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Neuroscience
and
Biobehavioral
Reviews
71
(2016)
294–312
Contents lists available at ScienceDirect
Neuroscience
and
Biobehavioral
Reviews
journal homepage: www.elsevier.com/locate/neubiorev
Review
article
A
review
of
caffeine’s
effects
on
cognitive,
physical
and
occupational
performance
Tom
M.
McLellana,
John
A.
Caldwellb,
Harris
R.
Liebermanc,∗
aTM
McLellan
Research
Inc.,
Stouffville,
ON
L4A
8A7,
CANADA,
Canada
bOak
Ridge
Institute
for
Science
and
Education,
Belcamp,
MD
21017,
USA
cMilitary
Nutrition
Division,
US
Army
Research
Institute
of
Environmental
Medicine
(USARIEM),
Natick,
MA
01760-5007,
USA
a
r
t
i
c
l
e
i
n
f
o
Article
history:
Received
12
February
2016
Received
in
revised
form
26
August
2016
Accepted
4
September
2016
Available
online
6
September
2016
Keywords:
Adenosine
receptors
Energy
drinks
Vigilance
Attention
Reaction
time
Time-to-exhaustion
Time-trial
Muscle
strength
and
power
High-intensity
sprints
Restricted
sleep
Sustained
wakefulness
a
b
s
t
r
a
c
t
Caffeine
is
consumed
by
over
80%
of
U.S.
adults.
This
review
examines
the
effects
caffeine
has
on
cognitive
and
physical
function,
since
most
real-world
activities
require
complex
decision
making,
motor
process-
ing
and
movement.
Caffeine
exerts
its
effects
by
blocking
adenosine
receptors.
Following
low
(∼40
mg
or
∼0.5
mg
kg−1)
to
moderate
(∼300
mg
or
4
mg
kg−1)
caffeine
doses,
alertness,
vigilance,
attention,
reaction
time
and
attention
improve,
but
less
consistent
effects
are
observed
on
memory
and
higher-order
exec-
utive
function,
such
as
judgment
and
decision
making.
Effects
on
physical
performance
on
a
vast
array
of
physical
performance
metrics
such
as
time-to-exhaustion,
time-trial,
muscle
strength
and
endurance,
and
high-intensity
sprints
typical
of
team
sports
are
evident
following
doses
that
exceed
about
200
mg
(∼3
mg
kg−1).
Many
occupations,
including
military,
first
responders,
transport
workers
and
factory
shift
workers,
require
optimal
physical
and
cognitive
function
to
ensure
success,
workplace
safety
and
pro-
ductivity.
In
these
circumstances,
that
may
include
restricted
sleep,
repeated
administration
of
caffeine
is
an
effective
strategy
to
maintain
physical
and
cognitive
capabilities.
Published
by
Elsevier
Ltd.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://
creativecommons.org/licenses/by-nc-nd/4.0/).
Contents
1.
Introduction
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2.
Pharmacology,
metabolism
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mechanisms
of
action.
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3.
Effects
on
cognitive
performance
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297
3.1.
Reaction
time
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298
3.2.
Vigilance
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298
3.3.
Attention
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298
3.4.
Acute
effects
on
memory
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299
3.5.
Chronic
effects
on
memory
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299
3.6.
Executive
function
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299
3.7.
Judgment
and
risk-taking
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300
3.8.
Summary
−
cognitive
performance
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300
4.
Effects
on
physical
performance
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301
4.1.
Endurance
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301
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302
4.2.
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303
4.3.
High-intensity
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303
∗Corresponding
author.
E-mail
addresses:
DrTom.McLellan@gmail.com
(T.M.
McLellan),
drjohncaldwell@gmail.com
(J.A.
Caldwell),
harris.r.lieberman.civ@mail.mil
(H.R.
Lieberman).
http://dx.doi.org/10.1016/j.neubiorev.2016.09.001
0149-7634/Published
by
Elsevier
Ltd.
This
is
an
open
access
article
under
the
CC
BY-NC-ND
license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
T.M.
McLellan
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
71
(2016)
294–312
295
4.4.
Effects
on
muscle
pain
and
perceived
exertion.
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.303
4.5.
Summary
−
effects
on
physical
performance
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304
5.
Combined
effects
on
physical
and
cognitive
performance
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304
5.1.
Exercise
studies
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304
5.2.
Occupational
studies
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304
6.
Side-effects
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306
7.
Overall
conclusions
−
cognitive
and
physical
performance
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307
Acknowledgements
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307
Appendix
A.
Supplementary
data
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307
References
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307
1.
Introduction
Caffeine
is
one
of
the
most
widely
consumed
foods
and
sup-
plements
in
the
world.
In
the
U.S.,
approximately
85%
of
adults
consume
caffeine
(Fray
et
al.,
2005;
Fulgoni
et
al.,
2015).
Most
caffeine
is
consumed
as
coffee
(Barone
and
Roberts,
1996)
but
caffeine
is
also
present
in
numerous
foods,
drugs
and
beverages
(Table
1).
Caffeine
is
psychoactive
in
doses
found
in
single
servings
of
many
beverages
(Lieberman
et
al.,
1987a;
Smith
et
al.,
1999)
and
is
the
active
ingredient
in
a
relatively
new
product
−
energy
drinks
(McLellan
and
Lieberman,
2012).
At
the
request
of
the
US
Food
and
Drug
Administration,
the
Institute
of
Medicine
recently
convened
a
workshop
to
review
the
safe
levels
of
caffeine
consumption
in
many
of
the
products
identified
in
Table
1
(Institute
of
Medicine,
2014).
A
wide
variety
of
benefits
and
risks
have
been
attributed
to
caffeine,
but
it
is
generally
agreed
that
for
healthy
adults,
daily
con-
sumption
of
up
to
400
mg
(∼5.5
mg
kg−1for
a
75
kg
individual)
of
caffeine
does
not
present
a
health
risk
(Doepker
et
al.,
2016;
Higdon
and
Frei,
2006;
Nawrot
et
al.,
2003).
Numerous
reviews
have
addressed
the
effects
of
caffeine
on
either
physical
or
cognitive
performance
alone
(Burke,
2008;
Davis
and
Green,
2009;
Graham,
2001;
Lieberman
et
al.,
2010;
Shearer
and
Graham,
2014;
Spriet,
2014).
However,
since
Weiss
and
Laties
did
so
in
1962
there
have
been
only
a
few
attempts
to
summarize
caffeine’s
effects
on
both
physical
and
cognitive
function
(Goldstein
et
al.,
2010;
Rogers
and
Dinges,
2005;
Sökmen
et
al.,
2008)
and
these
latter
reviews
focussed
on
issues
of
interest
to
the
sporting
community.
Nevertheless,
it
is
clear
that
there
are
doses
of
caffeine
available
in
foods
and
beverages
that
raise
plasma
concentration
to
levels
which
block
adenosine
receptors
(Fredholm,
1979,
1995;
Fredholm
et
al.,
1999),
and
exert
central
nervous
system
(CNS)
effects,
to
a
degree
that
impacts
both
cognitive
and
physical
func-
tion.
It
is
also
evident
that
there
are
many
occupational
settings,
as
well
as
sporting
and
leisure
activities,
where
optimal
physical
and
cognitive
function
is
critical
for
performance
success,
safety
and
productivity.
But
what
is
the
evidence-base
that
might
support
or
refute
the
use
of
caffeine
in
these
sporting
and
occupational
set-
tings,
and
is
there
a
dose
of
the
drug
and
timing
of
ingestion
that
will
positively
affect
both
cognitive
and
physical
function
or
are
the
potential
effects
mutually
independent
or
even
antagonistic?
These
issues
need
to
be
carefully
considered
since
rarely
do
the
physical
demands
in
sport
or
occupation
occur
in
isolation
from
complex
decision
making,
motor
processing
and
movement.
After
briefly
discussing
the
pharmacology
and
mechanisms
of
action
of
the
drug,
the
effects
of
caffeine
on
various
aspects
of
cognitive
function
will
be
addressed.
Due
to
the
immense
literature
on
the
behavioral
effects
of
caffeine
we
have
restricted
our
review
to
key
aspects
of
cognitive
function,
especially
those
that
may
be
related
to
occu-
pational
performance.
This
will
be
followed
by
a
review
of
studies
addressing
various
aspects
of
physical
performance
and
then
stud-
ies
that
have
addressed
the
effects
of
caffeine
on
both
physical
and
cognitive
performance
in
various
occupational
settings.
The
review
includes
an
assessment
of
peer-reviewed
publications
and
reports
available
through
end
Spring
2016.
2.
Pharmacology,
metabolism
and
mechanisms
of
action
Caffeine
(1,3,7-trimethylxanthine)
is
formed
when
three
methyl
groups
are
substituted
on
the
parent
compound
xanthine.
Fol-
lowing
ingestion,
caffeine
is
rapidly
absorbed
reaching
peak
concentrations
in
the
circulation
within
an
hour
(Blanchard
and
Sawers,
1983;
Robertson
et
al.,
1981),
although
there
is
consid-
erable
individual
variation
(Desbrow
et
al.,
2009;
Skinner
et
al.,
2013).
In
addition,
absorption
is
slower
when
caffeine
is
consumed
with
a
meal
(Dews,
1982;
Fleischer
et
al.,
1999),
but
absorption
is
faster
when
it
is
provided
in
gum.
Chewing
caffeine-containing
gum
allows
for
rapid
absorption
through
buccal
tissue
of
the
mouth
(Kamimori
et
al.,
2002).
Caffeine
is
rapidly
distributed
to
all
tissues
and
readily
crosses
the
blood-brain
barrier
to
exert
its
effects.
The
half-life
of
caffeine
in
the
circulation
is
normally
3–5
h
(Fredholm,
1995),
thus
it
interacts
with
many
tissues
for
prolonged
periods
of
time.
Furthermore,
smoking,
certain
dietary
choices,
liver
disease,
pregnancy
or
the
use
of
oral
contraceptives
can
alter
the
half-life
of
caffeine
(Collomp
et
al.,
1991;
Curatolo
and
Robertson,
1983;
Denaro
et
al.,
1990;
Peterson
et
al.,
2006,
2009).
Caffeine
is
structurally
similar
to
adenosine,
a
neuromodu-
lator,
whose
formation
is
dependent
on
the
relative
rates
of
ATP
breakdown
and
synthesis
(Fredholm,
1995).
Four
distinct
G-
protein-coupled
adenosine
receptors,
A1,
A2a,
A2b and
A3,
have
been
identified
(Fredholm
et
al.,
1994),
each
with
a
unique
tissue
distri-
bution
and
pharmacological
profile
(Fisone
et
al.,
2004;
Landolt,
2008).
Adenosine
receptor
density
and
sensitivity
can
vary
among
individuals
(Martin
et
al.,
2006),
and
receptors
are
up-regulated
as
caffeine
intake
increases
(Varani
et
al.,
2000).
Caffeine’s
mech-
anism
of
action
has
been
definitively
established
as
explained
by
Fig.
1.
Previously,
caffeine’s
effects
were
thought
to
be
due
to
inhi-
bition
of
phosphodiesterase
or
by
promoting
intracellular
Ca2+
release,
but
these
effects
occur
with
very
high,
non-physiological
concentrations
of
caffeine.
It
is
now
known
that
the
micromo-
lar
tissue
concentrations
of
caffeine
that
result
from
ingestion
of
low
to
moderate
doses
of
caffeine
block
A1and
A2a adenosine
receptors
(Fredholm,
1979).
Nevertheless,
as
will
be
reviewed
in
Section
4.2,
there
is
some
evidence
that
the
effects
of
caffeine
on
physical
performance
could
be
related
to
the
release
of
calcium
from
the
sarcoplasmic
reticulum
and
inhibition
of
its
reuptake,
which
subsequently
increases
nitric
oxide
via
the
activation
of
endothelial
nitric
oxide
synthase
(see
Cappelletti
et
al.,
2015).
These
actions
may
be
associated
with
changes
in
neuromuscular
function
and
increased
contractile
force
in
skeletal
muscles
that
could
be
ergogenic
(Tarnopolsky,
2008).
While
both
the
A1and
A2a adenosine
receptors
are
believed
to
be
responsible
for
the
behavioral
effects
of
caffeine,
their
relative
con-
tributions
have
not
been
established.
Both
receptor
subtypes
are
expressed
in
the
brain
and
periphery.
High
levels
of
A1receptors
are
found
in
the
hippocampus,
cortex,
cerebellum
and
hypothalamus
296
T.M.
McLellan
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
71
(2016)
294–312
Table
1
Estimated
caffeine
content
of
beverages,
foods
and
dietary
supplements
(Lieberman
et
al.,
2010;
McLellan
and
Lieberman,
2012).
Item
Caffeine
content
(mg/100
mL)
Serving
size
(mL)
Caffeine
content
(mg/serving)
Coffee
Drip
method 60–100
150
90–150
Instant
27–72
150
40–108
Decaffeinated
1–3
150
2–5
Tea
1-min
brew
6–22
150
9–33
5-min
brew
13–33
150
20–50
Iced
Tea 6–10 350
22–36
Chocolate
Products
Hot
cocoa
1–5
175
2–8
Chocolate
milk
1–3
235
2–7
Milk
chocolate
3–50
30
1–15
Baking
chocolate
115
30
35
Cola
Beverages
Coca-Cola®10
350
35
Diet
Coke®13
350
47
Pepsi®11
350
38
Diet
Pepsi®10
350
36
Other
soft
drinks
Dr.
Pepper®11
350
40
Mountain
Dew®16
350
55
Barq’s®Root
Beer
7
350
23
Energy
Drinks
Amp®30
235
71
Cocaine®120
235
280
Monster®34
235
80
Red
Bull®34
235
80
Rockstar®34
235
80
Energy
Shots
5-h
Energy®333
60
200
10-h
Time
Release®740
57
422
Over-the-counter
Medication
Anacin
(1
tablet)
–
−
32
Excedrin
(1
caplet)
–
−
65
Midol
(1
pill)
–
−
60
NoDoz
(1
tablet) –
−
200
1
oz
=
29.56
mL.
(Landolt,
2008).
The
A2a subtype
is
present
in
regions
of
the
brain
such
as
the
striatum,
nucleus
accumbens
and
olfactory
tubercle,
and
are
heavily
innervated
by
dopamine-containing
fibers
(Nehlig,
1999).
Adenosine
appears
to
inhibit
the
release
of
many
neuro-
transmitters
in
the
central
nervous
system
(Nehlig
et
al.,
1992).
In
animal
models,
adenosine
A1receptor
agonists
have
been
shown
to
inhibit
release
of
glutamate
(Ciruela
et
al.,
2006;
Flagmeyer
et
al.,
1997;
Marchi
et
al.,
2002;
Yang
et
al.,
2013),
serotonin
(Okada
et
al.,
1999),
acetylcholine
(Brown
et
al.,
1990;
Rainnie
et
al.,
1994),
noradrenaline
(Fredholm,
1979)
and
dopamine
(as
discussed
below).
Adenosine
receptor
antagonists,
such
as
caffeine,
therefore
would
promote
the
release
of
these
various
neurotransmitters.
For
example,
caffeine
has
been
linked
to
the
modulation
of
aggres-
sive
behavior
through
its
inhibitory
effects
on
serotonin
release
(Mahoney
et
al.,
2011),
and
methylxanthines,
such
as
theophylline
and
caffeine,
have
been
implicated
in
lowering
the
epileptic
seizure
threshold
through
antagonism
of
adenosine
on
glutamatergic
neu-
rons
(Boison,
2011;
Dunwiddie,
1980;
Fukuda
et
al.,
2010).
As
reviewed
elsewhere
(Ferré,
2010,
2016;
Fuxe
et
al.,
2005),
adenosine
A1and
A2a receptors
form
functional
and
pharmaco-
logically
active
heteromers
with
dopamine
D1and
D2receptors
in
different
regions
of
the
brain.
For
example,
by
blocking
A2a recep-
tors
in
the
striatum
caffeine
antagonizes
adenosine’s
effects
and
indirectly
promotes
dopamine’s
stimulatory
effects
on
psychomo-
tor
activity,
by
acting
on
its
D2receptor.
Genetic
polymorphisms
of
the
A2a and
D2receptor
in
humans
have
also
been
associated
with
caffeine’s
effects
on
anxiety
(Childs
et
al.,
2008).
Caffeine’s
effects
on
arousal,
especially
during
prolonged
periods
of
wakefulness,
appear
to
involve
both
direct
modulation
of
adenosine
A1receptors
in
the
basal
forebrain
as
well
as
indirect
effects
on
the
noradrenergic
and
hypothalamic
histaminergic
and
orexinergic
systems,
through
modulation
of
both
A1and
A2a receptors
(Ferré,
2010).
Neurochem-
ical
models
have
been
proposed
to
explain
the
ability
of
adenosine
A1and
A2a receptor
antagonists
to
increase
arousal
during
periods
of
sleep
loss
for
treatment
of
daytime
sleepiness
and
hypokine-
sia
during
Parkinson’s
disease
(Sil’kis,
2009,
2014).
According
to
these
models,
activation
of
adenosine
A1receptors
should
induce
long-term
depression
of
excitatory
inputs
to
striatonigral
neurons,
whereas
A2a receptor
activation
can
induce
long-term
potentia-
tion
of
inhibitory
inputs
to
striatopallidal
neurons.
Therefore,
the
use
of
caffeine
as
an
adenosine
receptor
antagonist
can,
in
the-
ory,
promote
excitation
of
striatonigral
neuronal
projections
and
reduce
inhibitory
signals
to
striatopallidal
neurons.
Both
of
these
responses,
therefore,
are
likely
involved
in
the
increase
in
arousal
and
enhanced
psychomotor
activity
that
follows
ingestion
of
caf-
feine
during
sleep
loss.
Single
nucleotide
polymorphisms
of
the
ADORA2A
gene,
which
codes
for
the
A2a receptor,
have
been
identified
as
thymine
and
cytosine
substitutions
at
position
1083.
Between
15–20%
of
individuals
are
homozygous
for
thymine,
whereas
about
35%
are
homozygous
for
cytosine
(Childs
et
al.,
2008).
These
poly-
morphisms
appear
to
influence
an
individual’s
response
to
the
stimulant
effects
of
caffeine
(Bodenmann
et
al.,
2012;
Yang
et
al.,
2010).
T.M.
McLellan
et
al.
/
Neuroscience
and
Biobehavioral
Reviews
71
(2016)
294–312
297
Fig.
1.
Concentration-effect
curves
for
caffeine
at
various
potential
sites
of
action.
Caffeine
markedly
affects
A1and
A2a receptors
at
low
micromolar
concentrations.
To
inhibit
phosphodiesterase
(PDE),
concentrations
20
times
as
large
are
required.
Approximate
caffeine
concentrations
resulting
from
a
single
cup
of
coffee
and
toxic
doses
of
caffeine
are
indicated.
(Modified
from
Fredholm
(1995)
with
permission
from
Elsevier.).
In
summary,
circulating
levels
of
caffeine
resulting
from
inges-
tion
of
caffeine-containing
beverages
or
food
products
result
in
the
antagonism
of
adenosine
A1and
A2a receptors
in
the
CNS
and
peripheral
tissues.
Clearance
of
caffeine
is
influenced
by
diet
and
genetics.
Lifestyle
and
genetics
affect
adenosine
receptor
number
and
sensitivity
and
can
impact
how
an
individual
responds
to
a
given
dose
of
caffeine.
3.
Effects
on
cognitive
performance
For
centuries,
caffeine,
often
in
the
form
of
coffee
or