Highlights in Science, Engineering and Technology GEMFE 2023

Volume 80 (2023)

Mechanism of Caffeine and Challenges of Caffeine

Dependence
Shu Zheng *
RDFZ International Curriculum Center, Beijing, 100000, China
* Corresponding Author Email: [email protected]
Abstract. By binding to adenosine A1 and A2A receptors, caffeine inhibits adenosine's inhibitory
effect on neurons, thereby increasing alertness and improving concentration. At the same time,
caffeine also stimulates the release of adrenaline and norepinephrine, further enhancing the sense
of wakefulness. Caffeine also induces the release of dopamine and glutamate in the nucleus
accumbens. They regulate human emotions, reward mechanisms, and memory. However, caffeine
dependence can cause side effects such as insomnia, anxiety, heart palpitations, digestive problems,
headaches, fatigue, and difficulty concentrating. To reduce dependency on caffeine, individuals can
gradually decrease their intake, opt for decaffeinated tea or coffee, and ensure they have sufficient
and restful sleep by adjusting sleep patterns. Maintaining overall health, a balanced diet, moderate
exercise and effective coping with stress can help increase natural energy levels and reduce the
need for caffeine. Seeking the help and guidance of a professional medical or mental health
professional is also recommended for reducing caffeine dependence.
Keywords: Caffeine; dependence; withdrawal.

1. Introduction
Many young individuals today are facing a concerning addiction to caffeine. A recent survey
conducted on beverage consumption in Asia revealed that every age and gender group within the
consumer population exceeds the recommended safe intake of caffeine. It is not limited to the familiar
sources like coffee, energy drinks, and tea. Caffeine is also added to a wide range of addictive food
products, including chewing gum, various cookies available in the market, sauces, and more. As a
result, caffeine has become an integral part of people's lives, serving both as a means to stay awake
and as a marketing strategy to encourage repeat purchases. Consequently, a significant segment of
the population has developed a dependency on caffeine. The phenomenon known as caffeine
dependence manifests when people experience sleepiness and headaches upon discontinuing caffeine
consumption. These symptoms can only be alleviated and improved in the short term by consuming
caffeine once again. Consequently, in order to prevent such symptoms, individuals find themselves
compelled to continue consuming caffeine. It is commonly referred to as caffeine dependence.

2. The Effects of Caffeine

Firstly, caffeine accompanies food as it travels to the stomach, eventually entering the bloodstream
through the digestive system. Its chemical properties enable it to breach the protective "blood-brain
barrier" and seep into the brain through the circulatory system.
Secondly, caffeine exhibits an affinity for a specific protein known as the adenosine receptor,
which is present on the surface of multiple neurons. Normally, when adenosine binds to this receptor,
it triggers a biochemical reaction that inhibits the transmission of electrical signals between neurons.
However, when caffeine enters the brain, it binds to adenosine receptors and blocks their activity,
preventing adenosine from inhibiting neuron activity. This mechanism, known as adenosine receptor
blockade, keeps neurons active and enhances brain function. Moreover, caffeine's effects extend
beyond neuron activity, as it can also impact memory, decision-making, and movement. Additionally,
consuming coffee triggers the pituitary gland to stimulate the release of adrenaline and norepinephrine
from the adrenal glands. This results in increased alertness shortly after consuming caffeine, with

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prolonged consumption leading to enhanced control over cognitive and decision-making processes.
The presence of dopamine and acetylcholine in the frontal region of the brain further improves focus
and cognition, facilitating quicker retrieval of memories [1].
Thirdly, caffeine increases the availability of dopamine receptors in the brain, which contributes
to the pleasurable sensations induced by dopamine. These effects typically peak around 30 minutes
after caffeine consumption and last for approximately 60 minutes. After initiating caffeine
consumption, people may develop a dependency due to the rewarding effects it provides. Caffeine
has the ability to stimulate the nerves and increase alertness. However, it can also disrupt sleep
patterns and create a reliance on its effects. Common symptoms associated with caffeine dependence
include headaches, drowsiness, and a persistent lack of energy. It is worth noting that caffeine is not
limited to coffee alone, as many snacks and beverages also contain this stimulant. Consequently,
individuals may unwittingly develop a dependence on caffeine [2].

3. The Mechanism of Caffeine

3.1. "Psychostimulant" - the Mechanism of Action of Caffeine
Caffeine is a very popular psychoactive drug because of its stimulant properties. The size of the
excitability depends on its ability to reduce adenosine transmission in the brain. Now, there is growing
experimental evidence that caffeine is an antagonist of two adenosine receptors. It stimulates
movement by conducting signals to the threaded body. Caffeine can do this because it is a molecular
target of the brain for physiological purposes. Caffeine acts as a competitive inhibitor of cyclic
nucleotide phosphodiesterase isoenzymes. As the concentration of caffeine increases, the effect
becomes more and more pronounced. Caffeine mobilizes calcium stored in cells. This step is very
important because it activates erythropurine-sensitive channels. If the Km value is close to the optimal
physiological concentration of adenosine, then the adenosine kinase will be above average [3].
In general, the ability of adenosine receptor antagonists will determine the effects of caffeine on
the brain. It has considerable specificity in the central nervous system. The ability of adenosine
receptor antagonists is determined by specific receptors in discrete regions of the brain. But because
the affinity between the receptor and adenosine is low, it can be negligible. So caffeine doesn't work
by blocking the receptor.
To understand its actual mechanism of action, numerous studies have been conducted. Studies
have shown that there are two types of receptors activated by adenosine. These two receptors are the
A1 receptor and the A2 receptor. And these two receptors have opposite biochemical effects. When
AMP is elevated, A1 receptors decrease and A2 receptors increase. This is because they have different
distribution in the brain. Scientists have found that the positive effects of caffeine, such as improving
attention, can be caused by coffee blocking A1 receptors. This process can also increase concentration,
alertness, and ability to get things done. The A2 receptor is completely different from the A1 receptor.
In the brain, A2 receptor expression is very restricted to areas innervated by dopamine fibers. And
these cells control human motor behavior. This is another effect that caffeine can have on the body.
This function is to prolong human motor activity. Caffeine promotes and prolongates motor behavior
in humans by controlling neurons in the thalamocortex. So studies have shown that caffeine works
by reducing endogenous adenosine and inhibiting striate dopamine transmission.
3.2. Caffeine Induces the Release of Dopamine and Glutamate in the Nucleus Accumbens
Dopamine is a crucial neurotransmitter in the brain that regulates various functions, including
mood, motivation, reward mechanisms, learning, memory, and motor control. It is mainly synthesized
by dopaminergic neurons and acts as a signaling molecule between neurons. The primary sites of
dopamine action are the D1 and D2 receptors, each serving different functions. Dopamine D1
stimulates adenylate cyclase through golf protein, increasing cAMP production, while dopamine D2
inhibits adenylate cyclase through gi coupling to go protein, reducing cAMP production [4].

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The process of dopamine action in the brain involves synthesis, release, signal transmission, and
reuptake. The first is to synthesize dopamine. Dopamine is synthesized mainly from tyrosine through
a series of enzymatic reactions. First, the conversion of tyrosine to ornithine is catalyzed by tyrosine
hydroxylase, and then the conversion of ornithine to dopamine by carboxylate decarboxylase. The
second is that when dopaminergic neurons fire, dopamine is released from the endings of the neurons
and enters the synaptic gap. This process is achieved through electrochemical signals, that is, when
the neuron is excited, calcium ions enter the cell, prompting the dopamine vesicles to fuse with the
cell membrane and release dopamine into the synaptic gap. The third is signal transmission.
Dopamine is in the synaptic gap and can bind to dopamine receptors on the target neuron. Dopamine
receptors are divided into a variety of subtypes, distributed in different regions of the brain. Different
subtypes play different roles in dopamine signaling, which either can increase or decrease neuronal
activity. In this way, dopamine can modulate different functions by activating or inhibiting target
neurons. [4]
And finally, the reuptake of dopamine. In order to maintain the balance of dopamine signaling,
dopamine needs to be quickly recovered after it has completed its function. Dopamine can be recycled
back into dopaminergic neurons through reuptake, or it can be degraded by enzymes, ending signaling
[5].
Similarly, glutamate, as an essential excitatory neurotransmitter, plays a crucial role in brain
function, including learning, memory, cognition, mood, and sensory functions. Its role in
neurotransmission is similar to dopamine, and it is vital for maintaining the normal functioning of the
brain. However, excessive glutamate release and excitatory transmission may lead to neuronal
damage and neurological diseases. Thus, the balance and regulation of glutamate are essential for
brain health.
Researchers are studying the effects of caffeine on the dopamine and glutamate systems in the
brain using mice as models. To mimic human caffeine consumption, they provided mice with a choice
of plain water or water containing moderate amounts of caffeine. Behavioral tests revealed that mice
consuming moderate caffeine showed higher activity levels and a tendency to explore new
environments, suggesting a stimulatory effect. Further analysis of brain chemistry showed a
significant increase in dopamine release in the striatum region of caffeine-consuming mice,
supporting the hypothesis that caffeine boosts dopamine release.
Molecular biology experiments revealed that caffeine consumption regulated the expression levels
of dopamine and glutamate receptors in the striatum. It up-regulated dopamine receptors and down-
regulated glutamate receptors, indicating caffeine's influence on the function of the dopamine and
glutamate systems through receptor expression.
In a long-term caffeine intake experiment, mice developed tolerance, requiring larger doses of
caffeine over time. These findings shed light on the mechanisms by which caffeine affects dopamine
and glutamate systems in the brain and provide insights into its psychoactive effects.
3.3. Effects of Caffeine on the Striatum
The striatum is part of the basal ganglia in the brain, a deep nucleus mass located in the center of
the brain. It consists of two main structures: the caudate nucleus and the putamen. The striatum plays
an important role in motor control, emotional regulation, learning, memory and cognition. As part of
the basal ganglia, the striatum has close neural connections with the cerebral cortex and other nervous
systems and is involved in coordinating and regulating a variety of complex physiological and
cognitive functions. It is also associated with neurological disorders such as Parkinson's disease and
Huntington's disease [5].
First, the striatum is closely related to the regulation of the dopamine system. The striatum is one
of the main projection areas of dopaminergic neurons, and dopamine is a neurotransmitter closely
related to emotion, motivation, and reward mechanisms. Studies have shown that caffeine can
increase dopamine release in the striatum. This means that caffeine may induce a certain level of
pleasure and excitement because dopamine plays an important role in the reward circuit and is

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associated with the formation of positive experiences and behaviors. Secondly, the striatum also has
some influence on glutamate. Glutamergic neurons are also found in the striatum, and glutamate is a
major excitatory neurotransmitter. Caffeine can increase the release of glutamate in the striatum,
which enhances excitatory transmission between neurons. This may lead to a certain level of
excitement and alertness, helping to improve concentration and reaction speed. Third, the striatum
also has an effect on the acetylcholine system. The neurons in the striatum are mainly composed of
dopaminergic neurons and acetyl cholinergic neurons. Acetylcholine is an important excitatory
neurotransmitter involved in motor regulation and learning and memory. Studies have found that
caffeine can inhibit the activity of acetyl cholinergic neurons, resulting in a decrease in acetylcholine
levels, which reduces inhibitory signals in the striatum, making excitatory signals more dominant.
Finally, the striatum plays an important role in regulating movement, and it is closely connected to
the cerebral cortex and other basal ganglia regions. The stimulant effects of caffeine may lead to an
enhanced motor response, making some people feel more active and excited after consuming large
amounts of caffeine [6].
In summary, caffeine's effects on the striatum primarily involve the regulation of various
neurotransmitter systems, including dopamine, glutamate, and acetylcholine. When consumed in
moderate amounts, caffeine can have positive effects on enhancing concentration, alertness, and
mood. However, excessive or long-term consumption of high doses of caffeine can lead to adverse
consequences, so it is prudent to consume it in moderation and be mindful of individual reactions [7].
3.4. Ways to Metabolize Caffeine
The body primarily metabolizes caffeine through the liver, where it undergoes a series of
enzymatic reactions, eventually transforming into harmless metabolites that are excreted in the urine.
When we consume caffeine-containing beverages, it quickly enters the bloodstream after absorption
through the stomach and small intestine. Once in the bloodstream, most of the caffeine is directed to
the liver for metabolism.
In the liver, caffeine is gradually broken down by enzymes from the cytochrome P450 enzyme
family, specifically CYP1A2 and CYP2E1, leading to the production of various metabolites. These
metabolites include paraxanthine, Para-methyl-aminobenzoic acid (theobromine), and para-methyl-
uracil acid (theophylline). After this initial metabolism, further conversions take place, resulting in
terminal metabolites like 3-methylxanthine and 1, 3-dimethylxanthine. These end metabolites possess
high water solubility and can be easily eliminated through the kidneys.
The excretion of caffeine and its metabolites occurs mainly through urine. The kidneys play a vital
role in removing waste from the body, and they achieve this by processes such as filtration,
reabsorption, and secretion of caffeine metabolites [8].
It is worth noting that the rate of caffeine metabolism can vary among individuals. Some people
have a higher capacity to metabolize caffeine, allowing them to clear it from their system more rapidly,
while others metabolize it more slowly. This variability is one of the reasons why people may
experience different effects after consuming caffeine, with some feeling its effects more quickly than
others.
In conclusion, the metabolism of caffeine in the human body is a complex process that primarily
occurs in the liver. Through this process, caffeine is transformed into harmless metabolites, which
are eventually excreted, ensuring the body's safe handling of this psychoactive substance.

4. Caffeine Dependence and Caffeine-Withdrawal Headache

People should aim to reduce their dependence on caffeine as it can lead to withdrawal symptoms,
specifically known as caffeine withdrawal headaches. These headaches are recognized as a common
and significant psychiatric disorder, supported by evidence from clinical settings, experimental
studies, and epidemiological research. This condition typically affects individuals who regularly
consume high amounts of caffeine, typically exceeding 500 to 600 mg per day. Over time, these

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individuals develop a tolerance to caffeine, and when they abruptly stop consuming it, they
experience headaches. Psychiatric inpatients are particularly susceptible to caffeine withdrawal
headaches, with a study finding that 22 percent of such patients consumed over 750 milligrams of
caffeine per day. Another report by Greden indicated that 11% of psychiatric inpatients reported
experiencing caffeine withdrawal headaches, emphasizing the impact of this condition in the
psychiatric population [9].
In summary, caffeine withdrawal headaches are a well-documented psychiatric disorder
characterized by frequent consumption of large amounts of caffeine, the development of tolerance,
and subsequent cessation of caffeine intake, leading to episodes of headaches. This syndrome is
particularly prevalent among psychiatric inpatients, especially those at higher risk. Treating caffeine
withdrawal headaches involves breaking the cycle of excessive caffeine consumption, tolerance
development, and intermittent withdrawal [10].
One common challenge in reducing caffeine intake is patient skepticism regarding the impact of
caffeine on their symptoms. Therefore, clinicians often need to initiate an educational program to
address this skepticism. This program should include an explanation of the potential harmful effects
of caffeine. Clinicians can provide information about the pharmacological effects of caffeine on the
body, emphasizing that excessive caffeine consumption can lead to various negative effects, such as
insomnia, anxiety, irritability, digestive problems, and even caffeine dependence. By providing this
information, clinicians aim to help patients understand the potential impact of caffeine on their
symptoms and overall well-being. It is important to emphasize that individuals may react differently
to caffeine, and some individuals may be more sensitive to its effects than others. Encouraging open
communication and addressing any concerns or doubts the patient may have can also help foster trust
and facilitate the patient's acceptance of the educational program.
In conclusion, an educational program is often necessary to address patient skepticism regarding
the relationship between caffeine and their symptoms. By explaining the potential adverse effects of
caffeine and tailoring the educational approach to individual patients, clinicians can enhance patients'
understanding and willingness to reduce their caffeine intake.

5. Conclusion
Caffeine exerts its effects by binding to adenosine A1 and A2A receptors, inhibiting the inhibitory
actions of adenosine on neurons. This blockade keeps neurons active, leading to increased alertness
and improved focus. Additionally, caffeine stimulates the release of epinephrine and norepinephrine,
further enhancing wakefulness. These actions of caffeine not only sharpen cognitive abilities but also
increase the availability of dopamine receptors, heightening the perception of reward stimuli, such as
food. However, the side effects of caffeine dependence can include insomnia, anxiety, heart
palpitations, digestive issues, headaches, fatigue, and difficulty concentrating. When individuals
abruptly stop consuming caffeine, they often experience drowsiness and headaches.
To reduce dependence on caffeine, several steps can be taken. Gradually decreasing caffeine intake
and replacing caffeinated beverages with decaffeinated alternatives, such as tea or decaf coffee, can
help. Adjusting sleep patterns to ensure sufficient and restful sleep is also important in reducing
caffeine dependence. Maintaining overall health and well-being through a balanced diet, moderate
exercise, and effective stress management can increase natural energy levels and reduce the need for
caffeine. Exploring alternative methods to enhance alertness, such as taking short naps, staying
hydrated, and consuming a nutritious diet, can also be beneficial. If caffeine dependence significantly
impacts one's quality of life, seeking professional assistance and guidance from a healthcare provider
or mental health professional is recommended.

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