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Caffeine is one of the
most comprehensively
studied ingredients in
the food supply. Yet,
despite our considerable
knowledge of caffeine
and centuries of safe
consumption in foods
and beverages, questions
and misperceptions about
the
potential health effects
associated with caffeine
persist.
This Review provides
up-to-date information
on
caffeine, examines its
safety and summarizes
the most
recent key research
conducted on caffeine
and health.
EXECUTIVE SUMMARY
Caffeine is added to
soft drinks as a
flavoring agent; it
imparts a bitterness
that modifies the
flavors of other
components, both sour
and sweet. Although
there has been
controversy as to its
effectiveness in this
role, a review of
the literature suggests
that caffeine does, in
fact, contribute
to the sensory appeal of
soft drinks. [Drewnowski,
2001]
Moderate intake of 300
mg/day (about three cups
of
coffee per day) of
caffeine does not cause
adverse health
effects in healthy
adults, although some
groups, including
those with hypertension
and the elderly, may be
more
vulnerable. Also,
regular consumers of
coffee and other
caffeinated beverages
may experience some
undesirable,
but mild, short-lived
symptoms if they stop
consuming caffeine,
particularly if the
cessation is abrupt.
However, there
is little evidence of
health risks of caffeine
consumption.
In fact, some evidence
of health benefits
exists for
adults who consume
moderate amounts of
caffeine.
Caffeine consumption may
help reduce the risk of
several
chronic diseases,
including diabetes,
Parkinson’s disease,
liver disease, and
colorectal cancer, as
well as improve
immune function. Large
prospective cohort
studies in the
Netherlands, Finland,
Sweden, and the United
States have
found caffeine
consumption is
associated with reduced
risk
of developing type 2
diabetes, although the
mechanisms
are unclear. Several
other cohort studies
have found that
caffeine consumption
from coffee and other
beverages
decreases the risk of
Parkinson’s Disease in
men, as well
as in women who have
never used
post-menopausal
hormone replacement
therapy.
Epidemiological
studies also
suggest that coffee
consumption may decrease
the risk of
liver injury, cirrhosis
and hepatocellular
carcinoma (liver
cancer), although the
reasons for these
results have not
been determined. In
addition, coffee
consumption appears
to reduce the risk of
colorectal cancer, but
this has not
generally been confirmed
in prospective cohort
studies. An
anti-inflammatory effect
has also been observed
in a number
of studies on caffeine’s
impact on the immune
system.
Most studies have found
that caffeine
consumption does
not significantly
increase the risk of
coronary heart disease
(CHD) or stroke.
Some
randomized controlled
trials have
found that caffeine
consumption increased
cardiovascular
disease risk factors to
some degree, including
blood
pressure. However, it
has been found to have a
protective
effect in men 65 years
and older and women aged
55-69
years who did not
previously have severe
hypertension.
[Greenberg, et al.,
2007; Andersen, et al.,
2006]
At present, there is
little evidence to show
consumption
of caffeine increases
the risk of cancer.
Studies have shown
no negative association,
and possibly some
protective effects,
between caffeine
consumption and several
types of cancer.
Most studies have found
that caffeine
consumption does not
reduce bone mineral
density in women
who consume adequate
calcium. However,
positive associations
between caffeine
consumption and hip
fracture risk in three
studies imply that
limiting coffee
consumption
to three cups per day
(about 300
mg/day of caffeine) may
help prevent
osteoporosis-
related fractures in
older adults.
Although epidemiological
data on the
effects of caffeine
during pregnancy are
conflicting, the
evidence suggests that
women who are pregnant
or are planning
to become pregnant, or
who are breastfeeding,
can safely consume
caffeine, but
should limit their
consumption to three
cups of coffee per day,
providing no more than
300 mg/day of caffeine.
Based on the data
reviewed, it can be
concluded that caffeine
consumption of 300
mg/day or less does
not cause adverse
effects on the
cardiovascular
or reproductive
systems, and does not
increase
risk of cancer or
osteoporosis.
Sources of Caffei ne
Caffeine is a naturally
occurring substance
found in the leaves,
seeds and/or fruits of
at least 63 plant
species worldwide and is
part of a group of
compounds known as
methylxanthines.
The
most commonly
known sources of
caffeine are coffee,
cocoa
beans, kola nuts and tea
leaves. [Barone
and Roberts, 1996; Frary
et al., 2005]
The amount of caffeine
in food products
varies depending upon
the serving
size, the type of
product, and preparation
method. With teas and
coffees, the plant
variety also affects the
caffeine content.
An eight-ounce cup of
drip-brewed coffee
typically has 65-120 mg
caffeine; an eight-ounce
serving of brewed tea
has
20-90 mg; and a 12-
ounce canned soft drink
has 30-60 mg. [Knight,
et al., 2004] Energy
drinks can contain 50-
160 mg or more per
eight-ounce serving,
plus
caffeine from guarana
and
other added sources not
normally declared
as caffeine; and one
ounce of solid milk
chocolate typically has
just six mg caffeine
(see Table 1).
[American Beverage
Association, 2007; Mayo
Clinic, 2005]
Other sources of
caffeine include
over-the-counter
pain relievers. Caffeine
is an adjuvant—it
increases the
rate at which the
medication is absorbed
into the body.
It is also present in
some stimulant tablets
and cold
medications. Caffeine
can be present in these
products
ranging from 16-200 mg.
[Cleveland Clinic, 2006]
Caffei ne and Coffee
Because caffeine is well
known as an ingredient
in coffee,
there is much confusion,
even in research
literature,
between the effects of
caffeine and those of
coffee. Coffee
contains many other
constituents that may
also
carry health benefits;
however, this Review
will only
address the
caffeine-related
implications
of coffee consumption.
Physi ologica l Effects
Caffeine is a
pharmacologically active
substance and, depending
on the amount
consumed, can be a mild
stimulant to the
central nervous system.
[Mandel, 2002]
Caffeine is not alone in
this respect. It is
one of several
ingredients in foods
capable
of exerting
pharmacological and
physiological
effects. For example,
capsaicin in hot peppers
causes
the familiar burning
sensation that often
evokes sweating.
When caffeine is
consumed orally, it is
rapidly absorbed
into body fluids and
distributed throughout
the body in its
“water phase” (i.e.
blood, urine etc.).
Additionally, it is
recognized
that caffeine readily
passes through the
blood-brain
barrier, enabling it to
exert physiological
changes. [Institute
of Medicine, 2001]
Elimination of caffeine
from the body
is accomplished mainly
through metabolism in
the liver
in a relatively short
time; the average
half-life, or time
taken for the body to
eliminate one-half of
the amount
consumed, is five hours.
[Donovan and DeVane,
2001]
Wit hdra wal
The American Psychiatric
Association’s (APA)
“Diagnostic
and Statistical Manual
of Mental Disorders
(DSM-IV,
1994) cites no evidence
for caffeine withdrawal.
Some
studies suggest that
abruptly discontinuing
consumption
of caffeine can lead to
mild symptoms such as
headache, insomnia and
anxiety, although the
intensity
of such symptoms varies
and it is unclear
whether they
constitute withdrawal.
[Bonnet, et al., 2005]
Symptoms
may be reduced by
gradually decreasing
caffeine
intake. [Higdon and
Frei, 2006] Reported
symptoms
are generally
short-lived and
relatively mild in the
majority
of people affected.
[Nawrot, et al., 2003]
A community-based
telephone survey
followed by a
randomized,
double-blind, controlled
study on 11,169
consumers concluded that
when participants were
unaware of the caffeine
withdrawal focus of the
study,
both the frequency and
severity of caffeine
sensitivity
was much lower than
previous reports.
Moreover,
clinically significant
symptoms may be less
common
among the general
population. [Dews, et
al., 1999]
People differ greatly in
their sensitivities to
caffeine,
a fact also acknowledged
in DSM IV. A number of
factors
contribute to effects of
caffeine on an
individual,
including the amount of
caffeine ingested,
frequency
of consumption,
individual metabolism,
and individual
sensitivity. [Dews,
1986] Menta l Per forma nce
It has long been
anecdotally reported
that caffeine has the
ability to improve
alertness and aid in
concentration.
Recent studies in a
number of laboratories
have consistently
demonstrated
increases in key aspects
of cognitive
function related to
alertness, even
among well-rested
volunteers.
Additionally,
caffeine enhances
self-rated moods such as
vigor,
efficiency, energy and
clear-headedness. These
effects are
present at consumption
levels as low as 32 mg
(less than
an eight-ounce cup of
hot tea). [Lieberman,
2001]
Additionally, a study at
the French National
Institute
for Health and Medical
Research in Montpellier,
France
showed that consumption
of at least three cups
of coffee
per day is associated
with a slower rate of
decline in cognitive
abilities in women.
Caffeine, which has
already been
associated with
increased mental
performance, has been
identified as the
ingredient most likely
contributing to
these results. These
beneficial effects on
cognitive decline in
women appear to increase
with age. [Ritchie, et
al., 2007]
Although there have been
reports of caffeine
causing
anxiety, a number of
reviews of the research
have shown
that only extremely high
levels of caffeine bring
on
anxiety (1,000-2,000 mg
caffeine per day), and
even
this has not been shown
to be consistent among
reviews.
[Smith, 2002; Stern, et
al., 1989]
Anxiety is
rarely seen
within the average range
of caffeine consumption.
While large amounts of
caffeine late in the
evening may
interfere with the onset
of sleep, consumption at
least eight
hours prior to sleep
will not affect sleep
onset. [Smith,
2002; Bonnet, et al.,
2005] Teenagers tend to
stay awake longer as the
school-week progresses,
gradually becoming more
sleep-deprived,
and may consume caffeine
to counteract
daytime sleepiness.
[Pollack and Bright,
2003] In practice, those
experiencing
sleeplessness learn to
moderate caffeine
consumption to levels
and time of day
that are more acceptable
to them. [Smith,
2002; Nawrot, et al.,
2003] Furthermore,
with regular consumption
of caffeine,
tolerance to some of its
effects can result,
reducing the severity of
those effects.
[Bonnet, et al., 2005]
Although not
well documented,
researchers have
suggested
that the familiar
caffeine “morning
pick-me-up” may
simply be the relief of
overnight withdrawal
symptoms. [Dews, et al.,
2002; British Nutrition
Foundation, 2007]
Research has also
shown that sleepdeprived
individuals
consuming caffeine
had improved memory
and reasoning.
[Lieberman, 2001]
Alertness
and performance also
improve
at levels of 75-150 mg
after acute
restriction of sleep,
and at intakes of
200-600 mg after one or
more nights
without sleep. [Bonnet,
et al., 2005]
Physica l Per forma nce
In addition to its
effects on mental
performance
and mood, evidence has
also
shown that physical
performance may be
improved following
caffeine consumption.
[Magkos and Kavouras,
2004] Also,
caffeine in amounts
greater than 220 mg
has been found to
significantly improve
performance in
simulations of driving
and industrial work.
[Smith, 2005]
Consuming 6 mg/kg body
weight of
caffeine, or about five
8-ounce cups of
coffee for a 155 lb.
male, significantly
increased muscle
endurance during brief,
intense exercise (4–6
min) performed
by recreational
athletes. [Jackman, et
al.,
1996] In addition, Bruce
et al. (2000)
reported that intake of
6 or 9 mg/kg of
caffeine, or about five
or seven 8-ounce
cups of coffee,
respectively, produced a
significant improvement
in performance
compared with a placebo
for competitive
male rowers during a
2,000-meter time
trial. Notably, the
lower dose of caffeine
(6
mg/kg) resulted in the
fastest performance
times. Caffeine
ingestion of 5 mg/kg
prior to a maximum
effort run resulted in
significantly greater
anaerobic metabolism
and performance among
recreational runners.
[Doherty, 1998]
Similarly, healthy
untrained subjects
performing a maximal
oxygen deficit cycling
test had significantly
improved endurance
following ingestion
of 5 mg/kg caffeine.
[Bell, et al., 2001] One
of the few caffeine
studies utilizing female
subjects found that 6
or 9 mg/kg caffeine
(about four or six
8-ounce cups of coffee
for a 132 lb. female,
respectively) produced
dose-dependent
improvements
during repeated
2,000-meter
time trials among
competitive oarswomen.
[Anderson, et al., 2000]
In another study on
cyclists, moderate
levels of caffeine (6
mg/kg) enhanced
the performance times
during a cycling
trial. [Cox, et al.,
2002] This result was
observed whether
caffeine was ingested
one hour before exercise
or in a series
of administrations
throughout the trial.
The researchers also
found support for
the observed practice of
consuming
commercial soft drinks
as a replacement
for sports drinks during
the last part of an
endurance event. In a
double-blind study,
soft drinks produced
enhanced performance
at the end of the task,
with the
benefits being largely
due to the ingestion
of a small amount of
caffeine (1.5 mg/kg).
Direct comparison of the
ingestion of
larger amounts of soft
drink suggests
that all types of
caffeinated beverages,
including soft drinks
and sports drinks,
are of equal and
worthwhile benefit to
the
performance of a
prolonged cycling task.
Consumption of caffeine
prior to
exercise has been shown
to improve
endurance during
physical exercise. One
suggested explanation
for this was that
caffeine enhanced fat
utilization during
exercise, instead of
burning muscle;
however, Laurent et al.
(2000) showed
that this was not the
case. Rather, caffeine
may lower the threshold
for exerciseinduced
ß-endorphin and cortisol
release,
hormones that produce
the so-called
“runner’s high,” which
may contribute to
the reported caffeine
exercise benefits.
Caffei ne and Childre n
Children consume
much less caffeine than
adults, even in
proportion
to their smaller
size. [Knight, et al.,
2004] Research shows
that children, including
those diagnosed as
hyperactive, are no more
sensitive to the effects
of caffeine than adults,
and, except for infants,
they metabolize
caffeine more quickly
than adults.
[Dews, 1986; Leviton,
1992] Interestingly,
in controlled studies,
most adverse
effects were reported by
“low-consumers”
of caffeine, rather than
“high-consumers.”
[Castellanos and
Rapoport, 2002]
At low levels of
caffeine (2.5 mg/kg),
improved performance on
attention tests
has been noted in
children.
A study was
conducted in which 21
children were
administered either a
placebo, a low dose
of caffeine, or a high
dose of caffeine. The
authors noted a
statistically
significant,
dose-dependent
improvement in
performance
on an attention test
after caffeine
administration compared
with the placebo
group. A significant but
non-dose related
improvement in hand-eye
coordination
was also noted.
[Bernstein, et al.,
1994]
Although there seems to
be little hard
evidence suggesting that
children, whose
nervous systems are
still developing, are
at risk of negative
effects from caffeine,
Health Canada recommends
that daily
caffeine intake by
children should be
limited to 2.5 mg/kg
body weight.
[Nawrot, et al., 2003]
This equates to
37.5 – 45 mg/day for a
1-5 year old (body
weight 15-18 kg) and
87.5 - 125 mg/day
for a 10-14 year old
(body weight 35-50
kg). [NHANES, 1988-94]
To put this
into perspective, recall
from the Caffeine
Consumption section of
this Review
that the average
caffeine consumption
for children ages 1-5
and 6-9 years is 14
and 22 mg/day, or 0.82
and 0.85 mg/kg
body weight per day,
respectively, which
is lower than these
recommendations.
Cancer
Most of the research on
possible links between
cancer and caffeine has
been conducted on coffee
and tea.
Therefore, it
is extremely difficult
to
isolate the effects of
caffeine
unless the research
specifically focuses on
caffeine. Consequently,
research on caffeine and
its effects on
cancer, if any, is
sparse. There are
however,
references in coffee and
tea research relating
to caffeine that are
generally positive.
Caffeine has not been
shown in animal
or human studies to be
carcinogenic.
[WHO IARC, 1991] In
addition, Nawrot
et al. (2003) concluded
in his review of
the research that
caffeine is unlikely to
be
a human carcinogen at
levels below five
cups of coffee per day
(or less than 500
mg caffeine per day).
Furthermore, the
overall evidence
indicates that caffeine,
as present in coffee,
does not cause breast
or bowel cancer.
Moreover, although
early case control
studies appeared to
link caffeine intake to
pancreatic, bladder
and ovarian cancers,
more recent, better
designed studies have
not supported these
conclusions. [Leviton,
1998; Tavani and
La Vecchia, 2000;
Zeegers, et al., 2004]
A number of case control
studies have
demonstrated reduced
risk of colorectal
cancer with coffee
consumption. [Tavani
2006] In a review,
Tavani and La Vecchia
(2004) showed that not
only was there
no risk of colon or
colorectal cancer with
caffeinated beverages,
but there may even
be a protective effect.
A study by Michels
et al. (2005) confirmed
that there is no
association between
rectal cancer and
consumption of
caffeinated beverages.
Car diovascu lar Hea lth
The relationship between
coffee, caffeine
and cardiovascular
health markers has
been explored, with
emphasis on cardiac
arrhythmia, heart rate,
serum cholesterol
and blood pressure.
In
his review, Nawrot
et al. (2003) concluded
that moderate caffeine
consumption (400 mg
or less, or four or
fewer
cups of coffee per day)
does not adversely
affect
cardiovascular health.
Insufficient data exist
to
be able to draw
conclusions
about the risk of
coronary heart disease
(CHD) or mortality
associated with
consumption of much
higher amounts.
Hypertension (high blood
pressure)
is a recognized risk
factor for CHD and
stroke. Caffeine can
acutely raise heart
rate and blood pressure
immediately after
consumption, although
regular caffeine
consumers can build up a
tolerance to
these effects. Although
the impact of
coffee on blood pressure
was first debated
nearly thirty years ago,
extensive
epidemiological
studies have confirmed
that
there is no link between
coffee consumption
and hypertension,
hyperlipidemia,
and coronary artery
disease (CAD).
One study has linked
caffeine intake
to abnormal heart
rhythms, particularly
premature atrial and
ventricular contractions
of the heart. In this
study, caffeine
taken in tablet form
resulted in blood
pressure elevations four
times greater than
for caffeinated coffee.
Thus, although
there appears to be no
clear evidence for a
strong causal
relationship between
caffeinated
coffee and abnormal
heart rhythms,
it is not as clear when
considering caffeine
alone or in beverages
other than coffee.
[Frishman and
Sonnenblick, 2002]
Although scientific
review author
James (2004) suggested
there is strong
experimental evidence
that blood pressure
remains reactive to
caffeine in the
diet, and that overall
epidemiological
evidence implicates
caffeine as a risk
factor
for hypertension, more
recent studies
on women have not
supported this.
According to the
American Heart
Association (AHA)’s
policy on caffeine,
“Whether high caffeine
intake increases
the risk of coronary
heart disease is still
under study.” [AHA,
2007] However, AHA
references two studies
of interest —Nurses’
Health Studies I and
II, carried out on
approximately 162,000
nurses over 26 years
[Winkelmeyer, et al.,
2005], and another
long-term study carried
out on 128,000 people
over 14-20 years in
Spain [Lopez-Garcia, et
al., 2006] – which
offer encouraging
results for caffeine.
In the study by
Lopez-Garcia et al.
(2006), researchers
found that coffee
consumption was not
associated with an
increased risk of CHD.
In the Nurses’
Health Studies I and II,
coffee consumption,
even at high levels,
appeared to have
no effect on blood
pressure; however, both
regular and diet colas
caused a modest
increase in blood
pressure. This apparent
contradiction was
thought to be due
either to an ingredient
other than caffeine
or by a protective
effect of another
component of coffee.
People already
suffering from high
blood pressure
should consult a
physician about their
caffeine intake, as they
may be more
sensitive to the effects
of caffeine on blood
pressure. [Winkelmeyer,
et al., 2005]
Car diac Arr hyt hmias
There appears to be no
connection between
caffeine consumption and
cardiac arrhythmias.
Frost and Vestergaard
(2005)
analyzed the association
between the
amounts of caffeine
consumed daily and
the risk of atrial
fibrillation (a disorder
in which the heart’s two
upper chambers
beat ineffectively,
possibly causing
clotting
and even stroke), or
flutter, among
47,949 participants over
seven years in
a large Danish study.
They found no
association
between caffeine
consumption
and risk of developing
this disorder. [Frost
and Vestergaard, 2005]
Furthermore, in a
study carried out in
dogs by Rashid et al.
(2006), the presence of
caffeine appeared
to lead to a reduction
in the propensity for
atrial fibrillation in
both
the healthy animals and
those with
susceptibility
for atrial fibrillation.
Str oke
Few studies have
specifically
reported associations
between
coffee consumption and
stroke, and those that
have did not observe
significant associations
between coffee
consumption and
the risk of stroke.
[Rashid, et al., 2006;
Adolfsson, et al., 1977;
Grobbee, et al.,
1990; Heyden, et al.,
1978]
One exception
was a 25-year study of
499 nonsmoking
men with hypertension
enrolled
in the Honolulu Heart
Study. In that
high-risk population,
the risk of ischemic
(clot-induced) stroke in
men who consumed
at least 24 ounces of
coffee per day
(about 300 mg caffeine,
or three 8-ounce
cups) was twice that of
men who did not
drink coffee. [Hakim and
Ross, 1998]
More research is needed
to determine
whether coffee or
caffeine consumption
increases the risk of
stroke in high-risk
groups, such as
individuals with
hypertension.
However, for those
having
survived a stroke, it
would be prudent to
seek advice from a
physician regarding
caffeine intake. [Ragab,
et al., 2004]
Heart bur n & Ger d
Those affected by
gastro-esophageal reflux
disease (GERD) and
heartburn sometimes
complain of discomfort
after drinking
coffee. However, there
is some suggestion
that in the elderly, the
microsomal
enzymatic system (the
cleansing function)
of the liver may
frequently become
exhausted, further
intensifying GERD and
heartburn symptoms, even
after consuming
small amounts.
[Zivkovic, 2000]
Three studies suggested
that consuming
decaffeinated coffee,
but not decaffeinated
tea, may reduce the
symptoms of GERD.
However, tap water with
and without
added caffeine had no
effect on GERD,
and reducing the
caffeine content of
coffee to that of tea
still induced symptoms
of GERD.
Therefore,
one can conclude that GERD may be brought
on by components of
coffee other than
caffeine.
[Pehl, et al., 1997;
Wendl, et al., 1994;
Boekema, et al., 1999]
A survey conducted
in Australia reported
heartburn
was aggravated by a
number of factors,
including spicy foods,
greasy or rich
foods, stress, alcohol,
overeating, smoking,
pregnancy, food allergy
and coffee.
[Bolin, et al., 2000] As
these other factors
of heartburn do not
relate to caffeine,
it can be deduced that
caffeine in coffee
is not the responsible
ingredient.
A large, evidence-based
review covering
research from 1975 to
2004 and 2,039
studies found that the
only lifestyle
change that favorably
impacts those
with GERD is sleeping
with the head
elevated. Removing
caffeine from the
diet did not improve
GERD symptoms,
leading the author to
conclude that
“there is insufficient
evidence to support
the routine
recommendation that
patients with GERD avoid
caffeinated
beverages.” [Kaltenbach,
et al., 2006] Repr
oductive Hea lth
There are several
comprehensive review
papers that examine the
relationship
between caffeine and
reproductive
health. A review by
Leviton and Cowan
[2002] specifically
examined outcomes
such as delayed
conception, miscarriage
(both chromosomally
normal and aberrant),
birth defects, premature
birth,
and low birthweight and
found that
caffeine does not cause
any of these
outcomes.
The authors
concluded that the
associations
found in the less
rigorously analyzed
studies could
possibly be due to other
factors, such as
smoking.
Christian and Brent
(2001) conducted a very
systematic
review on the
relationship between
caffeine consumption
by both pregnant women
and women of
child-bearing
age and the occurrence
of congenital
malformations, fetal
growth retardation,
small-for-date babies,
miscarriages,
behavioral effects,
maternal infertility and
genetic effects.
The only statistically
significant results were teratogenic
(birth defect) effects
in rats administered
extremely high
levels of caffeine
intravenously, which do
not necessarily
translate to humans and
also could never be
attained
merely by drinking
beverages containing
caffeine.
Ferti lity
Nawrot et al. (2003)
noted in their review of
caffeine
that most
epidemiological studies
on caffeine and
fertility
were affected by
methodological issues,
including
inadequate measurement
of caffeine intake,
inadequate
control for possible
confounding factors,
recall bias in
retrospective studies,
lack of data on
frequency of unprotected
intercourse and, in some
studies, inadequate
sample size.
Despite
these limitations, the
epidemiological
studies generally
indicate that
consumption of caffeine
at levels at or below
300 mg per day, or
approximately
three cups of coffee per
day, did not reduce
fertility in
otherwise fertile women.
[Nawrot, et al., 2003]
A study on the effects
of alcohol and caffeine
on
fertility demonstrated a
significant risk when
alcohol
and caffeine were
consumed together;
however no effects were
observed when
caffeine was consumed
alone. [Hakim
and Gray, 1998] This is
important
to note, given the
combination of
energy drinks with
alcohol that has been
observed in some
consumer groups.
Based on the available
data from
epidemiological studies,
Higdon and Frei
(2006) suggested that it
may be advisable
for women who are having
difficulty
conceiving to limit
caffeine consumption to
less than
300 mg/day, in addition
to eliminating tobacco
use and
decreasing alcohol
consumption. Further
studies by Sata et
al. (2005) in Japan have
suggested that only
women having
a particular genetic
make-up (i.e. possessing
homozygous
CYP1A21F alleles) are at
risk of reduced
fertility due to
even moderate caffeine
consumption (100-299
mg/day).
Miscarria ge
There have been numerous
epidemiological studies
examining
the relationship between
coffee or caffeine
intake
by pregnant women and
the risk of miscarriage.
Some
studies have observed
significant associations
between caffeine
intakes greater than 300
mg/day, particularly
from
coffee, and the risk of
miscarriage, whereas
other studies
have not. [Higdon and
Frei, 2006] While
individual
epidemiological studies
cannot prove cause and
effect, they
can contribute to the
wealth of information on
potential
observed effects.
However, they must be
taken within the
context of the entire
body of data. [Nawrot,
et al., 2003]
Three reviews were
carried out on the
effect of coffee and
caffeine on miscarriage,
but none of them were
able to draw
concrete conclusions due
to methodological issues
with
the studies reviewed.
[Signorello and
McLaughlin, 2004;
Lawson and LeMasters,
2004; Matijasevich, et
al., 2005]
Stein and Susser (1991)
hypothesized that the
nausea
commonly seen in
pregnancy may create an
erroneous
association between
caffeine consumption and
miscarriage.
Nausea is associated
with increasing hormone
levels during
a normal pregnancy and
is significantly less
common in pregnancies
that end in miscarriage.
A more recent study
by Lawson et al. (2002)
demonstrated that early
pregnancy
hormone metabolite
levels, pregnancy
symptoms, and
coffee consumption
patterns are
significantly associated
with each other. While
higher hormone levels
were associated
with coffee aversion,
lower (unhealthy) levels
were not. As a result,
caffeine is commonly
misperceived
to be associated with
miscarriage. In fact,
nausea due
to pregnancy leads to
coffee aversion by some
women.
The authors consider
this to be an important
variable in
investigating any
possible relationship
between coffee/
caffeine consumption and
miscarriage, as in many
cases
nausea is a
self-regulating
mechanism for reducing
caffeine
consumption by pregnant
women. [Lawson, et al.,
2002]
Matijasevich et al.
(2006) conducted a case
control study
to investigate the
relationship between
caffeine consumption
and miscarriage in
mothers in Montevideo,
Uruguay,
and found a positive
relationship between
high intakes of
caffeine (greater than
300mg/day) and
miscarriage. This
relationship persisted
despite accounting for
smoking
(possibly
underreported), prenatal
care, nausea/vomiting,
both parents’ education
levels, previous
abortions and
prenatal deaths,
maternal age, and
parity.
The study did
not account for alcohol
consumption, and the
authors
note that there could be
another compound in
coffee
other than caffeine that
may affect fetal
development. Cnattingius et al.
(2000) conducted a case
control
study in Sweden to
compare the risk of
spontaneous
first-trimester
miscarriage to caffeine
intake. They
measured plasma cotinine
(a metabolite of
nicotine)
to identify smokers and
controlled for fetal
karyotype
(chromosomal make-up).
The results showed that,
among
smokers, caffeine intake
had no effect on first
trimester
miscarriage. This could
be due to the effect of
smoking
overpowering that of the
caffeine, or smoking
causing
faster metabolism of
caffeine. For
non-smokers, an effect
was only present for
those fetuses with
normal chromosomal
make-up. The authors
suggested interpreting
the
results with caution, as
the reason for them is
not clear,
and under no
circumstances
recommended smoking.
Methodological issues
with these studies have
been
raised, including
limitations in
determining caffeine
intake and eliminating
risk factors for
miscarriage, such
as nausea and smoking.
Although the topic
remains
controversial, the
reviews by Nawrot et al.
(2003)
and Higdon and Frei
(2006) both concluded
that
maternal consumption of
no more than 300 mg/day
of caffeine, or
approximately three cups
of coffee per
day, is unlikely to
increase the risk of
miscarriage.
In early 2008, two
studies published on
this subject came
to significantly
different conclusions.
Savitz et al. (2008)
examined over 2,000
pregnancies and found
that caffeine
consumption of 200
mg/day during pregnancy
is not
related to increased
miscarriage risk. The
median caffeine
intake for the women in
this study prior to
becoming
pregnant was 350 mg/day,
and they reduced their
intake to
200 mg/day during
pregnancy.
The
researchers also noted
a possible “recall
bias,” in which women
may inaccurately
report prior caffeine
consumption after
miscarriage. In
contrast, in a smaller
study of 1,063
pregnancies, Weng
et al. (2008) found
consumption of 0-200 mg
caffeine
per day to be associated
with increased risk of
miscarriage,
with a greater risk for
intake levels above 200
mg/day. A
large percentage of
women in the study (59%)
miscarried
before enrollment,
increasing likelihood of
“recall bias.”
It is notable that the
women in the Savitz
study reduced
their caffeine
consumption during
pregnancy regardless of
whether they had
nausea/coffee aversion,
demonstrating
their previous awareness
of advice to pregnant
women to
reduce their caffeine
consumption. Such
recommendations
are already provided by
credible organizations
and
are generally recognized
and accepted by the
affected
population. For example,
the Organization of
Teratology
Information Specialists
(OTIS) [2006] states in
informational
resources on its Web
site for women trying to
become pregnant that
consuming 300 mg/day of
caffeine,
or about 3 cups of
coffee, should not
affect chances of
miscarriage. The March
of Dimes takes a more
conservative
approach by recommending
that pregnant women
limit caffeine
consumption to less than
200 mg/day.
Birt h Defects (Terat
ology)
The majority of
epidemiological studies
have found that
maternal caffeine
consumption is not
associated with
increased risk of
congenital
malformations, or birth
defects, in fetuses.
[Higdon and Frei, 2006]
At present,
there is no convincing
evidence from
epidemiological
studies that moderate
caffeine consumption by
pregnant
women ranging from
300–1,000 mg per day
throughout
the entire pregnancy
increases the risk of
birth defects.
[Nawrot, et al., 2003]
However, in light of
other women’s
health issues, such as
fertility and
miscarriage, pregnant
women are advised to
keep caffeine
consumption at or
below 300 mg/day (or
approximately three cups
of coffee).
Feta l Growth Grosso et al. (2001)
studied the effects of
caffeine consumption
on Intrauterine Growth
Retardation (IUGR) dur
ing the first and
seventh months of
pregnancy.
Mothers were interviewed
before
16 weeks of gestation
and just after birth
to determine their
caffeine consumption.
The babies were weighed
within 24 hours
of birth and given the
Ballard examination
(a standard test to
determine gestational
age). The study found no
relationship
between caffeine intake
and IUGR.
Another study attempted
to determine
whether a relationship
exists between
smoking and caffeine
intake and the birth
weight and size of
newborns. All weights
and sizes were lower for
smokers vs. nonsmokers.
However, both smoking
and nonsmoking
women with high caffeine
intake
gave birth to newborns
with significantly
lower weights compared
to women with
low caffeine intake. The
lengths and head
circumferences of the
newborns, however,
did not change
significantly. The
authors
concluded that smoking
was the constant
factor in the negative
results and should be
avoided, and that
caffeine intake should
be
kept at moderate to low
(300 mg/day or
less) levels during
pregnancy. [Balat, et
al.,
2003]
It is important to
note that studies
on other health
conditions (e.g. birth
defects) may demonstrate
different thresholds
for acceptable intake of
caffeine. This
fact has been reflected
in other sections
of this Review,
concluding that pregnant
women should not exceed
300 mg/day
(or approximately three
cups of coffee).
Bone Hea lth
Given the increased
awareness of the
incidence of
osteoporosis in
post-menopausal
women, research on the
relationship
between caffeine intake
and bone
health has been a
particular area of
focus.
Consumption of large
amounts of
caffeine (more than 744
mg/day) has been
shown to increase
urinary excretion of
calcium and magnesium.
[Tucker, 2003]
However, calcium
excretion is complex
and is affected by many
other dietary
constituents such as
calcium, potassium,
phosphorus, isoflavones,
antioxidants, salt,
oxalate, phytates, and
protein. [Massey,
2003; Atkinson and Ward,
2001]
Studies on caffeine and
calcium metabolism
and bone deterioration
show that, as
caffeinated coffee
consumption increases,
milk consumption
decreases. Bone
deterioration
becomes more pronounced
when
dietary calcium is
inadequate, and less
pronounced when dietary
calcium intake
is adequate. Calcium
lost from consuming
one cup of coffee per
day can be offset by
adding just two
tablespoons of milk to
the coffee. [Ilich and
Kerstetter, 2000]
Massey and Whiting
(1993) conducted
a literature review that
examined caffeine
intake and bone density,
and concluded
that moderate caffeine
intake did not
appear to have negative
effects in young
adult women. In a more
recent review,
Massey (1998) concluded
that the data
support the hypothesis
that older women
are more sensitive to
the effects of caffeine
on calcium metabolism,
and that caffeine
consumption may be a
risk factor for bone
loss in women over age
50. However,
Lloyd et al. (1997)
examined the effects of
long-term habitual
caffeine intake on the
bone status of healthy
post-menopausal
women aged 55-70, who
had minimal
or no previous exposure
to hormone
replacement therapy, and
found that
caffeine intake from
0–1,400 mg/day
was not associated with
any changes
in bone density in this
population.
Nawrot et al. (2003)
concluded that
caffeine’s potential to
adversely affect
calcium balance and bone
metabolism
is dependent on lifetime
caffeine and
calcium intakes, and is
critical for women.
Based on the data
reviewed, the authors
suggested that caffeine
intake of less than
400 mg/day does not have
significant
effects on bone density,
nor on calcium
balance in individuals
consuming at least
800 mg calcium per day.
Higdon and Frei
(2006) also suggested
that, although most
studies have not found
coffee or caffeine
consumption to reduce
bone mineral
density in women who
consume adequate
calcium, positive
associations between
caffeine consumption and
hip fracture
risk in three
prospective cohort
studies
10 suggest that limiting
coffee consumption to
three cups of coffee per
day (about 300
mg of caffeine per day)
may help prevent
hip-bone fractures in
older adults.
Fibrocystic Breast
Disease (FBD )
The debate over whether
caffeine has
negative effects for
breast disease was first
raised in the late
1970s. One researcher
published several
studies suggesting that
abstinence from caffeine
may alleviate
the symptoms of
fibrocystic breast
disease
(FBD), a condition of
benign (non-cancerous)
fibrous lumps in the
breast. Although
the studies did not find
a link between
caffeine and development
of the disease,
some women with FBD
reported feeling
less breast tenderness
when they eliminated
caffeine from their
diets. However, no
reliable conclusions can
be made from the
anecdotal reports from
these small studies.
The National Cancer
Institute (NCI)
examined this issue in a
case control study
involving 3,000 women
and found no
connection between
caffeine and benign
breast tumors, FBD, or
breast tenderness.
[Schairer, et al., 1986]
Both the NCI
and the American Medical
Association
(AMA) have concluded
that there is no
association between
caffeine consumption
and FBD. [Hogan, et al.,
2002]
Benefits of Caffei ne
Besides the mental and
physical performance
benefits of caffeine
described
above, several areas are
emerging in
which consumption of
caffeine could
be beneficial to health.
Much of this
research has been
carried out on coffee,
introducing other
components of
coffee, as well as
caffeine, which may
be responsible. Such
areas include reduced
risk of diabetes,
reduced risk of
Parkinson’s Disease (see
sidebar on p.10-
11), and recovery from
liver injury.
Reduce d Ris k of Dia
betes
Caffeine has been shown
to improve
glucose metabolism in
animal studies
and short-term human
studies. [Keijzers,
et al., 2002] However,
both caffeinated
and decaffeinated coffee
have also
been shown to reduce
insulin sensitivity
(a potential precursor
to diabetes). [van
Dam, 2006] Data from
epidemiological
and cross-sectional
studies in Japan,
Spain, and Sweden
suggest that habitual
coffee consumption
improves glucose
tolerance, and a
prospective cohort study
of more than 1,100 Dutch
men and
women found that coffee
intake reduced
the risk of developing
impaired glucose
tolerance over the next
six years. [Higdon
and Frei, 2006; van Dam,
et al., 2004]
Large prospective cohort
studies in the
Netherlands, Finland,
Sweden and the
United States have found
coffee consumption
to reduce the risk of
developing type 2
diabetes by as much as
55% for men and
79% for women. [Higdon
and Frei, 2006;
van Dam and Feskens,
2002; Tuomilehto,
et al., 2004] Other
cohort studies in
Finland and Sweden
demonstrated a
significantly lower risk
of developing
type 2 diabetes when
consuming at least
three cups of coffee per
day. [Carlsson,
et al., 2004; Rosengren,
et al., 2004]
The two largest
prospective cohort
studies to examine the
relationship between
coffee consumption and
type 2 diabetes are
the Health Professionals
Follow-Up Study
(41,934 men) and the
Nurses’ Health
Study (84,276 women).
[Salazar-Martinez,
et al., 2004] In these
studies, men who
drank at least six cups
of coffee per day
had a 54% lower risk of
developing type 2
diabetes than men who
did not drink
coffee at all, and women
who drank at
least six cups of coffee
per day had a 29%
lower risk than women
who did not drink
any coffee.
In both
cohorts, higher caffeine
intakes were associated
with significant
reductions in diabetes
risk. In contrast,
tea consumption did not
affect type 2
diabetes risk in either
study. [van Dam and Feskens, 2002;
Salazar-Martinez, et
al.,
2004] Van Dam and Hu
[2005] conducted
a systematic review of
nine cohort
studies, including more
than 193,000 men
and women, and found a
35% lower risk
of type 2 diabetes in
those who consumed
at least six cups of
coffee per day, and a
28% lower risk in those
who consumed between
four and six cups per
day, compared to those
who consumed less than
two cups per day. In
another
long-term study of the
relationship between
caffeinated
beverage consumption and
incidence of type 2
diabetes,
the authors followed
more than 41,000
participants over
ten years, assessing
coffee consumption every
two to four
years. The results
suggest that caffeine
intake from coffee
and other sources is
associated with a
significantly lower
risk for type 2
diabetes.
[Salazar-Martinez, et
al., 2004]
Rec overy From Liver
Injury
Several cross-sectional
studies have found
coffee intake to
reduce serum γ-glutamul
transferase (GGT)
activity, an
indicator of liver
injury. [Higdon and
Frei, 2006; Dorea
and da Costa, 2005]
Recently, Ruhl and
Everhart (2005)
analyzed the data from
the U.S. National Health
and
Nutrition Examination
Survey (NHANES)
[1988-1994],
and found that
consumption of either
coffee or caffeine
decreased the risk of
abnormally elevated
alanine
aminotransferase (ALT)
activities. They also
conducted
a prospective study to
examine the relationship
between
coffee and tea
consumption and
incidence of chronic
liver
disease. [Ruhl and
Everhart, 2005a] The
results showed
that individuals who
consume more than two
cups of coffee
or tea per day have less
than half the risk of
developing
chronic liver disease as
those who drink less
than one cup
of coffee per day.
Furthermore, several
case control studies
have demonstrated that
coffee consumption
reduces
the risk of cirrhosis
(chronic inflammation of
the liver),
with four cups per day
having the greatest
effect. [Corrao,
et al., 2001; Gallus, et
al., 2002; Higdon and
Frei, 2006]
Significant inverse
associations between
consumption of
one to three cups of
coffee and risk of liver
cancer have
also been observed in
several case control
studies in Europe
and Japan. [Gallus, et
al., 2002a; Wakai, et
al., 2007]
Emer ging Issues
Science is always
evolving into new
undiscovered areas.
Some of the emerging
areas of science that
have implications
for caffeine and health
include improved immune
function,
genetic susceptibility,
and benefits from high
intakes
of caffeine.
These are
new areas of research
that need more
exploration, but they
hold promise for
prevention and
identification of
various health
conditions in the
future. Impr ove d Immu ne
Functi on
Horrigan et al. (2006)
conducted a critical
review of
the effects of caffeine
on the immune system and
the
mplications for caffeine
consumers. A number of
in-vitro (in a test-tube
or petri-dish) and
in-vivo (in an
animal or human body)
studies showed that
caffeine
can alter various
aspects of the immune
function. These
studies indicate that
caffeine is largely
anti-inflammatory
when consumed at levels
of 400-600 mg, or about
4-6 cups of coffee, per
day. However, more
research is
needed to determine the
practical implications
of caffeine
on immunity for a
typical coffee consumer.
Genetic Suscepti bility
Genetic make-up is
becoming an increasing
area of interest
as it pertains to the
effects of caffeine.
Initial studies
have shown that certain
genetic predispositions
may
exist that could
pinpoint someone as part
of the sensitive
sub-population of
caffeine consumers. For
example,
a study by Sata et al.
(2005) referenced in the
Women’s
Health section of this
Review suggests that
only women
possessing homozygous
CYP1A21F alleles
(genetic markers)
are at risk of reduced
fertility from even low
levels
of caffeine consumption
(100-299 mg/day).
Furthermore,
a study by Cornelis et
al. (2007) suggests that
the
probability of having
the ADORA2A 1083TT
genotype
decreases as habitual
caffeine consumption
increases,
meaning there could be a
potential biological
basis for
caffeine consumption
behavior and that
individuals with
this genotype may be
less vulnerable to
caffeine’s effects.
Benefits of High Inta
kes of Caffei ne
In studies of various
health conditions,
maximum
recommended thresholds
for caffeine vary. For
example,
consumption of 300–1,000
mg caffeine per
day has been shown to be
acceptable in avoiding
birth
defects, whereas 300 mg
or less per day is the
threshold
for avoiding negative
effects on fetal growth.
Athletic performance has
also been shown to
improve
significantly with
consumption of moderate
and high
concentrations of
caffeine. As mentioned
in the Physical
Performance section of
this Review, studies
showed that
consumption of six and
eight cups of
caffeinated coffee
resulted in increased
muscle endurance during
brief,
intense exercise, and
improved performance in
timed trials,
respectively. [Jackman,
et al., 1996; Bruce, et
al., 2000]
High caffeine intakes
for reduced risk of
certain
health conditions and
improvement of athletic
performance
should be taken in the
context of the overall
health implications.
Caffeine levels observed
to have
beneficial effects for
some conditions could
have adverse
effects for other health
conditions, and
individuals
should consult a
physician about safe
caffeine intake
levels when faced with
multiple health
concerns.
13
history of heart
disease, may experience
effects at lower
levels of caffeine and
should limit their
consumption to
three cups of coffee per
day, or no more than 300
mg/
day, to avoid adverse
effects. These
individuals should
consult a physician
about caffeine
consumption.
For the healthy adult
population, moderate
caffeine
consumption of 300
mg/day is safe and can
even have beneficial
health implications as
part of
a healthful diet and
physically active
lifestyle.
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