This document is a literature review submitted by Justin T. Woodrow to fulfill requirements for a Master of Science in Nutrition and Human Performance degree. It discusses caffeine tolerance as a control parameter for evaluating the effects of caffeine on physical performance. Caffeine is widely consumed globally and has stimulant, addictive, and toxic effects depending on dosage. Caffeine is metabolized and distributed throughout the body within 45-120 minutes, with a half-life of 2.5-5 hours. Caffeine's proposed mechanisms of action include antagonizing adenosine receptors and inhibiting phosphodiesterase. These mechanisms can impact various physiological systems and may influence physical performance. If an individual develops tolerance to caffeine, its effects on performance

1. LOGAN COLLEGE OF CHIROPRACTIC IN ASSOCIATION WITH UNITED STATES
SPORTS ACADEMY
TOLERANCE: A CONTROL PARAMETER WHEN EVALUATING THE PHYSICAL
PERFORMANCE EFFECTS OF CAFFEINE
A literature review submitted to the site supervisor
of the Master of Science in Nutrition and Human Performance Internship
in partial fulfillment of the requirements for the degree of:
Master of Science
in
Nutrition and Human Performance
by:
Justin T. Woodrow, MS, DC
Site Supervisor: Thomas E. Sather, LCDR
Director of Nutrition: Conrad Woolsey, PhD, CHES, CC-AASP
August, 2014

2. INTRODUCTION
Caffeine is a globally-consumed psychoactive compound (Lovett, 2005). In regards to
consumption of caffeine, sources predominantly come from coffee, tea, soft drinks and energy
drinks, as well as chocolate. Since there is such a multitude of food and beverage choices that
contain caffeine, worldwide consumption is quite ubiquitous. In fact, roughly 90% of North
Americans consume caffeine on a daily basis, with an average intake of 193 mg/day (Baggott et
al., 2013; and Lovett, 2005).
From a chemical standpoint, caffeine, or 1, 3, 7-trimethylxanthine, is a hydrophilic and
partially hydrophobic xanthine alkaloid that is synthesized in plants from purine nucleotides (i.e.,
adenosine monophosphate), acting as a natural pesticide and reward-stimulating substance in
pollinating insects (Nathanson, 1984; Svenningsson et al., 1999; and Wright et al., 2013). As
such, caffeine is naturally-occurring and is commonly found in cocoa beans, kola nuts, and tea
leaves. Other sources include seeds of the coffee plant, yerba mate, guarana berries, guayusa,
and yaupon holly (Canadian Nutrient File, 2010). Caffeine can be extracted from these sources
and used during production of beverages, such as soft drinks and energy drinks.
Since caffeine is used so frequently by most members of the human species, there must
be effects that lure individuals to continue its use. There may be stimulant, addictive, tolerant,
and toxic effects, which depend on the frequency and duration of use, and quantity consumed
during each use. All of these effects seemingly play a role in caffeine use. But do these effects
influence things such as decision-making, reaction time or physical performance? If they do,
then would tolerance neutralize these effects?
If an individual can become tolerant to caffeine and caffeine can impose significant,
observable physiologic and/or psychologic effects, then the tolerant individual will likely

3. experience the effects of caffeine to a lessened extent; therefore, caffeine tolerance should be a
control parameter when evaluating caffeine’s effect on physical performance outcomes.
The purpose of this literature review is to enlighten the reader on caffeine and its
metabolites, describing how these substances play a role in human physiology and how caffeine
tolerance might alter the physiologic effects of these substances. After the reader has understood
the implications of caffeine and its effects, as well as caffeine tolerance, the reader will be
subjected to: (1) a discussion that examines the potential ramifications if caffeine tolerance is not
controlled for in studies focusing on the effects of caffeine and physical performance outcomes;
and (2) a conclusion regarding solutions for studies examining these effects.
CAFFEINE METABOLISM
Once caffeine is ingested, absorption via the small intestine takes place within 45
minutes. Subsequently, caffeine is distributed to all tissues within the body (Liguori et al.,
1997). Within this time frame (45-120 minutes), peak blood concentration is reached (Liguori et
al., 1997; and Baggott et al., 2013). First-order kinetics is responsible for caffeine elimination,
affording caffeine a half-life of 2.5-5 hours (Baggott et al., 2013). Caffeine metabolism results
in the formation of four metabolites via demethylation and oxidation mechanisms. The primary
metabolites of caffeine metabolism, termed dimethylxanthines, are paraxanthine (80% yield),
theobromine (12% yield), and theophylline (4% yield) (Regal et al., 2005). The fourth
metabolite, 1, 3, 7-trimethyluric acid, is seen only in negligible quantities (1% yield), and thus
will not be discussed in any great detail.
CAFFEINE: PROPERTIES AND EFFECTS
Caffeine is a stimulant drug, acting as a mild central nervous system and metabolic
stimulant (Okuro et al., 2010). Any substance in sufficient amounts can generate concentrations

4. that become toxic to the organism, and caffeine is no stranger to toxicity. Although usual intake
of caffeine is roughly 200 mg/day, toxic levels can be reached if 150-200 mg/kg are consumed
(Peters, 1967). The toxicity causes symptoms of the central nervous system (i.e., headache,
anxiety, tremulousness, and confusion), cardiovascular system (i.e., tachycardia, arrhythmias,
and angina), and gastrointestinal system (i.e., nausea and vomiting, abdominal pain, diarrhea,
and bowel incontinence) (Yew, 2014). These toxic effects exemplify the ability of caffeine to
induce physiologic and psychologic changes within humans, and thus mechanisms of action need
to be considered.
Caffeine, as well as other methylxanthines, is able to impose effects even at normal
physiologic doses (200-500 mg) due to proposed mechanisms of action, which include adenosine
receptor antagonism and inhibition of phosphodiesterase (Svenningsson et al., 1999). More
specifically, caffeine acts as a competitive inhibitor of adenosine and a competitive nonselective
phosphodiesterase inhibitor.
As a phosphodiesterase inhibitor, caffeine creates increases in intracellular second
messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate
(cGMP), causing their effects to be prolonged or enhanced. An increased concentration of these
second messengers permits activation of cAMP-dependent protein kinase, which can lead to
increased cellular activity via ion channel conductance modulation, increased glycogenolysis,
lipolysis, and glycolysis, smooth muscle relaxation, and apoptosis (Shchemelinin et al., 2006).
With strong focus on cAMP-dependent protein kinase, when its cytosolic concentration is
elevated it can have drastic effects on many organ systems, including skeletal, smooth, and
cardiac muscle, liver, kidney, adrenal glands, and brain. The effects of increased cAMP-
dependent protein kinase in these systems are typically metabolic, causing gluconeogenesis

5. (liver, skeletal muscle), glycogenolysis (liver, skeletal muscle), glycolysis (liver, skeletal
muscle), and lipolysis (adipose) (Shchemelinin et al., 2006). Other significant physiologic
effects could potentially occur as well, including activation of reward systems through
dopaminergic transmission within the amygdala, smooth muscle relaxation, retention of
hydrogen ions in renal tubules, and increased blood volume and pressure due to the pressor
action of elevated levels of renin (Guerreiro et al., 2008). Caffeine has an inhibitory effect on
aldosterone as well, leading to increased diuresis and possible dehydration (Maughan et al.,
2003).
As an adenosine receptor antagonist, caffeine causes a blockade at adenosine receptors
A1 and A2A, which results in a change in the associated cells’ function (Okuro et al., 2010). To
understand the potential effects of caffeine blockade of adenosine receptors, one must understand
the location and function of adenosine receptors. Adenosine A1 receptors are found in all tissues
within the body, but previous research has primarily focused on A1 receptors within the brain
and smooth muscle of vascular tissue. When agonism of A1 receptors occurs within the brain,
sleep promotion is encouraged via inhibition of wake-promoting cholinergic neurons; therefore,
if caffeine antagonizes the A1 receptors in brain regions responsible for sleep promotion, then
one would expect a result of wake-promotion. This mechanism may be responsible for a side
effect of caffeine: insomnia (Okuro et al., 2010). Adenosine agonism of A1 receptors within
vascular tissue causes vasodilation and modulates vascular tone; within cardiac tissue, this
agonism results in decreased heart rate. Ostensibly, caffeine antagonism in these regions will
inhibit vascular smooth muscle relaxation, and oppose adenosine-induced chronotropic effects
on the heart (Dixon & Bauch, 2002). Thus, these mechanisms are responsible for caffeine side
effects: increased blood pressure and heart rate (Chawla, 2013). Adenosine A2A receptors have

6. a similar function to the A1 receptors found in smooth and cardiac muscle, controlling cardiac
oxygen usage and coronary artery tone. With caffeine antagonism, these agonist effects would
be altered, leading to opposite effects. Additionally, studies have indicated that adenosine A2A
receptors found within the brain mediate the stimulatory effect of acute caffeine administration,
as well as an A2A receptor gene single nucleotide polymorphism associated with the anxiogenic
response to caffeine (Baggott et al., 2013; and Svenningsson et al., 1999). Moreover,
antagonism of adenosine receptors may lead to an increase in adrenal-derived plasma
catecholamines via disinhibition of adenosine’s effects on the renin-angiotensin system (Tseng et
al., 2001). Finally, some studies have shown that adenosine regulates glycogen metabolism and
carbohydrate usage (Erickson et al., 1987; Essig et al., 1980; Greer et al., 2000; and Spriet et al.,
1992). Antagonism of adenosine receptors in contracting myofibers caused a decrease in glucose
rate of disappearance; therefore, caffeine and other methylxanthines may limit the amount of
carbohydrate available for exercising muscle (Greer et al., 2000). However, one study has found
that adenosine antagonism within exercising muscle caused increased glycogenolysis, while
other studies have found that such antagonism resulted in “a glycogen sparing effect” of caffeine
(Erickson et al., 1987; Essig et al., 1980; and Spriet et al., 1992). Nonetheless, adenosine
receptors play a key role in metabolic function, and their antagonism should be considered when
discussing the physiologic effects of methylxanthines.
A third mechanism based on increases in intracellular calcium concentration may also be
responsible for the metabolic effects of caffeine and other methylxanthines (Greer et al., 2000).
This mechanism, which is described below, and phosphodiesterase inhibition seem only to be
appreciably experienced when there is administration of pharmacological doses of caffeine and
not physiological ones (Greer et al., 2000). These findings strongly suggest that any observed

7. effects of consumed caffeine and other methylated xanthines are likely due to the antagonism of
adenosine receptors. However, the other two mechanisms and their effects ought not to be
entirely abandoned, as there is evidence that interactive effects occurring among methylxanthines
may potentiate, synergize, or enhance the overall effects of consumed methylxanthines (Baggott
et al., 2013; and Svenningsson et al., 1999).
PARAXANTHINE: PROPERTIES AND EFFECTS
Unlike caffeine and the other primary methylxanthines, paraxanthine is not naturally-
occurring and is only found as a metabolite of caffeine and theobromine. Since paraxanthine
blood concentration is based on caffeine and/or theobromine metabolism, blood levels of
paraxanthine are dependent on intake of caffeine and theobromine. Its half-life is roughly 3
hours, having a similar clearance rate as caffeine (Lelo et al., 1986). Like caffeine, paraxanthine
is a competitive nonselective inhibitor of adenosine receptors and a competitive nonselective
phosphodiesterase inhibitor (Okuro et al., 2010). Thus, this methylxanthine potentially has
similar effects to caffeine. Compared to caffeine, paraxanthine has lessened anxiogenic effects
and is less toxic (Okuro et al., 2010). Paraxanthine has been found to be more potent than
caffeine at adenosine A1 and A2A receptors, which contributes to stronger antagonistic effects,
especially the enhancement of wake-promoting effects; however, paraxanthine is the weakest
blood-brain barrier penetrator of the primary methylxanthines (Okuro et al., 2010; and
Svenningsson et al., 1999). Nonetheless, the proposed mechanism of action responsible for the
wake-promoting effects of paraxanthine and caffeine is thought to rest on the activation of
ryanodine receptors. Such activation thereby causes a mild elevation of intracellular calcium in
dopaminergic neurons (Guerreiro et al., 2008). The increase in calcium leads to potassium
influx, ultimately leading to increased neuronal firing (Stocker, 2004). A similar event has been

8. found to occur in skeletal muscle whereby intracellular calcium concentrations increase, which
leads to signaling cascades, modulated phosphorylation events, and disruption of potassium
homeostasis via indirect effects of intracellular calcium on Na+
/K+
-ATPase activity (Hawke et
al., 2000). Such an effect places skeletal muscle in a subthreshold state making it readily able to
contract, which could be the partial reason for methylxanthine-induced muscle twitching,
spasms, and jitteriness in users. The fact that a similar mechanism occurs in neurons and
myofibers, resulting in either modulated or potentiated function, corroborates the effects of
paraxanthine (i.e., wake promotion and muscle excitability).
THEOBROMINE: PROPERTIES AND EFFECTS
Theobromine is a naturally-occurring methylxanthine found in some of the same sources
as caffeine, such as cocoa, chocolate, guarana, and tea leaves. After ingestion, peak blood
concentration of theobromine is seen at 2-3 hours; it has a half-life of 7.5 hours (Lelo et al.,
1986). Theobromine is one-tenth as potent as caffeine and is very much less active, having
“two- and threefold lower affinity than caffeine for A1 and A2A receptors (Baggott et al.,
2013).” It is also a less-efficacious phosphodiester inhibitor; thus, the effects of theobromine
tend to be smaller when compared to caffeine. Compared to caffeine, theobromine does not
penetrate the blood-brain barrier as readily but is a more potent cardiac stimulant (Baggott et al.,
2013). Studies have shown that theobromine administration at 300-600 mg/day causes coronary
artery dilation and at 979 mg/day with cocoa for three weeks, it decreased systolic blood pressure
and increased heart rate (van den Bogaard et al., 2010). However, typical intake for the 90th
percentile of theobromine users is 150 mg/day. Although smaller amounts of this
methylxanthine may not afford demonstrated effects, there may be interactive effects between
caffeine and theobromine (Baggott et al., 2013). Lastly, at 700 mg there have been observed

9. effects such as decreased blood pressure, decreased calmness, and increased interest in
performance of study tasks (Baggott et al., 2013). This observation associates theobromine with
common caffeine effects, namely nervousness and uneasiness with increased alertness and focus
on tasks.
THEOPHYLLINE: PROPERTIES AND EFFECTS
Theophylline occurs in nature, typically within cocoa beans and tea leaves. This
methylxanthine acts as a nonselective adenosine receptor antagonist, as well as a competitive
nonselective phosphodiesterase inhibitor. In relation to caffeine, theophylline is a more potent
adenosine antagonist (Greer et al., 2000) and has toxic effects similar to that of caffeine (Hymel,
2010). Its half-life is 6 hours; its metabolism is varied but can be increased via nicotine and
tetrahydrocannabinol, and certain diets (i.e., fatty meals) can increase likelihood of toxicity
(Hendeles et al., 1985; Lelo et al., 1986; and Regal et al., 2005). Theophylline was once a major
therapeutic agent for respiratory diseases, treating asthma and chronic obstructive pulmonary
disease; it is able to impose its therapeutic effects via adenosine A1, A2, and A3 receptor
antagonism and phosphodiesterase inhibition (Daly et al., 1987; and Deree et al., 2008). Aside
from its therapeutic effects, the main actions of theophylline include bronchodilation, positive
chronotropic and inotropic cardiac effects, increased blood pressure, increased renal perfusion,
and stimulation of medullary respiratory centers (Dixon & Bauch, 2002). Although
bronchodilation aids in the breathing of asthmatic patients, research has found that theophylline
has the ability to decrease leukocyte chemotaxis and superoxide production, which could mean
that suppressed immunity and diminished inflammatory responses underlie the favorable
respiratory effects of theophylline (Deree et al., 2008; and Yasui et al., 2000). In relation to
cardiac function, a study on exercise tolerance and theophylline found that theophylline had a

10. chronotropic effect on the heart that apparently increased exercise tolerance in persons with
bradyarrhythmias (Dixon & Bauch, 2002).
In summary of the physiologic effects and their related clinical presentations, caffeine
and related methylxanthines may induce changes in blood pressure, heart rate, urine excretion
and hydration levels, plasma catecholamine levels, and renin activity, and can potentially cause
tension-anxiety, jitteriness, nervousness, agitation, tremors, tachypnea, and insomnia (Chawla,
2013; Maughan & Griffin, 2003; and Okuro et al., 2010).
CAFFEINE TOLERANCE
Drug tolerance, or metabolic tolerance, is characterized by cellular adaptations to a
pharmacologically active substance whereby “increasingly larger doses are required to produce
the same physiologic or psychologic effect” that was once obtained with smaller doses
(Tolerance, 2014). Since caffeine has been shown to produce physiologic and psychologic
effects, caffeine tolerance should be considered.
Caffeine tolerance can be partly attributed to increased metabolism via hepatic clearance
mechanisms, particularly via the isozyme CYP1A2 of cytochrome P450 system (Regal et al.,
2005; and Svenningsson et al., 1999). This notion can be substantiated by the work of
Svenningsson and colleagues. They found that after the administration of caffeine in tolerant
animals there was a drastic increase in two caffeine metabolites: paraxanthine and theophylline.
Knowing that these two methylxanthines have a greater affinity for adenosine receptors than
caffeine, “the bioavailability of methylxanthines blocking adenosine receptors in the plasma is
increased in chronically caffeine-treated animals.” This indicates that in tolerant animals there is
a greater quantity of caffeine metabolites within the circulation, imposing their effects on
adenosine receptors. However, unlike caffeine, these two metabolites do not penetrate the blood-

11. brain barrier as efficiently as caffeine; therefore, “the enhanced metabolism of caffeine in the
periphery does not lead to increased amounts of active methylxanthines in the brain.” Thus,
there is a decreased stimulatory effect within brain regions due to an increased metabolism of
caffeine.
Other mechanisms have been proposed for caffeine tolerance, including the adaptive
responses of adenosine receptors A1 and A2A in specific brain regions (Svenningsson et al.,
1999). Caffeine has a biphasic effect, meaning that small amounts are stimulatory and large
amounts are inhibitory. Previous studies have shown that large doses of caffeine create complete
tolerance, whereas small doses create incomplete tolerance to psychostimulatory responses of
caffeine. In the Svenningsson study, they found that there was a “significant upregulation” of
A1 receptors in the lateral amygdala after administering small doses of caffeine. This increased
adenosine A1 receptor concentration may point to “caffeine’s ability to affect conditioned
learning processes, particularly those related to fear and anxiety.” An adaptive response likely
exists in this situation, one where upregulation of A1 receptors could potentially correlate with
the anxiogenic effects of caffeine.
In regards to adenosine A2A receptors, the Svenningsson study demonstrated a
downregulation with caffeine administration. Basically, if there is a downregulation of A2A
receptors, then caffeine as well as endogenous adenosine will have a diminished biological
effect. It is important to note that the A2A receptors that were examined in the Svenningsson
study were ones found in regions of the brain related to locomotion, specifically in globus
pallidus and striatopallidal regions. Moreover, caffeine was found to decrease the expression of
c-fos and NGFI-A (immediate early gene expression markers) in striatopallidal neurons.
Tolerance to the effects of caffeine on locomotion was concluded on the basis that “disinhibition

12. of striatopallidal neurons” leads to the ability of caffeine to induce c-fos mRNA in globus
pallidus. In other words, a decreased receptor count in striatopallidal neurons may lead to
decreased biological effect of caffeine, subsequently leading to increased caffeine availability for
induction of c-fos via cAMP-dependent protein kinase gene expression mechanisms in globus
pallidus. The induction of c-fos in globus pallidus is significant because the proposed cellular
involvement of c-fos is cell proliferation, differentiation, and survival. Hence, with induced
neuroplasticity within globus pallidus, an adaptive environment may afford normalized
subconscious movement; therefore, tolerance to the effects of caffeine on locomotion is possible.
Human studies that focus on caffeine tolerance typically have been based on subjective
findings. In a study from 1992, Evans and Griffith found that caffeine produced significant
subjective effects in the chronic placebo group but not in the chronic caffeine group. Essentially,
the chronic caffeine group experienced less caffeine effect, whether it be subjective or not, as
compared to the chronic placebo group (Evans & Griffith, 1992). Regardless of subjectivity and
qualitative parameters set forth by this experiment, there is strong correlative evidence for
induction of caffeine tolerance via chronic caffeine consumption.
DISCUSSION
Caffeine tolerance has been substantiated and the effects of caffeine have been reviewed;
the next step is to look at how tolerance could mitigate caffeine’s effects on reaction time, eye-
hand coordination, and gross and fine motor skills.
Reaction time is simply defined as “the time elapsing between the beginning of the
application of a stimulus and the beginning of an organism’s reaction to it (Reaction time,
2014).” Reaction time can be affected by aging, physical fitness, arousal or state of attention
(i.e., tiredness or fatigue, exhaustion, distraction, confusion, and nervousness), muscular tension,

13. overt relaxation, and anxiety (Easingwood, 2010). Thus, reaction time could be affected by
anything that causes any of the aforementioned states or conditions. As described above,
caffeine has been shown to cause anxiety and many other caffeine-induced physiologic states
previously mentioned.
So, how does anxiety affect reaction time? A dated study from 1955 found that “the
group with lower anxiety had superior performance ratings on a reaction-time task.” The
researchers further mentioned that although this superiority was considered to be a reflection of
higher intelligence, the effect of high anxiety levels on reaction time could not be ruled out
(Grice, 1955). Conversely, a study done in 2006 showed that moderate-state anxiety “improves
performance in visual and auditory response times both at reaction time and movement time
level.” Even though this finding suggests an anxiety-based advantage for reaction time, anxiety
levels are likely to vary across populations, and this sheds light on a concern relating to how low-
and high-state anxiety might potentially affect reaction times (Hainaut & Bolmont, 2006).
Adding fuel to the fire, Baggott et al. in 2013 stated, “Caffeine has been found to directly
decrease reaction time, whereas other methylxanthines, particularly theobromine, do not.”
However, with the indirect effects of caffeine on reaction time soon to be described, there may
be more evidence to suggest an overall increased reaction time when caffeine is consumed by
intolerant users. Lyvers and colleagues in 2004 showed that “According to attentional theory,
anxiety impairs processing efficiency because it reduces attentional control, especially in the
presence of threat-related distracting stimuli.” If processing efficiency can be impaired by
anxiety and caffeine can induce anxiety, then caffeine could indirectly cause impairment of
processing efficiency and thereby negatively affect reaction time. This particular study looked at
the effects of caffeine on cognitive and autonomic measures in heavy- and light-caffeine users,

14. and they concluded that tolerance can ameliorate the anxiogenic effects of caffeine (Lyvers et al.,
2004). Furthermore, another study from 2007 concluded that “anxious individuals are more
distracted” by task-irrelevant stimuli whether these stimuli are external (i.e., flying birds) or
internal (i.e., worry) (Eysenck et al., 2007). Increased distraction displaces the concentrative
capacity on tasks that may require decreased reaction time; therefore, anxiety could indirectly
lead to increased reaction time. Thus, tolerance to caffeine could potentially mitigate these
anxiogenic effects of caffeine on reaction time, especially if an individual has a single nucleotide
polymorphism that allows for adaptation to the anxiogenic effects of caffeine (Baggott et al.,
2013). However, as it relates to statements made in the Baggott study, if caffeine can directly
decrease reaction time, then in tolerant individuals there will likely be a short-lived decrease in
reaction time and/or a normal or baseline reaction time; therefore, persons wishing to use
caffeinated beverages to improve reaction time ought to do so in moderation, as to avoid
induction of tolerance. Baggott mentioned that other methylxanthines do not decrease reaction
time; maybe they have no effect, or maybe they have a negative effect on reaction time. No
literature has been found to confirm such effects of other methylxanthines on reaction time.
Nonetheless, possibly in the intolerant individual, the decreased reaction time produced directly
from caffeine consumption could offset or neutralize the anxiogenic effects of caffeine on
reaction time. This may be a direction for future studies, as well as ones that focus on the effects
of alternate methylxanthines on reaction time.
Anxiety, as well as nervousness, is thought to negatively affect gross and fine motor
skills. Many publications point toward a negative effect of high-state anxiety and nervousness
on gross motor skills (Beilock & Carr, 2001; Easingwood, 2010; and Lyvers et al., 2004). Fine
motor skills also have been shown to be negatively affected by anxiety, stress, and nervousness

15. (Beilock & Carr, 2001). Since gross motor skills (i.e., movement of shoulder, arm, and forearm)
and fine motor skills (i.e., movement of eyes and fingers) are required for eye-hand coordination,
it is probable that any alteration in either gross or fine motor skills will impact eye-hand
coordination. Ultimately, the effects of caffeine, anxiety, nervousness, and jitteriness on muscle
activity are quite profound, creating changes that diminish optimization of muscle coordination
and physical performance. Thus, if caffeine tolerance is acquired, then these caffeine-induced
effects could be lessened or even negated.
Dehydration has been found to affect motor skills (Booth et al., 2012). In general,
dehydration can cause signs and symptoms such as weakness, syncope, confusion, and dizziness.
Mild dehydration can create disturbances as well, such as mood changes, muscle cramps, and
decreased cognitive processing and energy levels (Kaneshiro, 2013). Physiologic changes that
occur with dehydration include but are not limited to decreased blood volume, increased blood
viscosity, decreased venous return, and decreased cardiac output (Jeukendrup & Gleeson, 2010).
These changes are directly related to the said signs and symptoms. Since caffeine can disturb
hydration status due to its effect on aldosterone, it is possible that mild dehydration could arise in
intolerant caffeine users. The effects of mild dehydration could at the very least exacerbate the
other physiologic and psychologic effects of caffeine. As dehydration relates to motor skill
dysfunction, the study by Booth and colleagues found that water supplementation improved
visual attention and fine motor skills. Apparently, maintaining proper fluid levels is paramount
during any activity, even while at rest. Relating caffeine tolerance to dehydration is rather
straightforward, because Maughan and Griffin in 2003 stated, “Chronic users become tolerant to
the diuretic effect of caffeine.” With tolerance comes a decreased risk of dehydration, which
helps protect the chronic, tolerant caffeine consumer from the deleterious physiologic effects of

16. dehydration, and such protection assists in maintaining an individual’s motor skills during
performance-based tasks.
In summary, caffeine can produce changes in blood pressure, heart rate, urine output,
plasma catecholamine levels, and renin activity, and cause tension-anxiety, jitteriness, and
nervousness. Each one of these changes or results, based on the evidence provided, can
effectively be reduced if tolerance has been acquired (Chawla, 2014).
CONCLUSION
Many studies have focused on the effects of caffeine in regards to physical performance,
some relating to perception of exertion, maintenance of alertness, suppression of fatigue, and
decreases in reaction time. Like any consumable substance, there are possible side-effects,
potential interactions, and toxicity concerns, but the effects mentioned throughout this review
have been directed at tolerance and how tolerance can potentially negate those effects. Although
the negative effects of caffeine may be negated via tolerance, positive effects may be negated
too. Thus, if caffeine should be used as an aid to provide its proposed positive effects, then the
potential negative effects as well as the tolerance effects need to be considered. Without
consideration of how tolerance can affect the overall effects of caffeine, studies aiming to find
how caffeine affects physical performance tasks will have ambiguous and/or inconclusive
findings, as this may predispose to confounding. As the Baggott study so wisely included in its
methods, they selected participants “who reported very low regular use of caffeine and related
methylxanthines, to minimize the effects of tolerance and withdrawal.” Without control for
tolerance, there may be resultant effects concerning physical performance that render studies
invalid.

17. Suggested solutions for avoiding these unfavorable scenarios rely on sound inclusion
criteria, which include evaluating usual caffeine intake prior to the study, rating perceptions and
subjective feelings related to caffeine intake, genotyping participants for polymorphisms related
to adaptation to caffeine and its effects (i.e., anxiety), testing participant intelligence quotients,
and gathering information on participants’ baseline motor skill performance prior to the study.
Establishing hydration status prior to the study as well as a follow-up hydration status evaluation
may be beneficial for ruling out dehydration effects.
Susceptibility to tolerance may be exposed via evaluation of chronic, heavy users of
caffeine and their physical performance outcomes, and if results differ, then the chronic users
that demonstrated the highest scores on performance should be grouped as the “tolerant chronic
users” or “pseudo-nonusers” and subsequently contrasted with non- and mild-users’ performance
outcomes. Hypothetically, the chronic users that scored the lowest (assuming baseline measures
were unequivocal among chronic, heavy user participants) will be considered the “non-tolerant
chronic user” group and then placed into the experimental comparison study regarding caffeine’s
effect on physical performance.
Because there is an unforeseeable dynamic that exists within human physiology, just as it
applies to caffeine, related methylxanthines, and their effects, there will likely never be just one
factor that reveals absolute truth or universal applicability. Many follow-up studies and study
designs of the future will need to be set forth, as to move forward leading to the answers that
science so fervently seeks. In the meantime, we shall continue to construct our studies wisely
and conduct them rapaciously, for the answers are out there awaiting our arrival.

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