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Nutraceuticals.
DOI: © 2012 Elsevier Inc. All rights reserved.2016http://dx.doi.org/10.1016/B978-0-12-802147-7.00030-9
30
INTRODUCTION AND BACKGROUND
Human Exposure to Caffeine: Current Trends
Caffeine is the one of the most widely consumed food 
ingredients in the world. Every day, millions of people 
around the world enjoy beverages and other foods con-
taining caffeine, including coffee, tea, soft drinks, and 
chocolate. It has been estimated that approximately 2.25 
billion cups of coffee, the major source of dietary caf-
feine, are served every day, and that more than 80% of 
the world’s population consume at least one caffeine-
containing beverage on a daily basis (Heckman et  al., 
2010). Global consumption of coffee for the year 2009–
2010 was estimated to be approximately 133.9 million 
bags (each bag weights approximately 60 kg) or approxi-
mately 4 million tons, making coffee the world’s most 
consumed substance (ICA, 2009–2010). As a food ingre-
dient, caffeine also has one of the longest histories of 
human consumption due to its natural occurrence in the 
beans, leaves, or fruit of more than 60 different plants, 
including coffee, tea, guarana, cola nuts, and cocoa pods. 
These genetically unrelated plants have evolved the 
same ability to synthesize caffeine in a process known 
as convergent evolution to ward off competition from 
other plants and insects that feed on the plant (Denoeud 
et al., 2014).
Regular human consumption of caffeine spread quickly 
following the European colonization in seventeenth and 
eighteenth centuries, which allowed widespread distri-
bution across different regions of the world (Heckman 
et al., 2010). Since that time, the cultivation of coffee, tea, 
and cocoa for human consumption has far exceeded that 
of other natural sources of caffeine. The principal natural 
dietary sources of caffeine are coffee and tea, accounting 
C H A P T E R 
Caffeine: An Evaluation of 
the Safety Database
Ashley Roberts
for up to 90% of total caffeine consumption in some geog-
raphies. Coffee, which is extracted from roasted beans of 
the coffee plant, contains the highest levels of caffeine per 
unit weight among natural sources. However, because of 
the high volume of other types of caffeinated beverages 
consumed per capita in some geographies, coffee may 
not be the major source of caffeine consumption in some 
regions. For instance, tea beverages are the major source 
of caffeine is some regions of Asia, whereas the popular-
ity of mate beverages in areas of South America makes 
Yerba Mate a major source of caffeine in that region. For 
comparison, an 8-ounce (237 mL) serving of plain brewed 
coffee is reported to contain approximately 133 mg of caf-
feine (16.6 mg/ounce or 0.56 mg/mL), whereas the same 
volume of tea (green or black) or Yerba mate contains 
two- to three-fold less caffeine at 47 mg (5.9 mg/ounce or 
0.20 mg/mL) and 78 mg (9.8 mg/ounce or 0.33 mg/mL), 
respectively. Other natural dietary sources of caffeine 
include cocoa and chocolate; however, their relative con-
tribution to the overall daily caffeine intake is considered 
negligible in most countries when compared to the levels 
of caffeine in coffee and tea (Heckman et al., 2010).
In addition to its natural occurrence in many plants, 
caffeine is also a food ingredient with a long history of 
safe use. As far back as the late 1800s, caffeine has been 
added to soft drinks, contributing its bitterness to the 
overall beverage flavor. The levels of caffeine added to 
soft drinks, however, are far less than those contained 
in an equivalent volume of brewed coffee or tea. For 
instance, a typical 12-ounce (355 mL) carbonated soft 
drink contains approximately 34 mg of caffeine, whereas 
the same volume of plain brewed coffee or tea contains 
200 and 80 mg of caffeine, respectively (Heckman et al., 
2010). The market and popularity for caffeine-containing 
beverages have grown extensively to the point that 
NUTRACEUTICALS
30. CAffEinE: An EvAluAtion of thE SAfEty DAtAbASE 418
caffeinated beverages represent a major dietary source 
of caffeine (following coffee and tea) in countries such 
as the United States and in Europe (EFSA 2015; Mitchell 
et al., 2014). Table 30.1 lists a compilation of some of the 
most commonly consumed beverages and their typical 
caffeine content in comparison to solid foods containing 
caffeine. Specialty coffees such as espresso contain caf-
feine with several-fold higher levels than regular brewed 
coffee. Carbonated soft drinks contain slightly lower but 
comparable levels of caffeine similar to those present in 
green tea. Notably, a similar amount of caffeine in an 
8-ounce carbonated soft drink may be ingested through 
the consumption of a dark chocolate bar.
Caffeine is considered a mild stimulant and, as 
such, is commonly ingested to enhance wakefulness, 
improve mood and energy levels, and even enhance 
athletic performance (Burns et  al., 2014). This stimula-
tory property of caffeine has opened a market of so-
called functional beverages that includes energy drinks, 
energy shots that contain a caffeine dose in a smaller 
volume of liquid (usually 50 mL) as compared to other 
beverages, an array of caffeine-concentrated specialty 
coffees, and even purified caffeine tablets. Interest has 
grown in understanding the contribution of caffeinated 
energy drinks to the total caffeine intake for different 
age groups in the US population because the market 
for these drinks has expanded dramatically since their 
introduction in 1997. Importantly, recent consumption 
studies in the United States do not suggest an increase 
in overall consumption of caffeine with the introduc-
tion of new caffeinated products, but rather a product 
substitution behavior by consumers (Fulgoni et al., 2015; 
Mitchell et al., 2014).
New uses of caffeine continue to be introduced in the 
marketplace, including dietary supplements, waffles, sun-
flower seeds, jelly beans, pancake syrup, flavored waters, 
and chewing gums. Moderate levels of caffeine are also 
present in some medicines, including pain relievers, 
diuretics, cold remedies, and weight control preparations 
(Heckman et  al., 2010; FDA 21 CFR 340.50). Caffeine is 
also used clinically at relatively high levels in the treat-
ment of apnea of prematurity in infants (Erenberg et al., 
2000). Caffeine levels more than 7.9 mg/kg body weight 
per day have been reported as being safe and effective in 
the treatment of apnea of prematurity in neonates born 
before 28 weeks of gestation (Francart et  al., 2013). The 
reported anti-aging, anticellulite, and antioxidant proper-
ties of caffeine have also resulted in the addition of caffeine 
to a growing number of cosmetic products. Caffeine has 
been reported to slow the photo-aging process of the skin 
by absorbing ultraviolet radiation, to exhibit anticellulite 
properties by preventing the accumulation of fat in cells, 
and to promote microcirculation of the skin through its 
antioxidant properties (Gajewska et  al., 2015). Thus, the 
uses of caffeine in consumer products including cosmetics 
continue to increase.
Although there is no evidence of moderate caffeine 
intake being associated with adverse health effects, the 
TABLE 30.1 Caffeine Content of Commonly Consumed beverages, foods, and Medications
Dietary source
Caffeine (mg/fluid 
ounce)
Caffeine 
(mg/mL)
Caffeine 
(mg/8 ounces) Reference
BEVERAGES
Specialty coffee (Espresso) 46.7–62.8 1.6–2.1 373.6–502.4 Mitchell et al. (2014)
Brewed coffee (regular) 11.9 0.40 95.2 Mitchell et al. (2014)
Energy drinks (regular) 10.0 0.34 80.0 Mitchell et al. (2014)
Black tea 5.9 0.20 47.2 Mitchell et al. (2014)
Green tea 3.1 0.10 24.8 Mitchell et al. (2014)
Carbonated soft drinks (cola type) 3.0 0.10 24.0 Mitchell et al. (2014)
Chocolate milk or drink 0.2–2.0 0.0068–0.068 1.6–16 Mitchell et al. (2014)
FOODS
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	30 Caffeine: An Evaluation of the Safety Database
	Introduction and Background
	Human Exposure to Caffeine: Current Trends
	Regulatory History of Caffeine in the United States
	Molecular Characterization of Caffeine
	The Pharmacokinetics of Caffeine
	Absorption
	Distribution
	Metabolism
	Excretion
	Pharmacokinetic Models for Caffeine
	The Biological Activity of Caffeine
	The Safety Data Available for Caffeine
	Safety Information from Animal Toxicity Studies
	Safety Information from Human Studies
	Summary of Human Safety Data
	Dietary Intake Studies of Caffeine
	Safety Characterization of Caffeine: Conclusion and Future Direction
	References27 mg/bar – – Dietitians of Canada (2014)
Milk chocolate 8–12 mg/bar – – Dietitians of Canada (2014)
Chocolate brownie 1–4 mg/brownie – – Dietitians of Canada (2014)
aA serving size assumed to be 60 mL or one-quarter cup.
419introDuCtion AnD bACkgrounD
NUTRACEUTICALS
increasing number of consumer products containing caf-
feine has triggered calls for regulatory agencies such as 
the US Food and Drug Administration (FDA) and the 
European Food Safety Authority (EFSA) to re-examine 
both the safety profile and dietary intake of caffeine. 
Years of scientific research have shown that moderate 
consumption caffeine is not associated with adverse 
health effects (Heckman et  al., 2010). On the contrary, 
numerous health-protective benefits associated with caf-
feine consumption have been reported. In this chapter, 
the safety and dietary intake information for caffeine in 
the US population is reviewed to affirm its safety.
Regulatory History of Caffeine 
in the United States
Currently, there are no official recommendations on the 
total daily caffeine intake in the United States. The FDA 
provided guidance in 2012 on the recommended total 
caffeine intake for the US population based primarily 
on a comprehensive review endorsed by Health Canada 
(Nawrot et al., 2003). The agency stated in a letter that 
caffeine intake up to 400 mg/day in healthy adults is not 
associated with adverse health effects (FDA, 2012). As a 
food ingredient, caffeine has been listed since 1959 as a 
Generally Recognized As Safe (GRAS) substance with 
tolerance set at 0.02% for addition to cola-type bever-
ages (21 CFR, Section 182.1180). The FDA has expressed 
concern that under the GRAS umbrella, food manufac-
turers may be adding caffeine indiscriminately, raising 
concerns about excessive exposure and safety (McGuire, 
2014). Further complicating the issue is the fact that the 
new and existing uses of caffeine as a food ingredient, 
dietary supplement, and cosmetic agent can fall under 
different regulatory frameworks. As a dietary supple-
ment, caffeine is considered a nutraceutical substance 
resulting from an array of benefits reported in the sci-
entific literature (e.g., protective effects against different 
types of cancer, Parkinson’s disease (PD), and metabolic 
syndrome); therefore, its uses as a dietary supplement 
could fall under the 1990 Dietary Supplement Health 
and Education Act (DSHEA) (Abdel-Rahman et  al., 
2011). Under the DSHEA framework, caffeine would be 
permissible in the market under the notion of “reason-
able expectation of no harm.” The second framework 
is the Food Additive Amendment to the Food, Drug, 
and Cosmetic Act of 1958, which addresses the safety of 
ingredients added to conventional foods for purposes of 
nutrition, flavor, and hydration. This second framework 
requires a higher level of safety based on “reasonable 
certainty of no harm” and there is a required pre-market 
approval process. The GRAS concept is an important 
feature of this framework because it does not require 
FDA pre-market approval, but there must be general 
recognition that the same stringent safety standard has 
been met based on publically available scientific data 
and information. Finally, the cosmetic uses of caffeine 
would fall under the Federal Food, Drug, and Cosmetic 
Act (FFDCA), which would not be directly regulated by 
the FDA in cosmetic products unless there is an indica-
tion of adulteration or misbranding in interstate com-
merce. Thus, different frameworks may be adapted to 
regulate an increasing number of uses of caffeine in con-
sumer products in the United States.
Molecular Characterization of Caffeine
As a naturally occurring substance with a long and 
widespread history of safe human consumption and 
approval for food use, the caffeine molecule has been 
thoroughly characterized. Importantly, the caffeine mol-
ecule is the same regardless of the method of preparation 
or purification from natural products (e.g., coffee) as 
long as the purity and the grade specifications are the 
same. As a molecule, caffeine is a member of the meth-
ylxanthine family of compounds that are biosynthesized 
from a purine ring backbone. Figure 30.1 shows the 
molecular structure of caffeine as the fully N-methylated 
form of xanthine (i.e., trimethylxanthine) along with the 
official assigned IUPAC name and CAS registry num-
ber (IPCS, 1998). When isolated or synthetically pro-
duced, caffeine is a white odorless powder with a bitter 
taste. It is a relatively lipophilic and water-soluble mol-
ecule as indicated by its octanol:water partition coef-
ficient (LogPow) of −0.07. Its water solubility has been 
estimated at approximately 2 g/100 mL of water. When 
pure, it has a melting point of 238°C and a 1% solution 
is slightly acidic, with a pH of 6.9 (IPCS, 1998). Sources 
of caffeine approved for food use include extraction and 
purification from coffee or tea and one-step synthesis 
from precursor compounds such as theobromine. The 
food-grade quality of caffeine has been specified by the 
major regulatory sources, including the Food Chemicals 
Codex (FCC), the United States Pharmacopoeia (USP), 
and the European Pharmacopoeia (EP).
FIGURE 30.1 Chemical structure and designation for caffeine.
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30. CAffEinE: An EvAluAtion of thE SAfEty DAtAbASE 420
THE PHARMACOKINETICS OF CAFFEINE
By definition, pharmacokinetics is the study of the 
absorption, distribution, metabolism, and excretion 
(ADME) of a substance (i.e., “what the body does to a 
chemical”). Pharmacokinetic analysis is critical for safety 
evaluation because it is the blood, or more specifically 
the target tissue, levels of a substance that ultimately 
determine its potential biological effects, and blood or 
tissue levels of a substance can be compared across spe-
cies, particularly those for which safety information may 
not available (i.e., interspecies extrapolation). A compa-
rable degree of effects can be expected for a comparable 
degree of internal dose levels in different species (tissue 
dose equivalence) (Rodriguez et al., 2007). The potential 
biological effect of a substance can also be informed by 
the degree of ADME in the body. Thus, a lower safety 
concern can be expected for a substance that is mini-
mally absorbed and/or quickly eliminated versus one 
that bioaccumulates and is slowly eliminated from the 
body (Barton et al., 2006).
Absorption
As one of the most researched substances in the 
world, the pharmacokinetics of caffeine has been well-
characterized following oral dosing at different dose 
levels and in multiple species, including humans. The 
available information suggests that when ingested, the 
absorption of caffeine is rapid and essentially complete. 
Oral bioavailability analyses indicate essentially com-
plete absorption from the gastrointestinal tract (GIT). 
Blanchard and Sawers (1983) reported on a study in 
which healthy human subjects (age range, 18.8–30 years) 
were administered caffeine at 5 mg/kg body weight 
either as an oral aqueous solution or as an intravenous 
(IV) infusion. Peak plasma levels of caffeine following 
dosing were reached rapidly within 30 min. When the 
resultant area under the plasma-time concentration 
curve (AUC) via the oral route was compared to that 
obtained via the IV route, the estimated oral bioavail-
ability was reported as 108.3 ± 3.6%, indicative of com-
plete absorption from the GIT (Blanchard and Sawers, 
1983). The fast and extensive absorption of caffeine into 
the systemic circulation is also supported by multiple 
studies in different species indicating very limited first 
pass metabolism (Burg, 1975; Lachance, 1982). For many 
substances, significant liver metabolism occurs before 
the absorbed substance reaches the systemic circulation 
(i.e., first-pass effect). In the case of caffeine, the impact 
of the first-pass effect is minimal and seems to be con-
sistent across different animal species tested. Burg (1975) 
reportedthe results of oral administration of 25 mg/
kg 14C-radiolabeled caffeine to different adult (nonpreg-
nant) animals species, including rats, hamsters, rabbits, 
and monkeys. The results indicate marked consistency 
in absorption, peak plasma levels, and elimination across 
all the species tested. The ranges of average peak plasma 
levels and elimination half-lives for caffeine were nar-
row at 2.8 to −3.7 µg/mL and at 2.8 to −3.7 h, respec-
tively (Burg, 1975).
A notable feature of the pharmacokinetics of caffeine 
is its linear behavior. Increasing administered oral doses 
of caffeine results in proportional increases in blood lev-
els of caffeine. In a study by Newton et al. (1981), a group 
of six healthy subjects were administered oral caffeine 
solutions at increasing dose levels of 50, 300, 500, and 
750 mg. When the resulting peak plasma concentrations 
were analyzed against administered doses there was a 
proportional relationship, indicating that caffeine exhib-
its linear pharmacokinetic behavior at the dose levels 
tested. Furthermore, when plasma AUCs were normal-
ized to administered dose per unit body weight, the 
plasma concentration time curves were superimposable, 
indicative of very consistent pharmacokinetic behaviors 
across different human subjects despite intrinsic indi-
vidual differences (Newton et al., 1981).
Distribution
Once absorbed into the systemic circulation, a fraction 
of caffeine (estimated at 10–30%) binds to plasma albu-
min and the rest distributes throughout the body with 
no evidence of tissue sequestration of the parent chemi-
cal or any of its metabolites (Bonati et  al., 1982, 1984). 
There is no evidence of physiological barriers limiting 
the distribution of caffeine as it has been reported to 
readily cross the blood–brain and placenta barriers and 
has also been found in bodily fluids such as amniotic 
fluid and human breast milk (Nawrot et al., 2003). This 
distribution pattern is consistent with its significant lipo-
philicity and water solubility, as indicated by its LogPow 
of −0.07 (IPCS, 1998). The mean volume of distribution 
of caffeine has been estimated in humans and other spe-
cies to be approximately 0.8 L/kg body weight, a value 
that is also consistent with distribution past the plasma 
compartment in the absence of any tissue sequestration 
(Bonati et al., 1984).
Metabolism
Caffeine is extensively metabolized in the liver by the 
cytochrome P450 (CYP450) enzyme system, particularly 
the CYP1A2 isozyme. The metabolism consists of oxida-
tive N-demethylation, resulting in the primary mono-
demethylated metabolites paraxanthine, theobromine, 
and theophylline. Figure 30.2 shows paraxanthine as the 
major human metabolite produced at more than 80% of 
a given oral dose of caffeine, followed by theobromine at 
approximately 11%, and theophylline at approximately 
421thE PhArMACokinEtiCS of CAffEinE
NUTRACEUTICALS
4% (Tang-Liu et al., 1983). Other metabolites have been 
reported as a result of further demethylation and oxida-
tion; however, these account for less than 6% of total caf-
feine metabolites. Overall, for a given ingested dose of 
caffeine, less than 3% of parent caffeine can be expected 
to be excreted in urine, the primary excretion route for 
caffeine and its metabolites (Tang-Liu et al., 1983). There 
is no evidence that caffeine or any of its metabolites are 
bioactivated to reactive intermediates capable of causing 
toxicity. In essence, metabolism represents a clearance 
pathway for caffeine in the body.
Given that CYP1A2 is a critical enzyme in the metabo-
lism of caffeine, any age-related, genetic, or environmen-
tal factors that affect the activity of this enzyme are likely 
to also affect the metabolism of caffeine. For instance, 
polycyclic aromatic hydrocarbons in cigarette smoke are 
known to be CYP1A2 inducers, and as a result smok-
ers are likely to be rapid metabolizers of caffeine (Cook 
et  al., 1996). Similarly, reductions of CYP1A2 activity 
during pregnancy have been associated with increases in 
the plasma half-life of caffeine during this time. Brazier 
et al. (1983) reported on pregnancy-related increases in 
the plasma half-life of caffeine that disappeared postna-
tally and were closely associated with CYP1A2 activity. 
The immature expression of hepatic metabolic systems 
in the neonate has also been identified as the primary 
cause for the much longer plasma half-life of caffeine in 
this age group as compared to adults. It is not until 5 to 
6 months of age when CYP1A2 activity increases and the 
corresponding mean adult plasma half-life of caffeine is 
approximated (Arnaud, 2011). All of these observations 
are consistent with the known ontogeny of CYP1A2 in 
human liver (Elbarbry et al., 2007).
There are several known caffeine–drug interactions 
associated with CYP1A2 metabolism. A number of pre-
scription and nonprescription drugs are also metabo-
lized by CYP1A2, which can result in significant changes 
in the pharmacokinetics of caffeine and/or the interact-
ing drug. For example, barbiturates and nicotine, induc-
ers of CYP1A2, can increase the metabolism of caffeine 
(Broderick et al., 2005). Caffeine clearance was increased 
(i.e., plasma half-life decreased) when CYP450 activ-
ity was induced by 3-methylcholanthrene; however, 
no effect on caffeine clearance or half-life was noted 
with phenobarbital (Aldridge et al., 1977; Aldridge and 
Neims, 1979). Caffeine also may act as a competitive 
inhibitor for CYP1A2 if it happens to be metabolized 
more slowly as compared to a given drug, resulting in 
reduced clearance of the drug with the possibility of 
subsequent toxicity. Caffeine has been reported to inhibit 
the metabolism of clozapine and olanzapine, both of 
which are antipsychotic agents primarily metabolized 
by CYP1A2 (Broderick et  al., 2005). Several clozapine–
caffeine interactions relating to adverse effects of exac-
erbated schizophrenic symptoms have been reported 
(Carrillo and Benitez, 2000).
Excretion
Urinary excretion is the primary route of excretion for 
caffeine and its metabolites. Following oral administra-
tion of caffeine at 7.5 mg/kg body weight to a group 
FIGURE 30.2 N-Demethylation of caffeine by CYP1A2.
NUTRACEUTICALS
30. CAffEinE: An EvAluAtion of thE SAfEty DAtAbASE 422
of six healthy subjects (one male, five females; 24 to 
32 years of age; body weight 61 to 80 kg), 70% of the 
administered dose was detected in the urine (Tang-Liu 
et  al., 1983). In another study, Callahan et  al. (1982) 
reported that 85.8% of a 14C-radiolabeled caffeine dose 
of 5 mg/kg body weight could be recovered in the urine 
from 12 healthy male volunteers (21 to 39 years of age) 
within 48 h. Recovery of the administered dose in feces 
and expired air was 2.0 and 1.3%, respectively (Callahan 
et al., 1982).
In summary, the extensive information on the phar-
macokinetics of caffeine does not raise a safety concern 
for moderate consumption of caffeine because, although 
absorption is fast and complete when ingested, there is 
no evidence of tissue sequestration of caffeine or any 
of its metabolites. Moreover, metabolism is extensive, 
serves as a clearance pathway, does not yield reactive 
species capable of causing toxicity, and human hepatic 
metabolic capacity is achieved early in life (approxi-
mately 5–6 months of age). Finally, the body eliminates 
caffeine rapidly, with a plasma half-life of approximately 
5 h; urine is the primary route of excretion of caffeine 
and its metabolites.
Pharmacokinetic Models for Caffeine
The consistency and predictability of the pharmacoki-
netic behavior of caffeine have allowed for the develop-
ment of pharmacokinetic models that are increasingly 
being used for extrapolating across different species, 
dose levels, and other situations for which there is no 
available information. In a recent report by Burns et al. 
(2014), the pharmacokinetics of caffeine was analyzed 
using linear one-compartment and two-compartmentpharmacokinetic models. The results showed that the 
population-level pharmacokinetic behavior of caffeine 
is best described by a one-compartment model with 
first-order absorption and elimination. The best fit to 
a simple one-compartment pharmacokinetic model is 
consistent with the observed pharmacokinetic profile of 
caffeine, which includes fast and complete absorption, 
distribution of caffeine throughout the body without any 
significant barrier or tissue sequestration, and relatively 
fast elimination. Using statistical analysis and plasma 
caffeine data obtained from 12 healthy subjects between 
the ages of 20 and 39 years old (11 males and 1 female) 
characterized as being moderate caffeine consumers (2 
to 4 cups of coffee consumed daily), Burns et al. (2014) 
estimated a population-level plasma half-life of 4.3 h 
with a 95% confidence interval of 3.5 to 6.1 h. The fast 
human plasma half-life of 3.5 to 6.1 is comparable to 
those reported for rats, hamsters, rabbits, and monkeys 
(Burg, 1975).
Although the pharmacokinetics of caffeine follow-
ing oral exposures can be simulated using a simple 
one-compartment model, more sophisticated models are 
being developed to accommodate dermal exposures rel-
evant to cosmetic uses and to help put into context find-
ings from in vitro systems. In a recent report, Gajewska 
et al. (2015) developed a physiologically based pharma-
cokinetic (PBPK) model to simulate plasma profiles from 
simultaneous oral and dermal exposures to caffeine. The 
same multi-route PBPK model was later parameterized 
with in vitro cell culture parameters and used to inves-
tigate the correlation between caffeine concentrations 
tested in in vitro hepatocyte cell systems to in vivo levels 
and oral intake levels. With the recent movement to use 
in vitro systems to assess the safety of substances, this 
type of in vitro to in vivo PBPK modeling approach holds a 
lot of promise in future safety studies and analyses 
involving caffeine.
THE BIOLOGICAL ACTIVITY 
OF CAFFEINE
The major mechanism of action of caffeine in the 
body is postulated to be antagonism of the all adenosine 
receptor subtypes, namely A1, A2A, A2B, and A3 receptors 
(Rivera-Oliver and Diaz-Rios, 2014). Adenosine acts as 
an inhibitory neurotransmitter that suppresses activity in 
the central nervous system (CNS) and other tissues by its 
ligand (agonist) action on its receptors. For instance, in 
the brain, adenosine slows metabolic activity by a combi-
nation of actions including reduction in synaptic vesicle 
release of glutamate and dopamine, whereas in the heart 
it reduces heart rate by suppressing the electrical impulses 
pacemaker function. The caffeine molecule is structurally 
similar to adenosine (Figure 30.3) and is capable of bind-
ing to adenosine receptors on the surface of cells without 
activating them (i.e., acting as an antagonist) (Layland 
et  al., 2014). In essence, caffeine opposes the effects of 
adenosine, including drowsiness. Because the activation 
of adenosine receptors in the CNS promotes drowsiness, 
when an individual is awake and alert little adenosine 
is present in the CNS neurons. However, over time in a 
continued wakeful state, adenosine begins to accumu-
late in the neuronal synapse and binds to and activates 
its receptors. When activated, these receptors produce a 
cellular response that ultimately increases drowsiness. 
When caffeine is consumed, it prevents adenosine from 
binding and activating its receptors, temporarily reliev-
ing drowsiness and restoring alertness (Lazarus et  al., 
2011; Landolt, 2015). It was recently reported using gene 
knockout technology that caffeine-induced wakefulness 
is insignificant because of its actions on the adenosine 
A2A receptor (Huang et al., 2005).
Other effects resulting from the antagonism of the 
adenosine receptors that may occur following high lev-
els of caffeine exposure include stimulation of the vagal 
423thE SAfEty DAtA AvAilAblE for CAffEinE 
NUTRACEUTICALS
nucleus, reduction in heart rate, constricting blood ves-
sels in the vasomotor center, and increasing respiratory 
rate in the respiratory center (Layland et al., 2014). The 
release of monoamine neurotransmitters and acetyl-
choline (ACh) has also been associated with adenosine 
receptor antagonists, including caffeine. Some of the 
findings from safety studies can be explained by the 
adenosine opposing actions of caffeine.
Recently, concerns have been raised about certain 
energy drink ingredients (McGuire, 2014). The ingredi-
ents of most interest include caffeine, taurine, D-ribose, 
and l-theanine. A review of the scientific literature 
revealed a relative paucity of publications specifically 
assessing the potential interactions of these ingredients. 
EFSA also assessed potential interactions between caf-
feine, taurine, and d-glucuronolactone (EFSA, 2009). 
Overall, the regulatory reviews have noted a lack of 
studies focused on ingredient interactions, except for 
perhaps caffeine and taurine. Although noted as a data 
gap, these reviews did not indicate that the potential 
for interaction posed a safety concern (EFSA, 2009). The 
weight of evidence of the pharmacological data avail-
able on the individual ingredients and on combinations 
of some of the ingredients, most notably caffeine, taurine, 
guarana seed extract, d-ribose, and l-theanine, provides 
no indication for any additive or synergistic interactions 
between any of the ingredients at the concentrations 
present in energy drinks.
THE SAFETY DATA AVAILABLE 
FOR CAFFEINE
The safety of caffeine (naturally occurring or synthetic) 
has been the subject of extensive investigation over the 
course of many years. An overwhelming body of evi-
dence from animal toxicity and human studies supports 
the safety of caffeine when consumed in moderation. 
In fact, caffeine may actually be protective of certain 
ailments such as PD and some cancers (Heckman et al., 
2010). Caffeine has been tested in animal toxicity studies 
of different durations reflective of acute, subchronic, and 
chronic/lifetime exposure scenarios. In all cases, caffeine 
has been consistently demonstrated to be well-tolerated 
at high dose levels.
Safety Information from Animal 
Toxicity Studies
The acute toxicity of caffeine has been evaluated, as 
with most substances, using oral intubation (or gavage) 
to achieve high intake dose levels in a single dosing 
event that would unlikely be achieved via dietary intake 
(i.e., solid food or drinking water). When evaluated 
for acute toxicity via oral gavage, caffeine has exhib-
ited relatively low acute oral toxicity in several species 
tested, including rats, mice, and rabbits. Reported effects 
at the high dose of 185 mg/kg body weight consist of 
depressed activity for approximately 2 days, followed 
by repetitive movements such as running backwards. 
Also reported were secondary effects on the adrenal and 
thymus glands consisting of increases in relative organ 
weights. Estimated LD50 values are relatively high, with 
127, 200, and 246 mg/kg body weight for mice, rats, and 
rabbits, respectively (IARC, 1991a).
The US National Toxicology Program (NTP) investi-
gated the safety of caffeine by performing a 90-day study 
in F344 rats in which caffeine was included in the drink-
ing water at concentrations of 0, 188, 375, 750, 1,500, or 
3,000 ppm, corresponding to dose levels of 0, 19.7, 42, 
85.4, 151, and 272 mg/kg body weight per day for males, 
and 0, 23, 51, 104, 174, and 287 mg/kg body weight per 
day for females, respectively. The major effect reported 
from the study was a decrease in body weight gain at 
the highest water concentration. Water consumption also 
decreased by approximately 10% in the group consuming 
FIGURE 30.3 Chemical structure of caffeine in comparison to adenosine.
NUTRACEUTICALS
30. CAffEinE: An EvAluAtion of thE SAfEty DAtAbASE 424
the highest caffeine concentration. No effects were noted 
based on clinical signs (up to1,500 ppm; clinical signs at 
3,000 ppm, if any, were not described), clinical chemis-
try, or for macroscopic lesions. Cell enlargement of the 
salivary gland was noted at all exposure levels but was 
considered to be an adaptive and reversible response to 
caffeine exposure. A conservative No Observed Adverse 
Effect Level (NOAEL) was set at 1,500 ppm (or 151 and 
174 mg/kg body weight per day for males and females, 
respectively) (OECD-SIDS, 2002).
Several 2-year rodent chronic toxicity/carcinogenicity 
studies have been performed to investigate the chronic 
toxicity and potential carcinogenicity of caffeine from life-
time dietary exposures. One study consisted of the admin-
istration of powdered freeze-dried coffee in the diets of 
Sprague-Dawley rats. The highest concentration tested was 
6% (corresponding to 60,000 ppm) and was not associated 
with any significant toxicity in the animals (Würzner et al. 
1977a,b). The estimated daily caffeine intake in the rats was 
estimated at approximately 100 mg/kg body weight. The 
effects reported were largely limited to a 20% reduction in 
body weight and a corresponding increase in feed intake 
in the animals. Such changes were not considered adverse 
and were attributed to thermogenic effects of caffeine and 
a related increase in motor activity in the treated animals. 
For animals consuming the freeze-dried coffee prepara-
tion, a protective effect was actually observed in the form 
of a negative correlation between tumor incidence and 
coffee consumption in exposed animals as compared to 
controls. Similar findings of no toxicity were reported in 
another chronic study in which Sprague-Dawley rats were 
exposed to caffeine in the drinking water at levels of 200, 
430, 930, or 2,000 mg/L for 2 years (Mohr et  al., 1984). 
Furthermore, there were no unusual tumors or sites of 
origin for neoplastic growth found in any animal as com-
pared to the control group. A NOAEL of 102 mg/kg body 
weight, the highest achieved dose for male rats, was estab-
lished based on reduced weight gain, an effect that was 
also attributed to caffeine-induced thermogenic effects 
and related motor activity increases.
The reproductive and developmental effects of caf-
feine have also been extensively evaluated in multiple 
animal species, including rats, mice, rabbits, and non-
human primates (Tarka, 1982; IARC, 1991a,b; Christian 
and Brent, 2001; Nawrot et al., 2003; Brent et al., 2011). 
In rodent studies at relatively high caffeine dose levels, 
the most common finding has been delayed ossifica-
tion, an effect that is reversible soon after birth (Collins 
et  al., 1987). At higher doses that resulted in maternal 
toxicity, caffeine produced reduced fetal body weight, 
resorption, and an increased incidence of malforma-
tions of the limbs and palate (Christian and Brent, 2001). 
The reported NOAEL for the developmental effects in 
rodents was between 80 and 120 mg/kg body weight per 
day (Brent et al., 2011).
There is no evidence that caffeine is mutagenic when 
tested in the Ames assay using Salmonella tester strains 
(IARC, 1991b). Genotoxicity assays based on in vitro 
mammalian systems lacking intrinsic metabolic capa-
bility have yielded equivocal results (i.e., both positive 
and negative findings), as have ex vivo genotoxicity stud-
ies in mice and rats (IARC, 1991a). Despite the equivo-
cal observations from in vitro/ex vivo systems, caffeine 
has been consistently reported to be noncarcinogenic 
in rats and mice. Moreover, there is no evidence from 
large prospective human cohort studies of any asso-
ciation between coffee/caffeine intake and tumor inci-
dences (Nawrot et  al., 2003; Nkondjock, 2009). The 
World Health Organization’s International Agency for 
Research on Cancer (WHO IARC) also has concluded 
that there is inadequate evidence to confirm that caffeine 
is carcinogenic (IARC, 1991a).
Caffeine, as a nonselective antagonist of the adenos-
ine receptors, can produce seizures in animals at high 
doses and can induce pro-convulsive effects in vitro 
(Chrościńska-Krawczyk et  al., 2011). Although caffeine 
is reported to promote seizures in animal models of epi-
lepsy, the convulsive threshold in experimental models 
of epilepsy are induced in healthy rats at toxic doses 
(i.e., >400 mg/kg body weight), and the effective dose 
eliciting a 50% convulsant response in mice is 400 mg/kg 
body weight (Czuczwar et al., 1990).
In summary, the evidence from animal toxicity studies 
suggests that caffeine is well tolerated at high dose lev-
els based on subchronic and chronic dietary exposures 
(drinking water or solid food). Besides mild effects on 
body weight or body weight gain, there is no evidence of 
systemic or direct organ specific toxicity. Moreover, the 
effects on body weight are attributed to a thermogenic 
effect characteristic of caffeine and related motor activ-
ity increases. No increases in rodent tumor incidences of 
any type have been observed. In fact, a consistent nega-
tive correlation between tumor incidences and caffeine 
consumption has been frequently observed in chronic 
toxicity studies, an effect that also has been reported in 
prospective cohort studies in humans. Developmental 
effects of concern such as reduced fetal weight, resorp-
tion, and malformation are only observed at high dose 
levels and in the presence of maternal toxicity, indicative 
of no increased susceptibility by the embryo/fetus.
Safety Information from Human Studies
Health concerns associated with caffeine consump-
tion have long been expressed with regard to pregnancy 
outcomes, the cardiovascular system, and the CNS. 
Numerous controlled human studies have evaluated the 
effects of caffeine and/or coffee on various physiological 
parameters such as blood pressure, heart rate, arrhyth-
mia, glucose tolerance, and calcium balance. Further, 
425thE SAfEty DAtA AvAilAblE for CAffEinE 
NUTRACEUTICALS
caffeine has been used safely and effectively at levels 
greater than 7.9 mg/kg body weight per day to treat 
apnea of prematurity in young infants (Erenberg et al., 
2000; Francart et  al., 2013). Epidemiological investiga-
tions, including retrospective and prospective cohort 
studies, have also evaluated the consumption of caffeine 
and/or coffee and the association with various health 
outcomes (e.g., cancer, cardiovascular disease, diabetes, 
pregnancy outcomes). A summary of the effects/associa-
tions between caffeine and various health outcomes is 
described, including several cases of reported caffeine 
intoxication.
Reports of caffeine intoxication are relatively rare, 
but when it happens the clinical signs include restless-
ness, nervousness, excitement, insomnia, facial flush-
ing, diuresis, and gastrointestinal symptoms. Plasma 
concentrations associated with these effects are reported 
to be in excess of 30 μg/mL (equivalent to 150 μmol/L) 
(Sawynok, 1995). Fatal reactions to acute exposures to 
caffeine are rare, but generally have been associated 
with blood caffeine concentrations in excess of 80 μg/
mL (Moffat et al., 2004). The fatal acute oral toxic dose of 
caffeine in adults is estimated to be in the range of 10 g 
(Nawrot et  al., 2003). Reports of death from consump-
tion of 6.5 g of caffeine have been reported and survival 
also has been reported for individuals consuming 24 to 
30 g of caffeine (James, 1990; Moffat et al., 2004). In chil-
dren, 3 g of caffeine (183 mg caffeine/kg body weight) 
has been shown to be fatal (Dimaio and Garriott, 1974).
Caffeine is known as a mild stimulant that can pro-
duce transient increases in heart rate and promotes 
vasoconstriction through antagonism of the adenosine 
receptor (Gronroos and Alonso, 2010). Findings from 
controlled human studies conducted in coffee consum-
ers and abstainers suggest that caffeine consumption 
at acute intakes exceeding 250 mg/person may produce 
mild, temporary increases in systolic and/or diastolic 
blood pressure of 5 to 15 mmHg and 5 to 10 mmHg, 
respectively(Josse et al., 2012; Nawrot et al., 2003). Slight 
decreases in heart rate of 1 to 3 beats per minute also 
have been reported in adolescent subjects consuming 
caffeine (Temple et al., 2010).
Caffeine withdrawal syndrome is probably one of 
the most common complaints associated with regular 
consumption of caffeine (Budney et  al., 2013). When a 
regular consumer of coffee suddenly stops, he/she expe-
riences symptoms such as headache, fatigue, decreased 
energy and alertness, drowsiness, and irritability. These 
withdrawal symptoms experienced by regular consum-
ers of caffeine are relatively mild and normally subside 
in a short time.
There are reports of slight to moderate increases in 
blood pressure, particularly systolic and mean arterial 
pressure, and inconsistent changes (both increases and 
decreases and/or no change) in heart rate following the 
consumption of energy drinks containing 80–200 mg caf-
feine per serving (Bichler et al., 2006; Franks et al., 2012; 
Grasser et al., 2014; Ragsdale et al., 2010). These effects 
are transient in nature and appear to be attenuated fol-
lowing habitual consumption, with tolerance develop-
ing within 1 to 3 days (Nawrot et  al., 2003; Robertson 
et al., 1981). In all cases, there is no evidence that caffeine 
affects electrocardiogram (ECG) parameters (Ragsdale 
et al., 2010; Steinke et al., 2009).
The effects of caffeine on cardiac arrhythmia have also 
been evaluated in controlled studies and using prospec-
tive cohorts of caffeine consumers (Conen et  al., 2010; 
Myers et al., 1987; Sutherland et al., 1985). Reviews of the 
available data have concluded that caffeine consump-
tion has minimal effects on ECG tracings and that mod-
erate consumption is well tolerated, even with persons 
with known arrhythmias (Pelchovitz and Goldberger, 
2011). Another review conducted by Cavalcante et  al. 
(2000) similarly concluded that a large body of evi-
dence supports the conclusion that moderate caffeine 
consumption does not increase the risk for atrial fibril-
lation (Cavalcante et al., 2000). In Cheng et al. (2014), a 
meta-analysis was conducted that included evaluation 
of dose-response, caffeine intake, and the incidence of 
atrial fibrillation. The meta-analysis included six pro-
spective cohort studies and 228,465 human subjects. The 
overall analysis indicated that caffeine exposure was 
weakly associated with a reduced risk for atrial fibrilla-
tion (Cheng et al., 2014).
The potential effects of caffeine on reproduction and 
development have been the subject of several systematic 
and comprehensive reviews (Brent et al., 2011; Da Silva, 
2011; Nawrot et al., 2003).The most recent and compre-
hensive review on the effects of caffeine consumption 
during pregnancy were conducted by Peck et al. (2010) 
and Brent et al. (2011). Peck et al. (2010) reviewed human 
studies published between January 2000 and December 
2009 and measured: (i) fertility; (ii) spontaneous abortion; 
(iii) fetal death; (iv) preterm birth; (v) congenital malfor-
mations; and/or (vi) fetal growth restriction. The results 
of the analysis did not support a positive relationship 
between caffeine consumption and adverse reproduc-
tive or perinatal outcomes. The review identified sig-
nificant methodological weaknesses common to studies 
of spontaneous abortion, fetal death, and fetal growth 
restriction, which limit confidence in causal interpreta-
tion (Peck et al., 2010). Consistent with the conclusion of 
a previous review (Leviton and Cowan, 2002), the studies 
available from January 2000 through December 2009 did 
not provide convincing evidence that caffeine consump-
tion increases the risk of any reproductive adversity. After 
reviewing the 2000 to 2010 scientific epidemiological lit-
erature concerning the reproductive and developmental 
toxicology risks of caffeine, Brent et al. (2011) concluded 
that confounding phenomena in caffeine studies makes 
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30. CAffEinE: An EvAluAtion of thE SAfEty DAtAbASE 426
it unclear whether the increased risk estimates for some 
developmental and reproductive effects at higher expo-
sures are due to caffeine or confounding factors. Their 
conclusion was that the dietary exposures of caffeine are 
not teratogenic (Peck et al., 2010).
IARC evaluated the carcinogenic potential of both 
caffeine and coffee in 1991 (IARC, 1991a). The agency 
concluded that, for coffee, there was limited evidence 
from epidemiological studies of carcinogenic effects in 
the urinary bladder and, therefore, classified coffee as 
possibly carcinogenic to the urinary bladder. However, 
for caffeine specifically, IARC (1991a,b) concluded that 
its carcinogenicity to humans is not classifiable based on 
inadequate evidence in humans and animals. Michels 
et  al. (2005) reported no association between caffeine 
(i.e., from coffee, tea, sodas, or chocolate) consumption 
of up to approximately 500 mg/day and the incidence of 
colon and rectal cancers in men or women in a prospec-
tive cohort that included almost 2 million person-years 
of follow-up. Using data from the NIH-AARP Diet and 
Health Study cohort, no association between the risk of 
dietary caffeine consumption and colorectal cancer was 
observed in a large prospective study of 489,706 men 
and women (Dubrow et al., 2012). In this study, 16% of 
the study population was estimated to consume four or 
more cups of coffee per day for a follow-up of 10.5 years, 
and individuals consuming four to five cups of coffee 
and six or more cups of coffee per day had a lower risk of 
colon cancer (hazard ratio of 0.85 and 0.74, respectively; 
Punderlying conditions is suggested in some 
reports (Babu et al., 2011; Calabro et al., 2012).
A recent prospective study by Dworetzky et al. (2010) 
did not identify an association between caffeine con-
sumption and seizure incidence in the Nurses’ Health 
Study cohort, a population of 105,941 participants, 
disease-free at enrollment, for a total of 1,440,850 per-
son-years of follow-up. It is noted that there is neither 
epidemiological evidence nor anecdotal evidence to sug-
gest that dietary caffeine represents an increased risk for 
seizure in otherwise healthy individuals, even among 
heavy, frequent consumers of caffeinated foods.
Summary of Human Safety Data
In summary, the information from human studies 
suggests that as a mild stimulant, caffeine can produce 
effects consistent with those actions, including increases 
in blood pressure and heart rate; however, such effects 
are transient, relatively mild, and can decrease with 
habitual consumption of caffeine. There is no evidence 
that moderate consumption of caffeine increases the risk 
of cardiac arrhythmias or atrial fibrillation or that it is 
associated with adverse reproductive or perinatal out-
comes. In the case of some cancers, there seems to be a 
protective effect, as indicated by reported inverse cor-
relations between caffeine consumption and cancers of 
the breast, prostate, liver, and colorectal cancers.
Because the plasma half-life of caffeine increases dur-
ing pregnancy, it can cross the placenta into the fetus, 
and the fetus as a result can have a longer half-life com-
pared to the mother due to immature metabolic systems 
(i.e., CYP1A2). Concern might be raised for pregnancy, 
which is a sensitive life-stage for caffeine consump-
tion. However, epidemiological studies do not support 
any association between caffeine/coffee consump-
tion and developmental effects. Further, caffeine has 
been used safely and effectively at levels greater than 
427thE SAfEty DAtA AvAilAblE for CAffEinE 
NUTRACEUTICALS
7.9 mg/kg/day in the treatment of apnea of prematurity 
in young infants 28–32 weeks postconception (Erenberg 
et al., 2000; Francart et al., 2013).
Dietary Intake Studies of Caffeine
Estimating the dietary intake levels of caffeine across 
the population is key to assessing the level of safety 
concern for current caffeine exposure. Caffeinated food 
products (primarily beverages) are consumed by virtu-
ally all segments of the population, including children, 
adolescents, and adults. However, there is significant 
variation not only in the types of caffeinated beverages 
but also in the daily volume (i.e., the amount of caffeine) 
consumed. For example, coffee has long been reported 
as the primary source of caffeine for adults, whereas 
carbonated soft drinks are presumably a major contrib-
utor of caffeine in adolescents (Mitchell et  al., 2014). 
Additionally, the caffeine content present in coffee, tea, 
cocoa, and other sources is highly variable depending 
on the type of coffee and method of preparation. A wide 
range of specialty coffees has risen in popularity, and it is 
challenging to assign caffeine values for these products 
because, unlike commercially available bottled coffees 
or caffeinated beverages, there is no label specifying the 
amount of caffeine. A key question to address is whether 
consumers substitute one caffeine source for another 
when they switch to a new caffeinated product intro-
duced in the market. For example, do consumers sub-
stitute energy drinks for coffee? If there is substitution, 
then the daily caffeine intake would not be expected to 
change significantly. With the increasing number of caf-
feinated consumer products, it is imperative to use the 
latest and most accurate consumer and product informa-
tion available, including the type of beverage consumed, 
the levels of caffeine, and the frequency of consumption. 
For example, consumer survey information prior to 2000 
likely did not include energy drinks because this type 
of caffeinated beverage was not popular at that time. 
Both the variety and popularity of energy drinks have 
increased since that time.
The most comprehensive population-based caffeine 
dietary intake study in the United States was reported 
by Mitchell et al. (2014). In collaboration with the Kantar 
World Panel, a company that specializes in documenting 
and analyzing trends in consumer behaviors, a relatively 
recent (2010–2011) population-based survey was used 
that included new caffeinated beverages such as energy 
drinks and energy shots. A total of 42,000 respondents 
representative of the US population based on relatively 
recent census data were recruited for the study. All panel 
participants were 2 years of age or older at the time of 
the study and were classified as caffeinated beverage 
consumers (drank one or more caffeinated beverages in 
7 days). Respondents were asked to complete a prospec-
tive 7-day survey that included, among other descriptors, 
the drinking occasion, the type and brand of beverage, 
and amount consumed. The collected consumption 
information was coupled with a comprehensive compi-
lation of beverage caffeine values from various sources, 
including the USDA Food and Nutrient Database for 
Dietary Studies, the USDA Food and Nutrient Database 
for Standard Reference, the Nutrition Data System for 
Research, and food and beverage industry websites.
The results of the study showed that 85% of the 
respondents consumed at least one caffeinated beverage 
per day. Several previously reported trends were also 
noted, including an increase in caffeine consumption 
(mg/day or mg/kg body weight) with age that seems 
to plateau after 64 years of age. Furthermore, nearly all 
the caffeine consumed came from coffee, tea, or carbon-
ated soft drinks. Figure 30.4 shows the caffeine intake 
FIGURE 30.4 Caffeine daily intake distribution for the US population. Source: Adapted from Mitchell et al. (2014).
NUTRACEUTICALS
30. CAffEinE: An EvAluAtion of thE SAfEty DAtAbASE 428
distribution for the different age groups evaluated. 
Adults in the age group 50–64 consumed the highest 
levels of caffeine, primarily through coffee. The contri-
bution of carbonated soft drinks was comparable to that 
of tea beverages for the adult age groups (35–49, 50–64, 
and ≥65 years old), but had a slightly greater contribu-
tion in the younger age groups, except for the youngest 
age group (2–5 years old), where tea seems to contribute 
slightly more to the total caffeine daily intake. Overall, 
the estimated mean and 90th percentile caffeine intake 
for adults (50–64 years old) consuming the highest levels 
of caffeine were 225 mg/day and 467.4 mg/day, respec-
tively. The corresponding mean daily caffeine intake for 
the younger age groups 6–12 and 13–17 years old was 
much less, at approximately 16.2 and 37% of adult values. 
An estimated 43% of children 2–5 years old consumed 
some type of caffeinated beverage, whereas essentially 
100% of adults older than 65 years old consumed caf-
feine. An important observation from the study is that 
energy drinks were found to contribute very little to the 
overall beverage caffeine daily intake for all age groups 
(Figure 30.4).
In a more recent caffeine consumption study in the 
US population, Fulgoni et al. (2015) examined temporal 
trends in caffeine consumption in adults 19 years of age 
or older from 2000 to 2010 using consumption data from 
the United States Department of Agriculture (USDA) 
National Health and Nutrition Examination Survey 
(NHANES) and caffeine content information compiled 
by Food and Nutrition Database Research, Inc. (Fulgoni 
et  al., 2015). NHANES is a continuous dietary intake 
study designed to collect nationally representative infor-
mation on health and nutrition status of the US general 
population. The consumption information is based on 
24-h recall information on 2 nonconsecutive days that is 
released in 2-year increments. Thus, for the time periodof 2001–2010, the individual 2-year periods evaluated 
by Fulgoni and coworkers were 2001–2002, 2003–2004, 
2005–2006, 2007–2008, and 2009–2010 (Fulgoni et  al., 
2015). The most important result from the analysis is 
that caffeine consumption has remained remarkably 
similar for US adults (19 years of age and older) dur-
ing the 10-year time period analyzed (i.e., 2001–2010), 
irrespective of the age or sex group. Figure 30.5 shows 
the individual results for each NHANES 2-year indi-
vidual consumption dataset (genders combined). Only 
actual caffeine consumers were included in the analysis. 
Men were found to have a higher rate (20–40%) of daily 
caffeine consumption than women, but the same gen-
eral trend was noted for both genders (Fulgoni et  al., 
2015). Such observation strongly supports the notion 
that caffeine consumption has not significantly increase 
in US adults and adds support to a product substitution 
behavior by consumers when new caffeinated products 
are introduced into the US market.
Caffeine daily intake was expressed on a per capita 
(i.e., nonconsumers were also included) basis as well 
as on actual consumers of caffeine. The results indicate 
qualitative and quantitative findings very comparable to 
those reported by Mitchell et al. (2014). The main drivers 
of caffeine intake reported were caffeinated beverages, 
particularly coffee. The mean caffeine intake on a per-
capita basis (i.e., caffeine nonusers were included) was 
estimated at 186 mg/day for adults 19 years or older, 
whereas for actual caffeine consumers of the same 
age range the estimated intake value was 211 mg/day 
FIGURE 30.5 Caffeine daily intake for different age groups based on consumption information from NHANES 2001–2010. Source: Adapted 
from Fulgoni et al. (2015).
429thE SAfEty DAtA AvAilAblE for CAffEinE 
NUTRACEUTICALS
(Fulgoni et  al., 2015). The comparable caffeine intake 
on a per capita basis and actual consumption basis sug-
gests that a very high percentage of the US population 
consumes caffeine on a daily basis. The percentage esti-
mated by Fulgoni et al. (2015) was approximately 89%, 
which is comparable with the 85% value estimated by 
Mitchell et al. (2014). The mean caffeine intake was high-
est at 275 mg/day for men in the age group 51–70 years 
old with a 90th percentile of 541 mg/day. Similar results 
were obtained in the study by Mitchell et  al. (2014) in 
which the estimated highest mean and 90th percentile 
caffeine intake were 225 mg/day and 467.4 mg/day, 
respectively, for adults 50–64 years old. Although only 
adults were evaluated by Fulgoni et  al. (2015), there 
are striking similarities to the results from both studies 
regarding the prevalence of caffeine consumption in the 
United States, caffeine intake estimates, the age group 
with the highest caffeine consumption, and the main 
driver of caffeine consumption being primarily coffee.
In 2010, the FDA published a caffeine intake study rep-
resentative of the US population. The study consisted of 
coupling the caffeine content of foods from the National 
Nutrient Database for Standard Reference (NBD) with 
the United States Department of Agriculture (USDA), 
National Health and Nutrition Examination Survey 
(NHANES), or the NPD’s Group Food Consumption 
Survey. The two surveys have strengths and limitations 
that need to be considered when deriving conclusions 
about caffeine dietary intake. For example, although 
the NHANES dataset is based on a greater number of 
respondents and thus provides a more robust popula-
tion distribution of daily consumption, it is not spe-
cific for caffeine (more than 60 food components were 
included) and does not provide information on the 
specific sources of caffeine. Further, NHANES data are 
based on 24-h recall information on 2 nonconsecutive 
days that is released in 2-year increments. Therefore, 
analysis based on the NHANES data may not necessar-
ily be reflective of current consumption patterns because 
the information was collected a minimum of 2 years 
beforehand. The FDA study was based on the 2005–2006 
NHANES survey information, the most recent dataset 
available at the time the caffeine study was performed 
in 2009. Nonetheless, a major strength of the NHANES 
data is that historical trends in consumer information 
can be obtained by comparing the previous 2-year pro-
files, as performed by Fulgoni et al. (2015).
The NPD Group’s survey was compiled in 2008 
from 14 consecutive days of 24-hr recall food diaries 
conducted in sequence throughout the year, with each 
2-week reporting period sequence completed by 60 
households. In contrast to the NHANES data, the NPD 
data show the specific source and quantity of caffeine 
and overall consumption by age and gender.
The FDA-sponsored study is robust in that the two 
data sources used (NHANES and NPD) were validated 
and adjusted if necessary using market information pro-
vided by the National Coffee Association, the US Tea 
Association, and the American Beverage Association.
The results of the 2005–2006 NHANES portion of 
the study are shown in Figure 30.6. In contrast to the 
Mitchell et al. (2014) study, the NHANES data provide 
gender-specific information regarding caffeine intake 
but not the contribution of the individual sources of 
caffeine. In general, the same trends are supported by 
the Mitchell study, namely that caffeine consumption 
increases with age, with the 50–59 age group (or 50–64 
age group in the Mitchell et al., 2014 study) exhibiting 
the highest caffeine daily intake. No major differences 
were noted between males and females.
Although the data obtained from the published 
reports herein described (Mitchell et  al., 2014; Fulgoni 
et al., 2015; FFDA-2005–2006 NHANES) are not directly 
comparable (Figures 30.4–30.6) because of mismatched 
age groups and other factors, the total caffeine daily 
intake estimated from the individual studies can be com-
pared. Thus, gender-specific values from the NHANES 
datasets (2001–2010 and 2005–2006) were averaged so 
FIGURE 30.6 Caffeine daily intake from the FDA study based on the 2005–2006 NHANES data. Source: Adapted from FDA and Oakridge 
National Laboratory (2010).
NUTRACEUTICALS
30. CAffEinE: An EvAluAtion of thE SAfEty DAtAbASE 430
that they could be compared to the total caffeine intake 
estimates from the Mitchell et al. (2014) report in which 
genders were combined. Figure 30.7 shows the aver-
age results for the most closely matched age groups in 
the three studies (coupled with brackets). Although the 
three datasets represent different time periods (Mitchell: 
2013, NHANES: 2001–2010, and NHANES: 2005–2006) 
and different methodologies (Mitchell: 7-day prospec-
tive survey and NHANES: 24-h recall information on 2 
nonconsecutive days), this analysis indicates remarkably 
similar caffeine daily intakes for the different age groups 
evaluated in all three studies. The only major difference 
noted was the caffeine daily intake for the 2–5 year age 
group, which was more than two-fold higher based on 
the Mitchell report; nonetheless, both datasets reported 
the lowest daily intake by this particular age group. This 
analysis strongly supports the conclusion that although 
there has been variation in the sources of caffeine among 
the different age groups of the US population, the overall 
daily intake has not dramatically increased during the 
time periods (2001–2010 and 2013) evaluated.
The NPD’s survey data compiled in 2008 provides 
the specific source of caffeine as well as the quantity 
consumed daily by participants. The results for the age 
groups assessed are shown in Figure 30.8. Overall, the 
caffeine daily intakes estimated from the NPD’s data are 
less than half of those estimated from the other studies 
(NHANES and Mitchell et al., 2014). The reason for this 
discrepancy was attributed to the estimated low caf-
feine content of several caffeinated products. Although 
quantitatively different, the NPD’s data still supportthe 
general trends that the younger age groups consumed 
much less caffeine because the main drivers of caffeine 
intake in the younger age groups are carbonated soft 
drinks and tea. Also supported is that coffee is the main 
contributor of caffeine in the adult population (noted as 
22 years or older) in Figure 30.8.
SAFETY CHARACTERIZATION 
OF CAFFEINE: CONCLUSION AND 
FUTURE DIRECTION
Whether synthetically derived or naturally occur-
ring, caffeine has a long history of safe and widespread 
human consumption. Reports of adverse health out-
comes are relatively rare, and the majority of these are 
associated with ingestion of caffeine-containing phar-
maceuticals, dietary supplements, or caffeine tablets. 
To put in context, blood concentrations of caffeine in 
excess of 30 µg/mL are associated with clinical signs of 
intoxication, such as anxiety, restlessness, and tachycar-
dia. Kempf et al. (2010) estimated that consumption of 
an equivalent eight cups of coffee per day for 1 month 
produced maximum 12-h fasting caffeine concentrations 
between 0.5 and 2.2 μg/mL. Assuming no body clear-
ance, there is a margin of exposure of 14–60 for someone 
consuming the equivalent of more than 1,000 mg/day of 
caffeine (each 8-ounce cup of plain, brewed coffee con-
tains approximately 133 mg of caffeine) each day for an 
entire month. This is a very conservative margin of expo-
sure estimate given that peak blood levels of caffeine 
are unlikely to be sustained for long due to the body’s 
fast elimination of caffeine and its metabolites through 
metabolism and urinary excretion (i.e., plasma half-life 
is approximately 5 h). The animal toxicity information 
FIGURE 30.7 Caffeine daily intake from the 2005–2006 FDA-NHANES, Fulgoni-NHANES 2001–2010, and Mitchell et  al. (2014) reports. 
Source: Adapted from Fulgoni et al. (2015), Mitchell et al. (2014), and FDA and Oakridge National Laboratory (2010).
431SAfEty ChArACtErizAtion of CAffEinE: ConCluSion AnD futurE DirECtion 
NUTRACEUTICALS
supports the notion that caffeine is well-tolerated at 
relatively high intake dose levels. As described earlier, 
reports on the effects from chronic exposures to caffeine 
being generally limited to reduced body weight gain and 
increased motor activity, which are not adverse in nature 
and characteristic of the thermogenic effects of caffeine. 
The most common finding from developmental toxic-
ity studies conducted with high dose levels is delayed 
ossification, an effect that is completely reversed follow-
ing birth. At higher doses, reduced fetal body weight, 
resorption, and an increased incidence of malformation 
of the limbs and palate are observed. However, these 
more serious developmental effects are only seen in the 
presence of maternal toxicity, suggesting that there is 
no increased susceptibility exhibited by the fetus. Brent 
et al. (2011) reported a rough estimate of the necessary 
human consumption of coffee to approximate the ani-
mal doses associated with developmental effects at more 
than 40 cups per day.
There is no evidence that caffeine represents a carci-
nogenic risk to humans. The International Agency for 
Research on Cancer (IARC) concluded in 1991 that there 
is inadequate evidence that caffeine (as present in cof-
fee) is carcinogenic (IARC, 1991a,b). On the contrary, the 
results of epidemiological studies suggest that regular 
coffee consumption actually reduces the risk of cancers 
of the liver and kidney, and to a lesser extent of the breast 
and colon (Nkondjock, 2009).
The daily caffeine intake of 400 mg/day of caffeine, 
which has become the standard guidance offered by reg-
ulatory agencies, was originally based on a 2003 review 
of the caffeine literature by Nawrot et  al. (2003) and 
reported as “not being associated with adverse health 
effects.” It should be noted that such value was based 
on the precautionary principle and does not represent a 
reference dose or threshold value above which adverse 
effects can be expected. EFSA recently published its 
Scientific Opinion on the Safety of Caffeine, whereby 
the 400 mg/day daily caffeine intake was again refer-
enced as “not giving rise to safety concerns” for adults 
(excluding pregnant and lactating women), noting that 
the 95th percentile in 7 out of 13 countries and as much 
as one-third of the adult population in these seven 
countries exceeded the 400 mg/day value (EFSA, 2015). 
Similarly, the value of 200 mg/day was referenced for 
pregnant and lactating women on the basis of either 
reported associations in prospective cohort studies or 
results from a dose-range study, respectively. No infor-
mation was reported on the percentiles that may exceed 
this value in the countries evaluated. In both cases, the 
scarcity of adequate caffeine data to characterize risk in 
pregnant and lactating women was noted. For children 
and adolescents, the same value for adults of 400 mg/
day was referenced, noting that there is no data indicat-
ing higher sensitivity. Chocolate beverages were noted 
as important contributors to the caffeine intake in chil-
dren and toddlers (EFSA, 2015).
The overall safety information reviewed in this evalu-
ation suggests that the safety level of concern for dietary 
exposure to caffeine is low. Unlike caffeine-containing 
medications and caffeine tablets, dietary exposure to caf-
feine is relatively low and usually separated by several 
hours. Therefore, it is highly unlikely that plasma levels 
of caffeine resulting from dietary exposures will build to 
levels associated with any type of toxicity, particularly 
given the fast pharmacokinetics exhibited by caffeine 
when taken orally in the diet. The data from human 
pharmacokinetic studies and the understanding of meta-
bolic development in human infants and children, cou-
pled with the safe use of relatively large doses of caffeine 
for apnea in premature infants, further demonstrate the 
safety of caffeine for all life stages.
FIGURE 30.8 Caffeine daily intake. Source: Adapted from the NPD’s 2008 dataset.
NUTRACEUTICALS
30. CAffEinE: An EvAluAtion of thE SAfEty DAtAbASE 432
Future safety studies for caffeine should be aimed at 
understanding the role of genetics and other factors in 
the observed wide range of caffeine intake levels, the 
role of timing of caffeine intake during the day, and other 
potential benefits not yet identified associated with caf-
feine consumption.
In conclusion, the critical safety and dietary intake 
information suggests that, when consumed at current 
dietary levels, caffeine is safe for all ages.
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