
iologically
verifiedin
allsubjects
With
in-subjectssta
tistical
analyses
show
edthat
30%,2
4%,2
4%,a
nd49%
ofsubjects,
respectiv
ely,
reporte
dsig
nific
ant
increasesin
headache,d
rowsin
ess,fatig
ue,o
rone
ormoreof
thesesymptom
son
decaffe
inated
days
comparedwith
caffe
inated
days
12.S
train
etal.(1994)
N=11
daily
caffe
ineusers(m
edian357mg/day)
who
met
DSM
-IVdiagnosticcriteria
fors
ubsta
ncedependence
oncaffe
ine;
with
in-subjectsdesig
n;subjectswereassessed
aftertwo2-dayperio
dsdurin
gwhich
they
consum
edcaffe
ine-fre
edietsand
wereadministered
capsules
containing
caffe
ine(m
atched
totheiru
sual
intake)o
rplacebo;a
bstin
ence
was
biologically
verified
Overall,
82%
show
edevidence
ofcaffe
inewith
draw
aldurin
gplacebo;
64%
reporte
dmaxim
alratin
gsof
headache;c
ompared
with
standardizednorm
s,27%
show
edextre
meincreasesin
fatig
ue(POMS),4
5%show
edextre
medecreasesin
vigor
(POMS),and
36%
show
edelevations
indepressio
n(BeckDepressionInventory);com
paredwith
caffe
ine,afterp
lacebo
55%
ofsubjectsshow
edsig
nific
antd
ecreases
inpsychomotor
perfo
rmance
(tappingspeed);4
5%reporte
danalgesic
usedespite
discouragement;73%
reporte
dfunctio
nalimpairm
entinnorm
aldaily
activ
ities
13.B
rauere
tal.(1994)
eN=
11daily
coffe
econsum
ers(mean480mg/day);w
ithin-subjectsd
esign;
over
a33-h
perio
dsubjectsconsum
edacaffe
ine-fre
ediet
andwereadministered
either
capsules
containing
placeboor
300-mgcaffe
ine;
abstinencewas
biologically
verified
Comparedwith
caffe
inemaintenance,3
3-habstinenceincreasedheadache
14.H
aleet
al.(1995)
N=18
adolescents(ages
11–15),d
aily
coladrinkers(m
ean2.3,12-ozcaffe
inated
colas/d
ay);with
in-subjectsd
esign;
sixtrialsa
tweeklyintervals;on
onedaysubjectsconsum
edcaffe
ine-fre
ecolasa
dlib
itum
andon
anotherd
ayconsum
edcaffe
inated
colas
adlib
itum
(33mg/8oz);assessmento
ccurredaftera
bout
24-h
abstinence;
abstinencenotb
iologically
verified
Comparedwith
thecaffe
ine,placeboincreaseddepressed,
drow
sy–sleepy,andfatig
ue–tire
d,anddecreasedirregular
heartbeat
andmoretalkative;
with
in-subjectsanalyses
revealed
that
33%
ofsubjectsshow
edsig
nific
ante
ffectson
oneor
more
symptom
ratin
gs15.H
ugheset
al.(1995)
N=11
daily
coffe
edrinkers(m
ean5.6cups/day)selectedforshowingcaffe
ineabstinencesymptom
sorc
affeinepreference
ina
screeningtest;
with
in-subjectsdesig
n;six
trialsat
weeklyintervals;on
onedaysubjectsconsum
eddecaffe
inated
coffe
ead
libitu
mandon
anotherd
ayconsum
edcaffe
inated
coffe
eadlib
itum
(eith
er25
mgor
50mg/serving);assessm
ento
ccurredafter
about2
4-habstinence;
abstinencenotb
iologically
verifiedf
Comparedwith
thecaffe
ine,
placeboincreaseddrow
sy–sleepy–tired,h
eadaches,fatigue–tire
d,lazy–sluggish
,and
depressed
anddecreasedstimulated–active–energetic–excited,
alert–attentive–able
toconcentra
te,a
ndvigor;with
in-subjectsanalyses
revealed
that
73%
ofsubjectsshow
edsig
nific
ante
ffectson
oneor
moresymptom
ratin
gs,w
ith45%
reporting
increasesin
drow
sy–sleepy–tired;2
7%reporting
decreasesin
stimulated–active–energetic–excited,
alert–attentive–able
toconcentra
te,
andvigor;18%
reporting
increasedfatig
ued–
tired,d
epressed,a
nddecreasedcontent–relaxed–
satisfie
d,and9%
reporting
increasedheadache,irritable–fru
strated–angry–cross,lazy–
sluggish
,and
decreasedtalkative
16.M
itchellet
al.(1995)
N=9daily
coffe
econsum
ers(m
ean686mg/day);w
ithin-subjectsdesig
n;subjectsconsum
edacaffe
ine-fre
ediet
andwere
administered
capsules
containing
placeboor
caffe
ine(50%
or100%
oftheiru
sualam
ounts)on
thedaybefore
andthedayof
assessment;abstinencewas
biologically
verified
Comparedwith
the50%
and100%
caffe
ineconditions,placebo(33.5-habstinence)
increasedheadachy,sluggish
,and
tired–
sleepy;
abstinencedidnota
ffect
amount
ofresponding
onan
operanttaskreinforced
bycoffe
edeliv
ery
17.R
ichardsonet
al.(1995)
N=49
regularc
affeineconsum
ers(m
ean252mg/day)
andN=
18non-consum
ers;four
groups:n
on-consumersandthree
consum
ergroups
who
absta
ined
from
caffe
inefore
ither
90min,o
vernight,o
r7days;subjectsin
each
groupreceived
capsules
containing
placebo,
70mgor
250mgin
counterbalancedorder;abstinencenotb
iologically
verifiedf
Overnight
abstinence(13–15
h)comparedwith
90-m
inabstinenceproduced
increasedratin
gsof
angry,tired,d
rowsy,d
ejected
anddecreasedratin
gsof
clearheaded,
friendly,
andcheerfu
l;overnighta
bstin
ence
comparedwith
7days
ofabstinence
produced
increasedratin
gsof
angry,
tired,d
rowsy
anddejected;o
vernight
abstinencecomparedwith
non-consum
ers
produced
increasedheadache,a
ngry,tire
d,drow
sy,d
ejectedanddecreasedclearheaded
18.R
ogerset
al.(1995)
N=24
low
caffe
ineusers(mean47
mg/day)
andN=
25moderatecaffe
ineusers(mean205mg/day);ten
experim
entalsessio
ns;
aftero
vernight
abstinencehalfthesubjectsconsum
edadrinkcontaining
70-m
gcaffe
ineandhalfconsum
edanon-caffe
inated
drink;
assessmento
ccurred1hlater;abstinencenotb
iologically
verified
Inmoderatecaffe
ineusers,comparedwith
subjectsreceivingcaffe
ine,
subjectsreceivingplaceboreporte
dincreasesin
tired
anddecreasesin
cheerfu
l,clearheaded,
energetic,a
ndliv
ely;
incontrast,
nosig
nific
antd
ifferenceswerefoundbetween
caffe
ineandplaceboin
low
caffe
ineusers
19.S
treuferte
tal.(1995)
N=25
caffe
ineuserswho
held
managerialp
ositions(m
ean565mg/day);w
ithin-subjectsdesig
n;subjectswereinstructedto
absta
infro
mcaffe
inefor3
6-hpriortoeach
of2assessmentd
ays;thedaypriortotheassessmentd
ayandmorning
ofthe
assessmentd
aysubjectsweregiveneither
capsules
containing
caffe
ine(m
atched
totheiru
sualintake)o
rplacebo;abstin
ence
was
biologically
verified
Comparedwith
caffe
ine,
placebowas
associated
with
increaseddrow
sy/sleepy,y
awning,lethargy/fatig
ue/tired/slu
ggish
,irritable/cross/g
rumpy
anddecreasedalert/attentive/observant,well-b
eing,a
bilityto
concentra
te,e
nergy/activ
e,need
topass
water
frequently
g ;comparedwith
caffe
ineplacebodecreasedsysto
licbloodpressure
anddecreasedperfo
rmance
oncomplex
simulated
tasks(i.e.,n
umbero
fdecisions,speedof
response
toinform
ation,
diversity
ofactio
n,numbero
fbackw
ard
integrations,a
ndappliedinitiative)
20.L
ader
etal.(1996)h
N=40
habitual
caffe
ineconsum
ers(m
ean360mg/day);w
ithin
andacross
groups
staggered
cohortdesig
n;afterb
aseline
assessmentd
uringusualc
affeineconsum
ption,
subjectsreceived
capsules
containing
either
placeboor
caffe
ine(m
atched
totheiru
sual
intake);subjectsreceived
placebocapsules
for2
consecutivedays
follo
wed
bycaffe
inecapsules
for2
days
or3
days;a
bstin
ence
was
biologically
verified
Comparedwith
baselin
e,placeboincreasedtiredness,lethargy,
sedatio
n,andmuzziness,a
nddecreasedalertnessand
concentra
tion;
theseeffectswerereversed
upon
caffe
inere-adm
inistratio
n;comparedwith
baselin
e,placeboincreasedEE
Galphapeak
magnitude
andratin
gsof
sleep
quality,a
nddecreasedskin
conductance,
systo
licbloodpressure,a
ndratin
gsof
onsettosle
ep;6
8%of
subjectsreporte
dincreasedtired
andlethargy;4
5%reporte
ddiffu
sethrobbingheadache,w
ith28%
ofthesealso
reporting
nausea
andsic
kness
21.C
omer
etal.(1997)
N=12
daily
caffe
ineusers;with
in-subjectsd
esign;
17-day
inpatient
study;subjectsg
iven
capsules
containing
300-mgcaffe
ine
daily
except
fortwo2-dayplacebosubstitutions
ondays
5–6and12–1
3;abstinencenotb
iologically
verifiedbutstudy
was
conductedin
aresid
entiallaboratory
Onplacebodays
subjectsreporte
dincreasedratin
gsof
headache,m
iserable,sedated,
sleepy,tired,u
nmotivated,and
yawning,
anddecreasedratin
gsof
alert,anxious,energetic,a
ndself-confident
22.L
iguoriet
al.(1997b)
[Exp
1]N=
8daily
caffe
inated
cola
consum
ers(m
ean157mg/day);w
ithin-subjectsdesig
n;six
trialsat
weeklyintervals;on
oneday
subjectsconsum
edcaffe
ine-fre
ecolasa
dlib
itum
andon
anotherd
ayconsum
edcaffe
inated
colasa
dlib
itum
(eith
er33
mgor
17mg/8oz);assessmento
ccurredaftera
bout
24-h
abstinence;
abstinencenotb
iologically
verifiedf
Comparedwith
the33-m
gcondition,p
lacebo
decreasedactiv
e/energy/excited,
moretalkative,
motivated
towork,
andwell-
being;
comparedwith
the17-m
gcondition,p
lacebo
increasedanxious/tense/nervous,a
nxiety
(POMS),c
onfusio
n(POMS),
irritable/fru
strated/angry/cross,a
ndsto
machache/upsetstomach,
anddecreasedwell-b
eing,frie
ndlin
ess(POMS),a
ndvigor
(POMS);w
ithin-subjectanalysisrevealed
that50%
ofthesubjectsin
the33-m
gcondition
and25%
ofthesubjectsin
the17-
mgcondition
show
edheadache,d
rowsin
ess,or
fatig
ue(63%
show
eddrow
sinessand/or
fatig
uein
oneor
both
ofthe
conditions)
Tab
le1(con
tinued)
4
Reference
Design
With
draw
alsig
nsandsymptom
sb,c
23.L
iguoriet
al.(1997b)
[Exp
2]N=
16daily
coffe
eandcola
consum
ers(m
ean579mg/day);w
ithin-subjectsdesig
n;six
trialsat
weeklyintervals;on
oneday
subjectsconsum
edcaffe
ine-fre
ecolasad
libitu
mandanotherd
ayconsum
edcaffe
inated
colasad
libitu
m(33mg/8oz);
assessmento
ccurredaftera
bout
24-h
abstinence;
abstinencenotb
iologically
verifiedf
Comparedwith
thecaffe
ine,
placeboincreaseddrow
sy/sleepy,fatigue/tired,
headache,lazy/slu
ggish
/slow
-moving,
and
stomachache/upsetstomach,
anddecreasedactiv
e/energetic/excited,
confident,motivated
towork,
well-b
eing,a
ndperfo
rmance
onapsychomotor/cognitiv
etask;d
rowsin
essandheadache
ordrow
sinessandfatig
uereliablyoccurre
din
2of
16participants
24.L
iguoriandHughes(1997)
N=11
daily
coffe
eandcolaconsum
ers(mean632mg/day);w
ithin-subjectsd
esign;
subjectswereteste
din
four
caffe
ineversus
nocaffe
ineconditionsusingprocedures
similartoLiguorie
tal.(1997b);thefour
caffe
ineconditionswerecola
33mg/
serving,
coffe
e33
mg/serving,
cola100mg/serving,
coffe
e100mg/serving;
assessmento
ccurredaftera
bout
24-h
abstinence;
abstinencewas
biologically
verified
Comparedwith
thecaffe
ine,placeboincreaseddrow
sy/sleepy,fatigue/tired,
lazy/sluggish/slow
-moving,
andnausea/vom
iting,
anddecreasedactiv
e/energetic/excited,
alert/attentive/able
toconcentra
te,c
onfid
ent,fre
quentu
rinationg,impatience,
motivated
towork,
stronger/m
orevigorous/m
oreenergy,w
ell-b
eing,a
ndperfo
rmance
onapsychomotor/cognitiv
etask
25.S
chuh
andGriffiths
(1997)
N=20
regularc
affeineconsum
ers(m
ean379mg/day);w
ithin-subjectsdesig
n;subjectswereassessed
aftertwo19-h
perio
dsdurin
gwhich
they
consum
edcaffe
ine-fre
edietsandwereadministered
capsules
containing
caffe
ine(m
atched
totheiru
sual
intake)o
rplacebo;a
bstin
ence
was
biologically
verified
Comparedwith
caffe
ine,placeboincreasedheadache,w
orn-out,andflu
-like
feelings,and
decreasedalert,well-b
eing,h
elpful,
andupsetstomach;
onadrug
versus
money
choice
procedure,subjectschoseto
forfe
itmoney
toavoidreceivingplacebo—
thiswas
signific
antly
diffe
rent
from
thecaffe
inecondition
26.G
arrettandGriffiths
(1998)
N=28
adults;
with
in-subjectsd
esign;
each
subjectw
asexposedto
four
conditionse
achof
which
involved
a9–12
dayexposure
(capsulescontaining
300mg/70
kgcaffe
ineor
placebo)
follo
wed
bya2-daychallenge(caffeineor
placebo):(1)
acute
abstinence(caffeinefollo
wed
byplacebo),(2)
chronicabstinence(placebo
follo
wed
byplacebo),(3)
acutecaffe
ine(placebo
follo
wed
bycaffe
ine),(4)
chroniccaffe
ine(caffeinefollo
wed
bycaffe
ine);a
bstin
ence
was
biologically
verified
Placebochallengeafterc
affeine(acute
abstinence)
resultedin
increasedconfusion–bewild
erment(PO
MS),fatigue
(POMS),
totalm
ooddistu
rbance
(POMS)
anddecreasedvigor(PO
MS)
comparedwith
each
oftheotherthree
conditions;acute
abstinenceresultedin
decreasedalert/attentive/observant,well-b
eing,abilityto
concentra
te,and
energy/activecomparedwith
thecaffe
inechallengeafterc
hronic
abstinenceandchroniccaffe
ine,
andincreasedirritable/cross/g
rumpy,d
epressed,a
nddrow
sy/sleepy
relativ
eto
placebochallengeafterc
hronic
abstinence;
subjectswerewillingto
forfe
itmoremoney
toavoid
receivingplacebowhenmaintainedon
caffe
ine(acute
abstinence)
comparedwith
chroniccaffe
ineandchronicplacebo
27.Jam
es(1998)
N=36
habitual
caffe
ineconsum
ers(about
370mg/day);w
ithin-subjectsdesig
n;subjectsreceived
capsules
throughout
the
study;fourc
onditio
ns:6
days
ofcaffe
inefollo
wed
by1dayof
placebo(acute
abstinence),6
days
ofcaffe
inefollo
wed
by1
dayof
caffe
ine(habitu
aluse),6
days
ofplacebofollo
wed
by1dayof
caffe
ine,
6days
ofplacebofollo
wed
by1dayof
placebo(chronic
abstinence);a
bstin
ence
was
biologically
verified
Subjectsin
theacuteabstinencecondition
reporte
dmorefre
quenth
eadaches
(47%
)thansubjectsin
thehabitualusecondition
(14%
)and
inthec
hronicabstinencec
onditio
n(31%
);subjectsin
acutea
bstin
ence
condition
also
experie
nced
mores
evereand
longer
headaches,less
alertness,bettersleep
quality
andduratio
n,andworsenedperfo
rmance
onacharacterrecognitio
ntask
than
theaverageof
thethreeotherc
onditio
ns28.P
hillips-ButeandLa
ne(1998)
N=31
daily
coffe
econsum
ers(mean603mg/day);w
ithin-subjectsd
esign;
subjectsabsta
ined
from
caffe
ineovernightand
then
consum
edeither
capsules
containing
250-mgcaffe
ineor
placebo4-hpriortoassessment;thus
4-habstinencewas
compared
with
anestim
ated
12–28habstinence;
abstinencenotb
iologically
verified
Comparedwith
4-habstinence,
overnighta
bstin
ence
increasedfatig
ue(POMS),sleepy,
andyawning,a
nddecreasedvigor
(POMS)
andsysto
licanddiastolic
bloodpressure
29.R
obelin
andRo
gers
(1998)
N=64
daily
caffe
ineconsum
ers(mean453mg/day);b
etweengroups
desig
n;aftero
vernight
abstinence,four
groups
ofsubjects
consum
edthreefru
it-fla
voreddrinks
spaced
at75–9
0min
intervals;conditionsw
erethreeplacebodrinks
or1,
2,or
3drinks
containing
caffe
ine(1.2-m
g/kg
orabout8
6-mgcaffe
ine);finalassessmento
ccurredafter≥
17hof
abstinence;abstinencenot
biologically
verifiedf
Comparedwith
subjectswho
received
1,2,
or3drinks
ofcaffe
ine,subjectswho
received
placeboshow
eddecreasedenergetic
moodandslo
wer
reactio
ntim
eperfo
rmance
30.V
anSo
eren
andGraham
(1998)
N=6maleathletes
who
weredaily
caffe
ineconsum
ers(m
ean761mg/day);w
ithin-subjectsdesig
n;subjectswereteste
dafter
receivingcapsules
containing
caffe
ineor
placeboafter0
,2,o
r4days
ofabstinencefro
mdietarycaffe
ine;
sixtrialswere
separatedby
≥10days;a
bstin
ence
was
biologically
verified
Alth
ough
notstatistically
analyzed,the
authorsreportedthatallsubjectsreportedwith
draw
alsymptom
slastin
gfro
m2days
to4days
includingsevere
headaches,fatig
ue,lethargy,
andflu
-like
symptom
s;tim
eto
exhaustio
non
acyclingtask
was
not
affected
bytheduratio
nof
dietarycaffe
ineabstinencein
either
theplaceboor
caffe
ineconditions
31.Y
eomanset
al.(1998)e
N=36
caffe
ineconsum
ers(m
ean329mg/day);w
ithin
subjecta
ndacross
groupdesig
n;on
4days
subjectsabsta
ined
from
caffe
ineovernighta
ndweregivenbeverages(herbaltea
andfru
it-fla
voreddrinks,respectively)
containing
either
caffe
ine
(100
mg)
orplaceboat
breakfasta
ndmidmorning
(2hlater);
therewerefour
experim
entalg
roups:(1)b
reakfastcaffe
ine/
midmorning
caffe
ine,
(2)b
reakfastcaffe
ine/midmorning
placebo,
(3)b
reakfastplacebo/midmorning
caffe
ine,
(4)b
reakfast
placebo/midmorning
placebo;
abstinencenotb
iologically
verifiedf
Mooddata
werecollapsed
across
the4days;c
omparedwith
subjectswho
received
caffe
ine,
subjectswho
received
placebo
with
breakfasth
adlower
ratin
gsof
livelyandenergetic
2hlater;comparedwith
subjectswho
received
placeboat
breakfast
andcaffe
inemidmorning,subjectswho
received
placeboat
both
breakfasta
ndmidmorning
hadlower
ratin
gsof
energy
30min
afterthe
midmorning
beverage;the
authorsinterpretedthediffe
rences
betweencaffe
ineandplaceboas
refle
cting
caffe
ine-with
draw
alreversal
effects
32.D
ewset
al.(1999)
N=57
daily
coffe
edrinkers
(mean200–
300mg/daycaffe
ineim
mediately
before
abstinence);three
groups
ofsubjectsgiven
insta
ntcoffe
efor1
4days;the
chroniccaffe
inegroupreceived
insta
ntcaffe
inated
coffe
ethroughout
thestu
dy,the
abrupt
abstinencegroupreceived
insta
ntdecaffe
inated
coffe
efor7
consecutivedays,the
gradualabstin
ence
groupreceived
gradual
reductions
incaffe
ineover
5days;a
bstin
ence
was
biologically
verified
Nosta
tistical
analyses
werereporte
d;theauthorsconcludedthat
39%
ofsubjectsshow
edwith
draw
alin
thefirst2days
ofabstinencein
theabrupt
abstinencegroupbasedon
acompositewith
draw
almeasure
deriv
edfro
mamoodandattitude
questio
nnaire
andspontaneously
reporte
dwith
draw
alsymptom
s(e.g.,headache
andtiredness);22%
show
edsubstantial
decreases(≥1.5pointson
a4pointscale)intheirratings
ofdaily
functio
ning;o
nthefirst2days
ofabstinence28%
ofthe
abrupt
abstinencegroupreporte
dheadache,w
hile
17%
ofthechroniccaffe
inegroupreporte
dheadache
33.E
vans
andGriffiths
(1999)
[Exp
1]N=
15daily
caffe
ineconsum
ers(m
ean241mg/day)
with
in-subjectsdesig
n;subjectsweremaintainedon
capsules
containing
300mgcaffe
ine/day;
2-dayplaceboperio
dwas
repeated
sixtim
eswith
5–9days
ofcaffe
inebetweenperio
ds;abstin
ence
was
biologically
verified
Comparedwith
caffe
inedays,o
nplacebodays
subjectsreporte
dincreasedheadache,h
eadache/poor
mood,
tiredness,flu-like
symptom
s,fatig
ue(POMS),a
nddecreasedvigor(PO
MS),frie
ndlin
ess(POMS),a
ndactiv
ity/alertn
ess
34.E
vans
andGriffiths
(1999)
[Exp
2]N=
17daily
caffe
ineconsum
ers(m
ean277mg/day);w
ithin-subjectsdesig
n;2-dayplaceboperio
dafters
ubjectswere
maintainedon
capsules
containing
100,
300,
or600mgof
caffe
ine/day;
each
subjectw
asexposedto
two2-dayplacebo
perio
dsat
each
caffe
inedose;a
bstin
ence
was
biologically
verified
Comparedwith
caffe
inedays,o
nplacebodays
aftere
achmaintenance
dose
subjectsreporte
dincreasedheadache,fatigue
(POMS),confusio
n–bewild
erment(PO
MS),and
tiredness;the
rangeandmagnitude
ofwith
draw
alsymptom
sincreased
with
maintenance
dose,w
ithsubjectsreporting
thefollo
wingadditio
nalsym
ptom
safte
rthe
highestd
ose:increasedheadache/poor
mood,
totalm
ooddistu
rbance
(POMS),a
ndflu
-like
symptom
s,anddecreasedfriendliness(POMS),v
igor
(POMS),a
ndactiv
ity–alertn
ess;specificity
ofwith
draw
aleffectscanbe
concludedbecausehigher
dosesof
caffe
ineproduced
greater
response
toplacebowith
nochange
inbaselin
eresponse
tocaffe
ine
Tab
le1(con
tinued)
5
Reference
Design
With
draw
alsig
nsandsymptom
sb,c
35.E
vans
andGriffiths
(1999)
[Exp
3]N=
19daily
caffe
ineconsum
ers(m
ean294mg/day);w
ithin-subjectsdesig
n;subjectsweremaintainedon
capsules
containing
300mgcaffe
ine/day;
approxim
atelyevery7days
alower
dose
ofcaffe
ine(200,1
00,5
0,25
mg)
orplacebowas
substituted
for2
days;a
bstin
ence
was
biologically
verified
Comparedwith
thecaffe
inemaintenance
dose
of300mg,
placebosubstitutionproduced
increasedheadache,h
eadache/poor
mood,tiredness,fatigue
(POMS),and
totalm
ooddistu
rbance
(POMS)
anddecreasedvigor(PO
MS)
andactiv
ity/alertn
ess;the
rangeandmagnitude
ofwith
draw
alsymptom
sincreasedas
afunctio
nof
decreasin
gdosesof
caffe
ine,
with
nowith
draw
alreporte
dat
200mgandfatig
ue(POMS)
andtiredness
reporte
dat
100mg
36.E
vans
andGriffiths
(1999)
[Exp
4]N=
25daily
caffe
ineconsum
ers(263mg/day);w
ithin-subjectsd
esign;
subjectsmaintainedon
capsules
containing
300mg/day
fore
ither
1,3,
7,or
14consecutivedays;e
achduratio
nof
caffe
ineexposure
was
follo
wed
by7days
ofplacebo;
abstinence
was
biologically
verified
Nowith
draw
alsymptom
swereshow
nin
response
toplaceboafter1
dayof
caffe
ine;placeboafter3
days
ofcaffe
ineresultedin
increase
headache/poorm
ood,
fatig
ue(POMS),tire
dness,flu
-like
symptom
s,andtotalm
ooddistu
rbance
(POMS)
and
decrease
activ
ity/alertn
ess;placeboafter7
days
or14
days
ofcaffe
ineproduced
headache
inadditio
nto
mosto
fthe
symptom
sthatoccurre
din
the3-daycondition;specific
ityof
with
draw
aleffectscanbe
concludedbecauselonger
duratio
nsof
caffe
ine
exposure
produced
greaterresponseto
placebo
37.Jones
etal.(2000)
N=10
daily
caffe
ineconsum
ers(m
ean333mg/day);w
ithin-subjectsdesig
n;before
twosessions
subjectsabsta
ined
from
caffe
inefor2
1handthen
received
capsules
containing
caffe
ine(m
atched
totheiru
sualintake)o
rplacebo;subjectsw
erealso
evaluatedwhile
consum
ingtheirn
ormal
caffe
ineintake
(baseline);a
bstin
ence
was
biologically
verified
Comparedwith
caffe
ine,placebodecreasedalert/attentive/observant,ability
toconcentra
te,energy/activ
e,vigor(PO
MS),and
friendliness(POMS)
andincreasedheavyfeelings
inarmsandlegs;p
lacebo
also
increasedvelocitiesin
middleandanterio
rcerebral
arterie
sandincreasedEE
Gthetapower;c
affeineandbaselin
econditionswerenotsignific
antly
diffe
rent
onany
measure
38.S
werdlow
etal.(2000)
N=12
males
(mean173mg/day)
inthecaffe
ineabstinencestu
dyand18
males
(mean147mg/daycaffe
ine)
inthenon-
abstinencestu
dy;inthea
bstin
ence
study
subjectsabsta
ined
for>
14hpriortotesting;inboth
studies
subjectsreceived
either
apillcontaining
200mgcaffe
ineor
placebo;
abstinencenotb
iologically
verified
Comparedwith
caffe
ineadministratio
n,placeboadministratio
nto
high
caffe
ineconsum
ers(asdeterm
ined
bymediansplit)
produced
signific
ante
levatio
nsin
acompositesomatic
symptom
scale(fe
elsic
k,queasy,d
izzy,a
ndperspirin
g).S
imilar
effectswereshow
nforthe
individual
symptom
s39.Y
eomanset
al.(2002b)
N=30
caffe
ineconsum
ers(mean330mg/day);w
ithin
subjectsandacross
groupdesig
n;aftero
vernight
abstinencethreegroups
ofsubjectsreceived
placebo,1-mg/kg,or2
-mg/kg
caffe
inein
aflavoreddrinkatbreakfasto
n2testdays;6
0min
afterthe
first
dose
subjectsreceived
adrinkcontaining
either
placeboor
1-mg/kg
caffe
inein
counterbalancedordera
crossthe
2testdays;
abstinencenotb
iologically
verified
Comparedwith
subjectsgivencaffe
ine,
subjectsgivenplaceboat
breakfasth
adslo
wer
reactio
ntim
esandlower
alertness
45min
later;relativ
eto
placebo,
caffe
inegiven60
min
afterb
reakfastdecreasedreactio
ntim
eandincreasedalertnessin
subjectswho
received
placeboatbreakfast,butn
otin
subjectswho
received
caffe
inea
tbreakfast;
thea
uthorsinterpretedthese
results
assuggestin
gthat
reversal
ofcaffe
inewith
draw
alisamajor
component
oftheeffectsof
caffe
ineon
moodand
perfo
rmance
40.R
ogerset
al.(2003)e[Exp
1]N=
10caffe
ineconsum
ers(m
ean355mg/day)
and10
non-consum
ers;betweengroups
desig
n;before
four
sessions
subjects
absta
ined
from
caffe
inefora
pproximately15
h;abstinencenotb
iologically
verifiedf
Afte
rabstin
ence,c
affeineconsum
erswereless
alerta
ndmoretensethan
non-consum
ers
41.R
ogerset
al.(2003)e[Exp
2]N=
22caffe
ineconsum
ers(m
ean372mg/day)
and20
non-consum
ers;betweengroups
desig
n;aftero
vernight
abstinence
subjectsreceived
either
100mgcaffe
ineor
placeboin
afla
voreddrink;
abstinencenotb
iologically
verifiedf
Afte
rabstin
ence,c
affeineconsum
erswereless
alertthannon-consum
ers
42.T
inleyet
al.(2003)e
N=45
caffe
ineconsum
ers(m
ean324mg/day);w
ithin
subjectsandacross
groups
desig
n;for2
-weeks
subjectsabsta
ined
from
theirn
ormalsourceso
fcaffeineandconsum
edteaandcoffe
eprovided
bytheexperim
enters;inonegrouptheteaandcoffe
ewerecaffe
inated
andin
theotherg
roup
they
werecaffe
inefre
e;subjectsabsta
ined
from
teaandcoffe
eovernightb
eforeeach
offour
testsessions
conductedover
the2-weekperio
d;subjectsreporte
dmoodbefore
andafterreceiving
asin
gleservingof
either
acaffe
inebeverage
(caffeinemaintainedgroup)
orcaffe
ine-fre
ebeverage
(caffeine-fre
egroup);a
bstin
ence
was
biologically
verified
Comparedwith
thegroupthat
was
chronically
maintainedon
caffe
ine-fre
ebeverages,thegroupthat
was
maintainedon
caffe
inereporte
dhigher
levelsof
headache
aftero
vernight
abstinence;
headache
was
alleviated
afterc
affeineadministratio
n
a Allstud
ieshadacaffeine-abstin
ence
period
of12
hor
greater
bAlleffectsarestatistically
sign
ificantat
P≤0
.05un
less
otherw
iseno
ted
c For
consistency,
whenplaceboandcaffeine
cond
ition
sarecompared,
theeffectsaredescribedas
theeffectsof
placeborelativ
eto
caffeine
dPOMSindicatesProfile
ofmoo
dstates
questio
nnaire
e Onlythosedesign
elem
entsthat
arerelevant
totheanalysisof
caffeine
abstinence
effectsaredescribed
f Alth
ough
abstinence
was
notbiolog
ically
verified,saliv
asamples
weretakenandsubjectswereledto
believe
that
samples
wou
ldbe
analyzed
forcompliance
gLikelyadirect
effect
ofcaffeine
rather
than
aneffect
ofcaffeine
with
draw
alhSom
eof
theresults
arebasedon
authors’
conclusion
sbecauseno
tallsign
ificantcomparisons
werepresented(Lader,person
alcommun
ication,
Aug
ust20
02)
Tab
le1(con
tinued)
6
Tab
le2
Sum
maryof
sing
le-blin
dandno
n-blindexperimentalstud
iesof
caffeine
with
draw
ala
Reference
Design
With
draw
alsig
nsandsymptom
sb,c
Single-blin
d43.D
riesbachandPfeiffe
r(1943)
N=22
adults;
with
in-subjectsd
esign;
caffe
ineadministered
incapsules
inincreasin
gdoseso
ver6
–7days
to650–
780mg/day;
onthe7th
or8thdayplacebowas
substituted
forc
affeinecapsules;a
bstin
ence
notb
iologically
verified
Placebosubstitutionafterc
affeineresultedin
lethargy
inmorning,cerebralfullnessatnoon,and
headache
inearly
afternoon,
reaching
peak
intensity
3–6hlater;82%
ofsubjectsreporte
ddefin
iteto
severe
headache;in33%
ofthesesubjectsheadache
was
accompanied
bynausea
andsometim
esvomiting
andserio
usrhinorrhea;in55%
oftrialsheadache
was
reporte
dto
beas
severe
asthesubjecth
adeverexperie
nced;h
eadachew
asalleviated
byre-adm
inistratio
nof
caffe
ine;otherw
ithdraw
alsymptom
swerenotedbutn
otsta
tistically
analyzed
(i.e.,m
entald
epression,
drow
siness,yawning,a
nddisin
clinationto
work);s
erum
protein,
serum
calcium,a
ndhematocrit
weresig
nific
antly
lower
durin
gheadache
andserum
inorganicphosphorus
was
slightly
higher
44.H
öfer
andBä
ttig
(1994a)
N=120habitualcoffe
eusers(mean5.7cups/day);betweengroups
desig
n;aftera
3-daybaselin
eperio
d,subjectsreceived
either
9days
ofcaffe
inated
insta
ntcoffe
e,9days
ofdecaffe
inated
insta
ntcoffe
eor
9days
ofinterm
ittentc
affeinated
anddecaffe
inated
insta
ntcoffe
e;abstinencewas
biologically
verified
Intheinterm
ittentg
roup,c
omparedwith
caffe
inedays,d
ecaffeinated
days
produced
increasednausea
andindisposition;inthe
decaffe
inated
group,
decaffe
inated
days
comparedwith
baselin
eproduced
increasedheadache,u
seof
analgesic
s,indisposition,h
eart
rate,and
decreasedwakefulness,w
ell-b
eing,d
aypositive,motor
activ
ity,and
problemsfallin
gasleep;inthedecaffe
inated
groupthese
effects(exceptfor
heartrate)
peaked
ondays
1or
2andprogressivelydecreasedtowardpre-with
draw
allevels;
subjectsin
the
interm
ittentg
roup
show
edmosto
fthese
effects;40
–50%
ofsubjectsreporte
dmoderateheadache
indecaffe
inated
groupand20–3
0%reporte
dmoresevere
headache
45.H
öfer
andBä
ttig
(1994b)
N=42
femalehabitual
coffe
edrinkers
(mean6cups/day);betweengroups
desig
n;aftera
3-dayphaseof
usualc
offeeconsum
ption
(baseline),subjectsenteredasecond
phaseconsistingof
either
3days
ofdecaffe
inated
insta
ntcoffe
eor
3days
ofcaffe
inetablets;
abstinencewas
biologically
verified
Caffe
inewith
draw
alwas
defin
edas
asta
tistical
interactionbetweengroupandphase,
with
thedecaffe
inated
coffe
egroupshow
ing
increasedheadache,m
uscle/jointa
che,
sleep
duratio
nanddecreasedwell-b
eing,ratings
ofdaypositive,
wakefulness,a
ndmotor
activ
ity;stomach/belly
ache
was
increasedin
thecaffe
inetablet
groupanddecreasedin
thedecaffe
inated
coffe
egroupd;d
esire
for
coffe
ewas
increasedin
thecaffe
inetablet
groupbutn
otchangedin
thedecaffe
inated
coffe
egroup
46.L
ane(1994)
N=14
habitual
coffe
edrinkers
(3.4
cups/day);with
in-subjectsdesig
n;aftero
vernight
abstinencesubjectsweregivenwater
containing
300mgcaffe
ineor
placebo;
abstinencenotb
iologically
verified
Comparedwith
caffe
ine,placeboproduced
increaseddrow
sy/sleepy,lethargy/fatig
ue/tired/sle
epy,headache,self-c
onfid
ence,and
heavy
feelings
inarmsa
ndlegs,and
decreaseddesireto
socialize/talkativeness;9of
14subjectsreporte
dmoreheadache
afterp
lacebo
andno
subjectsreporte
dmoreheadache
afterc
affeine;
placebowas
associated
with
decreasedlevelsof
urinaryepinephrinewhich
were
interpretedby
theauthor
asan
effect
ofcaffe
inerather
than
ofcaffe
inewith
draw
al47.R
ubin
andSm
ith(1999)
N=43
regularc
offeeor
teaconsum
ers(m
ean175mg/day);w
ithin-subjectsdesig
n;aftera
2-daybaselin
eperio
dof
norm
alcaffe
ine
consum
ption,
subjectsconsum
edcaffe
inated
coffe
e(ortea)for
2days
anddecaffe
inated
coffe
e(ortea)for
2days
incounterbalanced
order;abstinencenotb
iologically
verified
Asig
nific
antly
greatern
umbero
fsubjectsreportedheadache
durin
gthedecaffe
inated
perio
d(40%
)thandurin
gthebaselin
e(14%
)and
caffe
inated
perio
d(19%
);thesediffe
rences
weregreaterinindividualswho
corre
ctly
identifiedthepresence
orabsenceof
caffe
ine
(49%
indecaffe
inated
perio
d,7%
inbaselin
e,9%
incaffe
inated
condition)
48.F
ield
etal.(2003)
N=10
lowcaffe
ineconsum
ers(mean41
mg/day)
and10
high
caffe
inec
onsumers(mean648mg/day);w
ithin
subjectsandacross
groups
desig
n;before
twosessions,subjectsabsta
ined
from
caffe
inefor3
0h;
cerebral
bloodflo
wwas
assessed
with
perfu
sionmagnetic
resonanceim
aging60–90min
afterreceiving
capsules
containing
caffe
ine(250
mg)
orplacebo;
abstinencenotb
iologically
verified
Comparedwith
caffe
ine,
placeboproduced
greaterc
erebralb
lood
flow
velocitiesin
white
matter,anterio
rgraymatter,andposte
rior
gray
matterregions;h
ighcaffe
ineuserss
howed
agreaterc
affeine–placebodiffe
rencein
theanterio
rgraymatterthanlowusers;across
allsubjects,cerebral
bloodflo
win
theplacebocondition
increasedlin
early
with
daily
caffe
ineintake
Non-blin
d49.N
aism
ithet
al.(1970)
N=20
caffe
ineconsum
ers(560
mg/day);w
ithin-subjectsdesig
n;aftera
10-day
baselin
eperio
d,subjectssw
itchedto
decaffe
inated
coffe
eandabsta
ined
from
allo
ther
sourcesof
caffe
inefor1
4days;a
bstin
ence
notb
iologically
verified
Nosta
tistical
analyses
werereporte
d;allsubjectsreporte
dlassitu
deandsevere
headache
which
resolved
by48
h
50.R
oller(1981)
N=1malehabitualcoffe
euser
(900–1,100
mg/day);w
ithin-subjectsd
esign;
absta
ined
from
caffe
inefor7
2-hperio
d;24
hinto
this72-h
perio
dtheophyllin
ewas
administered;a
tthe
endof
72heither
caffe
inated
coffe
e(approx.
150mgcaffe
ine)
ordecaffe
inated
coffe
ewas
ingeste
din
ablindedfashion
Nosta
tisticalanalyses
werereporte
d;headache
starte
daftera
bout
6h;
shortly
thereafte
rthe
subjectreportedtiredness
orlassitu
de,then
rhinorrhea
andlegmusclepains,follo
wed
bydiaphoresis
;afte
r16hthesubjectreportedgeneralm
usclepains;thesesymptom
sgradually
increasedto
amaxim
umintensity
atalatertim
eandweresuppressed
bycaffe
inated
coffe
econsum
ptionbutn
otplacebo
51.E
delsteinet
al.(1983)
N=18
psychiatric
patientsw
hoconsum
edthreeor
morecaffe
inated
beveragesp
erday;
with
in-subjectsd
esign;
decaffe
inated
beverages
weresubstituted
forc
affeinated
beverages;abstinencenotb
iologically
verified
Nosta
tistical
analyses
werereporte
d;headache
increaseddurin
gthefirst1–2weeks
afterd
ecaffeinated
beveragesweresubstituted
for
caffe
inated
beverages
52.M
athew
andWilson
(1985)
N=8heavy(m
ean986mg/day)
and8lig
ht(m
ean126mg/day)
caffe
ineusers;with
in-subjectsd
esign;
afterb
aselineassessmentsubjects
absta
ined
from
caffe
inefor2
4h;
abstinencenotb
iologically
verified
Comparedwith
cerebral
bloodflo
wmeasurementsassessed
after2
-habstinence,
24-h
abstinenceproduced
increasedcerebral
blood
flow
inseveralfrontal
regionsbilaterally
inheavyusersbutn
otlig
htusers
53.R
izzo
etal.(1988)
N=20
daily
caffe
ineusers(m
ean606mg/day)
andN=
20caffe
inenon-users;with
in-subjectsdesig
n;twoexperim
entalsessio
nsseparatedby
7days;u
sers
absta
ined
from
caffe
inefor2
days
priortothesecond
session;
abstinencenotb
iologically
verified
Caffe
ineusershadslo
wer
reactio
ntim
esandsm
allerh
eartratedeceleratio
nsthan
non-usersdurin
gcaffe
ineabstinence(sessio
n2)
but
nota
tbaseline(sessio
n1)
54.C
outurie
retal.(1997)
N=20
adultspresum
edto
bedaily
caffe
ineusers;with
in-subjectsdesig
n;subjectswereassessed
atbaselin
e,24
hlatera
fterc
omplete
caffe
ineabstinence,and30
min
and120min
afterreceiving
capsules
containing
150mgcaffe
ine;abstinencewas
biologically
verified
Subjectsreporte
dheadache
aftera
bstin
ence
with
completerecovery
afterc
affeineadministratio
n;comparedwith
baselin
ecerebral
bloodflo
wvelocities(le
ftmiddlecerebral,b
asilar,andboth
poste
riorc
erebrala
rterie
s)increasedaftera
bstin
ence;c
omparedwith
abstinencecerebral
bloodflo
wvelocitiesdecreasedafterc
affeineadministratio
n;50%
ofsubjectsreporte
dmoderateto
severe
headache;1
0%reporte
dnausea
andvomiting
55.L
ane(1997)
N=16
daily
caffe
ineconsum
ers(m
ean612mg/day);w
ithin-subjectsdesig
n;subjectswereassessed
ontwooccasio
ns:a
fteru
sual
caffe
ineconsum
ptionandaftero
vernight
abstinence(estimated
12–2
8habstinence);a
bstin
ence
notb
iologically
verified
Comparedwith
adlib
itum
caffe
ineconsum
ption,
caffe
ineabstinenceincreasedheadache,d
rowsy/sleepy,fatigue
(POMS)
e ,lethargy/
fatig
ue/tired/slu
ggish
,muzzy/fo
ggy/notclearheaded,y
awning,flu-like
feelings,lightheaded/dizzy,heavy
feelingin
armsa
ndlegs,and
decreasedvigor(PO
MS),w
ell-b
eing,d
esire
tosocialize/talkativeness,ability
toconcentra
te,e
nergy/activ
e,content/satisfied,
mean
arteria
lblood
pressure;a
ftera
bstin
ence
63%
ofsubjectsreporte
dheadache,2
5%reporte
dmaxim
umratin
gsof
headache,a
nd31%
reporte
dflu
-like
symptom
s
7
Reference
Design
With
draw
alsig
nsandsymptom
sb,c
56.L
aneandPh
illips-
Bute
(1998)
N=30
daily
coffe
econsum
ers(mean569mg/daycaffe
ine);w
ithin-subjectsd
esign;
subjectswereassessed
ontwooccasio
ns:afte
rusual
caffe
ineconsum
ptionandaftero
vernight
abstinence(estimated
12–2
8habstinence);a
bstin
ence
notb
iologically
verified
Comparedwith
adlib
itum
caffe
ineconsum
ption,caffe
ineabstinenceincreasedheadache,drowsy/sleepy,irritable/cross/g
rumpy;fatigue
(POMS),lethargy/fatig
ue/tired/slu
ggish
,muzzy/fo
ggy/notc
learheaded,y
awning,a
nger–hostility
(POMS),c
onfusio
n–bewild
erment
(POMS),d
epression-dejection(POMS),a
nddecreasedvigor(PO
MS),w
ell-b
eing,d
esire
tosocialize/talkativeness,ability
toconcentra
te,energy/activ
e,alert/attentive/observant;urge
todo
task/work-relatedactiv
ities;h
otor
cold
spells,
need
topass
water
d ;on
avisualvigilancetask
abstinencedecreasedhit-rateandincreasedresponse
time,andabstinenceincreasedsubjectsratin
gsof
perceived
difficulty
anddecreasedperceivedim
porta
nceof
doingwella
ndperceivedsuccess;aftera
bstin
ence
47%
reporte
danyheadache
and
27%
reporte
dmoderateor
severe
headache
57.R
eeveset
al.(1995,
1997,2002);P
atric
ketal.
(1996)
N=13
or14
daily
caffe
ineusers(>300mg/day);w
ithin-subjectsdesig
n;subjectsevaluatedwhile
consum
ingtheirn
ormal
caffe
inediet
(baseline)
andagainafter1
,2,a
nd4days
ofabstinence;
evaluatio
nsincluded
topographicquantitativeEE
G,p
hysic
ianratin
gsof
caffe
inewith
draw
alseverityas
assessed
durin
gastructuredinterview,
andamusculoskeletalexam
inationof
thespine;abstinencewas
biologically
verified
Comparedwith
baselin
e,sig
nific
antq
uantitativ
eEE
Gchangesw
ere:increase
inthetaabsolutepower,increasein
delta
absolutepower
over
thefro
ntalcorticalareas,d
ecreasein
themeanfre
quency
ofboth
alphaandbetarhythm
,increasein
thetarelativ
epower,decrease
inbeta
relativ
epower,and
change
ininterhem
ispheric
coherence;
resumptionof
caffe
inefollo
wingabstinencereturned
alteredEE
Gvalues
tobaselin
elevels;
allsubjectsreportedcaffe
ine-with
draw
alsymptom
sand
77%
hadmoderateor
severe
with
draw
alseverityas
ratedby
aphysician;
comparedwith
baselin
e,thenumbero
fsom
atic
dysfunctions
from
themusculoskeletal
exam
inationwas
signific
antly
greatero
ndays
1,2,and4of
caffe
ineabstinence;thegreatestnumbero
fsom
aticdysfunctions
was
reporte
don
day2;
sixsubjectswho
hadbaselin
eEE
Gscontaining
diffu
separoxysm
alslo
wing(D
PS,a
minor
EEG
dysrhythmia)s
howed
signific
ant
increasesin
DPS
firingdurin
gwith
draw
alandareturn
tobaselin
efiringlevelsfollo
wingcaffe
ineresumption
a Allstud
ieshadacaffeine
abstinence
period
of12
hor
greater
bAlleffectsarestatistically
sign
ificantat
P≤0
.05un
less
otherw
iseno
ted
c For
consistency,
whenplaceboandcaffeine
cond
ition
sarecompared,
theeffectsaredescribedas
theeffectsof
placeborelativ
eto
caffeine
dLikelyadirect
effect
ofcaffeine
rather
than
aneffect
ofcaffeine
with
draw
ale POMSindicatesProfile
ofmoo
dstates
questio
nnaire
Tab
le2(con
tinued)
Tab
le3
Sum
maryof
survey
stud
iesof
caffeine
with
draw
al
Reference
Design
With
draw
alsig
nsandsymptom
s
58.G
oldstein
and
Kaizer(1969)
N=183femalecoffe
econsum
erssurveyed
aboutthe
effectsthey
would
experie
nceifmorning
coffe
ewas
omitted
Endorsem
ento
fsym
ptom
sincreased
asthenumbero
fcupso
fcoffeeconsum
edincreased;
amongheavycoffe
eusers(5–
10cups/day)the
percentagesreporting
specificsymptom
swere58%
feel
halfaw
ake,
24%
lethargic,
21%
irritable,
18%
sleepy,
16%
unable
towork
effectively,
15%
restless,8%
headache
59.W
inste
ad(1976)
N=135mostly
adultinpatientson
psychiatric
ward;
survey
ofoccurre
nceof
caffe
ine-with
draw
alsymptom
s26%
ofheavycaffe
ineusers(>500mg/day)
reporte
dexperie
ncing“anxiety
with
draw
alsymptom
s”60.G
redenet
al.
(1978)
N=83
psychiatric
inpatients;surveyed
aboutthe
occurre
nceof
headache
onom
issionof
morning
coffe
e11%
endorsed
experie
ncingheadache
61.G
redenet
al.
(1980)
N=205medical
inpatients;questio
nedaboutthe
occurre
nceof
headache
upon
stoppingcaffe
ine
20%
oftotalsam
ple(or2
8%of
thesampleof
152afterthose
who
answ
ered
“don
’tknow
”wereexcluded)reportedcaffe
ine-with
draw
alheadache;those
reporting
headache
hadhigher
meancaffe
ineintake
(616
mg/day)
than
thosenotreportin
gheadache
(395
mg/day)
62.V
ictore
tal.(1981)
N=124generalm
edical
inpatients;survey
oftheoccurre
nceof
caffe
ine-with
draw
alheadache
24%
ofsubjectsendorsed
having
experie
nced
caffe
ine-with
draw
alheadache
63.H
ugheset
al.
(1998)
N=162caffe
ineconsum
ers;surveyed
viatelephoneaboutc
affeineabstinenceandwith
draw
alsymptom
s44%
ofcaffe
ineconsum
ersreporte
dhaving
absta
ined
from
caffe
inefor≥
24hin
thepastyear;o
fthose,2
4%reporte
dheadache,2
7%drow
siness,21%
fatig
ue,1
0%anxiety,4%
depressio
n,3%
nausea
orvomiting,2
8%strongdesireto
use,20%
irritability,21%
yawning,
11%
difficulty
concentra
ting,
18%
less
motivated
towork
64.D
ewset
al.(1999)
N=6,815adultswho
reporte
ddaily
caffe
ineusewereaskedifthey
had“problem
sor
symptom
son
stoppingcaffe
inein
thepast”
11%
reporte
dwith
draw
alsymptom
supon
stoppingcaffe
ine;
ofthose,
25%
reporte
dsymptom
ssevere
enough
tointerfe
rewith
norm
aldaily
activ
ities
(e.g.,losttim
efro
mwork);h
eadachewas
themostc
ommon
symptom
reporte
d;itisunknow
nwhatp
ercentageof
daily
usershadactually
absta
ined
from
caffe
ine
65.K
endler
andPre-
scott(1999)
N=1,642wom
enin
apopulatio
n-basedtwin
registryinterviewed
abouttheircaffe
ineuse;
individualswho
reporte
dsto
ppingor
cutting
downtheirc
affeineconsum
ptionwereaskedaboutc
affeine-with
draw
alsymptom
s24%
ofsubjectswho
reporte
dsto
ppingor
cutting
downtheirc
affeineconsum
ptionreporte
dhaving
experie
nced
headache
plus
oneor
moreof
thefollo
wing:
markedfatig
ueor
drow
siness,markedanxietyor
depressio
n,andnausea
orvomiting
66.B
ernstein
etal.
(2002);O
berstare
tal.(2002)
N=36
adolescent
daily
caffe
ineconsum
ers(m
ean244mg/day)
who
endorsed
twoor
moreDSM
-IVcaffe
inedependence
criteria
durin
gtelephoneprescreening;interview
edandassessed
forc
affeinedependence
basedon
DSM
-IVsubstancedependence
criteria
;21of
these
subjectswerereassessed
1year
later
Basedon
both
interviews,81%
metthew
ithdraw
alcriterio
n;100%
ofsubjectswho
metcriteria
forD
SM-IV
caffe
inedependence
reporte
dwith
draw
alsymptom
s;thepercentage
ofsubjectsreporting
specificsymptom
swere59%
drow
sy/tired,
56%
fatig
ued,
56%
sluggish
/slo
wed
down,
56%
headache,3
2%restless/c
annotsitstill,
29%
nervous/a
nxious,2
1%sic
k/nauseated/vomiting,2
1%drinkcaffe
ineso
youdo
notfeelb
ad,a
nd9%
sad/depressed
8
Table 4 Summary of withdrawal symptoms reported in experimental and survey studies described in Tables 1, 2, 3a
Symptom Acute abstinenceversus baselineb
Acute abstinenceversus caffeineb
Acuteabstinencein caffeineconsumersversus non-consumersb
Acute abstinence versuschronic abstinenceb
Time-limitedabstinence effectsb
Percentage of subjects showing effect inexperimental studiesc
Percentage of subjects reportingsymptom in survey studiesd
Headache 4, 9, 20, 44, 45, 47,49, 50, 51, 54
1, 2, 5, 6, 7, 8, 9, 10,11, 12,13, 15, 16, 21, 23,25, 27, 30,33, 34, 35, 36, 43,46, 47, 55, 56
17 6, 8, 27, 42 4, 5, 7, 44, 49, 51 1: 25% of trials (heavy users) [control 3%] 58: 8% headache4: 100% headache (control 14%) 60: 11% headache6: 79% headachee* 61: 20% headache7: 42% headache (control 10%) 62: 24% headache9: 52% moderate or severe headache (control2%)
63: 24% headache
11: 30% headache* 65: 24% headache plus additionalsymptom
12: 64% maximum headache (control 0%) 66: 56% headache15: 9% headache*
20: 45% diffuse throbbing headache
27: 47% headache (control 14%)
32: 28% headache (control 17%)
43: 82% definite to severe headache, 55% oftrials severe as ever experienced
44: 40–50% moderate headache, 20–30% moresevere headache
46: 64% headache (control 0%)
47: 40% headache (control 14%)
49: 100% headache
54: 50% moderate or severe headache
55: 63% headache (control 6%), 25% maximumheadache (control 0%)
56: 47% headache, 27% moderate or severeheadache
Tiredness/fatigue 4, 9, 20, 49, 50 2, 5, 6, 8, 9, 11, 12,14, 15,16, 17, 18, 19, 21,23, 24,25, 26, 28, 30,
33, 34, 35, 36, 43,46, 55, 56
17 6, 8, 17, 26 4, 5, 17, 20, 49 6: 57% lethargy/fatiguee* 58: 24% lethargic9: 8% abnormal high fatigue (control 0%) 63: 21% fatigue11: 24% fatigue* 66: 56% fatigued12: 27% extreme fatigue (control 9%)
15: 18% fatigued/tired*
20: 68% tired and lethargy
49: 100% lassitude
Decreased energy/ac-tiveness
4, 9 2, 5, 6, 8, 9, 12, 15,18, 19,21, 22, 23, 24, 26,
28, 29, 31, 33, 34,35, 37, 55, 56
2 6, 26 4, 5 6: 64% ↓ energy/activee*
9: 11% abnormal scores (control 0%)
12: 45% extreme ↓ in vigor (control 0%)
15: 27% ↓ stimulated/active/energy/excited*
Decreased alertness/attentiveness
4, 20 2, 5, 6, 8, 15, 19, 21,24, 25,26, 27, 33,
34, 35, 36, 37, 39,56
2, 40, 41 6, 26 4, 5 6: 50% ↓ alert/attentivee*
15: 27% ↓ alert/attentive/able to concentrate*
Drowsiness/sleepi-ness
4, 9, 20, 44, 45 2, 6, 8, 9, 11, 14, 15,17, 19,21, 23, 24, 28, 46,55, 56
2, 17 6, 17, 26 4, 44 6: 64% drowsy–sleepye* 58: 18% sleepy, 58% feel-half awake11: 24% drowsiness* 63: 27% drowsiness15: 45% drowsy/sleepy/tired* 66: 59% drowsy/tired22: 63% drowsiness/fatigue*
23: 13% drowsiness*
Decreased contented-ness/well-being
9, 44, 45 2, 5, 6, 9, 17, 18, 19,21, 22,23, 24, 25, 26, 55,56
2 6, 26 5, 44 6: 64% ↓ well-beinge*, 50% ↓ content/satisfiede*
15: 18% ↓ content/relaxed/satisfied*
Decreased desire tosocialize
4, 9 2, 5, 6, 9, 10, 14, 17,22, 33,34, 37, 46, 55, 56
6 5 6: 79% ↓ social dispositione*
15: 9% ↓ talkative*
“Flu-like” symptoms 9 5, 6, 9, 25, 30, 33,34, 36, 55
6 5 55: 31% flu-like symptoms (control 0%)
Depressed mood 9 5, 6, 9, 12, 14, 15,17, 56
17 6, 17, 26 5 6: 14% depressede 63: 4% depression9: 11% abnormal scores BDI (control 2%) 66: 9% sad/depressed12: 36% elevations on BDI (control 0%)
15: 18% depressed*
9
data on the independence of specific caffeine-withdrawalsymptoms (e.g., factor analysis), the listing provides auseful framework for characterizing the results of caffeine-withdrawal studies. In Table 4, symptoms are sequencedfrom those documented (i.e., shown in columns 2–6) in thegreatest number of experimental studies to those docu-mented in the fewest. Table 4 also differentiates experi-ments according to five of the most frequently used
experimental methodologies that have been used to drawinferences about caffeine-withdrawal symptoms and signs.Finally, Table 4 shows the percentages of individualsreporting withdrawal symptoms in both experimental andsurvey studies.
Symptom Acute abstinenceversus baselineb
Acute abstinenceversus caffeineb
Acuteabstinencein caffeineconsumersversus non-consumersb
Acute abstinence versuschronic abstinenceb
Time-limitedabstinence effectsb
Percentage of subjects showing effect inexperimental studiesc
Percentage of subjects reportingsymptom in survey studiesd
Difficulty concentrat-ing
20 5, 6, 19, 26, 37, 55,56
6, 26 5 6: 79% ↓ able to concentratee* 63: 11% difficulty concentrating
Irritability 9 2, 5, 6, 9, 19, 22, 56 2 6, 26 5 6: 29% irritable/cross/grumpye* 58: 21% irritable15: 9% irritable/frustrated/angry/cross* 63: 20% irritability
Unmotivated forwork
9 5, 6, 9, 21, 22, 23,24, 56
5 6: 57% ↓ motivation for worke* 58: 16% unable to work effectively
6: 64% ↓ urge to do worke* 63: 18% ↓ motivated to work
Muzzy/foggy/notclearheaded
9, 20 6, 9, 17, 18, 55, 56 17 6 6: 71% muzzye*
Yawning 9 6, 9, 19, 21, 28, 55,56
6 6: 43% yawninge* 63: 21% yawning
Decreased self-confi-dence
9 5, 6, 9, 21, 23, 24, 46 6 5 6: 64% ↓ self-confidencee*
Confusion–bewilder-ment
9 6, 9, 22, 26, 34, 56 26
Total mood distur-bance
9 6, 9, 26, 34, 35, 36 26
Nausea/vomiting/upset stomach
22, 23, 24, 38, 43, 44 6: 29% upset stomache* 63: 3% nausea or vomiting
20: 13% nausea and sickness with headache 66: 21% sick/nauseated/vomiting
43: 33% nausea (sometimes vomiting) alongwith headache
54: 10% nausea and vomiting
Muscle pain/stiffness 45, 50 5, 6 6 5 6: 43% muscle paine*
Anxiety/nervousness 9 9, 22 2, 40 9: 8% abnormal scores anxiety (control 0%) 59: 26% anxiety withdrawalsymptoms
63: 10% anxiety
66: 29% nervous/anxious
Heavy feelings inarms and legs
9 9, 37, 46, 55
Increased sleep dura-tion/quality
20, 44, 45 27
Analgesics use 44 9, 12 44 9: 13% analgesics use (control 2%)
12: 45% analgesics use
Craving 5, 6 6 5 6: 43% craving for caffeine* 63: 28% strong desire to use
Lightheaded/dizzy 6, 38, 55
Blurred vision 9 6, 9 6 6: 14% blurred visione*
Anger/hostility 17, 56 17 17
Hot and cold spells 9 9, 56
aNumbers in table refer to the entry number in Tables 1, 2, 3bThe strengths and weaknesses of each of the types of comparisons presented in columns 2–6 are described in the text. Studies in columns4–6 are more rigorous because the effects are not confounded by the direct effects of caffeinecThis column (column 7) shows the percentage of subjects reporting the symptom in experimental studies (as summarized in columns 2–6).For comparison, when available, the percentage of subjects reporting the symptom in the control condition (i.e., baseline or caffeinecondition) is shown in brackets. For studies that conducted within-subject analyses of differences between the abstinence and controlconditions, an asterisk (*) indicates the percentage of subjects who showed a statistically significant difference at P<0.05dPercentage of subjects reporting symptom in survey studies: this column shows the percentage of individuals reporting the occurrence of asymptom presumably based on their previous experience in the natural environmenteIncidence data for this study were collapsed across two conditions: acute abstinence versus caffeine and acute abstinence versus chronicabstinence
Table 4 (continued)
10
Experimental methodologies
Several different experimental methodologies have beenused to draw inferences about the occurrence of caffeinewithdrawal. As understanding the strengths and weak-nesses of each of these methodologies is critical todrawing meaningful conclusions about the validity of thefindings, this section will briefly list and critique the mostcommonly used experimental methodologies. The firstfive experimental methodologies (corresponding to col-umns 2–6 in Table 4) involve different comparisons withacute caffeine abstinence.
Acute abstinence versus preceding caffeine baseline(not counterbalanced)
In this within-subjects comparison, symptoms or signsduring acute caffeine abstinence are compared with thoseduring a preceding baseline of ad libitum caffeineconsumption. This comparison may have good ecologicalvalidity because it can involve a naturally occurringpattern of caffeine consumption followed by abruptabstinence. A limitation of this comparison is that baselineversus abstinence differences may be due to the simpleabsence of the direct effects of caffeine during abstinence(i.e., a caffeine offset effect rather than a time-limitedwithdrawal effect). Another limitation is that observeddifferences could be confounded by order effects (i.e.,conditions are not counterbalanced).
Acute abstinence versus caffeine
In this comparison, which could involve within subjects oracross groups designs, symptoms or signs during acuteabstinence are compared with those during caffeineconsumption, with conditions counterbalanced or rando-mized across subjects. As with the comparison with apreceding baseline caffeine condition, this comparisonmay have good ecological validity in modeling naturallyoccurring effects of caffeine abstinence. Although notconfounded by order effects, this comparison has thelimitation that caffeine versus abstinence differences maybe due to the simple absence of the direct effects ofcaffeine during abstinence.
Acute abstinence in caffeine consumers versus non-consumers
In this between-groups comparison, symptoms or signsduring acute abstinence in caffeine consumers arecompared with those in non-consumers. As both groupsare caffeine abstinent, it can be concluded that anydifference observed is not confounded by the direct effectsof caffeine. However, the possible confounding effects ofpopulation differences between caffeine consumers and
non-consumers cannot be ruled out because of the self-selected nature of these groups.
Acute abstinence versus chronic abstinence
In this comparison, which could be within subjects oracross groups, symptoms or signs during acute abstinenceare compared with those during chronic abstinence (e.g.,1 week or more of caffeine abstinence). As both conditionsinvolve caffeine abstinence, it can be concluded that anydifference observed is not confounded by the direct effectsof caffeine. Although this comparison provides moreconclusive evidence of withdrawal effects than thepreceding comparisons, the approach is conservativebecause it may underestimate the incidence or magnitudeof withdrawal effects if symptoms or signs persist in thechronic abstinence condition.
Time-limited abstinence effects
By definition, a drug withdrawal symptom or sign shouldincrease upon acute abstinence and then decrease overtime with continued drug abstinence. A demonstration ofsuch time-limited effects is not confounded by the directeffects of caffeine and is important for confirming that theeffects observed are withdrawal related rather thanreflecting caffeine offset effects (i.e., a return to thenormal drug-free state).
Other methodologies
In addition to the five approaches described above, severalother types of experimental methodologies can help toinform the interpretation of caffeine-withdrawal effects.Although not included in Table 4, studies using these othermethodologies are discussed in the following section onsymptoms and signs of caffeine withdrawal.
Variation in caffeine maintenance dose Demonstration thatthe severity or incidence of a symptom or sign increaseswith increases in the daily caffeine maintenance dosebefore abstinence helps to confirm that the withdrawaleffect reflects a pharmacological process.
Acute decreases in caffeine maintenance dose When lowercaffeine doses are substituted for the usual caffeinemaintenance dose, the demonstration that the severity orincidence of a symptom or sign increases as the substituteddose decreases helps to confirm that the withdrawal effectreflects a pharmacological process.
Manipulation of duration of caffeine maintenance De-monstration that the severity or incidence of a symptom orsign increases with increases in the duration of dailycaffeine maintenance dose before abstinence helps toconfirm that the withdrawal effect reflects a pharmacolo-
11
gical process.
Re-administration of caffeine reverses abstinence effectsAfter a period of abstinence during which the severity orincidence of a symptom or sign develops, the demonstra-tion that re-administration of caffeine rapidly and dosedependently reverses the abstinence effects helps toconfirm that the withdrawal effect reflects a pharmacolo-gical process.
Symptoms and signs of caffeine withdrawal
Symptoms of caffeine withdrawal
In this section, the withdrawal symptoms (i.e., categoriesof self-reported changes in mood or behavior) that wereassessed in the studies listed in Tables 1, 2, and 3, andsummarized in Table 4, are individually discussed andevaluated. For some symptoms, relevant case reports arealso discussed if they contribute to the evaluation. As inTable 4, the symptoms are sequenced from those that weredocumented in the greatest number of studies to those thatwere documented in the fewest number.
Of relevance to the assessment of each symptom isinformation about the “hit-rate” (i.e., the ratio of thenumber of times a symptom was found to be significantrelative to the number of times it was assessed). For thisanalysis, the number of studies in which each symptomwas documented was taken from the 57 experimentalstudies described in Tables 1 and 2 (and summarized incolumns 2–6 of Table 4). The number of studies in whicheach symptom was assessed was obtained from anevaluation of the same 57 experimental studies. In severalstudies (Comer et al. 1997; Schuh and Griffiths 1997;Garrett and Griffiths 1998; Jones et al. 2000) all of thesymptoms assessed could not be determined from thepublished article, and this information was obtained fromthe authors. [Methodological note: in the rare instance inwhich a study used a compound symptom descriptor (e.g.,alert/attentive/observant/able to concentrate) that couldpotentially apply to two symptom categories (e.g., alert/attentiveness and difficulty concentrating), the data werecounted in the single category that it best represented (e.g.,alert/attentiveness was counted as assessed and difficultyconcentrating was coded as not assessed).]
In interpreting the hit-rate, it should be noted that mostof the statistically significant effects reported are based ongroup mean data. Thus, a high hit-rate indicates that theabstinence condition is readily differentiated from thecomparison condition and usually reflects an intermediateto high incidence of the symptom. A low hit-rate indicatesthat the abstinence condition is not readily differentiatedfrom the comparison condition. However, it is important torecognize that a low hit-rate does not mean that a symptomis not valid because such a symptom may have a lowincidence and thus be undetected in a group statisticalanalysis. Furthermore, a symptom with a low hit-rate mayalso be clinically important to the extent that it may have
profound effects in a small percentage of the population(e.g., psychotic symptoms in the general population).Finally, a failure to detect a particular effect may reflectmethodological shortcomings of a study (e.g., insufficientperiod of abstinence, small sample size, insensitivemeasures).
Validity criteria For purposes of this review, the criteria forconcluding that a symptom is valid was the statisticaldemonstration of the symptom in six or more studies thatinclude two or more double-blind studies that usedmethodologies in which the conclusion of caffeine-with-drawal effects was not confounded by the direct effects ofcaffeine (i.e., Table 4, columns 4–6). As a conservativeapproach, two studies that used the same group of subjects(i.e., studies 5 and 6 in Table 4) were considered to be asingle study for purposes of judging validity.
Headache (descriptors: headache and headachy) Head-ache has been the most frequently assessed symptom (48experimental studies and 6 survey studies). Headache wasfound in 37 of 48 (77%) of the experimental studies inwhich it was assessed. The median percentage ofindividuals reporting headache in 19 experimental studieswas 47%, ranging from 9% to 100% across studies(Table 4). Of the 7 experimental studies that assessedheadache severity, the median percentage of subjectsreporting moderate to severe or maximum headache was50%. In 7 survey studies, the median percentage ofcaffeine users reporting caffeine-withdrawal headache was24%, ranging from 8% to 56%.
Headache as a caffeine-withdrawal symptom has beendemonstrated in studies comparing acute caffeine absti-nence with a preceding baseline condition, a caffeineadministration condition, and a chronic caffeine abstinencecondition (Table 4) and by comparing acute caffeineabstinence in caffeine consumers with non-consumers(Table 4). Studies have also shown that abstinence-induced headache is time-limited (Table 4) and is rapidly(usually within 30–60 min) and often completely reversedafter re-administration of caffeine (Driesbach and Pfeiffer1943; Goldstein et al. 1969; Roller 1981; Couturier et al.1997; Tinley et al. 2003), with the magnitude of reversalbeing an increasing function of the re-administeredcaffeine dose (Goldstein et al. 1969). Studies have alsoshown that the severity and incidence of headache afterabstinence were increasing functions of caffeine mainte-nance dose (Goldstein 1964; Silverman et al. 1992; Evansand Griffiths 1999) and duration of caffeine dosing (Evansand Griffiths 1999) before abstinence. Finally, whendifferent caffeine doses were substituted for the usualmaintenance dose, the severity and incidence of headacheincreased as the substituted dose decreased (Evans andGriffiths 1999). Caffeine-withdrawal headache has beencharacterized in these experimental studies as well as incase reports as being gradual in development (Driesbachand Pfeiffer 1943; Greden et al. 1980; Roller 1981;Griffiths et al. 1990), diffuse (Driesbach and Pfeiffer 1943;Greden 1974; Greden et al. 1980; Lader et al. 1996),
12
throbbing (Driesbach and Pfeiffer 1943; Greden 1974;Greden et al. 1980; Lader et al. 1996), severe (Griffithsand Woodson 1988; cf. Table 4), intensified with exerciseand Valsalva maneuver (Driesbach and Pfeiffer 1943), andphenomenologically distinct from migraine headache(Driesbach and Pfeiffer 1943).
Clinical reports, correlational analysis, and clusteranalysis of withdrawal symptoms have indicated thatnon-headache symptoms and signs of caffeine withdrawaldo not always co-vary with the presence of headache andcan occur in the absence of headache (Griffiths andWoodson 1988; Griffiths et al. 1990; Lader et al. 1996;Garrett and Griffiths 1998; Evans and Griffiths 1999). Thisindicates that non-headache symptoms represent distinctfeatures of the caffeine-withdrawal syndrome that canoccur independently of headache.
In summary, headache has been very frequently studied,has an intermediate incidence, and has been demonstratedunder a wide range of different methodological conditions.It is concluded that headache is a valid withdrawalsymptom.
Tiredness/fatigue (descriptors: tiredness, tired, fatigue,lazy, sluggish, lazy/sluggish/slow-moving, lethargic, leth-argy/fatigue/tired/sleepy, sluggish/slowed down, worn-out,and lassitude) Tiredness/fatigue was demonstrated in 32 of38 studies (84%). In 7 experimental studies providingincidence data (Table 4), the median percentage ofindividuals showing tiredness/fatigue was 27%. In 3survey studies, the percentage of subjects reportingtiredness/fatigue ranged between 21% and 56%. Tired-ness/fatigue has been demonstrated in studies comparingacute caffeine abstinence with a preceding baselinecondition, a caffeine administration condition, and achronic caffeine abstinence condition (Table 4), and bycomparing acute caffeine abstinence in caffeine consumerswith that in non-consumers (Table 4). Studies have alsoshown that abstinence-induced tiredness/fatigue is timelimited (Table 4), completely reversed after re-administra-tion of caffeine (Roller 1981), and an increasing functionof the duration of caffeine maintenance before abstinence(Evans and Griffiths 1999). Furthermore, when differentcaffeine doses are substituted for the usual maintenancedose, the magnitude of tiredness/fatigue increases as thesubstituted dose decreases (Evans and Griffiths 1999).Severity of tiredness/fatigue also appears to increase athigher daily caffeine maintenance doses (Rogers et al.1995).
In summary, tiredness/fatigue has been very frequentlystudied, has a low to moderate incidence, and has beendemonstrated under a wide range of methodologicalconditions. It is concluded that tiredness/fatigue is avalid withdrawal symptom.
Decreased energy/activeness (descriptors: decreased en-ergy, energetic, active, stimulated/active/energetic/excited,vigor, lively, stronger/more vigorous/more energy) De-creased energy/activeness was demonstrated in 24 of 32experimental studies (75%). In 4 experimental studies
providing incidence data (Table 4), the median percentageof individuals showing decreased energy/activeness was36%. Decreased energy/activeness has been demonstratedin studies comparing acute caffeine abstinence with apreceding baseline condition, a caffeine administrationcondition, and a chronic caffeine abstinence condition(Table 4), and by comparing acute caffeine abstinence incaffeine consumers with that in non-consumers (Table 4).Studies have have also shown that abstinence-induceddecreased energy/activeness is time limited (Table 4) andis rapidly (i.e., within 30–60 min) and completely reversedafter re-administration of caffeine (Goldstein et al. 1969).Studies have also shown that the severity of decreasedenergy/activeness is an increasing function of the caffeinemaintenance dose before abstinence (Rogers et al. 1995;Evans and Griffiths 1999).
In summary, decreased energy/activeness has been veryfrequently studied, has an intermediate incidence, and hasbeen demonstrated under a wide range of methodologicalconditions. It is concluded that decreased energy/active-ness is a valid withdrawal symptom.
Decreased alertness/attentiveness (descriptors: decreasedalertness, alert/attentive/observant, alert/attentive/able toconcentrate, and activity/alertness) Decreased alertness/attentiveness was demonstrated in 22 of 31 experimentalstudies (71%). Two experimental studies reported inci-dence data of 27% and 50% (Table 4). Decreasedalertness/attentiveness has been demonstrated in studiescomparing acute caffeine abstinence with a precedingbaseline condition, a caffeine administration condition,and a chronic caffeine abstinence condition (Table 4), andby comparing acute caffeine abstinence in caffeineconsumers with that in non-consumers (Table 4). Studieshave also shown that abstinence-induced decreasedalertness/attentiveness is time limited (Table 4) and israpidly (i.e., within 30–60 min) and completely reversedafter re-administration of caffeine (Goldstein et al. 1969),with the magnitude of reversal being an increasingfunction of the re-administered caffeine dose (Goldsteinet al. 1969). In addition, deficits in alertness/attentivenessare an increasing function of caffeine maintenance dosebefore abstinence (Rogers et al. 1995; Evans and Griffiths1999). Finally, when different caffeine doses are sub-stituted for the usual maintenance dose, the magnitude ofalertness/attentiveness decreases as the substituted dosedecreases (Evans and Griffiths 1999).
In summary, decreased alertness/attentiveness has beenvery frequently studied, may have an intermediateincidence, and has been demonstrated under a widerange of methodological conditions. It is concluded thatdecreased alertness/attentiveness is a valid withdrawalsymptom.
Drowsiness/sleepiness (descriptors: drowsiness, sleepy,drowsy/sleepy/tired, sedated, feel half awake, and de-creased wakefulness) Drowsiness/sleepiness was demon-strated in 21 of 27 experimental studies (78%). Across 5experimental studies providing incidence data (Table 4),
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the median percentage of individuals showing drowsiness/sleepiness was 45%. In 3 survey studies, the percentage ofsubjects reporting tiredness/fatigue ranged between 18%and 59%. Drowsiness/sleepiness has been demonstrated instudies comparing acute caffeine abstinence with apreceding baseline condition, a caffeine administrationcondition, and a chronic caffeine abstinence condition(Table 4), and by comparing acute caffeine abstinence incaffeine consumers with that in non-consumers (Table 4).Studies have also shown that abstinence-induced drowsi-ness/sleepiness is time limited (Table 4) and is rapidly (i.e.,within 30–60 min) and completely reversed after re-administration of caffeine (Goldstein et al. 1969), with themagnitude of reversal being an increasing function of there-administered caffeine dose (Goldstein et al. 1969).Severity is positively correlated with daily caffeine dosebefore abstinence (Silverman et al. 1992).
In summary, drowsiness/sleepiness has been veryfrequently studied, has an intermediate incidence, andhas been demonstrated under a wide range of methodo-logical conditions. It is concluded that drowsiness/sleepiness is a valid withdrawal symptom.
Decreased contentedness/well-being (descriptors: de-creased contentedness, content/satisfied, well-being, daypositive, cheerful, happy, and increased miserable)Decreased contentedness/well-being was demonstrated in17 of 28 experimental studies (61%). In 2 experimentalstudies, 18% and 64% of participants showed decreases inmeasures of contentedness/well-being (Table 4). De-creased contentedness/well-being has been demonstratedin studies comparing acute caffeine abstinence with apreceding baseline condition, a caffeine administrationcondition, and a chronic caffeine abstinence condition(Table 4), and by comparing acute caffeine abstinence incaffeine consumers with that in non-consumers (Table 4).Studies have also shown that abstinence-induced de-creased contentedness/well-being is time limited (Table 4)and is rapidly (i.e., within 30–60 min) and completelyreversed after re-administration of caffeine (Goldstein etal. 1969), with the magnitude of reversal being anincreasing function of the re-administered caffeine dose(Goldstein et al. 1969). Severity also appears to increasewith higher daily maintenance caffeine doses beforeabstinence (Rogers et al. 1995).
In summary, decreased contentedness/well-being hasbeen very frequently studied, may have an intermediateincidence, and has been demonstrated under a wide rangeof methodological conditions. It is concluded thatdecreased contentedness/well-being is a valid withdrawalsymptom.
Decreased desire to socialize (descriptors: decreaseddesire to socialize, talkativeness, social disposition, andfriendliness) Decreased desire to socialize was demon-strated in 15 of 28 experimental studies (54%). Oneexperimental study reported incidence data of 79% fordecreased social disposition and a second study reported9% for decreased talkativeness (Table 4). Decreased desire
to socialize has been demonstrated in studies comparingacute caffeine abstinence with a preceding baselinecondition, a caffeine administration condition, and achronic caffeine abstinence condition (Table 4). Studieshave also shown that abstinence-induced decreased desireto socialize is time limited (Table 4) and that themagnitude is an increasing function of caffeine mainte-nance dose before abstinence (Evans and Griffiths 1999).
In summary, decreased desire to socialize has been veryfrequently studied with varied incidence. Although it hasbeen demonstrated under several different methodologicalconditions, it does not presently fulfill the criteria forvalidity.
Flu-like symptoms (descriptors: “flu-like symptoms” and“flu-like feelings”) An increase in this category wasdemonstrated in 9 of 17 (53%) experimental studies. Oneexperimental study reported incidence data of 31% for flu-like symptoms (Table 4). Flu-like symptoms as a symptomcategory have been demonstrated in studies comparingacute caffeine abstinence with a preceding baselinecondition, a caffeine administration condition, and achronic caffeine abstinence condition (Table 4). Studieshave also shown that abstinence-induced flu-like symp-toms are time-limited (Table 4) and that the severity of flu-like symptoms is an increasing function of caffeinemaintenance dose before abstinence (Lane and Phillips-Bute 1998; Evans and Griffiths 1999).
In summary, the flu-like symptoms category has beenfrequently studied, appears to have an intermediateincidence, and has been demonstrated under severalmethodological conditions. In addition to the foregoingstudies, one study (Swerdlow et al. 2000) showedcaffeine-abstinence-induced increases in a compositescale that included flu-like symptoms (i.e., feel sick,queasy, dizzy, and perspiring). It seems plausible thatendorsement of flu-like symptoms is related to aconstellation of somatic symptoms that include nausea/vomiting, muscle pain/stiffness, and heavy feelings inarms and legs (these individual symptoms are discussedbelow). Although most of the experimental studiesdemonstrating statistical increases in flu-like symptomshave involved comparisons of caffeine abstinence to acaffeine administration condition, the category appears toreflect a genuine withdrawal effect because endorsementof flu-like symptoms is time limited (Griffiths et al. 1990)and it is implausible that such placebo versus caffeinedifferences represent a direct effect of caffeine insuppressing naturally occurring flu-like symptoms. Thus,even though the flu-like symptoms category fails to meetour a priori criteria for validity, the category appears to bea valid caffeine-withdrawal effect. Furthermore, the flu-like symptoms category may be clinically importantbecause it may reflect significant distress.
Depressed mood (descriptors: depression, dejection, sad/depressed, and elevated scores on the Beck DepressionInventory) Symptoms of depressed mood were demon-strated in 9 of 29 experimental studies (31%). In 4
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experimental studies providing incidence data, the medianpercentage of individuals reporting depressed mood was16% (range 11–36%; Table 4). In 2 survey studies, thepercentage of subjects reporting depression was 4% and9%. Depressed mood has been demonstrated in studiescomparing acute caffeine abstinence with a precedingbaseline condition, a caffeine administration condition,and a chronic caffeine abstinence condition (Table 4), andby comparing acute caffeine abstinence in caffeineconsumers with that in non-consumers (Table 4). Studiesalso showed that abstinence-induced depressed mood istime limited (Table 4).
In summary, depressed mood has been very frequentlystudied, has a low to moderate incidence, and has beendemonstrated under a wide range of methodologicalconditions. It is concluded that depressed mood is avalid withdrawal symptom.
Difficulty concentrating (descriptors: difficulty concen-trating, decreased concentration, and decreased ability toconcentrate) Difficulty concentrating was demonstrated in8 of 12 experimental studies (67%). One experimentalstudy reported incidence data of 79% and one surveystudy found that 11% of respondents reported difficultyconcentrating (Table 4). Difficulty concentrating has beendemonstrated in studies comparing acute caffeine absti-nence with a preceding baseline condition, a caffeineadministration condition, and a chronic caffeine abstinencecondition (Table 4). Studies have also shown that absti-nence-induced difficulty concentrating is time limited(Table 4), and the severity is positively correlated withdaily caffeine dose before abstinence (Lane 1997).
In summary, difficulty concentrating has been moder-ately frequently studied, may have a high incidence, andhas been demonstrated under a wide range of methodo-logical conditions. It is concluded that difficulty concen-trating is a valid withdrawal symptom.
Irritability (descriptors: irritability, irritable/cross/grum-py, and irritable/frustrated/angry/cross) Irritability wasdemonstrated in 8 of 23 experimental studies (35%). Twoexperimental studies reported incidence data of 29% and9% (Table 4). In 2 survey studies, the percentage ofsubjects reporting irritability during caffeine abstinencewas 21% and 20%. Irritability has been demonstrated instudies comparing acute caffeine abstinence with apreceding baseline condition, a caffeine administrationcondition, and a chronic caffeine abstinence condition(Table 4), and by comparing acute caffeine abstinence incaffeine consumers with that in non-consumers (Table 4).Studies have also shown that abstinence-induced irritabil-ity is time limited (Table 4) and is rapidly (i.e., within60 min) and completely reversed after re-administration ofcaffeine (Goldstein et al. 1969), with the magnitude ofreversal being an increasing function of the re-adminis-tered caffeine dose (Goldstein et al. 1969).
In summary, irritability has been very frequentlystudied, has a low to moderate incidence, and has beendemonstrated under a wide range of methodological
conditions. It is concluded that irritability is a validwithdrawal symptom.
Unmotivated for work (descriptors: decreased motivationfor work, urge to do tasks/work-related activities, andincreased unmotivated) Being unmotivated for work wasdemonstrated in 8 of 16 experimental studies (50%). Oneexperimental study reported incidence data of 57% fordecreased motivation for work and 64% for decreased urgeto do work (Table 4). In 2 survey studies, the percentage ofsubjects reporting being unmotivated for work was 16%and 18%. Unmotivated for work has been demonstrated instudies comparing acute caffeine abstinence with apreceding baseline condition and with a caffeine admin-istration condition (Table 4). Studies have also shown thatabstinence-induced “unmotivated for work” is time limited(Table 4), and the severity is positively correlated withdaily caffeine dose before abstinence (Lane 1997).
In summary, unmotivated for work has been frequentlystudied, has an intermediate incidence, and has beendemonstrated under several methodological conditions. Ithas also been described anecdotally (Driesbach andPfeiffer 1943). Although the data are suggestive, furtherresearch is needed to determine the validity of beingunmotivated for work as a withdrawal symptom.
Muzzy/foggy/not clearheaded (descriptors: muzzy/foggy/not clearheaded, muzziness, muddled, and decreasedclearheaded) Muzzy/foggy/not clearheaded was demon-strated in 7 of 18 experimental studies (39%). Oneexperimental study reported incidence data of 71%(Table 4). Muzzy/foggy/not clearheaded has been demon-strated in studies comparing acute caffeine abstinence witha preceding baseline condition, a caffeine administrationcondition, and a chronic caffeine abstinence condition(Table 4), and by comparing acute caffeine abstinence incaffeine consumers with that in non-consumers (Table 4).Studies have also shown that abstinence-induced muzzy/foggy/not clearheaded is time limited (Table 4), and theseverity is positively correlated with daily caffeine dosebefore abstinence (Lane 1997).
In summary, muzzy/foggy/not clearheaded has beenfrequently studied, may have a high incidence, and hasbeen demonstrated under a wide range of methodologicalconditions. It is concluded that muzzy/foggy/not clear-headed is a valid withdrawal symptom.
Yawning (no other descriptors) Self-reported yawning wasdemonstrated in 7 of 12 experimental studies (58%). Oneexperimental study reported incidence data of 43% andone survey study found that 21% of respondents reportedyawning (Table 4). Yawning has been demonstrated instudies comparing acute caffeine abstinence with apreceding baseline condition, a caffeine administrationcondition, and a chronic caffeine abstinence condition(Table 4). Studies have also shown that abstinence-induced yawning is time limited (Table 4), and theseverity is positively correlated with daily caffeine dosebefore abstinence (Silverman et al. 1992).
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In summary, yawning has been moderately frequentlystudied, may have an intermediate incidence, and has beendemonstrated under several methodological conditions.Although the data are suggestive, further research isneeded to determine the validity of yawning as awithdrawal symptom.
Decreased self-confidence (descriptors: decreased self-confidence and confident) Decreased self-confidence wasfound in 7 of 17 experimental studies (41%). Oneexperimental study reported incidence data of 64%(Table 4). Decreased self-confidence has been demonstra-ted in studies comparing acute caffeine abstinence with apreceding baseline condition, a caffeine administrationcondition, and a chronic caffeine abstinence condition(Table 4). Studies have also shown that abstinence-induced decreased self-confidence is time limited(Table 4).
In summary, decreased self-confidence has beenfrequently studied and may have an intermediate inci-dence. Although it has been demonstrated under a severaldifferent methodological conditions, it does not presentlyfulfill criteria for validity.
Confusion–bewilderment [POMS] (no other descriptors)Confusion/bewilderment was found in 6 of 21 experi-mental studies (29%). Confusion–bewilderment has beendemonstrated in studies comparing acute caffeine absti-nence with a preceding baseline condition, a caffeineadministration condition, and a chronic caffeine abstinencecondition (Table 4). Studies have also shown that absti-nence-induced confusion–bewilderment is time limited(Table 4).
In summary, confusion–bewilderment has been veryfrequently studied and has been demonstrated underseveral methodological conditions. Although the data aresuggestive, it does not presently fulfill criteria for validity.
Total mood disturbance [POMS] (no other descriptors)Total mood disturbance has been shown in 6 of 12experimental studies (50%). Total mood disturbance hasbeen demonstrated in studies comparing acute caffeineabstinence with a preceding baseline condition, a caffeineadministration condition, and a chronic caffeine abstinencecondition (Table 4). Studies have also shown that theseverity of total mood disturbance is an increasingfunction of caffeine maintenance dose before abstinence(Evans and Griffiths 1999).
In summary, total mood disturbance has been moder-ately frequently studied and has been demonstrated underseveral methodological conditions. Although the data aresuggestive, further research is needed to determinevalidity.
Nausea/vomiting (descriptors: nausea/vomiting, nauseaand sickness, sick/nauseated/vomiting, vomiting, queasy,and upset stomach) Nausea/vomiting has been demon-strated in 6 of 24 experimental studies (25%). In 4experimental studies providing incidence data (Table 4),
the median percentage of individuals reporting nausea/vomiting was 21% (range 10–33%). In 2 survey studies,the percentage of subjects reporting nausea/vomitingduring caffeine abstinence was 3% and 21%. Nausea/vomiting has been demonstrated in studies comparingacute caffeine abstinence with a caffeine administrationcondition (Table 4).
In summary, nausea/vomiting has been very frequentlystudied and has a low to moderate incidence. Although inexperimental studies nausea/vomiting has only beendemonstrated statistically by comparing caffeine absti-nence with a caffeine administration condition, it appearsto be a genuine withdrawal symptom because it isimplausible that such placebo versus caffeine differencesrepresent a direct effect of caffeine in suppressingnaturally occurring nausea/vomiting. Instances of with-drawal-induced nausea/vomiting have been reported incase reports (Rainey 1985; Cacciatore et al. 1996),experimental studies (Griffiths et al. 1990; Silverman etal. 1992; Strain et al. 1994), and survey studies (Hughes etal. 1998; Oberstar et al. 2002). Thus, even though nausea/vomiting fails to meet our a priori criterion for validitybased on experimental studies alone, nausea/vomitingappears to be a valid caffeine-withdrawal symptom.Furthermore, it may be a clinically important symptombecause it is likely to reflect significant distress. It seemsplausible that this symptom is related to a constellation ofsymptoms that include other somatic complaints andendorsement of flu-like symptoms.
Muscle pain/stiffness (descriptors: muscle pain/stiffness,muscle joint ache, general muscle pains, and leg musclepains) Muscle pain/stiffness has been demonstrated in 4 of15 experimental studies (27%). The incidence of musclepain/stiffness was 43% in one study (Table 4). Musclepain/stiffness has been demonstrated in studies comparingacute caffeine abstinence with a preceding baselinecondition, a caffeine administration condition, and achronic caffeine abstinence condition (Table 4). Onestudy also showed that abstinence-induced muscle pain/stiffness is time limited (Table 4).
In summary, muscle pain/stiffness has been studiedfrequently, may have an intermediate incidence, and hasbeen demonstrated under a range of methodologicalconditions. The symptom of muscle pain/stiffness hasbeen described in case reports (Cobbs 1982; Stringer andWatson 1987) and is consistent with one report, whichinvolved a musculoskeletal examination during caffeineabstinence (Reeves et al. 1997). Although additionalstudies are needed to fulfill our a priori validity criteria, theconclusion that muscle pain/stiffness represents a truewithdrawal symptom unconfounded by the direct effectsof caffeine seems reasonable because it is improbable thatcaffeine suppresses naturally occurring muscle pain/stiffness.
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Anxiety/nervousness (descriptors: anxiety, anxious, ner-vous, tense, and elevated scores on the State-Trait AnxietyInventory) Increased anxiety/nervousness has been dem-onstrated in 4 of 34 experimental studies (12%; Table 4)].However, decreased anxiety/nervousness has been dem-onstrated in 2 of the 36 studies (Griffiths et al. 1990;Comer et al. 1997). One experimental study reportedincidence data of 8% for increased anxiety (Table 4). In 3survey studies, the percentage of subjects reportingincreased anxiety during abstinence ranged between 10%and 29%. Anxiety/nervousness has been demonstrated instudies comparing acute caffeine abstinence with apreceding baseline condition and a caffeine administrationcondition (Table 4), and by comparing acute caffeineabstinence in caffeine consumers with that in non-consumers (Table 4).
Despite the fact that marked anxiety is proposed as acaffeine-withdrawal symptom in DSM-IV-TR (AmericanPsychiatric Association 2000), anxiety/nervousness doesnot fulfill the validity criteria. It is of note that 32experimental studies using a variety of methodologiesfailed to show increased anxiety/nervousness, none of thepositive studies used the most rigorous experimentaldesign involving a chronic abstinence condition, and 2experimental studies demonstrated significant decreases(Griffiths et al. 1990; Comer et al. 1997). However, it isalso noteworthy that anxiety/nervousness has beendescribed as a withdrawal symptom in case reports(Gibson 1981; Cobbs 1982; Rainey 1985; Adams et al.1993) and that anxiety/nervousness is also endorsed as awithdrawal symptom at low to moderate rates in threesurvey studies (Table 4). Although further research isneeded, it may be that the increased anxiety/nervousnessassociated with caffeine withdrawal in non-blind casereports and survey studies reflects increased anxiety inanticipation of experiencing unpleasant effects of caffeineabstinence.
Heavy feelings in arms and legs (no other descriptors)Heavy feelings in arms and legs were demonstrated in 4 of9 experimental studies (44%). Heavy feelings in arms andlegs have been demonstrated in studies comparing acutecaffeine abstinence with a preceding baseline condition, acaffeine administration condition, and a chronic caffeineabstinence condition (Table 4). Although the data aresuggestive, further research is needed to determine thevalidity of heavy feelings in arms and legs as a withdrawalsymptom.
Increased nighttime sleep duration/quality (descriptors:self-report ratings of sleep quality, duration, and onset tosleep) Self-reported increased nighttime sleep duration/quality was demonstrated in 4 of 4 experimental studies. Inthe two studies that assessed sleep duration, the increasewas about 30 min (Höfer and Bättig 1994b; James 1998).Increased nighttime sleep duration/quality has been dem-onstrated in studies comparing acute caffeine abstinencewith a preceding baseline condition and a caffeineadministration condition (Table 4).
Although increased nighttime sleep has been rarelystudied during caffeine abstinence, the magnitude ofincreased sleep duration is notable. The limited methodol-ogies in which it has been assessed do not permitdifferentiation between an effect of caffeine in decreasingsleep and a time limited caffeine-withdrawal effect.Further research is needed to determine whether this is avalid withdrawal symptom.
Analgesic use (no other descriptors) Self-reported anal-gesic use was demonstrated in 3 of 3 experimental studies.Two of these studies explicitly discouraged analgesic use(Silverman et al. 1992; Strain et al. 1994). Twoexperimental studies reported incidence data of 13% and45% (Table 4). Analgesic use has been demonstrated instudies comparing acute caffeine abstinence with apreceding baseline condition and a caffeine administrationcondition (Table 4). Studies also showed that abstinence-induced analgesic use was time limited (Table 4).
Although analgesic use during caffeine abstinence hasbeen rarely assessed, it is a potential indicator of theclinical significance of caffeine-withdrawal distress and isworthy of future study. Whether avoidance of caffeinewithdrawal contributes to chronic use of caffeine-contain-ing analgesics as suggested by some reports (Strain andGriffiths 1998; Bigal et al. 2002; but cf. Feinstein et al.2000) also merits further study.
Craving/strong desire to use (no other descriptors)Craving/strong desire to use was demonstrated in 2 of 2experimental studies. One experimental study reportedincidence data of 43% and one survey study reported that28% of respondents reported a strong desire to use(Table 4). Craving/strong desire to use has been demon-strated in studies comparing acute caffeine abstinence witha caffeine administration condition and has been shown tobe time limited (Table 4).
Although craving is often reported anecdotally duringcaffeine abstinence in the natural environment (Rippere1984; Gilbert 1986), it has been rarely assessed as acaffeine-withdrawal symptom. Further research is neededto determine its validity. Given its potential importance forunderstanding habitual caffeine consumption, a priorityshould be given to including measures of craving in futurecaffeine-withdrawal research.
Blurred vision (no other descriptors) Blurred vision wasdemonstrated in 2 of 11 experimental studies (18%). Theincidence of blurred vision was 14% in one experimentalstudy (Table 4). It has been demonstrated in studiescomparing acute caffeine abstinence with a precedingbaseline condition, a caffeine administration condition,and a chronic caffeine abstinence condition (Table 4). Onestudy also showed that abstinence-induced blurred visionwas time limited (Table 4).
In summary, blurred vision has been studied moderatelyfrequently, may have a low incidence, and has beendemonstrated under several methodological conditions.The symptom of blurred vision is also consistent with a
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case report (Cobbs 1982). Further research is needed todetermine its validity.
Lightheaded/dizzy (no other descriptors) Lightheaded/dizzy was demonstrated in 3 of 18 experimental studies(17%). Lightheaded/dizzy has been demonstrated only instudies comparing acute caffeine abstinence with acaffeine administration condition.
Although lightheaded/dizzy has been frequently stu-died, it has only been demonstrated in three studies, one ofwhich was not blind. It is concluded that there is littleevidence supporting lightheaded/dizzy as a caffeine-with-drawal symptom.
Anger/hostility (descriptors: anger–hostility and angry)Anger/hostility was demonstrated in 2 of 20 experimentalstudies (10%). It has been demonstrated in studiescomparing acute caffeine abstinence with a caffeineadministration condition and a chronic caffeine abstinencecondition (Table 4), and by comparing acute caffeineabstinence in caffeine consumers with that in non-consumers (Table 4). Studies have also shown thatabstinence-induced anger/hostility is time limited(Table 4).
Although anger/hostility has been very frequentlystudied using various methodologies, it has only beendemonstrated in two studies, one of which was not blind.It is concluded that there is little evidence to suggest thatanger/hostility is a caffeine-withdrawal symptom.
Hot and cold spells (no other descriptors) This symptomwas demonstrated in 2 of 8 experimental studies (25%).Hot and cold spells have been demonstrated only instudies comparing acute caffeine abstinence with abaseline or a caffeine administration condition. Furtherresearch is needed to determine the validity.
Rhinorrhea (runny nose) [(descriptors: rhinorrhea andrunny nose)] Not shown in Table 4, rhinorrhea wasdemonstrated in one non-blind study (Roller 1981) of 12experimental studies that used a variety of methodologies.Caffeine-withdrawal-induced rhinorrhea was also de-scribed anecdotally in two reports (Driesbach and Pfeiffer1943; Greden et al. 1980). It is concluded that there is littleevidence to suggest that rhinorrhea is a caffeine-with-drawal symptom.
Diaphoresis (perspiration) [(descriptors: diaphoresis,perspiring, and sweating)] Not shown in Table 4, thissymptom was demonstrated in 2 of 19 experimentalstudies (11%). It is concluded that there is little evidence tosuggest that diaphoresis is a caffeine-withdrawal symp-tom.
Limb tremor (no other descriptors) Not shown in Table 4,this symptom was demonstrated in none of 10 experi-mental studies using a variety of methodologies. Theseobservations are consistent with seven studies that failed todocument objective measures of hand tremor during
caffeine abstinence (discussed below). It is concludedthat there is little evidence to suggest that self-reportedlimb tremor is a caffeine-withdrawal symptom.
Miscellaneous symptom categories for which there is noempirical support Several additional symptoms of poten-tial interest were evaluated in the studies described inTables 1 and 2 and were not significantly affected bycaffeine abstinence in any study. The symptoms, with thenumber of studies in which they were evaluated indicatedin parentheses, are heart pounding/palpitations (15),frequent urination (13), jittery/shaky (11), difficultysleeping (10), increased hunger/appetite (10), musclecramps (8), loss of sex drive (8), diarrhea (7), calm/relaxed (7), muscle twitches (5), irregular heartbeat (5),ringing in ears (5), thirsty (5), restless (4), shaky/weakness(3), constipation (2), chills (1), and numbing or tingling ofextremities (1).
Signs of caffeine withdrawal
In this section, withdrawal signs (i.e., objectively mea-sured behavioral or physiological effects) that wereassessed in the studies listed in Tables 1 and 2 areindividually discussed and evaluated.
Impaired behavioral and cognitive performance Thiscategory is comprised of tasks designed to assess variousaspects of performance impairment. Of 23 experimentalstudies that assessed performance during caffeine absti-nence, 11 (48%) reported significant impairment on one ormore measures. More specifically, impairment of tappingspeed occurred in 3 of 8 studies (Bruce et al. 1991;Silverman et al. 1992; Strain et al. 1994), impairment ofvisual vigilance occurred in 2 of 4 studies (Lane andPhillips-Bute 1998; Yeomans et al. 2002b), decreasedreaction time occurred in 2 of 7 studies (Rizzo et al. 1988;Robelin and Rogers 1998), impaired performance on adigit symbol substitution task occurred in 2 of 11 studies(Liguori and Hughes 1997; Liguori et al. 1997b), impairedperformance on a character recognition task occurred in 1study (James 1998), and impairment in 5 of 7 measures ina complex cognitive problem-solving task occurred in 1study (Streufert et al. 1995). Four studies assessingmemory found no evidence for impairment during caffeineabstinence. With regard to incidence, one experimentalstudy reported incidence data of 55% for decreasedtapping speed (Strain et al. 1994). Methodologically,impaired performance has been demonstrated in studiescomparing acute caffeine abstinence with a precedingbaseline condition (Silverman et al. 1992), a caffeineadministration condition (Silverman et al. 1992; Strain etal. 1994; Streufert et al. 1995; Liguori and Hughes 1997;Liguori et al. 1997b; James 1998; Lane and Phillips-Bute1998; Robelin and Rogers 1998; Yeomans et al. 2002b),and a chronic caffeine abstinence condition (Bruce et al.1991), and by comparing acute caffeine abstinence incaffeine consumers with that in non-consumers (Rizzo et
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al. 1988). Studies have also shown that abstinence-inducedimpaired behavioral performance is time limited (Bruce etal. 1991).
In summary, impaired behavioral or cognitive perfor-mance has been very frequently studied, may have anintermediate incidence, and has been demonstrated under arange of methodological conditions. Furthermore, thetypes of impairments observed (i.e., psychomotor speed,vigilance, and cognitive performance) appear consistentwith the profile of validated withdrawal symptoms such astiredness/fatigue, decreased alertness, and difficulty con-centrating. It should be noted, however, that this categoryis comprised of heterogeneous measures of performanceimpairment and, at present, there is not enough informa-tion to reach a conclusion about the validity of any specificperformance measure. Future research should focus onmeasures that appear to be most sensitive to caffeineabstinence, including tapping, vigilance, reaction time, andcomplex cognitive problem solving.
Increased cerebral blood flow Increased cerebral bloodflow velocity has been demonstrated in 4 of 4 experi-mental studies (Mathew and Wilson 1985; Couturier et al.1997; Jones et al. 2000; Field et al. 2003; cf. Tables 1, 2).Increased cerebral blood flow has been demonstrated instudies comparing acute caffeine abstinence with apreceding baseline condition (Mathew and Wilson 1985;Couturier et al. 1997) and a caffeine administrationcondition (Jones et al. 2000; Field et al. 2003). Themagnitude of this effect is positively correlated with dailycaffeine dose before abstinence (Mathew and Wilson1985; Field et al. 2003).
The several studies indicating that caffeine abstinence isassociated with increases in cerebral blood flow are ofparticular interest because the effect may be related to avascular mechanism underlying the common withdrawalsymptom of headache (cf. Jones et al. 2000). However, themethodologies of the studies conducted to date do notpermit differentiation of the effects of caffeine per se oncerebral blood flow from the effects of caffeine withdraw-al. Further research is needed to determine the validity ofincreased cerebral blood flow as a withdrawal sign.
Changes in EEG Changes in quantitative electroenceph-alography (EEG) during caffeine abstinence was demon-strated in 3 of 3 experimental studies (Lader et al. 1996;Jones et al. 2000; Reeves et al. 2002; cf. Tables 1, 2).Effects included increases in EEG theta power (Jones et al.2000; Reeves et al. 2002), which have been associatedwith drowsiness. However, across studies, findings havebeen inconsistent across different EEG measures. Changesin EEG have been demonstrated in studies comparingacute caffeine abstinence with a preceding baselinecondition (Lader et al. 1996; Reeves et al. 2002) and acaffeine administration condition (Jones et al. 2000).
Although a few studies suggest that quantitative EEGmeasures might provide a physiological measure orcorrelate of caffeine withdrawal, the methodologies donot permit differentiation of the effects of caffeine per se
on EEG from the effects of caffeine withdrawal. Furtherresearch is needed to validate changes in EEG as awithdrawal sign.
Decreased blood pressure Of 11 experimental studies thatassessed blood pressure, three demonstrated decreases insystolic blood pressure (Streufert et al. 1995; Lader et al.1996; Phillips-Bute and Lane 1998) and one each showeddecreases in diastolic (Phillips-Bute and Lane 1998) andarterial (Lane 1997) blood pressure. The small magnitudeof this effect (about 6 mmHg for systolic blood pressure)suggests that, if this effect is time limited, it is notclinically important. Decreased blood pressure has beendemonstrated in studies comparing acute caffeine absti-nence with a preceding baseline condition (Lader et al.1996) and a caffeine administration condition (Streufert etal. 1995; Lane 1997; Phillips-Bute and Lane 1998). Onestudy showed the effect to be time limited (Lader et al.1996).
The studies cited above, as well as several studies thatexplicitly focused on cardiovascular outcome measures(Robertson et al. 1981; Ammon et al. 1983), do notprovide convincing evidence that caffeine abstinenceacutely decreases blood pressure.
Decreased motor activity Decreased motor activityassessed using electronic activity monitors was demon-strated in 2 of 2 experimental studies (Höfer and Bättig1994a,b; cf. Table 2). Decreased motor activity has beendemonstrated in studies comparing acute caffeine absti-nence with a preceding baseline condition (Höfer andBättig 1994a,b), and the effect was time limited (Höfer andBättig 1994a).
Although decreased motor activity has been only rarelystudied, it has face validity as a caffeine-withdrawal signbecause it plausibly could co-vary with the well-validatedsymptoms of increased tiredness/fatigue and decreasedenergy/activeness. Further research is needed to establishthe validity.
Skin conductance One experimental study assessed andfound a significant effect (decrease) in skin conductanceduring caffeine abstinence relative to a preceding baselinecondition (Lader et al. 1996; cf. Table 1). Further researchis needed to establish its validity.
Urinary epinephrine and norepinephrine Of two studiesthat assessed urinary epinephrine and norepinephrine(Robertson et al. 1981; Lane 1994; cf. Tables 1, 2), oneshowed decreased levels of epinephrine during caffeineabstinence relative to a caffeine condition (Lane 1994).The author interpreted this as an effect of caffeine ratherthan caffeine withdrawal. Further research is needed.
Heart rate Of 9 experimental studies that assessed heartrate, only one reported a significant effect (increase)during caffeine abstinence (Höfer and Bättig 1994a). Theeffect was neither time limited nor reversed by re-administration of caffeine (Höfer and Bättig 1994a). It is
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concluded that there is no meaningful evidence thatcaffeine abstinence affects heart rate.
Hand tremor Of 7 experimental studies that assessedobjective measures of hand tremor, none showed asignificant effect of caffeine abstinence. These observa-tions are consistent with 10 studies that showed thatcaffeine abstinence did not affect subjective measures oflimb tremor (reviewed in Tables 1, 2, and discussedabove). It is concluded that there is little to suggest thatcaffeine abstinence affects hand tremor.
Incidence of clinically significant distress or impairmentin daily functioning
In individuals reporting caffeine-withdrawal symptoms,the severity can vary from mild to extreme. Clinicallysignificant distress and/or impairment of normal dailyactivities (e.g., work absence or going to bed because ofsymptoms) upon caffeine abstinence have been reported inclinical evaluations and experimental studies dating backover 170 years (Kingdon 1883; Bridge 1893; Driesbachand Pfeiffer 1943; Goldstein and Kaizer 1969; Greden etal. 1980; Rainey 1985; Smith 1987; Griffiths et al. 1990;Silverman et al. 1992; Adams et al. 1993; Weil and Rosen1993, p 187; Hampl et al. 1994; Strain et al. 1994;Cacciatore et al. 1996; Lader et al. 1996). Informationabout the proportion of regular caffeine consumers whoare at risk for experiencing clinically significant distressand/or functional impairment during abrupt caffeineabstinence is available from both prospective experimentalstudies and retrospective survey studies.
Prospective experimental studies showing clinicallysignificant distress or impairment
Six prospective experimental studies provide informationon the incidence of clinically significant distress orfunctional impairment during caffeine abstinence. Withregard to the experimental studies, in one double-blindstudy of 11 people who fulfilled criteria for DSM-IVsubstance dependence applied to caffeine use (medianintake 357 mg/day), 73% experienced significant disrup-tions in normal daily activities during a period ofexperimentally induced caffeine abstinence, includingleaving or missing work, making errors or costly mistakesat work, inability to care for children, and inability tocomplete school work (Strain et al. 1994). Five experi-mental studies have been conducted in normal subjectpopulations. One study, conducted in 22 medical andgraduate students who consumed 650–780 mg/dayexperimentally administered caffeine before abstinence,reported that headache “as extreme in severity as thesubjects had ever experienced” occurred in 55% of 38trials (Driesbach and Pfeiffer 1943). A double-blind studyof 62 caffeine consumers (mean intake 235 mg/day), whohad no knowledge that the study was about caffeine, found
that during caffeine abstinence 52% of subjects reportedmoderate to severe headache, and 8–11% showedabnormally high scores on standardized depression andfatigue scales (Silverman et al. 1992). In an open-endedinterview, several of these subjects also reported severefunctional impairment. In another double-blind study, 45%of 40 caffeine consumers (mean intake 360 mg/day)reported a “diffuse, throbbing headache,” with 28% ofthose also reporting “nausea and sickness” (Lader et al.1996). A third double-blind study evaluated the incidenceof functional impairment during abrupt caffeine abstinencein a group of 18 subjects (mean intake 231 mg/day) whoreported having had problems or symptoms whenpreviously stopping caffeine (Dews et al. 1999). Thestudy found that 39% of subjects spontaneously reportedcaffeine-withdrawal symptoms and 22% showed substan-tial decreases (≥1.5 points on a 4 point scale) in theirratings of daily functioning (e.g., at work and leisureactivities), although none of the subjects reported symp-toms judged to be “incapacitating” by the authors.Limitations of this study, which have been discussedelsewhere (Griffiths et al. 2003), include the relativelyunstructured and unmonitored conditions under whichdata were obtained and the relatively low caffeinemaintenance dose. Finally, one non-blind trial of caffeineabstinence reported 10% of 20 caffeine consumersreported nausea and vomiting (Couturier et al. 1997).
Overall, the incidence of clinically significant distress orfunctional impairment in prospective experimental studieswith normal subjects has varied from about 10% to as highas 55% (median 13%). The estimate of 13% is lower thanthe 73% rate of functional impairment shown in subjectswho met DSM-IV criteria for substance dependenceapplied to caffeine (Strain et al. 1994). The difference isnot due to differences in caffeine intake (the usualmaintenance dose in the dependent subjects was in therange of that of the studies in the normal subjects),suggesting that the caffeine-dependent subjects mayrepresent a subpopulation vulnerable to severe withdrawaleffects. It should be recognized that the 13% incidence ratefor normal subjects could underestimate the rate ofoccurrence in the general population. Although unstudied,it seems reasonable to suppose that there may be asubstantial subject selection bias in caffeine research in thegeneral population, with individuals who experienceclinically significant withdrawal being less likely tovolunteer for a study in which caffeine abstinence mightbe a possibility.
Retrospective survey studies showing clinicallysignificant distress or impairment
Four retrospective survey studies provide information onthe percentage of respondents reporting clinically signif-icant distress or functional impairment during caffeineabstinence. A survey study of 183 women showed that thepercentage endorsing that they would experience classiccaffeine-withdrawal symptoms (headache, lethargy, and
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sleepiness) without their morning coffee increased as afunction of the number of cups of coffee consumed(Goldstein and Kaizer 1969). Consistent with functionalimpairment, endorsement of being “unable to workeffectively” also increased with cups consumed, with theeffect reported by 9% of all coffee consumers and 16% ofheavy consumers (>5 cups/day). In a population-basedrandom digit dial telephone survey study, caffeineconsumers were questioned about their experience withcaffeine withdrawal (Hughes et al. 1998). Of 71 whoreported having stopped or reduced caffeine for at least24 h during the past year, 11% reported experiencingheadache and other withdrawal symptoms that interferedwith their performance. This figure was 24% among thesubgroup who reported stopping caffeine in an attempt atpermanent abstinence. A third study asked a wide varietyof questions of people who telephoned to volunteer for apaid clinical research trial (Dews et al. 1999). Of 6,815daily caffeine consumers, 2.6% reported that problems orsymptoms during caffeine abstinence were severe enoughto interfere with normal activity (e.g., inability to concen-trate at work; lost time at work). The low rate ofendorsement of functional impairment in this study mayhave been due to a failure to exclude individuals who hadnot actually abstained from caffeine, as well as possibleunder reporting of symptoms because of a desire toparticipate in a paid research trial. A final retrospectivesurvey was conducted in 36 adolescent caffeine consumerswho endorsed two or more DSM-IV substance depen-dence criteria applied to caffeine use (Oberstar et al.2002). Twenty-one percent reported the caffeine-with-drawal symptom of “sick/nauseated/vomiting.”
Overall, the percentage of respondents reportingclinically significant distress or functional impairment inretrospective survey studies varied between 2.6% and 11%(median 9%) in general survey studies, and was 21% incaffeine-dependent adolescent subjects. The median esti-mate from the general survey studies is quite similar to theestimate from prospective experimental studies (9% and13%, respectively). As with the experimental studies, thereare several limitations inherent to survey studies that mayresult in underestimates. First, a portion of habitualcaffeine consumers may be unaware of caffeine-with-drawal symptoms because they never have had a period ofsustained abstinence. Furthermore, it has been demonstra-ted that as little as 25 mg/day of caffeine can prevent somewithdrawal symptoms (Evans and Griffiths 1999). Thus,small amounts of caffeine that are unknowingly consumedon days believed to be “caffeine-free” days may lead to anunderestimation of the incidence of clinically significantdistress during complete abstinence. Finally, it is possiblethat caffeine-withdrawal symptoms such as headache,fatigue, nausea, and muscle aches could be misattributedto other causes or ailments (e.g., common cold).
Expectancies and caffeine withdrawal
It has been speculated that knowledge and expectation arethe prime determinants of caffeine-withdrawal symptoms(Rubin and Smith 1999; Dews et al. 2002), leading to theconclusion that caffeine withdrawal is “controversial”(Dews et al. 1999; Rubin and Smith 1999). In drugresearch, the importance of expectancies has long beenacknowledged (Marlatt and Rohsenow 1980; Fillmore1994), and double-blind experimental methodologies wereexplicitly developed to help control for expectancy effects.However, what is known about withdrawal symptomsfrom abused drugs, including alcohol, opioids, sedatives,and cocaine, has been inferred from clinical observationsrather than documented in experimental studies in whichplacebo was substituted for active drug under blindconditions (Martin 1977; Weddington et al. 1990). Incontrast, the great majority (74%) of the 57 experimentalstudies of caffeine withdrawal outlined in Tables 1 and 2were conducted under double-blind conditions, with anadditional 11% conducted under single-blind conditions.Thus, caffeine-withdrawal research, in particular, seems todistinguish itself as having controlled for expectancyeffects better than most other research on drug withdrawal.
One approach to assessing the impact of expectancieson caffeine withdrawal is to compare the incidence ofcaffeine-withdrawal headache that has been reported indouble-blind and single-blind studies (studies 1–48 inTables 1 and 2) to that reported in non-blind studies(studies 49–55 in Table 2). The median incidence ofheadache (derived from column 7 of Table 4) for the blindand non-blind studies that reported such data is 45% and57%, respectively, suggesting a modest effect of expect-ancy.
However, it is important to recognize that the impact ofexpectancies is not entirely eliminated using double-blindmethods. Even in double-blind studies, expectancies canplay a role if subjects have knowledge of the purpose andconditions of the study. For instance, in extreme cases,subjects could be told that the purpose of a study is toinvestigate caffeine withdrawal and that they will bereceiving either caffeine or placebo. This informationcould functionally unblind subjects if they could dis-criminate between conditions based on immediate phar-macological effects or on early symptoms of withdrawal(Dews et al. 1999; Rubin and Smith 1999).
To address this issue, the blind studies in Tables 1 and 2were re-reviewed for information relevant to possibleexpectancy effects. This analysis revealed that many of theblind studies provided or probably provided sufficientinformation such that subjects could have been aware thatthe study involved caffeine or caffeine withdrawal.However, a substantial number of blind studies went tosome lengths to keep subjects uninformed about purposeor experimental conditions. For example, several studiesconducted at Johns Hopkins (Silverman et al. 1992; Schuhand Griffiths 1997; Garrett and Griffiths 1998; Jones et al.2000) instructed subjects that they could receive a varietyof compounds found in foods and beverages (e.g.,
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chlorogenic acids, determines, caffeine, tannin, sugar,theophylline, or inactive placebo). To further divertattention away from caffeine, the dietary restrictionswere written without reference to caffeine and includedvarious foods and substances that do not contain caffeine(i.e., saccharin, aspartame [Nutrasweet], oysters, mussels,almonds, coconuts, poppy seeds, and all beverages exceptmilk, fruit juice, and water). Furthermore, as the researchunit at Johns Hopkins conducts a large number of studieswith a wide range of drugs other than caffeine, it isunlikely that conduct of these studies at that site wouldhave created subject expectations that the study involvedcaffeine. Two studies from other laboratories also usedinstructions and methods that reduced the likelihood ofexpectancy effects (Comer et al. 1997; Dews et al. 1999).Finally, several studies ruled out expectancy effects byusing debriefing procedures to explicitly determine whatsubjects understood or inferred about the experimentalconditions (van Dusseldorp and Katan 1990; Rogers et al.1995; James 1998; Robelin and Rogers 1998; Yeomans etal. 1998, 2002b; Tinley et al. 2003). From these studies inwhich expectancy effects are judged to be unlikely, themedian incidence of headache (derived from column 7 ofTable 4) for the studies that reported such data is 42%,which is similar to the incidence of headache for all blindstudies (45%). Furthermore, the profile of other symptomsdemonstrated in these studies in which expectancy effectswere unlikely is similar to those demonstrated in the largerset of studies.
In conclusion, while it is undoubtedly true that, as withthe assessment of other clinical phenomena, expectanciescould play some role in caffeine withdrawal, the evidencethat caffeine withdrawal is pharmacologically based isoverwhelming, and analysis of the published data does notsupport the hypothesis that expectancies are a primarydeterminant of caffeine-withdrawal symptoms. It shouldalso be recognized that, to the extent that expectanciesmay modestly enhance caffeine-withdrawal symptoms (assuggested from the comparison of blind and non-blindstudies described above), blind research studies mayactually underestimate the incidence and severity ofwithdrawal that occurs under more naturalistic clinicallyrelevant conditions. Future research should evaluate thispossibility using a methodology such as the balancedplacebo design, which experimentally manipulates bothcaffeine abstinence and expectancy of abstinence (Marlattand Rohsenow 1980; Juliano and Brandon 2002).
Time course of caffeine withdrawal
Numerous studies have shown that caffeine-withdrawalsymptoms typically emerge 12–24 h after abrupt caffeineabstinence (Driesbach and Pfeiffer 1943; Goldstein 1964;Goldstein et al. 1969; Griffiths et al. 1986, 1990;Richardson et al. 1995; Schuh and Griffiths 1997;Swerdlow et al. 2000; Tinley et al. 2003), which isconsistent with the short half-life of caffeine (4–6 h). Someevidence suggests that symptoms may emerge later
(>24 h) after abstinence from higher doses (e.g.,900 mg/day) of caffeine (Bruce et al. 1991; Evans andGriffiths 1992). In the few studies that provided detailedtime-course information for individual subjects, onset ofwithdrawal symptoms have been reported as early as 6 h(Roller 1981) and as late as 43 h (Griffiths et al. 1990)after abstinence. Caffeine-withdrawal symptoms havebeen shown to reach peak intensity between 20 h and51 h after abstinence (Griffiths et al. 1986, 1990; Evansand Griffiths 1992; Brauer et al. 1994; Höfer and Bättig1994a,b; Lader et al. 1996). The duration of caffeinewithdrawal has been shown to be 2–9 days (Griffiths et al.1986, 1990; van Dusseldorp and Katan 1990; Höfer andBättig 1994a), and the possibility of withdrawal headachesoccurring up to 21 days has been suggested (Richardson etal. 1995).
Parametric determinants of caffeine withdrawal
Chronic caffeine maintenance dose
There is good evidence that the incidence or severity ofcaffeine withdrawal increases with increases in the chronicdaily caffeine maintenance dose. The best evidence for thisrelationship comes from a prospective study that experi-mentally manipulated caffeine maintenance dose (100,300, and 600 mg/day) and showed monotonic increases inseveral withdrawal measures, with significantly greaterheadache and headache/poor mood demonstrated afterabstinence from 600 mg than 100 mg/day (Evans andGriffiths 1999). This study and a previous study (Griffithset al. 1990) also demonstrated that significant caffeinewithdrawal occurred after abstinence from a dose as low as100 mg/day.
The relationship between withdrawal incidence orseverity and usual caffeine dose has also been demonstra-ted in studies of self-reported caffeine maintenance dose,including retrospective survey studies (Goldstein andKaizer 1969), experimental studies (Goldstein 1964;Silverman et al. 1992; Rogers et al. 1995; Lader et al.1996; Lane 1997; Lane and Phillips-Bute 1998), andstudies of post-operative headache (Galletly et al. 1989;Fennelly et al. 1991). It should be noted, however, that therelationship between withdrawal and self-reported caffeineintake appears relatively weak because it has not beendemonstrated in some studies (Verhoeff and Millar 1990;Hughes et al. 1993; Höfer and Bättig 1994a), andsignificant correlations between withdrawal measuresand caffeine intake are low and inconsistent acrossdifferent withdrawal measures (Silverman et al. 1992;Lane 1997; Lane and Phillips-Bute 1998).
Acute decreases in caffeine maintenance dose
When lower caffeine doses are substituted for the usualmaintenance dose, withdrawal severity increases as thesubstituted dose decreases. One study maintained indivi-
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duals on 300 mg caffeine/day and then substituted a rangeof lower doses (Evans and Griffiths 1999). The studyshowed that a substantial reduction in caffeine dose (to≤100 mg/day) was necessary to produce caffeine with-drawal and that even a dose of 25 mg/day was sufficient toavoid significant caffeine-withdrawal headache. Thisresult suggests that a substantial percentage reduction incaffeine consumption is necessary to manifest the fullcaffeine-withdrawal syndrome.
Duration of caffeine maintenance
Three studies demonstrated that caffeine withdrawal canoccur after a relatively short duration of caffeine mainte-nance (Driesbach and Pfeiffer 1943; Griffiths et al. 1986;Evans and Griffiths 1999). One of these studies (Evansand Griffiths 1999), which was conducted in caffeineconsumers who were caffeine abstinent for 7 days beforethe period of caffeine maintenance, showed no withdrawaleffects after a single day of exposure to caffeine (300 mg/day). However, significant withdrawal symptoms occurredafter 3 consecutive days of caffeine, with somewhatgreater severity demonstrated after 7 and 14 consecutivedays of exposure. Another study (Driesbach and Pfeiffer1943) showed that caffeine-withdrawal headache occurredin three individuals who normally totally abstained fromcaffeinated beverages, but who were given increasingdoses of caffeine over 6 days or 7 days up to 650–780 mg/day.
Within-day frequency of dosing during caffeinemaintenance
Most studies of caffeine withdrawal have involvedcaffeine abstinence after a maintenance period thatinvolved multiple caffeine doses each day. The onlystudy to vary the within-day frequency of caffeine dosingshowed that the range and severity of caffeine-withdrawalsymptoms was similar when caffeine maintenance in-volved 300 mg taken as single dose in the morningcompared with 100 mg taken at three time points acrossthe day (Evans and Griffiths 1999). This indicates thatonce-a-day dosing with caffeine is sufficient for producingwithdrawal symptoms.
Re-administration of caffeine reverses abstinenceeffects
After a period of abstinence during which the severity orincidence of a symptom or sign develops, re-administra-tion of caffeine rapidly (usually within 30–60 min) andoften completely reverses withdrawal (Driesbach andPfeiffer 1943; Goldstein et al. 1969; Roller 1981;Couturier et al. 1997; Tinley et al. 2003), with themagnitude of reversal being an increasing function of there-administered caffeine dose (Goldstein et al. 1969).
Individual differences in caffeine withdrawal
There are differences within and across individuals withrespect to the incidence of caffeine withdrawal. Asdiscussed above and shown in Table 4, only about 50%of subjects in experimental studies report headache afterany single occasion of caffeine abstinence, and theseverity of headache can vary from mild to extreme.One study that examined six repeated blind abstinencetrials in seven subjects maintained on 100 mg/day ofcaffeine documented differences within and across sub-jects: one subject never showed substantial headache,some subjects showed consistent headaches, while othersreported headaches on some trials but not others (Griffithset al. 1990). A second study that analyzed the effects of sixrepeated abstinence trials showed that at least 36% ofsubjects, who showed statistically significant elevations inheadache, failed to report this effect consistently acrossrepeated trials (Hughes et al. 1993). There is evidence thatgenetic factors may play a role in some differences amongindividuals. One study of 1,934 female twins found thatthere was significantly greater concordance of DSM-IV-defined caffeine withdrawal among monozygotic twins(41%) than dizygotic twins (18%), yielding an estimatedbroad heritability of 35% (Kendler and Prescott 1999).
Other than the role of chronic maintenance dose(discussed previously), very little is known about thedeterminants of individual differences in caffeine with-drawal. The results of one study suggested that individualswho eliminated caffeine slowly were less likely toexperience sedation during withdrawal (Lader et al.1996). Whether females, individuals with histories ofprevious drug dependence including cigarette smoking, orindividuals with polymorphisms in the A1 and A2A
adenosine receptor genes are at greater risk of caffeinewithdrawal is worthy of future research (Strain et al. 1994;Dews et al. 1999; Alsene et al. 2003).
The role of caffeine withdrawal in the habitualconsumption of caffeine
Research indicates that avoidance of abstinence-associatedwithdrawal symptoms plays a central role in the habitualconsumption of caffeine. This relationship has been shownin retrospective questionnaire studies (Goldstein andKaizer 1969) and in double-blind experimental studiesthat assessed direct behavioral measures of caffeinereinforcement or preference (Griffiths et al. 1986; Hugheset al. 1993; Liguori and Hughes 1997; Schuh and Griffiths1997; Garrett and Griffiths 1998) and beverage flavorpreferences (Rogers et al. 1995; Yeomans et al. 1998,2000a, 2001, 2002a; Tinley et al. 2003).
One study of caffeine reinforcement, for example,showed that moderate caffeine consumers who reportedcaffeine-withdrawal symptoms (i.e., headache, drowsi-ness) after drinking decaffeinated coffee were more thantwice as likely to choose caffeinated over decaffeinated
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coffee in choice tests (Hughes et al. 1993). In studies thatprospectively manipulated caffeine physical dependence,subjects chose caffeine more than twice as often when theywere physically dependent than when they were notphysically dependent (Griffiths et al. 1986; Garrett andGriffiths 1998).
Withdrawal also plays an important role in the devel-opment of preferences for flavors paired with caffeine. Inthese studies, caffeine consumers who abstained fromcaffeine overnight and were repeatedly exposed to a novelflavored drink paired with caffeine showed increasedratings of drink pleasantness or preference compared withcaffeine consumers who received placebo-paired drinks(Rogers et al. 1995; Yeomans et al. 1998). It has beendemonstrated that the development of such flavorpreference requires that subjects be caffeine deprived attraining and testing (Yeomans et al. 1998, 2000b, 2001,2002a). Furthermore, the effects are not observed incaffeine non-consumers or in long-term abstinent con-sumers (Rogers et al. 1995; Tinley et al. 2003). It seemslikely that, in the natural environment, withdrawal-depen-dent conditioned flavor preferences play an important rolein development of strong consumer preferences forspecific kinds of caffeine-containing beverages.
DSM-IV-TR and ICD-10 diagnostic criteria for caffeinewithdrawal
The potential for caffeine withdrawal to cause clinicallysignificant distress or impairment in functioning isreflected by the inclusion of caffeine withdrawal as anofficial diagnosis in ICD-10 (World Health Organization1992a,b) and as a proposed research diagnosis in DSM-IV-TR (American Psychiatric Association 2000). Caffeinewithdrawal was included in DSM-IV as a proposeddiagnosis rather than an official diagnosis to encouragefurther research on the range and specificity of caffeine-withdrawal symptoms (Hughes 1994). The DSM-IV-TRproposed research criteria for withdrawal are: (A)prolonged daily use of caffeine; (B) abrupt cessation ofcaffeine use or reduction in the amount of caffeine used,closely followed by headache and one (or more) of thefollowing symptoms: (1) marked fatigue or drowsiness,(2) marked anxiety or depression, (3) nausea or vomiting;(C) the symptoms in criterion B cause clinically significantdistress or impairment in social, occupational, or otherimportant areas of functioning; (D) the symptoms are notdue to the direct physiological effects of a general medicalcondition (e.g., migraine, viral illness) and are not betteraccounted for by another mental disorder.
The official ICD-10 diagnosis for withdrawal fromcaffeine does not specify specific symptoms for makingthe diagnosis (World Health Organization 1992a,b). TheICD-10 diagnostic criteria for research includes thediagnosis of a “withdrawal state from other stimulants,including caffeine” (World Health Organization 1993).The criteria involve: (A) cessation or reduction of caffeineuse after prolonged use; (B) dysphoric mood (for instance,
sadness or anhedonia); and (C) two or more of thefollowing: (1) lethargy and fatigue, (2) psychomotorretardation or agitation, (3) craving for stimulant drugs,(4) increased appetite, (5) insomnia or hypersomnia, (6)bizarre or unpleasant dreams.
Proposed revision of DSM-IV-TR and ICD-10diagnostic criteria for caffeine withdrawal
The great majority of the research literature on caffeinewithdrawal has been published since the DSM-IV WorkGroup (in 1994) and the World Health Organization (in1993) formulated their respective criteria for proposedresearch diagnoses (cf. Tables 1, 2, 3). This sectionfocuses on a proposed revision of the DSM, althoughmany of the considerations would be applicable to arevision of ICD-10. The research summarized in thisreview further documents that caffeine withdrawal may besevere enough to warrant clinical attention, which wasquestioned in DSM-III-R (American Psychiatric Associa-tion 1987). Moreover, the research literature now providesa sound empirical basis for updating the criteria forcaffeine withdrawal. Problems with the DSM-IV-TRcriteria are that they (1) do not reflect the apparentindependence of headache and non-headache withdrawalsymptoms (cf. section on headache); (2) do not includesymptoms that have now been well-validated; and (3)include a symptom (i.e., anxiety) for which there is littleempirical support.
Based on the current evaluation of the researchliterature, we now propose that part B of the DSMresearch criteria be changed to indicate that a caffeine-withdrawal diagnosis requires: abrupt cessation of caffeineuse or reduction in the amount of caffeine used, closelyfollowed by three or more of the following: (1) headache,(2) fatigue or drowsiness, (3) dysphoric mood, depressedmood, or irritability, (4) difficulty concentrating, and (5)flu-like somatic symptoms, nausea, vomiting, or musclepain/stiffness.
The proposed five clusters of symptoms are based onthe 13 symptoms from this review that are the bestcandidates for describing the caffeine-withdrawal syn-drome. The new criteria address the 1994 DSM-IV WorkGroup concerns that there were too few validated symp-toms and there may be overlap between fatigue anddrowsiness (Hughes 1994). The decision to propose thediagnosis based on three of the five clusters is aconservative strategy to prevent over-diagnosis of thedisorder, which was also a concern of the DSM-IV WorkGroup (Hughes 1994). Although some of the proposedsymptoms have high prevalence and other etiologies, thisis also true of other withdrawal diagnoses recognized byDSM (e.g., cocaine withdrawal, nicotine withdrawal,opioid withdrawal).
It should be recognized that although the individualsymptoms have been empirically validated, the symptomclusters are conceptually rather than empirically derived. Itwould be informative if future research with a suitably
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large group of individuals assessed all of the symptomsvalidated in this review and used statistical procedures toempirically differentiate among clusters of symptoms(e.g., cluster analysis or multiple regression), as well asdetermine their ability to predict clinically significantdistress.
Summary/conclusions
The present paper represents the most comprehensivereview and analysis of the effects of caffeine abstinence inhumans published to date. The purpose of this analysiswas to empirically validate specific symptoms and signs,and to appraise important features of the caffeine-withdrawal syndrome.
Of 49 symptom categories and 9 sign categoriesidentified from 57 experimental and 9 retrospective surveystudies, the following 10 symptom categories fulfilledmethodologically rigorous validity criteria: headache,tiredness/fatigue, decreased energy/activeness, decreasedalertness/attentiveness, drowsiness/sleepiness, decreasedcontentedness/well-being, depressed mood, difficulty con-centrating, irritability, and muzzy/foggy/not clearheaded.In addition, flu-like symptoms, nausea/vomiting, andmuscle pain/stiffness were judged likely to representvalid symptom categories. The percentage of subjectsreporting headache was 50% in experimental studies and24% in retrospective survey studies. The percentage ofsubjects reporting clinically significant distress or func-tional impairment was 13% in prospective experimentalstudies and 9% in retrospective survey studies.
Data supporting the following 13 symptom and signcategories were judged as suggestive and in need offurther research: decreased desire to socialize, unmoti-vated for work, decreased self-confidence, total mooddisturbance (POMS), yawning, heavy feelings in arms andlegs, increased nighttime sleep quality/duration, analgesicuse, craving/strong desire to use, impaired behavioral andcognitive performance (objectively measured), decreasedmotor activity (objectively measured), increased cerebralblood flow, and EEG changes.
Onset of withdrawal symptoms typically occurs 12–24 h after abstinence, with peak intensity occurring at 20–51 h, and duration of withdrawal ranging between 2 daysand 9 days. Re-administration of caffeine rapidly and oftencompletely reverses withdrawal. The incidence or severityof symptoms increases with increases in the chronic dailymaintenance dose. Symptoms may occur upon abstinencefrom chronic caffeine exposure at doses as low as 100 mg/day, and upon abstinence following only 3–7 days ofcaffeine exposure at higher doses. There is good evidencethat avoidance of withdrawal symptoms plays a centralrole in the habitual consumption of caffeine by increasingthe reinforcing effects of caffeine and preference for tastespaired with caffeine. Overall, the evidence that caffeinewithdrawal is pharmacologically based is overwhelming,and analysis of the published data does not support the
hypothesis that expectancies are a primary determinant ofcaffeine-withdrawal symptoms.
In addition to the previously discussed researchpriorities concerning the DSM-IV diagnosis of caffeinewithdrawal, future studies should determine the validity ofthe symptom and sign categories identified above as inneed of further research, and investigate how vulnerabilityto caffeine withdrawal is affected by gender, drug abusehistories, caffeine metabolism, genetics, behavioral con-ditioning, personality, and other factors. It would bevaluable if future reports of research on caffeine with-drawal provided individual subject data in addition to theusual group data to provide further information aboutindividual differences in severity of the withdrawalsyndrome. Future research should provide more detailedinformation about the time course (i.e., onset, duration,and offset) of individual withdrawal symptoms. Further-more, the impact of gradual reduction of caffeine onwithdrawal symptoms should be characterized. Althoughtolerance and withdrawal are thought to be functionallyrelated phenomena, no research has investigated therelationship between the extent of caffeine tolerance andmagnitude of withdrawal. Finally given the high rate ofcaffeine use in children, caffeine withdrawal in childrendeserves much more systematic study (Goldstein andWallace 1997; Bernstein et al. 1998).
In conclusion, although descriptions in the medicalliterature of the caffeine-withdrawal syndrome date backmore than 170 years, a solid empirical parametric analysisof the phenomenon has only begun to emerge in recentyears. Arguably, the caffeine-withdrawal syndrome hasbeen more rigorously and completely characterized thanwithdrawal from any other drug and can now serve as amodel system for evaluating drug withdrawal phenomena.Despite this progress, we can anticipate that futureresearch with caffeine will provide further valuableinsights into the world’s most widely consumed mood-altering drug, as well as insights into drug withdrawaleffects more generally.
Acknowledgements Preparation of this manuscript was supported,in part, by National Institute on Drug Abuse grant R01 DA03890.Roland Griffiths has been a consultant to pharmaceutical companies,International Food Information Counsel, International Life SciencesInstitute, and the legal profession on issues related to caffeineeffects, withdrawal, and dependence. The authors thank KristenMcCausland and Kimberly Mudd for their assistance with datamanagement.
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Appendix A—Studies that did not statistically documentsymptom or sign
Symptom or sign Studiesa
Alertness/attentiveness 10, 14, 16, 22, 23, 28, 38, 46, 55Anger/hostility 4, 6, 9, 10, 15, 18, 22, 25, 26, 27, 28, 33,
34, 35, 36, 37, 46, 55Anxiety/nervousness 4, 5, 6, 10, 14, 15, 16, 17, 18, 19, 20, 21,
23, 24, 25, 26, 27, 28, 29, 33, 34, 35, 36,37, 41, 44, 45, 46, 55, 56
Blood pressure 3, 13, 38, 43, 44, 45, 54Blurred vision 5, 19, 21, 25, 26, 37, 46, 55, 56Calm/relaxedb 16, 17, 18, 21, 27, 31, 39Chills 21Circular lights taskb 4Confusion–bewilder-ment
4, 5, 10, 15, 17, 18, 21, 25, 28, 33, 35, 36,37, 46, 55
Constipationb 5, 6Contentedness/well-being
4, 10, 14, 15, 20, 27, 28, 29, 37, 39, 46
Depression 2, 4, 10, 18, 19, 20, 21, 22, 23, 24, 25, 28,29, 33, 34, 35, 36, 37, 46, 55
Desire to socialize 15, 18, 19, 21, 23, 24, 25, 26, 27, 28, 29,35, 36
Diaphoresis 5, 6, 9, 14, 15, 19, 20, 21, 22, 23, 24, 25,26, 37, 46, 55, 56
Diarrheab 5, 6, 14, 15, 22, 23, 24Difficulty sleeping/insomniab
9, 14, 15, 19, 21, 22, 23, 24, 46, 55
Difficulty concentrating 21, 25, 28, 46Digit symbol substitu-tion task
9, 14, 15, 20, 21, 22, 28, 37, 55
Divided attentionb 21Drowsiness/sleepiness 5, 10, 18, 22, 25, 37Energy/activeness 10, 14, 16, 17, 25, 36, 42, 46Flu-like symptoms 19, 21, 26, 28, 35, 37, 46, 56Frequent urinationb 9, 14, 15, 19, 22, 23, 24, 25, 26, 37, 46,
55, 56Grammatical/logicalreasoningb
28, 55
Hand tremor (objec-tively measured)b
14, 15, 17, 20, 22, 23, 24
Headache 14, 19, 22, 24, 26, 28, 29, 31, 37, 40, 41Heart pounding/palpita-tions
9, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26,37, 46, 55, 56
Heart rate 3, 13, 19, 38, 43, 45, 54, 55Heavy feelings in armsand legs
19, 21, 25, 26, 56
Hot and cold spells 19, 25, 26, 37, 46, 55Hunger/appetiteb 17, 18, 20, 21, 22, 23, 24, 29, 31, 42Irregular heartbeat 14, 15, 22, 23, 24Irritability 4, 10, 14, 15, 16, 20, 21, 23, 24, 25, 28,
29, 37, 46, 55Jittery/shakyb 5, 6, 9, 28, 31, 37, 40, 41, 42, 46, 55Lightheaded/dizzy 5, 9, 14, 15, 19, 20, 21, 22, 23, 24, 25, 26,
37, 46, 56Limb tremorb 5, 6, 9, 19, 25, 26, 37, 46, 55, 56Loss of sex driveb 9, 19, 25, 26, 37, 46, 55, 56Memory/recallb 9, 21, 28, 37Muscle crampsb 9, 19, 25, 26, 37, 46, 55, 56Muscle pain/stiffness 9, 19, 20, 21, 25, 26, 37, 44, 46, 55, 56Muscle twitchesb 14, 15, 22, 23, 24Muzzy/foggy/not clear-headed
5, 8, 19, 25, 26, 28, 29, 31, 37, 42, 46
Nausea/vomiting/upsetstomach
2, 4, 5, 6, 9, 10, 14, 15, 19, 20, 21, 25, 26,37, 45, 46, 55, 56
Numbing or tingling inextremities
21
Symptom or sign Studiesa
Numerical Stroop taskb 9Problem solving tasks 19Reaction time 9, 17, 28, 41, 55Restlessb 21, 22, 23, 24Rhinorrhea 5, 6, 9, 19, 21, 25, 26, 37, 46, 55, 56Ringing in earsb 14, 15, 22, 23, 24Self-confidence 17, 18, 19, 22, 25, 26, 29, 37, 55, 56Shaky/weaknessb 22, 23, 24Symbol copy testb 20Tapping speed 17, 20, 28, 29, 55Thirst/thirstyb 17, 18, 29, 31, 42Tiredness/fatigue 10, 22, 27, 31, 37, 42Total mood disturbance 10, 25, 33, 37, 41, 46Unmotivated for work 14, 19, 25, 26, 28, 37, 46, 55Urinary epinephrine ornorepinephrine
3
Yawning 5, 25, 26, 37, 46Visual vigilance 20, 21aNumbers in table refer to the entry number in Tables 1 and2bSymptom or sign was not documented in any study
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