CAFFEINE

COGNITIVE AND PHYSICAL

PERFORMANCE ENHANCER

or Psychoactive Drug?
ABSTRACT: To many people, caffeine seems like more of a necessity to start the day, or keep the day

going. Caffeine is the most popular drug in the world and is often marketed for its physical and cognitive

performance benefits. Caffeine and caffeine-containing products can lead to neurotoxicity with their

locomotor activity stimulation and anxiogenic effects. Furthermore, because caffeine consumption occurs

usually on a daily basis, caffeine abuse and dependence are becoming more common which puts

individuals at risk for premature death and unnatural death. The following report details certain aspects of

caffeine’s pharmacokinetics, toxicokinetics, mechanism of action, use, dependence, intoxication, and its

neurobehavioral effects.

INTRODUCTION

Caffeine is probably the most frequently ingested self-administered psychoactive drug in existence. It is

estimated that caffeine is consumed each day by approximately 80% of world’s population (7), with a

mean intake of 193 mg per day (6).

Coffee arabica is an exceptionally hardy self-pollinating plant from which coffee is derived. This plant

finds its origins in Ethiopia, and Rhazes, a Persian physician was the first to mention it in his manuscripts.

The word “coffee” finds its roots in Arabia, where it is called “qahwah”, as Yemen was the first country

to cultivate the coffee plants and Turkey was the first to roast the green coffee beans. In the 17th century,

the English word “coffee” found its way in the European languages from the Italian word “caffe”. Over

the centuries, the habit of drinking coffee spread from Arabia to all across the world (5).

Caffeine (1,3,7-trimethylxanthine) is a member of methylxanthine class of alkaloids that include

theobromine and theophylline. Caffeine is a natural alkaloid found in coffee beans (Coffee arabica and C.

robusta), tea leaves (Camellia thea), cocoa beans, cola nuts and other plants of the family Rubiaceae,

Sterculiaceae, and Theaceae. It is a bitter white powder in its free base form that is moderately soluble in

water – 21.7mg ml -1 (6).

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Worldwide, caffeine is found in common beverages such as coffee (70%), tea (15%), soft drinks (16%),

energy drinks, energy shots, foods (energy mints and chocolates), and prescription and non-prescription

drugs (7). Coffee and tea are major sources of caffeine in the adult diet, whereas soft drinks and chocolates

are a major source in the diet of children. Xanthine as caffeine is also used in the therapeutic field as an

adjunct in analgesics, in weight loss products, and to treat apnea in infants. Given its stimulant effects, it

is often consumed in pursuit of mental or physical performance benefits such as improved physical

endurance, weight loss, cognitive alertness, and reduction of fatigue (7).

Caffeine content of different Beverages, Foods, and Medicines (7)

CAFFEINE SOURCE CAFFEINE CONTENT (in order of strength)

Coffee:
Expresso 1.74 mg/ml
Drip 0.61mg/ml
Brewed 0.45 mg/ml
Instant 0.24 mg/ml
Decaffeinated 0.01 mg/kg
Tea:
Brewed 0.20 mg/ml
Instant, Green 0.11mg/ml
Other hot drinks:
Mate 0.36mg/ml
Mochaccino 0.18mg/ml
Hot chocolate 0.09mg/ml
Soft Drinks (Pepsi, Diet Pepsi, Diet Coke, Approx. 0.13mg/ml
Mountain Dew)
Energy Drinks:
Orange rush 1.06mg/ml
Red Bull, Demon energy drink 0.32mg/ml
Energy Shots:
6-hour power 2.08mg/ml
Ammo Energy Shot 5.78mg/ml
Demon Energy Shot) 3.33mg/ml
NOS Energy Shot 4.16mg/ml
Foods:
Foosh energy mints 100mg/tablet
Dark chocolate 0.71mg/kg
Milk chocolate 0.21mg/kg

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 Non-prescription drug:
No Doz 100mg/tablet
Panadol Extra 65mg/tablet
Midol 32.4mg/tablet
Anacin 32mg/tablet
Prescription drug:
Cafergot 100mg/tablet
Fioricet 40mg/tablet
Dristan 16mg/tablet

While caffeine is generally thought to be safe in moderate amounts, it is clearly not a harmless compound

and can cause significant toxicity and even lethality. Food and Drug Administration (FDA) has cited

400mg/day (four or five cups of coffee) as a safe amount of daily caffeine for healthy adults i.e. an amount

not associated with negative effects. There is no set level for children, but the American Academy of

Pediatrics has discouraged the consumption of caffeine and other stimulants by children and adolescents

(4).

PHARMACOKINETICS AND PHARMACODYNAMICS

Caffeine is rapidly absorbed through the gastrointestinal tract after oral ingestion and is readily distributed

to tissues and organs in the human body. Peak plasma concentrations are typically observed between 30

and 60 min (1), with 10 – 35% of the fraction of caffeine bound to plasma protein (6). It passes across the

blood brain-barrier, through the placenta into amniotic fluid and the fetus, and into breast milk due to its

moderate lipophilic property (5).

The liver is the primary site for the first pass metabolism of caffeine. The hepatic microsomal enzyme

responsible for caffeine metabolism is cytochrome P450 1A2 (CYP450 1A2), which accounts for 95% of

caffeine clearance (5). Along with the CYP450 1A2, xanthine oxidase and N-acetyltransferase 2 (NAT2)

also controls the caffeine metabolism rate. CYP450 1A2 is also produced by brain and kidney, suggesting

that these tissues are also able to metabolize caffeine. Caffeine’s plasma half-life is highly dependent on

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dose and individual’s metabolism, but generally, it ranges from 2 to 10 h with 0.5% - 3.5% of its content

excreted in the urine (3).

Paraxanthine (4%), theobromine

(12%), and theophylline (84%)

are the primary metabolites that

are further transformed in the liver

through demethylation and

oxidation, resulting in the

production of urates (3).

Image Source: wikidoc.com

Several factors influence metabolic and excretion rates of caffeine, such as gender, genetics, diet, physical

activity, pregnancy, smoking, and frequency of consumption of certain drugs. For instance, females

reportedly have 20 – 30% shorter caffeine half-life than males (8). Smokers metabolize caffeine about

twice as fast as non-smokers because smoking stimulates the enzyme action of CYP450 1A2 causing a

faster demethylation (5). Also, physical exercise can up-regulate CYP450 1A2, thus increasing the rate of

caffeine metabolism (3). In turn, alcohol consumption inhibits caffeine metabolism by increasing its half-

life (3). Caffeine half-life is prolonged during pregnancy i.e. tripled in the second and third trimesters of

pregnancy and in individuals with liver disease (5). Neonates have a markedly increased caffeine half-life

(80–100 h) due to immature liver enzyme systems which are fully developed at approximately 6 months

of age (3). Also, females using oral contraceptive steroids have caffeine half-life approximately twice that

observed for ovulatory females (8).

MECHANISM OF ACTION

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 There are three mechanisms of action that explain the potential effects of caffeine at the cellular level: the

antagonism of adenosine receptors, the mobilization of intracellular calcium storage, and the inhibition of

phosphodiesterase (5). However, typical dietary doses of caffeine are believed to be too low to be

significantly influenced by the no adenosine mechanisms. Thus, the main proposed molecular target of

caffeine at physiologically relevant concentrations are the adenosine receptors and its effects are primarily

mediated by direct antagonism of adenosine and indirect enhancement of brain dopamine activity (7).

ADENOSINE CAFFEINE Mechanism of action of

ADENOSINE RECEPTOR
caffeine
Caffeine and adenosine have a
ADENOSINE RECEPTOR similar molecular structure.
Thus, caffeine binds to the
adenosine receptors in the
brain similarly to the
adenosine in AMP, blocking
their calming effect and
making you feel more alert
and awake (3).

Caffeine vs Adenosine
molecular structure
Part of adenosine that
resembles caffeine.
Image source (9)
CAFFEINE ADENOSINE

MOL
Adenosine is an endogenous purine nucleoside that can increase or decrease cellular concentrations of

cyclic adenosine monophosphate (cAMP) by acting on different receptors. It generally exerts inhibitory

effects throughout the central and peripheral system, such as excitatory neurotransmitter inhibition,

suppression of motor activity, and inhibition of gastric secretion (6). When the brain is active, it consumes

lots of ATP (adenosine triphosphate) as an energy source. As the ATP is used it leaves behind a by-

product, AMP (adenosine monophosphate). The longer the brain remains active, the more AMP builds up

over time. Specialized adenosine receptors detect the increasing levels of AMP and send a signal that

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reduces alertness and increases drowsiness until eventually, you fall asleep. While sleeping, the brain has

a chance to clear out the AMP and you wake up feeling alert and rested (6).

Caffeine blocks the adenosine receptors, mainly adenosine 1(A1) and adenosine 2A (A2A) subtypes, and

competitively inhibit their actions by binding on to the cell surface without activating them (an

“antagonist” mechanism of action) (6). A1 receptors are widely expressed throughout the brain, whereas

A2A receptors are concentrated in dopaminergic-rich areas, such as the striatum. By inhibiting adenosine,

caffeine excites the central nervous system and allows for continued stimulation of neurons that otherwise

would not fire or would not release neurotransmitter into the synapse. For instance, caffeine enhances

dopamine activity indirectly by competitive antagonism of A2A receptors that are co-localized and

functionally interact with dopamine (8). This most likely explains caffeine’s psychostimulant and

dopaminergic effects. Also, antagonism of A1 receptors results in an increased release of catecholamines.

Therefore, caffeine is a non-selective competitive A1 and A2A receptor antagonist producing a variety of

central and peripheral effects (stimulatory effects) that are opposite of the inhibitory effects of adenosine

receptors (6). The more caffeine you take, the more receptors are “turned off” giving the brain the illusion

that the AMP has been flushed out resulting in an alert and rested feeling as if you had just woken up (7).

One of the primary actions of adenosine is to make us tired or sleepy, caffeine, by blocking the uptake of

adenosine, keeps us from feeling the effects of fatigue. But scientists have learned that, largely as a

consequence of its blockade of adenosine receptors, caffeine also has profound effects on most of the other

major neurotransmitters, including dopamine, acetylcholine, serotonin, and, in high doses, on

norepinephrine (8). By affecting these other neurotransmitters, it is able to deliver a major boost to our

capacities even when we are well-rested, something that could not be explained by the inhibition of

adenosine alone (8). By increasing the transmission of dopamine, caffeine improves our mood and may

protect brain cells from age and disease-related degeneration (8). By increasing the activity of

acetylcholine, caffeine increases muscular activity and may also improve long-term memory. By raising

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and adjusting serotonin levels, caffeine relieves depression, makes us more relaxed, alert, and energetic,

and relieves migraine headaches (8).

NEUROBEHAVIORAL ASPECTS OF CAFFEINE

 Effects of caffeine on psychomotor performance and memory enhancement:

Numerous investigations have examined that caffeine enhances performance on tasks that require

alertness, wakefulness, vigilance, short reaction time, sustained concentration, and efficient information

processing. However, because impaired performance can occur, caffeine’s effects can be best explained

by the well-known inverted U-shaped relationship between increased arousal and performance (7).

Any benefits of caffeine are expected to be

dose-related. In other words, small

increases in arousal (low doses) can

improve but large increases (higher doses)

can have no effect or even impair (7).

Image Source (7)

Various factors that can determine the type of effects of the size of the caffeine dose are as follows ():

1. Prevailing level of baseline arousal before the drug is experienced: This means that if baseline arousal

is high, then a dose that might normally improve performance when arousal is low may have the

opposite effect (7).

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2. Constitutional characteristics of the individual, such as the sex: Women can have higher baseline

arousal levels than men, therefore, further increases in arousal with caffeine may result in less

improvement or even impairment for them, compared to men. Because of slower estrogen-related

caffeine clearance, this effect for women may be even greater during the late luteal phase of the

menstrual cycle (7).

3. Personality type, such as an introvert or an extrovert: For example, introverts experience greater

caffeine-related impairment of cognitive performance than extroverts. Thus, in the presence of

caffeine’s arousing influence, the arousal of the introverts further increases beyond an optimum level

leading to the descending side of the inverted U-shaped curve (7).

4. The degree of tiredness: The performance of tired and thus low-aroused individuals is expected to

benefit more from caffeine than those who are not tired. This is relevant in context to the habitual

caffeine consumers who experience an increased level of alertness following a morning caffeinated

drink merely due to the reversal of the tiring effects of overnight caffeine withdrawal (7).

It is therefore very important to take into account baseline arousal levels and possible reversal of

withdrawal reactions when interpreting the effects of caffeine on psychomotor performance and possibly

other forms of behavior such as anxiety, mood, and memory (8).

 Effects of caffeine on anxiety and mood:

1. Anxiogenic Effects

It is suggested that the anxiogenic effect of caffeine may arise from blockade of benzodiazepine binding

sites on gamma-aminobutyric acid A (GABAA) receptors, which would require a concentration of the

drug that is 5–10 times higher than that needed to block adenosine receptor. However, the drug is still

capable of producing anxiety symptoms in the absence of changes in norepinephrine. Therefore,

antagonism of adenosine receptors seems to be the most likely reason for caffeine-induced anxiety,

specifically antagonism of the A1 rather than A2A subtype (7).

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It is important to distinguish between acute and chronic administration and habitual consumers and non-

consumers when assessing effects of caffeine on anxiety. Habitual consumption of high daily doses (>600

mg/day), which are in excess of normal caffeine intake for most consumers, can be anxiogenic (7).

However, it is significant to note that a single large dose of caffeine (200 mg) can increase anxiety in a

similar way to several smaller doses (65 mg) experienced over several hours, thereby suggesting that acute

administration may not be too different from chronic administration (7). Also, people who are prone to

stress-related anxiety or panic attacks tend to be hypersensitive to the anxiogenic effects of caffeine and

thus, they should consciously limit their intake (8).

2. Anxiolytic and Mood-Elevating effects:

A fairly widely held view is that, whereas high doses of caffeine are anxiogenic, low doses may be

anxiolytic (7). Mood-elevating effects have been described with doses as low as 10 mg. A dose-related

improvement in subjective measures of calmness and interest were found after consuming caffeine,

suggesting that mood improvement may depend on baseline arousal (7). Highly-fatigued subjects may be

more likely to experience larger subjective mood changes than none- or moderately-fatigued subjects (8).

Older adults seem to be more sensitive to the mood-enhancing effects of caffeine than younger individuals

(8). Mood effects are also influenced by the time of consumption, with the most prominent effects showing

in the late morning (7). In fact, one study has suggested that caffeine could potentially be used as a nutrition

supplement for older adults, enhancing mood and improving cognitive performance in their daily living

tasks (8).

CAFFEINE TOLERANCE, DEPENDANCE AND WITHDRAWAL

1. Caffeine Tolerance: Daily caffeine consumption can lead to tolerance. Tolerance can occur in

relation to the subjective, sleep-disrupting and physiological effects of caffeine. Tolerance with

regards to other physiological effects develops to the effects of caffeine on diuresis, parotid gland

salivation, metabolic rate, plasma norepinephrine and epinephrine levels, and plasma renin activity.

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 The degree of caffeine tolerance depends on several factors including the dose, frequency of

administration and individual difference in elimination rate (7).

2. Caffeine Dependence: It varies considerably depending on the amount of caffeine consumed per day

and on the types of caffeine-containing products consumed on the daily basis (coffee, tea, soft

drinks). Problems associated with caffeine dependence include anxiety, insomnia, stomach problems,

and cardiovascular problems, but these problems are not trivial (7).

3. Caffeine Withdrawal: Cessation or reduction of daily caffeine consumption results in withdrawal

symptoms in many caffeine users. One of the symptoms is caffeine withdrawal headache, which

develops gradually and is described as diffuse, throbbing, severe, and phenomenon logically distinct

from a migraine headache. Other withdrawal symptoms that have been reliably observed are fatigue,

decreased energy/activeness, decreased alertness, drowsiness, depressed mood, difficulty

concentrating, irritability, foggy/not clear-headed, nausea/vomiting and muscle pain/ stiffness. The

severity of caffeine withdrawal symptoms can range from mild to extreme depending on the dose,

frequency of consumption, and the elimination rate of an individual (7).

CONCLUSION: It is clear that caffeine is a widely available psychoactive drug consumed at different

levels by most segments of the population to increase their productivity and performance in a variety of

circumstances. A variable amount of caffeine is contained in coffee, tea, and other drinks, but it is difficult

to reach lethal doses of caffeine exclusively through one of these products. Caffeine is safe for adults to

consume, but also has limited effects. Facilitation of psychomotor performance does occur often although

this is probably due to either increased arousal level or reversal of caffeine withdrawal for regular con-

sumers. Examples of impaired performance are probably due to arousal increases that exceed an optimum

level. Similar reasons may also account for caffeine-related enhancement or impairment of memory rather

than effects of the drug on neural consolidation. Whereas caffeine in high doses can be anxiogenic, the

opposite outcome (anxiolysis) can accompany lower doses around 100 mg possibly through reversal of

withdrawal (7). While it is generally accepted that caffeine’s effects arise mainly from the antagonism of
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A1 and A2A receptors (6), evidence for the development of tolerance and dependence with habitual use

(similar to that characterizing other psychostimulants) is not consistent even though upregulation of these

receptors is well established, and withdrawal reactions of varying severity can be experienced (7).

Therefore, any spectacular claim as to the power of caffeine, whether they are positive or negative, should

be examined carefully before you believe them.

Reference

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Update. Clinical Pediatric Emergency Medicine,18(3), 197-202. doi: 10.1016/j.cpem.2017.07.002

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https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm350570.htm

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https://www.wikidoc.org/index.php/Caffeine

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