Graduation Project

Title
The efffect of coffee and

caffeine consumption for

health and performance

By/

1- Asmaa Elmaghwry Megahed 2- Aml Tarek Fathy Awad

3- Eman AbdelKader Elsady 4- Aya Selmy Abdelrahman

5- Shahd Ahmed Elsayed

Dietetic Program - Level 4

Faculty of Agriculture – Mansoura university

Supervisors:
Dr. Mohammed Samir Darwish Dr. Asmaa Abd-Allah El-Awady
Associate Prof. of Dairy Technology Lecturer of Dairy Technology
Dairy Science Department, Dairy Science Department,
Faculty of Agriculture, Faculty of Agriculture,
Mansoura University. Mansoura University.

2021/2022

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No Subject Page

Abstract 9

Introduction 01

1 Caffeine 01

1.1 General Information 02

1.2 Dietary Sources Of Caffeine 02

1.3 Average caffeine content in foods, beverages, 15

and medications

2 Pharmacology Of Caffeine 01

2.1 Pharmacokinetics: absorption, distribution, 01

metabolism, excretion.

2.1.1 Genetic Variation 09

2.2 pharmacodynamics of caffeine. 20

2.2.1 Antagonism of Adenosine 20

2.2.2 Mobilization of Intracellular Calcium 22

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2.2.3 Inhibition of Phosphodiesterases 21

2.2.4 Increase of Post-exercise Muscle 23

Glycogen Accumulation

2.2.5 Increase of Fatty Acid Oxidation 23

3 The Role of Caffeine in Various Systems in the 24

Human Body

3.1 Central Nervous System. 25

3.1.1 Caffeine Impact on Children and Adolescent 25

3.1.2 Caffeine and Taste Perception 26

3.1.3 Caffeine and Alzheimer’s Disease 26

3.1.4 Caffeine and Parkinson’s Disease 27

3.1.5 Caffeine and Mental Health 28

3.1.6 Caffeine and Perception of Pain 29

3.2 The Immune System 29

3.3 Digestive System 31

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3.3.1 Caffeine Action on the Small and Large Intestine 31

3.3.2 Caffeine and the Liver 32

3.3.3 Caffeine and Glycaemia 33

3.3.4 Caffeine and Digestive Tract Cancer 33

3.4 Respiratory System 33

3.4.1 Caffeine and Asthma. 34

3.4.2 Caffeine and Breathing Problems 34

3.4.3 Caffeine and Lung Cancer 35

3.5 Circulatory System 36

3.5.1 Caffeine and Arrhythmia 37

3.6 Urinary Tract 37

3.6.1 Caffeine and Urinary Incontinence 39

3.6.2 Caffeine and Kidney Stones 39

3.7 Skeletal and Muscular System 40

3.7.1 Caffeine and Bones 47

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3.7.2 Caffeine Action on Muscle Filaments and 41
Muscular Strength
3.8 Reproductive Effects 41

3.9 Birth Weight Effects 42

3.10 caffeine effects on lactation 42

3.11 Caffeine effects on Fibrocystic Breast Disease 43

3.12 Other Health Concerns 44

3.12.1 .Is Caffeine Addicting? 45
4 . Caffeine consumption and performance 46
4.1 Optimal Prescription of Use 47
4.2 Caffeine Habituation 48
4.3 Caffeine and endurance exercise. 50
4.4 Caffeine and muscular endurance, strength and 50
power.
4.5 Caffeine and sport-specific performance. 51
5 Caffeine Dependence 53
6 Toxicity of Caffeine 55
7 Caffeine–Drug Interactions 57
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8 Contraindications. 59
9 Recommendations Safe Intake 61
Conclusion 63
References 66

N0 Table page
Table Average caffeine content in foods, beverages, 15
1 and medications
Table The main effects of caffeine action on the 30
2 nervous system and the most likely mechanisms
of its action
Table The effects of caffeine action in respiratory 35
3 system diseases

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 No Picture page
Figure The most popular plants and products 12
1 containing caffeine. Based on de Mejia et al
Figure The scheme of the main effects of caffeine 32
2 action on the digestive system. ALT—alanine
aminotransferase, AST—aspartate
aminotransferase, GGT—γ-glutamyltransferase.
↓↓↓—decrease, ↑↑↑—increase
Figure The main effects of caffeine action on the 38
3 kidneys. The main effects of caffeine action on
the kidneys. ↓↓↓ ↓↓↓—decrease, —
decrease, ↑↑↑ ↑↑↑ —increase

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 Acknowledgement
Thanks to Allah by the grace care of whom indeed , we could find our way Out to Complete
this work and have it come out to light.

We would like also to express thank to (Dr. Mohammed Samir Darwish) Associate Prof. of
Dairy Technology Dairy Science Department , fac . of Agric . , Mansoura University , for her
kind help and continuous encouragements facilities and support .

The authoress wishes to express their deepest gratitude and sincere appreciation to (Dr.
Asmaa Abd Allah El - Awady) Lecturer of Dairy Technology Dairy Science Department , fac .
of Agric . , Mansoura university for her kind and continuous guidance throughout the
experimental work .
The authoress grateful to all members stuff in Dairy science and technology Department for
their encouragements.
It Wants Dedicate This Work to our parents Thanks , are also due to all my friends and may
colleagues who helped us in various ways during this Study and .
We Hope that This Work may have Won admiration From Reads and also we hope that
through this work, we can guide and raise all people on safe consumption of caffeine to
benefit from its benefits and avoid damage and its side effect .

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Abstract
Caffeine is the most widely consumed psychoactive drug in the world. Natural sources of
caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to
promote arousal, alertness, energy, and elevated mood. Over the past decade, the
introduction of new caffeine-containing food products, as well as changes in consumption
patterns of the more traditional sources of caffeine, has increased scrutiny by health
authorities and regulatory bodies about the overall consumption of caffeine and its
potential cumulative effects on health and performance, So we will review in this research
the caffeine sources and its content in food and beverages and its important to show how
the body deal with caffeine through discussing its pharmacodynamics and pharmacokinetics
,its optimum dosage , withdrawal symptoms, toxicity and some warning and precautions . Of
particular concern is the rate of caffeine intake among populations potentially vulnerable to
the positive and negative effects of caffeine consumption and their effects on body systems,
pregnant and lactating women, children and adolescents, young adults, athletes ,and people
with underlying some health conditions. We report that, for healthy adults, caffeine
consumption is relatively safe , but that for some vulnerable populations, caffeine
consumption could be harmful, including impairments in cardiovascular function , Nervous
System and sleep.

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Introduction

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 Introduction
Caffeine (1,3,7-trimethylxanthine) is the world's most widely consumed drug with its main
source found in coffee (1). Estimates of daily caffeine consumption in the United States in
1978 indicated that approximately 200 mg was consumed daily by adults over the age of 18
with coffee accounting for about 75% of the total caffeine consumed (2). An average cup of
coffee contained approximately 85 mg of caffeine; hence average consumption was slightly
over two cups of coffee per day.

Caffeine is rapidly absorbed in the stomach and small intestine and metabolized primarily in
the liver. It is excreted in 24-h urine as dimethylxanthines, uric acid derivatives, and 2.4%
caffeine (3). The plasma half-life ranges from 2.3 to 12 h (3). with caffeine plasma
concentrations reaching peak levels at 45 rain to 2 h after ingestion (1). The half-life of
caffeine is increased for those with liver disease, in newborns, and during pregnancy
(1).Caffeine produces central nervous system stimulation and has been found to positively
influence human performance.

In two separate studies, in which caffeine doses of 60 mg and 100 mg were administered,
caffeine affected human performance by speeding reaction time and increasing alertness
(4,5). The effects of low dosage have been investigated with as little as 32 mg improving
auditory vigilance and visual reaction time (6).

Further, it has been suggested that caffeine might improve road safety since driving
simulation tests have found that caffeine ingestion increases alertness and driving
performance (7).

Although there are beneficial effects of caffeine ingestion, there may also be potentially
harmful effects. There has been considerable study of the effects of caffeine on the
cardiovas-cular system. In one study in which doses of 45-360 mg of caffeine were
administered, both systolic and diastolic pressures in-creased, with a significant heart rate
increase after the 360-mg caffeine dose (8). In another study, it was concluded that anxiety
may be increased with doses of 300 mg or higher (9), and a separate study found increased
anxiety with as little as 125 mg of caffeine (10). Care should be exercised when consuming
caffeine with medications such as bronchodilators (both stimulate the central nervous
system), quinolones (increases caffeine levels leading to excitability and nervousness), and
anti-anxiety drugs (lessens effects of drug) (11).

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Caffeine

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1-Caffeine
1.1-GENERAL INFORMATION:-

Caffeine (1,3,7-trimethylcanthie or 3,7-dihydro-1,3,7-trimethyl-1H-purine-2,6-dione), a well-

known purine alkaloid, was described by Gennaro (12) as a white, odorless powder with a
slightly bitter taste. Its chemical formula is C8H10N4O2.

Caffeine occurs in more than 60 plant species globally [13]. This substance is produced by
extraction from green coffee beans, tea leaves, and cola nuts, and also by synthetic
procedures (e.g., methylation of various xanthines and theophylline) [12].

Figure 1. The most popular plants and products containing caffeine. Based on de Mejia et al.
[181].

1.2.DIETARY SOURCES OF CAFFEINE:-

Adults commonly consume caffeine in coffee and tea, both of which contain natural caffeine
in their leaves or beans.

Energy drinks often contain caffeine from natural products such as extracts from guarana
leaves. In addition to coffee, tea, and energy drinks, caffeine is also naturally present in
cocoa beans and thus in chocolate.

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 The amount of caffeine in chocolate varies by the percentage of cocoa it contains, with
100% cocoa chocolate (unsweetened baking chocolate) containing around 240 mg
caffeine/100 g, 55% cocoa (bittersweet) containing 124 mg caffeine/100 g, and 33% cocoa
(milk chocolate) containing 45 mg caffeine/100 g . Synthetic caffeine is also added to soda
and energy drinks, which are commonly consumed by children and adolescents worldwide,
and to other food and non-food products with niche markets for subsets of consumers, such
as juice, chewing gum, water, cookies, hot sauce, candy, beef jerky, mints, syrup, waffles,
shampoo, soap, lip balm, eye cream, body scrub, and body lotion.

These products are primarily marketed with claims that they provide energy, alertness, or
are “age-defying.” Last year, the FDA announced that it will begin investigating the safety of
caffeine added to food products, with a special emphasis on children and adolescents.
Caffeine is a constituent of many over-the-counter pain relievers and prescription drugs
because the vasoconstricting and anti-inflammatory effects of caffeine act as a compliment
to analgesics, in some cases increasing the effectiveness of pain relievers by up to 40%.
Caffeine is used for general pain relief in medications such as Midol™ and Vanquis™, which
contain doses rang-ing from 33 to 60 mg. It is used therapeutically in combination with
ergotamine to treat migraine headaches and in combination with non-steroidal anti-
inflammatory analgesics. Anacin™, Excedrin™, Goody’s™ headache powder, and pain
reliever plus contain between 32 and 65 mg of caffeine, and prescription headache
medications, including Fiorinal, Orphenadrine, and Synalgos, contain between 30 and 60 mg
of caffeine. Alone, caffeine is used as a somnolytic to counteract drowsiness (e.g., NoDoze™
and Vivarin™ each contain 200 mg of caffeine), to enhance seizure duration in
electroconvulsive therapy, and to treat respiratory depression in neonates, postprandial
hypotension, and obesity . Similar synergistic additive effects of caffeine and medications
also occur in treatments for asthma and gall bladder disease, attention deficit-hyperactivity
disorder, shortness-of-breath in newborns, low blood pressure, and weight oss . Between 50
and 200 mg of caffeine is added to some weight-loss supplements (Dexatrim™,
Hydroxycut™, and Nutrisystem™ Energi-Zing Shake) for its purported effects on appetite
suppression and increased metabolism and ]14[.

1.3.Average caffeine content in foods, beverages, and medications:-

The amount of caffeine contained in a cup of coffee can vary greatly, depending on its
origin or the composition of the blend, the brewing method, and the strength of the brew.
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Instant (also known as soluble) coffee generally contains less caffeine than roast and ground
coffee, but is usually consumed in greater volumes. Robusta coffees contain about twice as
much caffeine than arabicas. A cup is usually assumed to contain 180 ml of coffee, but an
espresso may contain as little as 40 ml (15)Decaffeinated coffee, regardless of the method
of decaffeination, must contain less than 0.1% caffeine by dry weight to comply with
regulations. This corresponds to about 3-5 mg of caffeine in a cup of decaffeinated coffee.
Tea contains more caffeine than coffee by dry weight, but less weight is used, in general, to
brew a cup of tea. Both the type of tea and the infusing time can affect the amount of
caffeine.

The caffeine content of a cup of tea is usually less than 60 mg, but a strong cup of tea may
contain more caffeine than a weak cup of regular coffee ]Table 1[.

Cocoa and chocolate drinks contribute to the diet with 4-5 mg of caffeine per cup, dark
chocolate and cooking chocolate with 0.7-0.9 mg per gram. Numerous soft drinks, including
colas and peppers, contain caffeine, which, as well as being present in cola nuts, is often
added as a flavoring agent. About 180 ml of a soft drink contain 30-70 mg of caffeine. The
major brands of cola sold in Europe contain about 120 mg of caffeine per liter ]Table 1[.

Caffeine is present in many prescription and nonprescription(i.e., over-the-counter)

medications, including some taken for headache, pain relief, cold, appetite control, staying
awake, asthma, and fluid retention. The caffeine content of drugs varies from 16 mg to 200
mg per tablet.

Energy drinks contain high concentrations of caffeine, as well as other performance-

enhancing substances, such as guarana, taurine, and B vitamins. They claim to provide its
consumers with extra energy.

Table1. Average caffeine content in foods, beverages, and medications (adapted from
Cherniske, 1998 [16]).

Servings Item Total Caffeine (in

per day mg)
Coffee (180 ml cup) Drip brewed 100 mg per 180 ml
Percolated 120 mg per 180 ml
Instant 90 mg. per 180 ml
Brewed decaffeinated 5 mg per 180 ml
Instant decaffeinated 3 mg per 180 ml
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 Tea (180 ml cup) Green 35 mg per 180 ml
Black 70 mg per 180 ml
Canned ice tea 35 mg per 360 oz can
Cocoa Cocoa beverages 13 mg per 180 ml
Chocolate Milk chocolate 6 mg per 30 ml
Baking chocolate 35 mg per 30 ml
Small candy bar 25 mg per bar
Soft drinks (360 ml Leading colas (regular and diet) 45 mg
can) Dr. Pepper 40 mg
Mello Yello 53 mg
Mountain Dew 54 mg
Mr. Pibb 41 mg
OK Soda 40 mg
Jolt Cola 72 mg
Medications (per Anacin 32 mg
tablet) Dristan (i.e., acetylsalicylic acid+caffeine) 16 mg
Dexatrim (i.e., 16 mg
phenylpropanolamine+caffeine)
Excedrin (i.e., 200 mg
acetaminophen+acetylsalicylic
acid+caffeine)
Midol (i.e., acetaminophen+pyrilamine 32 mg
maleate+caffeine)
Nodoz (i.e., caffeine) 100 mg
Vivarin (i.e., caffeine) 200 mg
Vanquish (i.e., 33 mg
acetaminophen+acetylsalicylic
acid+caffeine)
Energy drinks 28 Energy Drink 80 mg
6 Hour Power 125 mg
BANG Energy Drink 357 mg
Biggby Iced Coffee 192 mg
Caffeine Energy Drink 140 mg
Chameleon Cold Brew Coffee 2160 mg
Cocaine Energy Drink 280 mg
Diablo Energy Drink 95 mg
Guayaki Empower Mint 140 mg
.

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pharmacology

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2- pharmacology of caffeine
2.1 pharmacokinetics: absorption, distribution, metabolism, excretion.

After ingestion, caffeine is quickly absorbed from the gastrointestinal tract into
the circulatory system .The maximum plasma concentration is reached after 30-
60 minutes from consumption. However, maximum plasma concentrations
reached between 15 and 120 min have been reported, due to inter-individual
differences and delayed gastric emptying. Caffeine is widely distributed through
the body.

The pre-systemic (i.e., first-pass) metabolism takes place in the liver, since orally
ingested substances are absorbed through the small intestine into the portal
circulation, before entering the systemic one. Caffeine’s pre-systemic metabolism
is negligible and, once caffeine is absorbed, it promptly gets into all the body
tissues and crosses the blood-brain, blood-placenta, and blood-testis barriers .

The hepatic microsomal enzyme system is in charge of caffeine metabolism in the

liver. The main enzyme responsible for caffeine metabolism is cytochrome P450
1A2 (CYP1A2), which accounts for about 95% of caffeine clearance. Caffeine
metabolism rate is controlled not only by CYP1A2, but also by xanthine oxidase
and N-acetyltransferase 2 (NAT2). Only from 0.5% to 2% of ingested caffeine is
excreted as such in the urine, as it undergoes an almost complete tubular
reabsorption .

Caffeine’s half-life in humans ranges from a minimum of 2 to a maximum of 12

hours , mainly due to the inter-individual variability in absorption and
metabolism. When levels of intake are higher, a prolonged duration of action can
be observed, possibly because of a delay in caffeine clearance and an
accumulation of paraxanthine and other xanthines.

In fact, caffeine is subjected to demethylation, resulting mostly in the release of

paraxanthine (84%), followed by the obromine (12%) and theophylline (4%).

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The chemical structure of the xanthines theobromine and theophylline is very
similar to that of caffeine . These metabolites are further transformed in the liver
through demethylation and oxidation, resulting in the production of urates .there
are significant inter-individual differences in the metabolism, clearance, and
elimination of caffeine and its metabolites. Several extrinsic factors influence
metabolic and excretion rates, such as smoking, food intake, gastric emptying
speed, pregnancy, hepatic and cardiovascular diseases, viral infections, and
concomitant drug use.

In particular, smokers are characterized by a metabolism rate that is almost twice

the one of nonsmokers . Cigarettes contain polycyclic aromatic hydrocarbons that
promote a greater liver enzyme activity, thereby increasing caffeine metabolism .
Smoking may accelerate the pre-systemic (i.e., first-pass) and systemic (i.e.,
second-pass) metabolism of caffeine, with the hepatic microsomal oxidative
enzymes causing a faster demethylation.

Pregnancy decreases the clearance and excretion of caffeine, thus the latter and
its metabolites(17).

2.1.1.Genetic Variation.

The CYP1A2 gene, which encodes for a cytochrome P450 enzyme, has a large
genetic variability. At least 150 single-nucleotide polymorphisms can accelerate
caffeine clearance . The metabolic consequences of this polymorphism on
caffeine down-stream effects should be studied in humans. Genetic variation (i.e.,
increased or decreased activity of the cytochrome P450 oxidase enzyme) may
increase or decrease the possible harmful effects of caffeine (e.g., during
pregnancy) and any beneficial effects (e.g., on memory and learning during aging
or in pathologies, such as Alzheimer’s disease). The half-life of caffeine may also
be increased in liver diseases, which decreases P450 activity .The molecular
targets of caffeine, namely the adenosine receptors, also have great genetic
variability. For example, common variants of the gene encoding for the A2a
receptor can disrupt sleep or cause anxiety in some individuals after ingesting
caffeine.
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 More studies are needed to determine the effects of genetic variants on the
consequences of caffeine consumption , not only in the central nervous system
but also in other organs, such as the heart .

 Circadian Rhythms:-
The expression of the cytochrome P450 epoxygenases is regulated in a circadian
manner . Although this effect was discovered in cultured rodent cells, it may apply
to many species, including humans . The implications are particularly important
because the effects of caffeine (at least the duration of its activity) will differ
during the circadian cycle. Because caffeine can alter sleep, it may also change the
circadian rhythm, leading to a change in expression patterns for the cytochrome
P450. One interesting hypothesis is whether caffeine consumption in adolescents
and adults disrupts the expression of P450 in relation to its circadian rhythm. If
the expression is down regulated, the effects of caffeine could be prolonged and
produce a negative feedback loop.

 Steroid Hormones:-
The cytochrome P450 oxidase enzyme system is the same enzyme that
metabolizes steroid hormones . Thus, steroid hormones slow caffeine metabolism
In women, this effect slows the metabolism of caffeine during pregnancy and
when taking oral contraceptives (57). However, studies have not found marked
differences in caffeine metabolism between the luteal and follicular phases of the
menstrual cycle . Oral contraceptives tend to double the half-life of caffeine

 Pregnancy:-
The half-life of caffeine is on average 8.3 h longer during pregnancy and may be as
much as 16 h longer than usual . This longer half-life means that the effects of
caffeine will be longer lasting in women and in the fetus. Given the effects that
caffeine may have on brain development, this increased half-life in pregnant
women should be taken into account when considering safety issues. Infancy
Caffeine is eliminated more slowly during early infancy, requiring perhaps 80 h in
preterm and healthy-term neonates, because of the reduced efficiency of
cytochrome P450 . Elimination is likely to be at least as slow in the fetus.

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 Fetal exposure to caffeine during pregnancy may potentially have long-lasting
effects, especially in the brain. By age 6 months, infants eliminate caffeine at the
same rate as that of adults .

 Substance Use:-
Cigarette smoking doubles the rate of caffeine clearance by increasing liver
enzyme activity, which may explain the higher rate of caffeine consumption
among smokers . Substantial alcohol intake increases the half-life of caffeine and
decreases its clearance [ 183].

2.2pharmacodynamics of caffeine.

The potential effects of caffeine, at the cellular level, can be explained by three
mechanisms of action: the antagonism of adenosine receptors, especially in the
central nervous system; the mobilization of intracellular calcium storage; the
inhibition of phosphodiesterases.

2.2.1 Antagonism of Adenosine

Caffeine blocks adenosine receptors, mainly A1 and A2Asubtypes, competitively

antagonizing their action [18] and causing an increased release of dopamine,
noradrenalin, and glutamate [19].

Caffeine is able to reduce cerebral blood flow [20]. It is also able to reduce
myocardial blood flow, by inhibiting A1, A2A and A2B adenosine receptors in
blood vessels and limiting adenosine-mediated vasodilation [21].

A1 receptors can be found in almost all brain areas. The highest concentration is
in the cerebral and cerebellar cortices, the hippocampus, and a number of
thalamic nuclei [22], whereas only a modest concentration is found in the corpus
striatum, i.e. the caudate and putamen, and the nucleus accumbens. Pre-synaptic
A1 receptors inhibiting the release of neurotransmitters are present in almost all
types of neurons.

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The ability of caffeine to block adenosine receptors can be observed also at low
doses, such as those contained in a single cup of coffee. Other mechanisms of
action, such as the mobilization of intracellular calcium and the inhibition of
phosphodiesterases, require higher doses of caffeine, unlikely to be obtained with
the common daily dietary sources of caffeine.

2.2.2 Mobilization of Intracellular Calcium.

Caffeine can induce calcium release from the sarcoplasmic reticulum [23] and can
also inhibit its reuptake [24].

Through these mechanisms, caffeine can increase contractility during

submaximal contractions in habitual and nonhabitual caffeine users. Intracellular
calcium determines the activation of endothelial nitric oxide synthase (eNOS),
with the production of higher quantities of nitric oxide [25].

Therefore, some of the effects induced by caffeine might be partly mediated by

neuromuscular function modulation and contractile force increase in the skeletal
muscles [26].

A potential counter effect of caffeine is represented by diuresis stimulation,

accountable for ergolytic effects in endurance athletes during prolonged
workouts and competitions[27].

2.2.3 Inhibition of Phosphodiesterases

Caffeine acts as a nonselective competitive inhibitor of phosphodiesterases [28].

These enzymes hydrolyze the phosphodiester linkages in molecules, such as cyclic
adenosinemonophosphate (cAMP), inhibiting their degradation. cAMP stimulates
lipolysis by triggering the activity of the hormone-sensitive lipase (HSL) and has a
vital role in the adrenaline cascade [29]. It also activates protein kinase A, which
in turn phosphorylates several enzymes implicated in glucose and lipid
metabolism [30].

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These mechanisms of action require very high doses of caffeine, unlikely to be
present in the standard diet, which contains moderate amounts of caffeine.
Further mechanisms of action describe the use of caffeine in sport activities and
as a dietary supplement that are described below.

2.2.4 Increase of Post-exercise Muscle Glycogen Accumulation.

Faster recovery following intense exercise, mediated by a higher rate of glycogen

resynthesis, has been described [31].

It has been maintained that caffeine ingestion has no effect on glycogen stacking
during recovery from exercise in recreational athletes [32]. However, a recent
study has found that caffeine (8 mg/kg body weight), coingested with
carbohydrates, is responsible for higher rates of post-exercise muscle glycogen
stacking in comparison to the ingestion of carbohydrates alone in well-trained
athletes after the depletion of glycogen that follows exercise [33].

Although this finding deserves further investigation in broader population

samples (recreational and professional athletes, untrained individuals) and
occasions (during exercise or recovery), caffeine in addition to post-exercise
carbohydrates consumption seems to be able to stimulate glycogen resynthesis.

2.2.5 Increase of Fatty Acid Oxidation

The increase of lipolysis determines a decreased dependence from glycogen use

[34]. Caffeine switches the substrate preference from glycogen to lipids by
stimulating HSL activity and inhibiting glycogen phosphorylase activity [35]

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The Role of Caffeine in Various
Systems in the Human Body

24 | P a g e
3. The Role of Caffeine in Various Systems in the Human Body

3.1. Central Nervous System.

Caffeine has multiple targets in the brain such as adenosine, ryanodine, γ-

aminobutyricacid receptors, and cyclic nucleotide phosphodiesterase isoenzymes.
Its action on A2ARs may explain the psychomotor stimulant effect, mediated by
dopaminergic mechanisms. Caffeine, through antagonism of ARs, affects brain
functions such as sleep, cognition ,learning, and memory, and modifies brain
dysfunctions and diseases: Alzheimer’s dis-ease, Parkinson’s disease, Huntington’s
disease, epilepsy, pain/migraine, depression, and schizophrenia [36].

Another possible mechanism of caffeine’s action on the nervous sys-tem is

inhibition of the neurotransmitter acetylcholinesterase (AChE) [37].

This may bean important discovery for many studies on the effects of caffeine,
clinically proven, but with unknown mechanisms of action. At low doses (<2
µg/mL in blood), caffeine stimulates the central nervous system but high blood
concentration of caffeine (10–30 µg/mL)may produce restlessness, excitement,
tremor, tinnitus, headache, and insomnia [38]. This conclusion was reported by
Kaplan et al. [39], who observed that a lower dose (250 mg)of caffeine produced
more positive effects (elation, peacefulness, pleasantness) than the higher dose
(500 mg), which produced more negative effects (tension, nervousness, anxiety,
excitement, irritability, nausea, palpitations, restlessness).

3.1.1. Caffeine Impact on Children and Adolescent

Caffeine intake has an impact not only on adults but also on children. In a
subsequent study, Watson et al. [40] examined 309 Australian children (aged 8–
12 years) on the basis of an interview conducted from the parents containing
information about the consumption of caffeine (mostly in coffee, tea, and sodas)
from 0 to 151 mg per day. This study showed that increased age, higher puberty
scores, and higher morning tiredness values were associated with increased
caffeine consumption. Otherwise, decreased total caffeine consumption was
correlated with better internalization and decreased total behavior problems.
25 | P a g e
Moreover ,higher caffeine consumption was associated with a worse sleep
routine, morning tiredness ,and restless sleep.

3.1.2. Caffeine and Taste Perception

Caffeine can also affect taste perception. Circulating adenosine intensifies the
sweet-tasting signals in the taste buds [41].

Caffeine blocks adenosine receptors [42] and negatively affects the perception of
sweet tastes [43].

The bitter taste of caffeine may have an influence on how the human body reacts.

The results of some studies suggest that bitter products can enhance
performance and also give the signal to our brain that the organismis ready for
action [44]. These aspects are still to be examined.

3.1.3. Caffeine and Alzheimer’s Disease

Alzheimer’s disease is the reason for 50–70% of neurodegenerative dementia

cases and is characterized by a progressive decline in cognitive function, and
pathologically by loss of synaptic integrity and neurons, amyloid plaques
composed of amyloid beta (Aβ),and neuronal tangles composed of
hyperphosphorylated tau protein [45]. Li et al. [46]described a mechanism
whereby caffeine protects against Aβ generation.

This mechanismincludes suppression of LDL cholesterol-enhanced amyloidogenic

processing of amyloidbeta protein precursor (AβPP) by blocking AβPP
internalization via its actions on adeno-sine receptors—A3Rs. Additionally,
neuronal cell cultures with Aβ in the presence of anA2AR antagonist completely
prevented Aβ-induced neurotoxicity [47].

The neuro modulatory effects mediated by caffeine rely on a balanced activation

of the inhibitory A1R and excitatory A2AR receptors [48]. There are also premises
that caffeine may have a neuro modulatory effect via receptors RyRs and
inhibition of PDEs, and this ap-plies to all doses of caffeine within the range of
normal, habitual consumption, so the only molecular targets for caffeine at
nontoxic doses are the adenosine receptors in the brain ,especially the inhibitory

26 | P a g e
A1R and the faciliatory A2AR [49]. Upregulation of adenosinereceptors A1R and
A2AR is observed in AD. Activation of ARs affects synaptic neurotrans-mission and
the release of various neurotransmitters (acetylcholine, glutamate) [50].

The consumption of some caffeinated drinks, and caffeine itself, is correlated

withlower risk of AD and dementia. The neuroprotective effect of caffeine has
been demon-strated by Maia et al. [51] in a study among 54 patients with AD who
consumed73.9 ± 97.9 mg/day of caffeine during the 20 years before diagnosis of
AD in relation to individuals without AD who consumed 198.7 ± 135.7 mg/day
during the corresponding20 years of their lifetimes. Authors showed that caffeine
consumption was associated withlower risk for AD.

Kolahdouzan and Hamadeh [6] also stated that caffeine is protective in AD and
the dosages of caffeine at which this effect is noticeable is 3–5 mg/kg body
weight.

According to Ritchie et al. [52], consumption of at least three cups of coffee per
day is associated with less decline in verbal memory.

3.1.4. Caffeine and Parkinson’s Disease

Parkinson’s disease (PD) is a neurodegenerative disease with motor and non-

motor Symptoms [53].

Some studies reported that caffeine intake is beneficial for PD patients,Similarly

to Alzheimer’s disease. First of all, caffeine intake is associated with lower Risk of
Parkinson’s disease.

Ross et al. [54] analyzed data on 8004 Japanese-AmericanMen (aged 45–68 years)
drinking at least 28 ounces (421 mg of caffeine) of coffee, whoWere 5-times less
exposed to PD, and this risk decreased as coffee consumption increased.Another
study by Liu et al. [55] examining 187,499 men and 130,761 women showed That
higher caffeinated coffee consumption was associated with lower PD risk in a
dose Dependent manner, but consumption of other caffeine-containing
beverages (soft drinks,Hot tea, and iced tea) was not associated with the risk of
PD

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3.1.5. Caffeine and Mental Health

Depression, anxiety, and suicide are becoming an increasingly common

problemAmong children and adults. It has already beenDocumented that caffeine
intake is associated with depressive symptoms. Lucas et al. [56]Indicated that the
risk of depression is associated with the dose of consumed caffeine.

They showed that people who drank more than two cups of caffeinated coffee
per dayWere 24% less exposed to depression than those who did not drink coffee.
In addition,Richards and Smith [57] found that the incidence of depression
decreased as the dose of Caffeine intake increased, but they did not verify the
differences between men and women.Botella et al. [58]Kendler et al. [59]
analyzed data from the Virginia Twin Registry of about 3600 adultTwins and
reported that the risk of developing anxiety increased after consumption of>6
cups of caffeinated coffee per day. Additionally, Bertasi et al. [60], in their study
among114 college students, showed that high caffeine intake is associated with
higher levels Of anxiety.

Botella et al. [61] examined 3323 students (11–17 years old) and showed that
The effect of caffeine on anxiety is significant mainly in boys—the anxiety
increased with Increased dose of caffeine intake Some studies have examined the
effect of a single instance of caffeine intake on neu-Rocognitive performance.
Konishi et al. [62] investigated the effect on driving performance In 100 healthy
Japanese volunteers (50 males, 50 females, aged 22–59 years) with a validDriver’s
license. In this double-blinded, randomized, placebo-controlled study, half of the
Participants formed a caffeine intake group and the other a placebo group.
Individuals Did not consume caffeine for three days before the examination, then
the “caffeine group” Was given 200 mg of caffeine. Thirty minutes after
administration, cognitive functions Were evaluated via the Symbol Digit Coding
Test (SDC), the Stroop Test (ST), the Shift-Ing Attention Test (SAT), and the Four
Part Continuous Performance Test (FPCPT). After These tests, the authors
checked driving performance (brake reaction time and standard Deviation of the
lateral position) using a driving simulator. Research showed that the“caffeine
group” had more appropriate responses than the placebo group on the SAT,
madeLess mistakes, and had shorter times in the brake reaction time test.

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3.1.6. Caffeine and Perception of Pain

Caffeine is a constituent of many over-the-counter pain relievers and prescription

drugs because the vasoconstricting and anti-inflammatory effects of caffeine act
as a compliment to analgesics, in some cases, increasing the effectiveness of pain
relievers by up to 40% [80]. Studies conducted on 62 people (aged 19–77 years)
by Overstreet et al. [63]showed that habitual dietary caffeine consumption was
associated with a higher pain threshold, higher heat pain tolerance, and higher
pressure pain threshold. The mechanism by which caffeine can reduce pain
sensation appears to be closely related to its direct effects on adenosine
receptors, especially through the central blocking of those receptorsthat influence
pain signaling or block peripheral adenosine receptors on sensory afferents.

The antagonism of adenosine receptors as well as the inhibition of

cyclooxygenase activity in some places may explain the anti-nociceptive effect of
caffeine and its supportive effect [64].

This is the reason why low-dose caffeine is present as an adjuvant in con-junction

with antidepressants, acetaminophen, and non-steroidal anti-inflammatory
drugsin many over-the-counter (OTC) pain medications [65].

3.2 The Immune System

The immune system is complex and is made up of various cells and proteins that
are Responsible for the body’s resistance, particularly through the immune
response, which Is a weapon against foreign antigens [66]. More and more
attention is paid to the two-Way relationship between the immune system and
diet [67].

The role of caffeine in the Functioning of the immune system reaches the cells
themselves. Gibbs et al. [68] reported That caffeine in high concentrations (5 mM)
inhibits the mammalian target of rapamycin (mTOR) in human myeloid leukemia
cells, primary human acute myeloid leukemia cells,And primary human basophils,
and affects glycolysis and the release of pro-inflammatory Cytokines. Additionally,
in monocytes, the effect of caffeine was potentiated by its ability To inhibit

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xanthine oxidase (purine catabolism), and in basophiles, caffeine increased
Intercellular cAMP levels [69].

It turned out that caffeine (50 µM) decreased tumor necrosis factor-alpha (TNF-α)
fromLPS activated-CBM by 20% and TNF-α gene expression by 30%, in
conjunction with aMinimum 2-fold increase in cAMP. This suggests that caffeine
increases cAMP production And inhibits pre-transcriptional TNF-α production by
CBM via A1R blockade.

Shushtari et al [70] used mesenchymal stem cells (MSCs)isolated from bone

marrow and treated them with different concentrations of caffeine (0,0.1, 0.5,
and 1 mM) for 72 h, out of which 24 h consisted of incubation with macrophages.

The authors observed that MSCs treated with caffeine enhanced phagocytosis
and the expression of reactive oxygen species, nitric oxide, and IL-12 by
macrophages. These results proved that caffeine augments the instruction of anti-
inflammatory macrophages and showed the potential mechanism of the
immunomodulatory and anti-inflammatory effects of caffeine [71].

However, the presented results indicate the therapeutic properties of caffeine,

high doses of caffeine necessary to obtain certain effects, but it may be toxic to
the human body.

Table 2. The main effects of caffeine action on the nervous system and the most
likely mechanisms of its action. [181

Aβ—amyloid beta, Ars—adenosine receptors, AChE—acetylcholinesterase,

RyRs—ryanodine receptors. ↓—decrease, ↑—increase.

30 | P a g e
3.3 Digestive System

Caffeinated coffee consumption is one of the causes of gastrointestinal

discomfort reported by patients as well as digestive system problems noted by
doctors.

The main pharmacologically active substance in coffee is caffeine, which may

increase gastric acid secretion [72], relax smooth muscles by increasing gastrin
concentration [73], and stimulate the secretion of hydrochloric acid [74], causing
higher risk of inflammation of the intestinal mucosa and stomach. On the other
hand, caffeine is said to be antioxidant and to have anti-inflammatory activity
[75], thanks to which caffeine can reduce alanine aminotransferase(ALT),
aspartate aminotransferase (AST), and bilirubin level in serum [76]. There is also
connection between coffee consumption and γ-glutamyl transferase (GGT)
activity—together with higher coffee consumption, lower GGT activity was
observed [77].

It should be noted, however, that coffee ingredients may disturb iron absorption
*78+, and zinc’sbioavailability *79+. It is suggested that coffee and its compounds
may also affect intestinalmicrobiota, especially Bacteroides, and increase its level
[80].

3.3.1. Caffeine Action on the Small and Large Intestine.

Caffeine has an impact on net fluid movement and transit times, although the
data inthis respect are not conclusive.

It has been reported that caffeine ingestions (75–300 mg)caused increased net
secretion in jejunum for a minimum of 15 min, and 35 min later in ileum in the
same doses of caffeine [81]. The results of another study showed that caffeine
affects esophageal function by decreasing the pressure on the lower esophageal
sphincter,leading to its relaxation [82]. Relaxed lower esophageal sphincter may
be a reason for gastric reflux [83].

Moreover, it was also documented that caffeinated coffee stimulatesgallbladder

contraction and colonic motor activity, but there were no connections
betweencoffee consumption and dyspepsia [84].

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It is still unclear whether and to what extent the consumption of caffeinated
coffeeand caffeinated products affects gastrointestinal transit time and whether
this is an effectof caffeine content.

Figure 2. The scheme of the main effects of caffeine action on the digestive
system. ALT—alanine aminotransferase, AST—aspartate aminotransferase, GGT—
γ-glutamyltransferase. ↓↓↓—decrease, ↑↑↑—increase [181]

3.3.2. Caffeine and the Liver.

Animal models (mice and rats) have shown that caffeine may play a potential role
in the stimulation of β-oxidation in hepatic cells, intrahepatic lipid content
reduction, and hepatic autophagy [85], which suggests that caffeine ingestion
suppresses inflammation and lipogenesis [86], reduces lipid peroxidation [87],
and is linked with lower risk for nonalcoholic fatty liver disease [88]. Caffeine is
inversely associated with the risk of cirrhosis [89] and the risk of hepatocellular
carcinoma, especially among people with the hepatitis C virus and other liver
diseases[90] .

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3.3.3. Caffeine and Glycaemia

High doses of caffeine increase glucose tolerance [91] and decrease insulin
sensitivity [92]. It has been shown that decaffeinated coffee, in contrast to
caffeinated, reducesHbA1c levels [93] used in glycaemia monitoring, which
suggests that coffee contains other substances that may improve glucose
metabolism, and this needs to be examined. The studies on caffeine consumption
among people with type 2 diabetes do not show any correlation between
decaffeinated coffee and improvement in glycemic control [94], and should be
confirmed by additional research, since the results of another study have shown
that frequent (at least seven cups per day) coffee consumption may reduce the
risk of type 2 diabetes by 50% [95].

3.3.4. Caffeine and Digestive Tract Cancer

Some studies indicate that coffee with caffeine may reduce the probability of
digestive tract cancer occurrence, especially liver cancer [96] and colon cancer
[97]. Liuet al. [98] used human gastric cancer cells in in vitro studies to show that
caffeine treatment suppressed gastric cancer cell growth and viability, and
activated the caspade-9/-3pathway, which induced apoptosis. Taking the above
into consideration, it seems that caffeine may be useful as a sustained anticancer
agent in the therapy of gastric cancer, however, these observations should be
confirmed by additional studies.

The meta-analysis conducted by Li et al. [99] consisting of 25 case-control and 16

cohort studies showed that the risk of colorectal cancer was reduced by 15% for
the highest coffee drinkers compared to low or non-drinkers.

3.4. Respiratory System

The effect of caffeine on the respiratory system is mainly described as beneficial

,regardless of whether it is administered individually, as a component of drugs, or
synergistically with applied therapy [100]. Caffeine acute ingestion (3 mg/kg body

33 | P a g e
weight) may improve peak aerobic performance and increase peak pulmonary
ventilation. The role of caffeine in this effect may be explained by its ability to
affect respiratory muscle [101].

Supinski et al [102] examined the effect in six healthy people of single, orally
administered doses of caffeine (600 mg) on diaphragmatic muscle, and showed
that caffeine increased trans-diaphragmatic pressure, probably by increases in
muscle contractility. This suggests that caffeine may be used in the treatment of
patients with respiratory muscle weakness. Another possible mechanism of
caffeine action is without a doubt its influence on receptors.

3.4.1. Caffeine and Asthma.

An important action of caffeine is the stimulation of the respiratory system, hence

caffeine is a common ingredient in bronchodilators [103]. Welsh et al [104]
examined75 people with mild to moderate asthma and showed that caffeine
(even at less than5 mg/kg body weight) improved lung function for up to two
hours after consumption (differences in forced expiratory volume in one second
about 5%). The authors concluded that caffeine improves airway function
modestly, for up to four hours, in people with asthma [105].

3.4.2. Caffeine and Breathing Problems

Aranda et al. [106] in their study examined 12 infants with infantile apnea and
observed significant increases in ventilation, tidal volume, and mean inspiratory
flow with plasma concentrations of caffeine ranging from 8 to 20 mg/L. The above
results show that caffeine may be valuable medicine, but more studies are
required for confirmation of these findings. Another study was conducted by
Kassim et al [107] among 18 prematurely born infants being weaned from
mechanical ventilation. The infants were given caffeine(5 mg/kg body weight/24
h), and after 6 h, measurements were made.

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 The maximum pressures generated by occlusions at end inspirations and end
expirations, and lung volume,had significantly improved. This suggests that
caffeine administration increases respiratory muscle function, and is associated
with lung function improvement.

3.4.3. Caffeine and Lung Cancer

Baker et al. [108] examined 993 individuals (624 male and 369 female) with
primary incident lung cancer and observed an elevated lung cancer risk for
drinkers of at least two cups of caffeinated coffee per day, as confirmed in a
meta-analysis conducted by Wang et al The authors reported a linear relationship
between coffee consumption and increased risk of lung cancer, especially for
consumers of ≥3 cups coffee per day *109+.

Table3. The effects of caffeine action in respiratory system diseases. [181]

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3.5. Circulatory System.

In general, an acute intake of caffeine stimulates a modest increase in blood

pressure(both systolic and diastolic) [110].

In volunteers who abstained from caffeine-containing products, a bolus dose of

250 mg led to a 5–10% increase in both systolic and diastolic blood pressure for
1–3 h.

Theses effects due to systemic release of epinephrine, norepinephrine, and renin

The primary mechanism of the pressor effect is peripheral vasoconstriction. There
is little change in cardiac output owing to the balanced effects of caffeine in
directly increasing and indirectly (via baroreceptor-mediated reflexes) decreasing
heart rate and contractility.
Caffeine reduces liver and mesenteric blood flow, effects that may contribute to
beneficial actions in patients with postprandial orthostatic hypotension .
Caffeine increases renal excretion of sodium and water, both by increasing
glomerular filtration rate slightly and by inhibiting tubular reabsorption of sodium
and water.

It is noteworthy in regard to tolerance that in regular coffee drinkers the pressor

response to caffeine in the morning is inversely correlated to the basal level of
caffeine in the blood . Thus, people with short caffeine half-lives experience
greater cardiovascular effects, at least in the morning, than those with longer
half-lives. In high doses, such as from self-poisoning, caffeine causes hypotension
as a result of vasodilation (beta adrenergic mediated), and marked tachy-cardia
with systemic catecholamine release in very high levels Meta-bolic (lactic)
acidosis, hypokalemia, and hyperglycemia may accompany catecholamine
release. [111].

Some studies have documented that coffee consumption and the type of coffee
plays a role in lipid metabolism. Boiled coffee increases serum total and LDL
cholesterol concentrations, but filtered coffee does not significantly change
serum cholesterol levels [112].

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3.5.1 Caffeine and Arrhythmia.

One of the possible mechanisms of caffeine action is blocking ARs (mainly

subtypes A1and A2) [113] and causing a higher release of dopamine and
noradrenalin [114]. It inhibits the action of natural adenosine, and can cause
tachycardia and arrhythmias due to the increased activation of the β1-receptor
[115].

As a nonselective competitive inhibitor of A2ARs,caffeine might attenuate the

vasodilator effect of adenosine, and increase sympathetic activity, yielding to
capillary derecruitment and leading to decreased myocardial perfusionreserve
[116].

Seitz et al [117] in their study showed that caffeine reduced the

myocardialperfusion reserve index (MPRI).

The authors examined 25 patients (84% male, median age 69 years) with
substantial myocardial ischemia and coffee addiction (3–4 cups per day),who
underwent repeat adenosine stress perfusion imaging by cardiovascular magnetic
resonance after a prior intake of two cups of coffee (about 200 mg of caffeine) 1 h
before examination, which confirmed the need for abstinence from caffeine .

Caffeine is also a nonspecific inhibitor of phosphodiesterases that is able to

intensifyproduction of cAMP and cGMP, which affects cardiac contractility, and
this may predisposeto arrhythmias [118]. The meta-analysis conducted by
Greenland [119] was based on 22 studies, and the author showed that drinking at
least five cups of coffee per day may enhance the risk of myocardial infraction or
coronary death.

3.6. Urinary Tract

The well-known diuretic effect of caffeine is related to the maintenance of the

water–salt balance in different segments of the nephron in which adenosine plays
a complex role, depending on the differential expression of its receptors.
Therefore, caffeine increases the rate of glomerular filtration, counteracting by
the vasoconstriction of renal afferent arteriole mediated by adenosine via type 1
AR during tubuloglomerular feedback.

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It should also be emphasized that caffeine inhibits Na+reabsorption at the level
of the proximal renal tubules and disrupts the hepatorenal reflex through sensory
nerves in Mall’s intrahepatic spaces [120].

Caffeine may increase urine production [121], and excessive caffeine intake(more
than 400 mg/day) may increase the risk of detrusor instability (unstable bladder)
in women [122].

In the kidneys, caffeine induces diuresis and natriuresis [123]. A study

byLohsiriwat et al [124] on nine women and three men (aged 21–40 years) with
overactive bladder symptoms who drank 8 mL/kg body weight of water with or
without caffeine at two separate sessions showed that caffeine at 4.5 mg/kg body
weight caused diuresis and decreased the threshold of sensation at the filling
phase, with an increase in flow rate and voided volume. In conclusion, caffeine
can promote early urgency and frequency of urination.

Figure3.. The main effects of caffeine action on the kidneys. The main effects of
caffeine action on the kidneys. ↓↓↓ ↓↓↓—decrease, —decrease, ↑↑↑
↑↑↑ —increase [181]

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3.6.1. Caffeine and Urinary Incontinence.

Jura et al [125] conducted a prospective cohort study of 65,176 women (37–39

years old) without urinary incontinence, using questionnaires to measure caffeine
intake The authors associated risk for urgency incontinence with high caffeine
intake and showed that this risk was higher in patients who consumed more than
450 mg of caffeine, and 25% of incident urgency incontinence may be attributable
to caffeine consumption. One year later, in 2012, Hirayama et al. [126] showed
that caffeine was not associated with a higher risk of urinary incontinence in a
group of 683 men and 298 women (aged 40–75 years) from Japan.

In 2013, Gleason et al. [127] examined 4309 non-pregnant women (>20 years
old) with urinary incontinence (from mild to severe forms) and showed that
caffeine intake ≥204 mg/day was associated with urinary incontinence, but not
with severe forms of it.

3.6.2. Caffeine and Kidney Stones

Studies by Curhan et al. [128] showed that there is an association between intake
of caffeinated drinks and risk of kidney stones. The authors based their data on
the study of 553,081 women, of which 719 had documented kidney stones. They
reported that risk for stone formation decreased by 10% for caffeinated coffee
and 8% for tea for each 240 mL serving consumed daily.

Peerapen and Thongboonkerd [129] in their study investigated the formation of

calcium oxalate monohydrate (COM) (which is one of the main causes of kidney
stones) in vitro after use of different doses of caffeine (1 to 10 µM).

The authorsexamined the crystallization process, crystal growth, and crystal-cell

adhesion, and found that caffeine reduced the crystal number and crystal-binding
capacity of renal tubular cells in a dose-dependent manner. The study results
showed significantly decreased levels of annexin A1 in the apical surface (a
protein that belongs to the annexin family of calcium-dependent phospholipid-
binding proteins that plays a significant role in controlling intercellular calcium
release), because this protein is translocated into the cytoplasm of the caffeine-

39 | P a g e
treated cells. This mechanism may decrease the crystal-binding capacity of renal
tubular epithelial cells .

3.7. Skeletal and Muscular System.

Caffeine’s capacity to improve exercise performance and cognitive functions

makes it a very common dietary supplement in sports nutrition [130]. It is
suggested that the most important mechanism of caffeine activity in muscle work
is antagonism of ARs.

Preventing the decrease in neuronal activity by blocking the ARs is associated with
the possibility of increasing muscle fiber recruitment [131].

Another mechanism of the caffeine effect is the opening of the ion channel RyRs,
especially in muscles and myocytes [132].

There is a reserve of Ca2+ in the sarcoplasmic reticulum (SR), which can be

additionally released in the presence of caffeine, resulting in improved muscle
speed and strength [133]. Caffeine can increase contractility during submaximal
contractions through induction calcium release from SR and inhibition of its
reuptake [134]. The ability of caffeine to boost adrenaline rush, release calcium
ions, improve Na+/K+-ATPase, and reduce pain perception [135] seems to be
directly related to improved sports performance. Caffeine may also have a direct
positive effect on the mechanical activity of skeletal muscle.

3.7.1 Caffeine and Bones.

The connection between caffeine and osteogenic activity was examined by Shin et
al. [136] in a study on 51 two-week-old male rats. The authors showed that high-
caffeine consumption (120 and 180 mg/kg/day) for four weeks led to a significant
decrease in body mass gain with proportional decreases in lean body mass and
body fat. Additionally, in dual-energy X-ray and F-NaF positron emission
tomography, a decrease in bone mass and in vivo osteogenic activity was
observeda shorter and lighter tibia, femur, and vertebral column

40 | P a g e
 Caffeine intake may have a small negative effect on calcium levels, but there is
not enough evidence to show an association between coffee consumption and
risk of osteoporosis [137]

3.7.2. Caffeine Action on Muscle Filaments and Muscular Strength.

Caffeine, an activator of the calcium and cAMP/protein kinase A (cAMP/PKA)

path-way, enhances glucose uptake, fat oxidation, and mitochondrial biogenesis
in skeletal muscle cells. Yokokawa et al. [138] reported that caffeine may increase
myoglobin expression via the cAMP/PKA pathway in skeletal muscle by using L6
myotubes. The authors showed that caffeine increased myoglobin expression and
activated the cAMP/PKA pathway in muscle cells.

Moreover, cAMP increased myoglobin expression . Tazzeo et al. [139]proved that

caffeine decreases actin filament binding to phosphorylated myosin heads and
increases the ratio of globular to filamentous actin in pre-contracted tissues, and
concluded that caffeine interferes with actin function (decreased binding by
myosin, possibly with depolymerization), and for this reason, relaxes smooth
muscle .

Caffeine in a dose of 3 mg/kg body weight induced changes in muscle oxygen

satura-tion during submaximal workloads [140].

3.8.Reproductive Effects.

Caffeine consumption is associated with fertility indices in some studies but not in
others. An extensive literature review by the Oak Ridge National Laboratory
concluded that chronic caffeine intake in humans is related to adverse effects on
conception and reproduction, such as delayed conception and decreased
fecundity.

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These effects appeared at caffeine doses above 200 mg/day compared to a no or
very low caffeine intake reference group (0–50 mg/day during pregnancy), every
additional 100 mg/day of caffeine (about the amount contained in a typical cup of
coffee) increased the risk of pregnancy loss (both miscarriage and stillbirth) by 7%
[141].

In addition, among women consuming more than 700 mg/day, the risk of
pregnancy loss was increased by 72%.

Other comprehensive reviews have reported ,some evidence that caffeine

intakes of more than 300 mg/day have been associated with spontaneous
abortion and low birth weight, but all have stressed the need for further research
before a causal relationship can be established [142]. A recent study from the
Nurses Health Study shows pre-pregnancy coffee consumption at levels
≥4 serving/day is associated with an increased risk of spontaneous abortions,
particularly at 8–19 weeks gestational age [143].

3.9.Birth Weight Effects.

Several studies have reported a significant negative association between maternal

caffeine consumption and birth weight [144].Two separate meta-analyses of
different sets of studies by Rhee et al. [146] and Chen et al. [147] reported odds
ratios of having a newborn classified as low-birth weight (less than 2,500 g) for
maternal caffeine consumption above 50 mg/day when compared to intakes
below 50 mg/day. Furthermore, both meta-analyses found an increased risk of
low-birth weight offspring for every 100 mg/day increase in maternal caffeine
consumption (OR, 1.03–1.62). Another study by Hoyt et al. found the odds ratios
of having a low-birth weight baby increased to a range of 1.3–2.1 in women
consuming more than 300 mg/day of caffeine during pregnancy [145].

3.10. caffeine effects on lactation.

Caffeine may cause irritability and sleep disruption in nursing infants whose
mothers consume caffeine [148], but the findings are equivocal . In addition,
some evidence indicates that caffeine intake can reduce production of breast milk
.

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 Mothers are often advised by their doctors to reduce or eliminate caffeine intake
if they feel that their infant shows signs of caffeine sensitiv-ity, but there is no
evidence in the literature of detrimental effects of caffeine ingestion during
lactation in the general population. Behavioral issues, such as fussiness,
jitteriness, and poor sleep patterns, have been reported among infants breastfed
by mothers who consumed 10 or more cups of coffee (~1 g of caffeine) per day .

The effects of caffeine in breast milk can be amplified in preterm infants or

infants less than 5 months old because they metabolize caffeine so slowly . In
addition, an intake of more than 450 mL (about two cups) of coffee per day may
decrease breast milk iron concentrations, which could contribute to infant anemia
[149].

However, the European Food Safety Authority concluded that a single dose of
200 mg or less of caffeine (about two cups) consumed by lactating women, as well
as chronic intakes at or below 200 mg, pose no safety concerns for breastfed
infants [150].

3.11. Caffeine effects on Fibrocystic Breast Disease.

The work of Minton et al was instrumental in arousing considerable anxiety about

caffeine as a potential cause of fibrocystic breast disease (FBD), believed by some
to be a risk factor for breast cancer. More rigorous follow-up studies have
suggested that caffeine is not causally related to FBD but a persistent distrust of
these data persists among medical practitioners, indicating a need for further
study.
This distrust may be attributable to the dramatic results reported in the early
studies examining the remission of symptoms in which the major-ity (65%) of
women with benign lumps experienced complete regression within one to six
months of abstinence from caffeine. Also, the per-
sistence of positive findings such as in the recent work of Bullough,

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Hindi-Alexander, and Fetouh 'which uncovered a significant association between
methylxanthine consumption and FBD. Such studies strengthen a belief in the
clinical wisdom of restricting caffeine from patients with FBD.
Wolfrom and Welsch summarize the current situation when they state that "no
consistent beneficial effect on fibrocystic breast dis-ease symptoms has been
shown when methylxanthine consumption is eliminated or reduced. Similarly,
studies have shown no consistent role of methylxanthines in the etiology of
fibrocystic breast disease[175].

3.12.Other Health Concerns

As noted previously, caffeine is available in over-the-counter and pre-scription

medications as well as in illicit drug combinations containing sympathomimetic
drugs (primarily phenylpropanolamine or ephedrine).
Additive or synergistic drug interactions may promote toxicity. For example,
intoxication with phenylpropanolamine may produce severe hyper-tension with
resultant stroke or myocardial injury (175). Caffeine may potentiate the
hypertensive effects of other sympathomimetic drugs (176).
Several deaths have been attributed to ingestion of caffeine-containing "look-
alike" stimulants (177).
Chronic ingestion of analgesic mixtures (containing aspirin, acetamino-phen,
and/or phenacetin) is associated with an increased risk of chronic tubulo-
interstitial renal disease (analgesic nephropathy), a common cause of renal failure
in some populations. Caffeine, possibly by blocking adenosine-mediated
vasodilation in the renal medulla, may con-tribute to medullary ischemia and
associated tissue injury produced by nonsteroidal antiinflammatory drugs and
acetaminophen or phenacetin (178). As caffeine dependence may promote
chronic analgesic abuse, it is prudent to remove caffeine from analgesic
combinations.

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3.12.1.Is Caffeine Addicting?

Many physicians have treated patients who continue to drink large quantities of
caffeinated beverages in the face of information that caffeine is harmful to their
health and advice to quit. Such behavior suggests that these people are addicted
to caffeine.
Addiction liability can be analyzed according to criteria recently presented by the
United States Surgeon General (179). The three major criteria for addiction
liability are psycho-activity, drug-reinforced behavior, and compulsive use. That
caffeine is psychoactive and that some people consume caffeine compulsively is
clear. That caffeine reinforces its consumption has recently been demonstrated in
people, although reinforcement is highly dependent on the dose, with excessive
doses producing dysphoria (180) .
Minor criteria for addiction liability include the development of tolerance,
physical depen-dence, and recurrent intense desire for the drug, all of which are
charac-teristic of regular caffeine consumers. Thus, there is a group of coffee
drinkers who appear to be addicted to caffeine, although the extent of caffeine
addiction in the population is unknown.

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Caffeine consumption and performance.

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4. Caffeine consumption and performance.
4.1. Optimal Prescription of Use.
Does the method of administration influencethe effects of caffeine? It is not
possible to give acomplete answer to this question, as the necessarycomparisons
have not been done. Caffeine and othermethylxanthines can be administered by
suppository, intramuscular injection, venous infusion, ororal ingestion. Most
investigations have administered caffeine as a pure anhydrous drug orally, ei-ther
in capsules or dissolved in water. In most stud-ies, oral ingestion has involved a
single dose, but in a few investigations, repeated doses have been given. Which
made or pattern of administration isoptimal, and when a given dose of caffeine
causes the optimal performance conditions, remains unclear.

4.1.1. Timing.

Most investigators have had the participants in-gest a caffeine dose, rest an hour,
and then exercise.

This protocol has been selected because caffeine is rapidly absorbed and plasma
concentrations approximate a maximum level in 1 hour. While this timing for
administration and exercise may be optimal, itis remarkable how rarely the
investigators have mea-sured the circulating concentration of the drug theyare
studying. Most studies offer no information about the plasma concentration of
caffeine or its variation among study participants. Caffeine is slowlycatabolised
(half-life is 4 to 6 hours) and individuals maintain a circulating concentration close
to this level for 3 to 4 hours. It has been suggested that waiting 3 hours is optimal
because this is when caffeine-induced lipolysis produces the highest FFA level.
However, this hypothesis has not been tested and the ergogenic role of such
lipolysis is very suspect (see section 8). The author is unaware of any systematic
examination of lipolysis in relation to the time between caffeine ingestion and
exercise onset.[182]

47 | P a g e
4.1.2. Dose.

Surprisingly, some scientists have given caffeine in an absolute dose, rather than
as one indexed for body mass . This could create large variability in responses. A
few studies have given caffeine per unit lean mass. However, caffeine is both
water-and lipid-soluble and it is unlikely that body fat is an important factor in
caffeine distribution. As note above, most investigators have not measured
plasma caffeine concentrations of study participants and this severely limits
understanding of why some results are inconsistent with the literature.

There have been only a few dose-response studies. Perkins and Williams did not
find any ergogenic benefit of any caffeine dose, but their protocol led to a very
rapid fatigue. Cohen et al. also failed to show any improvements with 2 different
doses of caffeine, while Cadarette et al. did not find conclusive results. The latter
study reported that the middle dose of 4.4 mg/kg was effective, but suggested
that this was caused by the results from 1 individual. These findings are difficult to
interpret because the investigators also reported that participants in the placebo
condition had plasma caffeine concentrations equivalent to a dose of about 3
mg/kg of caffeine As indicated in section 6, these studies are in the minority in
finding no ergogenic effect of caffeine Examination of doses of 3 to 9 mg/kg at the
author’s laboratory revealed that even 3 mg/kg was effective for increasing
endurance in prolonged exercise. Subsequently, Pasman et al. confirmedthis
finding. Bruce et al reported that doses of6 and 9 mg/kg were equally effective in
increasing performance/power in a simulation of 2000m rowing. Similarly, Kovacs
et al. found that, when ingesting caffeine with a sport drink, the lowest dose used
(2.1 mg/kg) was ergogenic, but doses of 3.2 and 4.5 mg/kg had a greater effect. It
appears that a dose of 3 to 6 mg/kg is optimal. It is not clear what are the minimal
and maximal doses [182].

48 | P a g e
4.2. Caffeine Habituation.

Does an athlete who regularly ingests caffeine still benefit from an acute ingestion
of caffeine?

Rarely have the caffeine habits of individuals been considered within the context
of applied physiology. There is ample evidence from animal models that some
tissues adapt to long term exposure to caffeine by up-regulating adenosine
receptor number, whereas other tissues adapt by altering post-receptor actions.
However, these studies also found that some tissues do not appear to adapt to
habitual exposure .When we do not know what tissues are criticalin mediating the
ergogenic responses to caffeine, it is difficult to speculate about the importance
of ha-bituation within specific tissues. In 1991, Dodd etal. compared habitual
caffeine users to caffeine-naive individuals. At rest, the latter were more re-
sponsive in heart rate, ventilation and oxygen consumption ,but there were no
differences during anincremental exercise protocol. One study com-pared
caffeine-users and non-users and found that they differed only in the degree of
increase in plasma adrenaline following caffeine ingestion. Similarly, Bangsbo et
al. found that habitual caffeine users, after 6 weeks of increased caffeine
ingestion, had less increase of adrenaline in response to a standard dose of
caffeine. Given the lack of evidence for a major role for the caffeine-induced
increase in adrenaline (section 8.6), it is impossible to speculate about the
importance of this alteration. Wileset al.found no relationship between caffeine
habits and degree of performance response in 1500m runners, nor did
Tarnopolsky and Cupido find a difference between caffeine users and non-users
indegree of caffeine-induced muscle force develop-ment. Caffeine habituation
needs further study, but thus far the differences caused by caffeine habitsdo not
appear to be major[182].

49 | P a g e
4.3.Caffeine and endurance exercise.

Caffeine has consistently been shown to improve endurance by 2–4% across

dozens of studies using doses of3–6 mg/kg body mass . Accordingly, caffeine is
one of the most prominent ergogenic aids and is used by athletes and active
individuals in a wide variety of sports and activities involving aerobic endurance.

Caffeine has been shown to benefit several endurance-type sports including

cycling , running, cross-country skiing and swimming. caffeine has been
consistently shown to be effective as an ergogenic aid when taken in moderate
doses (3–6 mg/kg), during endurance-type exercise and sport[162].

4.4.Caffeine and muscular endurance, strength and power.

Strength and power development through resistance exercise is a significant

component of conditioning pro-grams for both fitness and competitive sport. The
most frequently consumed dose of caffeine in studies using strength tasks with
trained or untrained individuals usually ranges from 3 to 6 mg/kg body mass (with
2 mg to11 mg representing the entire range), ingested in the form of pills or
capsules 30 to 90 min before exercise. In resistance exercise, strength is most
commonly assessedusing 1 repetition maximum (1RM) [151], or different
isometric and isokinetic strength tests [152]. Muscular endurance assesses the
muscle’s ability to resist fatigue and is an important quality in many athletic
endeavors(e.g., swimming, rowing). Muscular endurance may be tested with
repetitions of squats, maximal pushups ,bench press exercises (load
corresponding to 60–70% of1RM) to momentary muscular failure, or by isometric
exercises such as the plank or static squat [153].

50 | P a g e
Although several studies exploring the effects of caffeine on strength
performance have been published since the 2010 ISSN caffeine position stand
[154], some uncertainty surrounding the benefits of caffeine in activities involving
muscular endurance, strength and power remains Caffeine was shown to be
ergogenic for muscular en-durance in two meta-analyses reporting effect sizes
ranging from 0.28 to 0.38 (percent change range: 6 to 7%)[155]. However, others
have shown that it enhances strength but not muscular endurance [156], and
when studies have examined multiple strength-muscular endurance tasks, there
were benefits across the board[157], none at all [158], or even impairments in
muscular endurance with caffeine use [159]. Ingesting caffeine prior to a muscular
endurance task is likely to delay muscular fatigue, but these effects are not
consistent among all studies.

Three meta-analyses explored the acute effects of caffeine on strength, and all
reported ergogenic effects[160]. However, the effects in these meta-analyses
were small, ranging from 0.16 to 0.20 (percent change: 2 to 7%). Such small
improvements in muscular strength likely have the greatest practical
meaningfulness for athletes competing in strength-based sports, such as
powerlifting and weightlifting (athletes which already seem to be among the
highest users of caffeine [161].

4.5.Caffeine and sport-specific performance.

several studies have also explored the effects of caffeine on sport-specific

exercise tasks using sport simulation matches.

Many studies conducted among athletes competing in team and individual

sports, report that caffeine may enhance performance in a variety of sport tasks.
However, there are also several studies that report no effects as outlined below:_
Basketball increased jump height, but only in those with the AA version of the
CYP1A2 gene , increased number of free throws attempted and free throws
made, increased number of total and offensive rebounds , but did not improve
sprint time, nor dribbling speed.

51 | P a g e
 Soccer increased total distance covered during the game, increased passing
accuracy, and jumping height, but the consumption of a caffeinated energy
drink did not enhance performance in the “T test” in female soccer players,
nor during match play in young football players.

 Volleyball increased number of successful volleyball actions and

decreased the number of imprecise actions , although caffeine did not
improve physical performance in multiple sport- specific tests in
professional females , nor performance in volleyball competition Football
- did not improve performance for anaerobic exercise tests used at the NFL
Combine.

 Rugby increased the number of body impacts running pace, and muscle
power during jumping but did not impact agility.

 Field hockey increased high-intensity running and sprinting , and may

offset decrements in skilled performance associated with fatigue .

 Ice-hockey has limited impact on sport-specific skill performance and RPE,

but may enhance physicality during scrimmage.

 Combat sports increased number of offensive actions and increased the

number of throws.

 Cross country skiing educed time to complete a set distance and improved
time to task failure [163]

52 | P a g e
CAFFEINE DEPENDENCE

53 | P a g e
5.CAFFEINE DEPENDENCE
Abstinence from a drug such as caffeine that has produced a high degree of
tolerance commonly results in withdrawal symptoms, referred to as physical
dependence. Withdrawal symptoms after prolonged consumption of caffeine
include headache and fatigue most prominently, with anxiety, impaired
psychomotor performance, nausea/vomiting, and/or an intense desire for coffee
as less common features [164]. Withdrawal symptoms typically begin at 12-24 hr
and peak at 20-48 hr after cessation of caffeine consumption. Symptoms may
persist for a week.

Relief of withdrawal symptoms appears to be a substantial component of the

satisfaction of coffee drinking, particularly the first cup of the day. In support of
the idea that the pleasurable effects of caffeine are related to relief of withdrawal
is an experimental study showing that heavy coffee drinkers prefer caffeinated
over decaffeinated coffee after they have been drinking caffeinated coffee for a
week or more, but do not have a preference when given a choice after they have
been drinking decaffeinated coffee [165].

54 | P a g e
Toxicity of Caffeine

55 | P a g e
6.Toxicity of Caffeine: -
A single dose consumption of 200 mg of caffeine, or less, by healthy people
without comorbidities and pharmacokinetic disturbances, is usually not
associated with toxic effects [166,167].

However, a dose above 300 mg at once can cause caffeine intoxication, the
symptoms of which are mainly related to its stimulating effect. The most common
ones are: restlessness, nervousness, excitement, insomnia, facial flushing,
increased urination, gastrointestinal disorders, muscle tremors, chaotic flow of
thoughts and speech, irritability, arrhythmia, tachycardia, and psychomotor
agitation. The severity of the undesirable effects of caffeine consumption is dose
dependent [168]. The threshold of caffeine toxicity appears to be about 400
mg/day in healthy adults (19 years or older), 100 mg/day in healthy adolescents
(12–18 years old), and 2.5 mg/kg/day in healthy children (less than 12 years old)
[169,170].

56 | P a g e
Caffeine–Drug Interactions

57 | P a g e
7.Caffeine–Drug Interactions:-
According to www.drugs.com (a site owned by The Drug site Trust, a privately
held Trust administered by two New Zealand Pharmacists), 85 drugs (430 brand
and generic names) are known to interact with caffeine, of which 11 can lead to
major interactions.

Because caffeine consumption is at an all-time high and prescription drug use is

more prevalent than ever, the risk of negative caffeine and prescription drug
interactions is increasing [171].

Because of the popularity of caffeine, clinicians should be conscious of the

pharmacokinetic interactions between dietary caffeine and over-the-counter and
prescription medications, and they should provide the necessary guidance to the
patient including dietary restrictions. We also recommend that the potential
interaction with these drugs be appropriately addressed on the labeling.

58 | P a g e
Contraindications

59 | P a g e
8.Contraindications.
Although there are no absolute contraindications to caffeine, there are some
medical conditions in which caution is necessary, which includes:

 Severe anxiety
 Cardiovascular disease or symptomatic cardiac arrhythmias
 Peptic ulcer disease or gastroesophageal reflux disease
 Hepatic impairment
 Renal impairment
 Seizures (as may lower seizure threshold)
 Pregnancy

American College of Obstetricians and Gynecologists (ACOG) considers 200 mg

daily safe during pregnancy.

There is no evidence to suggest caffeine increases the risk of congenital

malformations. However, some studies have concluded that high caffeine
consumption during pregnancy (more than 400 mg per day) may be associated
with lower birth weights from intrauterine growth restriction, increased risk of
miscarriage, but not preterm birth.

However, the evidence regarding lower birth weight and miscarriage is presently
inconclusive and pending further investigation. Caffeine is considered a pregnancy
class C drug [172].

60 | P a g e
RECOMMENDATIOS ON SAFE
INTAKE

61 | P a g e
9-.RECOMMENDATIOS ON SAFE INTAKE
LEVELS AND LIMITS ON INTAKE the European Food and Safety Authority considers
3-mg/kg body weight/day of habitual caffeine consumption to be safe for children
and adolescents [172].

A comprehensive review of the effects of caffeine consumption on human health

concluded that for healthy adults, moderate chronic intakes of caffeine up to
400 mg/day are not associated with adverse effects on cardiovascular health,
calcium balance and bone status, behavior, cancer risk, or male fertility [174].

However, the recommended intake is much lower for pregnant or nursing

mothers. The European Commission’s Scientific Committee of Food Safety
Authority and Health Canada both recommend that women consume no more
than 300 mg of caffeine/day during pregnancy. In addition, despite conflicting
results regarding the association between caffeine consumption and spontaneous
abortion, the American College of Obstetricians and Gynecologists recommends
that pregnant women restrict their caffeine intake to less than 200 mg/day [173].

For most children, adolescents, and young adults, safe levels of caffeine
consumption have not been established.

62 | P a g e
Conclusion

63 | P a g e
Conclusion.
It is not easy to define unequivocally whether caffeine has a positive or negative
effect on the human organism. Through interaction with receptors such as ARs,
RyRs, and GABA receptors and inhibition of PDEs, caffeine’s action is multi-
directional and reaches most of the human body systems. Its prevalence in plants,
medicinal and other products means that most people are exposed to its use, and
its rapid absorption and complex metabolism contribute to its effects on cell
function. Caffeine’s action depends on age, sex, source, and consumed dose.

At low doses, caffeine is said to have a positive effect on cognitive performance,

memory, and brain function, but at high doses, it may be responsible for
nervousness, anxiety etc. The positive effects of caffeine are observed in many
diseases (AD, PD, asthma, cirrhosis, fibrogenesis, kidney stones, some cancers,
etc.) as well as negative effects (Huntington’s disease, arrythmia, tachycardia,
lung cancer etc.).

Caffeine is also considered to have a therapeutic impact on pain. Thanks to its

anti-inflammatory and antioxidant properties, it may be useful medication not
only in pharmacology, but also in cosmetology.

Many studies have focused on caffeine’s ability to improve motor and respiratory
functions, which seems to be important in sport.

Caffeine in its many forms is a ubiquitous substance frequently used in military,

athletic and fitness populations which acutely enhance many aspects of exercise
performance in most, but not all studies.

Supplementation with caffeine has been shown to acutely enhance many aspects
of exercise, including pro longed aerobic-type activities and brief duration, high
intensity exercise.

Caffeine is ergogenic when consumed in doses of 3–6 mg/kg body mass. The most
commonly used timing of caffeine supplementation is 60 min pre-exercise.

The optimal timing of caffeine ingestion likely depends on the source of caffeine.
Caffeine’s effects seem to be similar in both trained and untrained individuals.

64 | P a g e
It's seems that the dangers of caffeine are related to the wide diffusion of the
substance, which results in an only partially conscious high consumption, due to
the difficulty of ascertaining the actual amount of caffeine ingested daily and the
inability to predict specific effects in relation to the triggering role that caffeine
may have – even at doses considered to be “safe” on underlying and not
necessarily known cardiovascular conditions.

The multi-directional action of caffeine is a very interesting research direction,

and therefore this topic was, is, and we will contribute to increase social
awareness of the effects of caffeine consumption, and constantly expanding
knowledge about this commonly used stimulant.

65 | P a g e
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66 | P a g e
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