European Journal of Medicinal Chemistry Reports 10 (2024) 100138

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European Journal of Medicinal Chemistry Reports

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Pharmacology of caffeine and its effects on the human body

Vundrala Sumedha Reddy a, *, S. Shiva a, b, Srinidhi Manikantan a, Seeram Ramakrishna a
a
Centre for Nanotechnology & Sustainability, Department of Mechanical Engineering, National University of Singapore, Singapore, 117574, Singapore
b
School of Bioscience and Technology, Vellore Institute of Technology, Vellore, 632014, India

A R T I C L E I N F O A B S T R A C T

Keywords: Caffeine is the world’s most popular stimulant and psychoactive substance. Given the ubiquitous use of caffeine,
Caffeine it is crucial for us to comprehend how our body interacts with caffeine. The pharmacokinetics of caffeine and its
Pharmacological effects action mechanisms have been reviewed in this paper. The safety and recommended dosage of caffeine in healthy
Pharmacokinetics
adults and vulnerable populations like children and pregnant women are also discussed in this paper. While
Mechanism
Pregnancy
caffeine consumption is generally safe, this review paper also examines the potential effects that caffeine could
Drug delivery have on human health and development. Studies indicated that caffeine exhibits neuroprotective properties,
potentially serving as a preventive measure against the onset of neurodegenerative conditions such as Alz­
heimer’s and Parkinson’s disease. The article also explores various physiological effects of caffeine on the body,
in addition to investigating novel drug delivery techniques, particularly nano-delivery systems designed to
efficiently administer caffeine.

1. Introduction prescription and over-the-counter medications used to treat headaches,

colds, and allergies. These medications analgesic effects are said to be
Caffeine is the world’s most popular stimulant and psychoactive enhanced by caffeine. Apart from medication it can also be used
substance [1]. More than 60 different plant species, including cacao cosmetically and is an active component in several cellulite-reducing
beans and tea leaves, naturally contain it in varying degrees [2]. treatments. Caffeine’s ergogenic properties also makes it one of the
Caffeine can be present in a variety of plant parts, including leaves, widely utilized performance-enhancing supplements used by athletes
beans, and fruits. For instance, caffeine may go by different names from different sports modalities.
depending on where it is found—guaranine in guarana berries, theine in Caffeine (1,3,7-trimethylxanthine) is a methylxanthine derivative
tea plants, or mateine in yerba mate plants [3]. The main dietary with a molecular formula of C8H10N4O2 [9]. It is considered to be an
caffeine sources in the world are roasted coffee beans like robusta and alkaloid compound as it is a metabolite of nitrogen metabolism [10].
arabica and tea leaves [4]. In addition to naturally occurring caffeine, it Caffeine is a heterocyclic organic compound with a purine base. The
can also be artificially produced in labs and added during chemical structure of caffeine, with the purine base highlighted in a box
manufacturing. Between natural and manufactured caffeine, there is is shown in Fig. 1 below. This structure is very similar to the structures of
essentially no molecular difference. Caffeine is typically produced using other metabolic compounds like purines [9].
chemicals like urea, dimethylurea, and chloroacetic acid [5] where This specific chemical structure of caffeine was only confirmed in the
caffeine citrate and dicaffeine malate are some of the synthesized late 19th century, after the isolation of pure caffeine in 1819 by Friedlieb
caffeine [6]. . Numerous manufactured products, including the majority Runge [11](12). Even before caffeine was discovered and isolated,
of sodas and energy drinks, contain this produced caffeine. people from different countries were consuming caffeine-containing
The most popular dietary sources of caffeine are coffee, tea, choco­ plants as an energy source and for medical uses [13]. Caffeine con­
lates, and soft drinks [7]. Main source of caffeine consumed by adults sumption is suggested to have begun as far back as 2737 BC when the
tends to be coffee, while soft drinks and tea are more predominant Chinese made tea using tea leaves [4]. Ever since its discovery, caffeine
sources of caffeine among adolescents. Depending on the plant species containing foods and beverages started emerging. For instance, coffee
and brewing technique used, the amount of caffeine in brewed bever­ originated in Ethiopia in the 9th century and caffeinated soft drinks were
ages varies substantially [8]. Caffeine can also be consumed through introduced in the late 1800s [4]. Today, about 80% of the people in the

* Corresponding author.
E-mail address: sumedha@[Link] (V.S. Reddy).

[Link]
Received 10 December 2023; Received in revised form 20 February 2024; Accepted 25 February 2024
Available online 27 February 2024
2772-4174/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
([Link]
V.S. Reddy et al. European Journal of Medicinal Chemistry Reports 10 (2024) 100138

Table 1
Brief summary of the physical and chemical properties of pure caffeine.
Properties Description

Molar Mass 194.19 g mol− 1

Appearance White powder
Smell and Taste Odorless and very bitter
Density 1.2 g/cm3 at 25 ◦ C and 100 kPa
Volatility 0.5%
Melting Point 238 ◦ C
Boiling Point/ 178 ◦ C (Caffeine sublimes at its boiling point)
Sublimation Point
Vapor Pressure 101 kPa at 178 ◦ C
Fig. 1. Chemical structure of caffeine. Solubility Slightly soluble in water
Very soluble in boiling water
Slightly soluble in petroleum ether, ether & benzene
world consume caffeine-containing meals or beverages almost every day Moderately soluble in alcohol & acetone
[14]. In terms of consumption, Finland ranks as one of the highest Soluble in ethyl acetate, chloroform, pyrrole,
consumers of caffeine per capita. Fig. 2(a) shows the consumption of pyrimidine, tetrahydrofuran
Ph 6.9 (almost neutral)
coffee beans across the globe and also the production of coffee beans Acidity (pKa) 10.4 at 40 ◦ C
across 2017–2021 [15]. In terms of production it’s been noted that Optical Activity None
Vietnam is the second largest producer lately. Brazil is the largest pro­
ducer and exporter of coffee beans in the world and Brazil’s coffee in­
dustry is a significant contributor to global caffeine production, Fig. 2 more sensitive to the effects of caffeine than adults [17]. Although no
(b). safe dosage has been established, children should not ingest more than
Several of the physical and chemical properties of pure caffeine are 2.5 mg per kilogram body weight [18]. Overconsumption can cause a
summarized in Table 1. In general, it is recommended for a healthy adult number of symptoms, such as sleeplessness, restlessness, and occasion­
to limit daily caffeine intake to 400 mg in order to avoid any adverse ally muscular tremors. Blood concentrations of 80 mg/ml of caffeine are
health effects [16]. There have been some concerns that children may be reported to be lethal [19]. Despite the rarity of caffeine intoxication, it is

Fig. 2. (a) Consumption of coffee globally and (b) the export quantity across the years 2017–2021.

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important to note that the side effects can be profound given caffeine’s achieving rapid alertness. However, the side effects such as jitteriness,
ability to affect different types of receptors. If timely treatment is not nervousness, increased heart rate, and insomnia remain persistent but
provided, it can even potentially result in morbidity and mortality. the effect changes with the dosage and the physiology of the individual.
Despite the extensive research on caffeine, certain effects are still Following ingestion, caffeine is quickly and almost completely
unclear, and different studies have produced contradictory findings. For absorbed into the bloodstream [20]. This reflects caffeine’s 100%
more than a century, the safety of caffeine has been debatable [14]. bioavailability and its high solubility in water and organic solvents [12].
Given the ubiquitous use of caffeine, it is crucial for us to comprehend 80% of caffeine is absorbed through the gastrointestinal tract while the
the pharmacology of the substance and its action mechanisms. These remaining 20% is absorbed by the stomach [21]. Oral mucosa, the
concepts on potential impacts of caffeine on human development and mucous membrane lining inside the mouth also plays a role in caffeine
health will be reviewed in this article. absorption [22]. Various studies have already reported faster absorption
with comparison to capsule based delivery systems. After ingestion,
2. Routes and pharmacokinetics of caffeine almost 99% of caffeine is absorbed and it reaches peak plasma con­
centrations in approximately 1 h after consumption [16](23). However,
Pharmacokinetics explains how the body interacts with the chemical. this can be delayed with food intake as food slows down gastric
It studies the absorption, distribution, metabolism, and excretion emptying [16]. Different types and volumes of food consumed can affect
(ADME) of a substance. An overview of the pharmacokinetics of caffeine the rate of plasma absorption. For instance, caffeine absorption from soft
is illustrated along with multiple administering routes in Fig. 3. drinks occurs at a slower rate compared to that absorbed from tea and
coffee. Hence, there can be a wide variation in the time in which the
maximum plasma concentration of caffeine is obtained.
2.1. Absorption
Furthermore, before being absorbed into the bloodstream, most
substances will be metabolized by the liver. However, in the case of
Caffeine-based injections, specifically through intravenous admin­
caffeine, this hepatic first-pass (The effect of rapid transformation of
istration, are a method for delivering caffeine. One such intravenous
drug when administered orally leading to reduce bioavailability) effect
caffeine drug is caffeine citrate, known by the tradename ‘cafcet,’ which
occurs very minimally and this explains the rapid absorption of caffeine
is used to treat apnea. This drug contains 20 mg of caffeine citrate per
[24]. Due to this limited first-pass metabolism, absorption of caffeine
milliliter. The solution is prepared by combining 10 mg of caffeine in its
occurs independent of age, sex, health status as well as the consumption
anhydrous form, 5.0 mg of citric acid monohydrate, 8.3 mg of sodium
of nicotine, drugs or alcohol [22]. Caffeine also has a linear pharma­
citrate dihydrate, and water for injection. Although caffeine can also be
cokinetic behavior, where increasing doses of caffeine intake results in
administered intramuscularly, it is not typically recommended due to its
proportionate increase in caffeine levels in the blood plasma [24].
unpredictable and slower absorption rate, considerations related to
neonatal use, and the desire to avoid complications at the injection site.
However, caffeine citrate can be administered intravenously or through 2.2. Distribution
oral mucosa to achieve the desired therapeutic effects, particularly in
stimulating heart rate and respiration. Rectal administration of caffeine Once absorbed, about 10%–30% of caffeine is reversibly bound to
is also possible by means of caffeine-based suppositories which usually plasma proteins like albumin [25](12). The rest of the caffeine mole­
melt in body temperature and the caffeine content is absorbed through cules are extensively and quickly distributed to the different body tissues
rectal mucosa. This route allows a faster and easier route of adminis­ and organs [16](22). The mean distribution volume for caffeine is
tration of caffeine where conventional administration via oral or intra­ estimated to be 0.7 L/kg body weight which suggests the hydrophilic
venous is not possible. This less common method in comparison to other nature of caffeine. This allows caffeine to be distributed freely into the
methods is used for the treatment of migraine headaches and for intracellular tissue water. Moreover, caffeine molecules are also

Fig. 3. Overview of caffeine pharmacokinetics.

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lipophilic enough to pass through all biological membranes, including Table 2

the blood-brain barrier and the placental barrier. There have been no Main roles of primary caffeine metabolites.
physiological barriers found to limit the distribution of caffeine [18]. Caffeine metabolites Roles
This explains why it can be easily detected in different types of body
Paraxanthine Breaks down fats
fluids, including human breast milk and amniotic fluid [18]. Although Increases glycerol and fat levels in blood
there is no accumulation of caffeine in any tissues or organs, high con­ Theobromine Dilates blood vessels
centrations of caffeine can be found in the brain. It is reported based on Increases urination ▾ Diuretic effect
animal studies that about 80% of plasma caffeine is found in the brain Theophylline Dilates airways
Used in the treatment of asthma.
[1]. This is because caffeine’s primary mode of action is the blockage of
adenosine receptors which are mainly distributed at different parts of
the brain [1]. Furthermore, this distribution does not change as a person individual variation and other physiological and environmental factors.
ages. It is however, notably higher in women and obese individuals [22]. Since CYP1A2 is an important enzyme in the metabolic pathway of
caffeine, any factors that affect its activity will also affect the meta­
bolism and half-life of caffeine [24]. For instance, smoking increases the
2.3. Metabolism rate of caffeine metabolism and decreases the half-life because cigarette
smoke contains polycyclic aromatic hydrocarbons which are CYP1A2
Metabolism of caffeine takes place extensively in the liver by the inducers [32]. On the other hand, pregnancy slows down the rate of
microsomal cytochrome P450 enzyme system [26]. Two of the cP450 caffeine metabolism because it leads to reductions in CYP1A2 enzyme
isoenzymes (CYP1A2 and CYP2C9) are important in the demethylation activity [24]. Hence, this will result in a longer half-life for caffeine in
of caffeine [26]. The majority of the metabolic reactions (90%) are
pregnant women. The human hepatic metabolic capacity is only ach­
catalyzed by CYP1A2 isozyme. CYP1A2 enzyme itself accounts for about ieved approximately at 5–6 months of age and prior to that the immature
95% of caffeine breakdown [14]. Oxidative N-demethylation of caffeine
expression of the hepatic metabolic system will result in a longer
results in primary mono-demethylated metabolites such as para­ half-life for caffeine as well [24,33].
xanthine, theobromine and theophylline, which have similar biological
activity to caffeine [12]. The primary initial step in humans is 3-deme­
thylation of caffeine into paraxanthine [17]. Most of the caffeine 2.4. Elimination
follow this route and about 80% of them are converted into para­
xanthine, which is the major human metabolite [17]. The remaining are Almost all the caffeine ingested is metabolized, largely in the liver,
converted into theobromine (~11%) and theophylline (~4%), Fig. 4 before elimination occurs [17]. The primary route of elimination for
[27]. caffeine and its metabolites is by the kidneys through urine excretion
The roles of these primary metabolites are given in Table 2 below [27]. Only a small percentage, of about less than 3% of caffeine are
[28]. These metabolites can undergo further oxidation and demethyla­ excreted unchanged from the body [29]. This is because after glomer­
tion to give rise to urates and an acetylated uracil derivative [29]. These ular filtration in the kidneys, most of the caffeine molecules (98%) are
accounts for the remaining total caffeine metabolites (~6%). Moreover, strongly reabsorbed back into the bloodstream by the renal tubules [34].
it should be noted that none of these caffeine metabolites yield reactive Hence, this reflects that caffeine elimination is very dependent on renal
intermediates that have potential to cause toxicity [24]. Other enzymes blood and urine flow.
like xanthine oxidase, mono-oxygenate and N-acteyltransferase-2 are The rate of caffeine elimination varies across different individuals
also involved in the metabolic pathways of caffeine [30]. depending on environmental and genetic factors. Moreover, caffeine
The rate of caffeine metabolism differs greatly, with half-life ranging elimination is dose dependent, and it follows the Michaelis-Lenten ki­
from about 2 to 12 h [31]. The average half-life of caffeine is about 4–5 h netics [12]. Generally, at low to moderate caffeine concentrations, it
in healthy adults [14]. The differences in half-life are due to genetic follows first order kinetics and at higher concentrations, it reaches

Fig. 4. Major metabolic pathways and chemical structures of caffeine metabolites.

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enzyme saturation and follows zero order kinetics. Hence, at higher 3. Mechanism of action
concentrations, the decline of caffeine concentrations is longer. Some of
the caffeine and its metabolites are also eliminated through faeces and Caffeine has different biochemical targets and several mechanisms
through transdermal pathway by sweat and saliva. These modes of through which it exerts its effects: 1) Antagonism of adenosine re­
elimination are not significant forms or effective ways as only a small ceptors, 2) Inhibition of phosphodiesterase enzyme, 3) Calcium release
percentage is eliminated [27]. from intercellular stores and 4) Antagonism of GABAA receptors [30].
These different mechanisms of action occur at different concentrations
2.5. Caffeine interaction with other drugs of caffeine. There are a few additional suggested modes of action for how
caffeine is presumed to work. However, there isn’t much research done
Taking caffeine with other stimulants like amphetamines, cocaine, on these mechanisms as they are not dominant. One such mechanism
ephedrine, or medications for ADHD can increase side effects like would be the potentiation of prostaglandin synthesis inhibitors [47].
jitteriness, rapid heartbeat, and anxiety [35,36]. The stimulant effects
can compound. Caffeine can oppose the effects of blood pressure med­
ications like beta blockers and diuretics, blunting their effectiveness at 3.1. Antagonism of adenosine receptors
lowering blood pressure [37]. Certain antibiotics like ciprofloxacin and
norfloxacin can also affect the metabolism of caffeine and the longer The blockade of adenosine receptors, mainly A1 and A2A receptors,
presence of caffeine in blood can be lethal [38]. A gap of a few hours appears to be the most important mode of action for caffeine [48]. This
should be allowed between taking these antibiotics and caffeine how­ mechanism of action can be observed with typical levels of caffeine
ever some studies also report the synergistic effect of caffeine with an­ consumption [31]. These receptors are physiologically stimulated by
tibiotics including gentamycin, amoxyllin, azithromycin, cefepime, adenosine. A1 receptors have high adenosine affinity while A2A re­
benzylpenicillin, and novobiocin [39,40]. Additionally, caffeine can ceptors have low adenosine affinity [30] Adenosine, through these G
decrease the sedative effects of benzodiazepines used for anxiety or sleep protein couples receptors, regulates several physiological functions by
like diazepam and lorazepam, making them less effective [41]. altering cellular concentrations of cyclic adenosine monophosphate
There are also concerns about interactions with thyroid medications (cAMP) [26,30]. When adenosine binds to the A1 receptor, adenyl
and clozapine and can lead to toxicosis [42]. Caffeine also reduces the cyclase will be inhibited via a guanyl nucleoside binding protein (Gi)
absorption of levothyroxine, requiring a gap of at least 4 h between and this decreases the concentration of intracellular cAMP [49]. When
taking this medication and caffeine [43]. The stimulant effects of adenosine binds to the A2A receptor, adenyl cyclase will be stimulated
caffeine should also be used cautiously in people with anxiety disorders, via a different guanyl nucleoside binding protein (Gs) and this increases
cardiac conditions, and sleep disorders as it can exacerbate symptoms the concentration of intracellular cAMP, which can be seen in Fig. 6(a)
and medical advice should be considered before consumption of caffeine [49]. This increase in cAMP levels can trigger several metabolic, car­
in any form while consuming medications. The discussion is also diovascular, and neuronal responses [50].
graphically summarized as Fig. 5. Caffeine is structurally similar to adenosine as depicted in Fig. 6(b)
[16]. Caffeine can non-selectively bind to the adenosine receptors and
competitively inhibit them. Hence, caffeine acts as an antagonist and

Fig. 5. This image illustrates drugs that should not be combined with caffeine consumption due to potentially dangerous interactions. Caffeine is a stimulant that can
exacerbate the effects of these drugs, leading to increased side effects and toxicity. The drugs pictured that have negative or adverse interactions with caffeine include
alcohol, Monoamine oxidase inhibitors, beta blockers like propranolol, benzodiazepines, clozapine, heart medications, theophylline, levothyroxine, and warfarin.
Patients taking these medications should limit or restrict caffeine intake to avoid reduced efficacy or dangerous health consequences. Consulting a pharmacist or
doctor can help identify safe caffeine limits for individuals on these medications. Being aware of caffeine interactions allows patients to make informed decisions
about limiting dietary sources of caffeine including coffee, tea, soda, energy drinks, and chocolate [31,44–46].

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Fig. 6. (a) Mode of action of adenosine, 6(b) Similarity in the Chemical structures of caffeine and adenosine.

inhibits adenosine stimulation of the receptors [26]. For instance, receptors and hence has weak antagonistic effects on the GABAA re­
binding of adenosine to the receptors in the central nervous systems will ceptors. Caffeine is a stronger antagonist of adenosine receptor than it is
promote drowsiness [24]. Nerve cells are unable to differentiate be­ of benzodiazepine receptor. From various studies, they have found that
tween adenosine and caffeine. Thus, after caffeine is consumed, caffeine caffeine changes and opposes the effects of benzodiazepines on human
will inhibit the adenosine from binding and activating the receptors behavior [41].
[24]. This will result in temporary relief of drowsiness, and this is why
we feel more alert when we consume caffeine [24]. Adenosine receptors
3.5. Peripheral effects
play a huge role in affecting individual sensitivity to caffeine. For
instance, the ADORA2A gene encodes for adenosine A2A receptors [51].
In addition to its stimulant effects on the central nervous system,
A human study conducted showed that polymorphisms of this gene can
caffeine exerts several effects on peripheral tissues and organs outside
lead to individuals reacting differently to the same dosage of caffeine
the brain and spinal cord. One of the most prominent peripheral effects
[51].
of caffeine is to increase heart rate, known as a positive chronotropic
effect [31]. By blocking adenosine receptors in pacemaker cells in the
3.2. Inhibition of phosphodiesterase heart, caffeine removes the braking effect of adenosine, leading to
activation of cAMP and acceleration of heart rate [55]. For those with
This mode of action is minimal at normal levels of consumption but is underlying heart conditions, this increase in heart rate could exacerbate
more commonly observed at higher doses. Caffeine and its metabolites issues. Caffeine also leads to peripheral vasoconstriction and increased
are weak competitive inhibitors of enzyme phosphodiesterase [12,26]. blood pressure through its stimulatory actions on the sympathetic ner­
The role of phosphodiesterase is to breakdown cAMP. At higher doses, vous system and release of catecholamines [56]. Increased blood pres­
caffeine will inhibit phosphodiesterase activity [24]. This will prevent sure could raise risks of cardiovascular events. Caffeine acts as a diuretic
the breakdown of cyclic AMP and lead to cAMP accumulation [30]. This by inhibiting sodium and water reabsorption in the renal tubules of the
will result in an increase in the duration and effect of cAMP action [26] kidneys, thereby increasing urine output, which can lead to dehydration
(12). cAMP is a key intracellular second messenger involved in several [57].
signal transduction for many biological reactions [52]. For instance, in At the level of smooth muscle, caffeine has variable effects, causing
the presence of caffeine, cAMP level increases. High cAMP levels acti­ relaxation of smooth muscle in bronchioles which opens up airways,
vate the hormone sensitive lipase in the adipose tissue, which is required while also stimulating smooth muscle contraction in the colon and
for lipolysis, Hence, caffeine promotes lipolysis which causes the release gastrointestinal tract, which can promote bowel movements which is all
of fatty acids and glycerol [53]. contributed by the actin depolymerization [58]. Caffeine increases
gastric acid secretion in the stomach by stimulating gastrin release and
3.3. Calcium release H2 receptors, which can worsen ulcers [59]. Through its effects on ad­
ipose tissue metabolism, caffeine triggers the breakdown of triglycerides
This mode of action only occurs at very high, non-physiological and release of free fatty acids into the bloodstream, which could
concentrations of caffeine [16]. Caffeine at very high concentrations potentially alter lipid metabolism [60]. Regarding skeletal muscle,
(beyond average consumption), can readily diffuse into cells and acti­ caffeine enhances muscle contraction strength by increasing calcium ion
vate calcium channels that are found in the endoplasmic and sarco­ release from the sarcoplasmic reticulum, which can enhance athletic
plasmic reticulum [12]. This causes the release of stored calcium and performance which is already discussed in the above section [61].
translocation of calcium through the plasma membrane. This results in a Finally, the generalized stimulant effects of caffeine lead to widespread
decrease in intracellular calcium accumulation. This mechanism can constriction of blood vessels (arterioles) throughout the peripheral cir­
affect neurotransmission since synaptic transmission is dependent on culatory system, which leads to significant increase in blood pressure.
calcium influx into nerve endings [52]. Mobilization of calcium also
affects other reactions that are sensitive to calcium concentrations. For 4. Caffeine use during pregnancy
instance, in muscles caffeine restricts the uptake and storage of calcium
by the sarcoplasmic reticulum. This action results in an increase in the High levels of caffeine consumption during pregnancy have been
strength and endurance of cardiac and skeletal muscles [54]. associated with various prenatal risks. Pregnant women and their fetus
may be susceptible to the possible harmful effects of caffeine [14].
3.4. Antagonism of GABAA receptors Hence, pregnant mothers are advised to limit their caffeine consumption
[23]. According to the World Health Organization, the recommended
This mechanism occurs only at toxic levels of caffeine and is not very amount of caffeine intake during pregnancy is below 300 mg per day
common [30]. Caffeine has weak binding affinity to the benzodiazepine [62]. Fig. 7 provides a general depiction of the effects of caffeine

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Fig. 7. Consequence of caffeine intake during pregnancy.

consumption during pregnancy. 4.3. Effects on pregnancy and birth outcomes

4.1. Placental and fetal metabolism Many studies have shown that there is a greater risk of miscarriage
associated with high caffeine consumption during pregnancy [70]. This
Maternally ingested caffeine can easily cross the placental barrier association still exists even after controlling for potential confounders
into the fetus where an equilibrium is reached between maternal and like pregnancy related symptoms and aversion to caffeine consumption.
fetal plasma [63]. However, both the placenta and the fetus is unable to A recently conducted cohort study shows an association between
metabolize caffeine. Caffeine cannot be metabolized by the human pre-pregnancy coffee consumption of more than 400 mg per day with an
placenta because it only has CYP1A1 isozymes and lacks CYP1A2 iso­ increased risk of spontaneous abortion, especially at weeks 8–19 of
zymes [64]. On the other hand, as the fetus lacks the liver enzymes pregnancy [73].
required, it is unable to metabolize caffeine [65]. These enzymes are Moreover, caffeine intake during pregnancy is also found to increase
only developed and present from the eighth month of pregnancy [66]. the risk of fetal growth restriction [74]. This is because exposure to high
Moreover, the caffeine clearance rate is slowed down in pregnant amounts of caffeine is likely to affect the skeletal growth of the fetus
mothers due to a decrease in CYP1A2 enzyme activity. All these factors adversely [54]. A recent study in male rodents have shown that prenatal
will lead up to accumulation of caffeine in the systemic circulation of the caffeine exposure induces developmental abnormality in the adrenal
mother and fetus [14]. gland and suppress its synthesis of steroid hormones like glucocorti­
coids. This could be a possible mechanism through which intrauterine
4.2. Effects on fetal development programming mechanisms are affected which can possibly lead to
growth restriction. The same study suggested that this mechanism could
Various studies have shown that caffeine has the ability to influence be a probable cause for the high risk of developing metabolic syndrome
fetal development. One hypothesis is that caffeine increases cellular like obesity for offspring with prenatal caffeine exposure [47]. This is
cAMP level by inhibiting phosphodiesterase, which may interfere with further supported by another clinical study which demonstrated that
cellular development [67,68]. It is suggested that fetal asphyxia, where maternal caffeine intake was associated with an increase in skin fold
the fetus is deprived of sufficient oxygen supply, may be associated with thickness in offspring at 3 months of age [75]. In addition, caffeine
high cAMP levels [69]. consumption has an invariable association with low birth weight, where
Caffeine also has the effect of promoting catecholamines release in the birth weight of the infant is less than 2500 g [68]. The risk of low
maternal blood circulation [70]. This can cause catecholamine - medi­ birth weight seems to increase linearly with dosage of caffeine intake
ated uteroplacental vasoconstriction which can lead to a decrease in [69]. Low birth weight could be due to either a shorter gestational
blood flow within the intervillous space [66,68]. This might result in an period or due to intrauterine growth retardation which results in the
inadequate blood supply and the fetus may not be able to obtain suffi­ infant born being small for its gestational age [63]. Fetal growth re­
cient oxygen and nutrients [66]. Reduction in uteroplacental blood striction and low birth weight are associated with a higher risk of
circulation is strongly linked with a decline in fetal growth [71]. perinatal morbidity and mortality [71].
Moreover, the structure of caffeine resembles adenine and guanine, Although there are many epidemiological studies analyzing the
which are nitrogenous bases of deoxyribonucleotides, the building relationship between high caffeine consumption and adverse pregnancy
blocks of DNA. Hence, caffeine might be accidently incorporated into outcomes, there is still a lot of uncertainty associated with inconsistent
the DNA macromolecule during DNA synthesis in mitosis [70]. Hence, findings. It is also difficult to establish causality due to methodological
caffeine may work as a DNA intercalator and cause chromosomal issues which complicates interpretation [14]. There was a systematic
anomalies and affect fetal growth. In addition, adenosine plays a role in review that accessed the adverse effects of caffeine and reported no
maintaining an equilibrium between the availability and usage of oxy­ significant concern regarding maternal caffeine intake of up to 300 mg
gen by body tissues [72]. Since caffeine blocks adenosine receptors, this per day with adverse effects such as birth weight, spontaneous abortion
increases the risk of maternal hypoxia. Maternal hypoxia can possibly and intrauterine growth restriction [51]. The recommended safe dosage
affect fetal growth and the cardiovascular function of the fetus nega­ of daily caffeine consumption is up to 300 mg during pregnancy.
tively [69]. Studies also reveal that just one dose of caffeine during However, a recent study conducted in 2021 revealed that prenatal
pregnancy is sufficient to affect the heart development of the fetus [47]. caffeine consumption was associated with negative effects in child’s
brain development and behavior event at the currently recommended
safe dose. Given the widespread consumption of caffeine, including in
pregnant women, it is imperative to reassess the recommended safe

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dosage guidelines and review if further refinements are required to catalase was investigated in a study by [Link] al. [77]. Their research
avoid any prenatal risks. showed that caffeine treatment significantly increased the levels of these
enzymes in physically trained rats, improving the organism’s natural
5. Pharmacological effects and impact of caffeine on medical ability to combat oxidative stress but also it reduced High Density Li­
conditions poprotein (HDL) cholesterol levels. In one of the studies, nine
thio-caffeine analogues were synthesized and tested their impact on
5.1. Anti oxidative property human erythrocytes, examining their ability to prevent oxidative he­
molysis induced by AAPH, a common free radical generator. 8-[(pyrro­
As an antioxidant, caffeine works by scavenging reactive oxygen lidin-1-ylcarbonothioyl) sulfanyl] caffeine exhibited exceptionally
species (ROS), chelating metal ions, and enhancing the body’s own strong antioxidant properties and effectively protected human erythro­
antioxidant defenses. Supporting this, numerous studies have demon­ cytes against AAPH-induced oxidative damage, Fig. 8(a) [78]. The
strated that caffeine has the potential to eliminate ROS like hydroxyl antioxidant effect of caffeine relies on dose, exposure time, and the
radicals and superoxide anions. Using electron paramagnetic resonance oxidative stressors being studied. While some studies have noted the
spectroscopy, they utilized this technique to elucidate how caffeine positive antioxidant benefits; others, especially at larger dosages or
could directly neutralize hydroxyl radicals. Their findings revealed a under certain circumstances, have raised the possibility of pro-oxidant
dose-dependent reduction in hydroxyl radical levels in the presence of qualities.
caffeine, providing robust evidence for its ability to scavenge reactive
oxygen species (ROS). Additionally, it has been demonstrated that
5.2. Anti diabetic property
caffeine contains metal-chelating capabilities, which support its anti­
oxidant effect. Caffeine’s capacity to chelate metals was explored by
Diabetes mellitus, a metabolic condition marked by abnormalities in
looking at how it interacted with copper ions. The findings showed that
glucose metabolism, is a growing global health problem. For instance,
caffeine efficiently chelated copper ions, lowering oxidative damage and
type 2 diabetes is directly linked to poor glucose homeostasis and insulin
copper ions’ pro-oxidative effects. Given that transition metals like
resistance. Caffeine has aroused scientific interest as a possible inter­
copper may catalyze the production of ROS in biological systems, this
vention in the field of diabetes care because of its capacity to modify a
chelation characteristic is very desirable [76]. Coffee has been shown to
variety of physiological processes, including those linked to glucose
influence endogenous antioxidant defenses. The effect of caffeine on the
metabolism. Influencing insulin sensitivity is one of the main ways that
production of antioxidant enzymes including superoxide dismutase and
caffeine is thought to exert its anti-diabetic benefits. Research by Wedick

Fig. 8. (a) Image depicting the C8-substitution of caffeine molecule by (pyrrolidin-1-yl) carbothioylsulfanyl group which resulted in increase of antioxidant and
cytoprotective in vitro activity [78]. 8(b)showing the decrement in serum sorbitol level aided by caffeine content understood by spectroscopic study [81]. 8(c) is an
excerpt form an epidemiological study on influence of caffeine in antiproliferative activity [84]. 8(d) Illustration revealing Physiological effects of caffeine on the
cardiovascular system [88]. 8(e) shows the influence of caffeine on articular cartilage with comparison to normal structural system [93]. 8(f) shows the various
neuroprotective mechanisms including Aβ theory, Tau protein theory and ApoE4 theory [98]. 8(g) shows the hepatoprotective effects of caffeine and the potential
mechanisms by which it mitigates alcoholic liver disease (ALD), liver fibrosis, and NAFLD [107]. 8(h)Illustrates how coffee powder helps in mitigation of wound
healing by protecting the vulnerable cells [111].

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V.S. Reddy et al. European Journal of Medicinal Chemistry Reports 10 (2024) 100138

et al. [79] in a cohort study with a sizable female participant population an illustration of the immediate and long-term physiological impacts of
revealed that caffeine use was negatively correlated with the risk of type caffeine on the cardiovascular system.
2 diabetes. According to this finding, those who consume more coffee
may have better insulin sensitivity, which might reduce their risk of 5.5. Orthopedic effects
developing diabetes. Moreover, investigations have delved into the in­
fluence of caffeine on insulin release and the maintenance of glucose Caffeine’s ability to impair calcium absorption is one of the main
balance [53]. Research findings revealed that in diabetic rats, caffeine issues with its use. High caffeine consumption has been linked in some
treatment led to heightened insulin secretion in response to glucose studies to decreased intestinal absorption of calcium, which may have
stimulation. This effect was also observed in placebo-controlled trials effects on bone health. Caffeine’s effects on calcium balance were
involving human subjects [80]. This might have been caused by an in­ studied and results highlighted a possible negative influence on calcium
crease in cyclic adenosine monophosphate (cAMP) levels in pancreatic retention. Chronic consumption of coffee has been linked to a slight
beta-cells resulting in improved glucose control. One specific research decline in bone mineral density (BMD), especially in postmenopausal
study established and applied the connections between blood glucose women [89]. This decline in BMD is an osteoporosis risk factor. In
levels, insulin levels, sorbitol, and caffeine within the human body for postmenopausal women, research by Hallström et al. (2006) [90]
potential therapeutic use in addressing diabetic neuropathy, Fig. 8(b) evaluated coffee intake and BMD finding an unfavorable association
[81]. between the two. Consuming a lot of coffee may increase the incidence
Caffeine’s effects on diabetes are complex and may potentially entail of osteoporotic fractures [91], especially in older population. Because it
modification of other metabolic pathways, such as the adenosine re­ can increase the efficacy of analgesic drugs, caffeine is often found in
ceptor system, thus care is advised when interpreting these results. In over-the-counter pain medicines. It is important to comprehend caf­
any therapeutic application, caffeine’s possible adverse effects, feine’s involvement in pain modulation, especially in relation to or­
including its impact on blood pressure and sleep patterns, must be thopedic pain treatment. The ability of caffeine to improve muscular
carefully examined. endurance and contractility has been studied [92]. This feature is
pertinent to orthopedics since it could have effects on sports medicine
5.3. Anti proliferative effect and rehabilitation. A review focused on the relationship between
Caffeine, Osteoarthritis, and Longitudinal Bone Growth Inhibition.
Caffeine’s primary mechanism of action is the inhibition of the Articular cartilage disruptions can result in joint dysfunction, pain, and
enzyme phosphodiesterase (PDE), which results in increased intracel­ disability. Hyaline cartilage, which is also found in the growth plate,
lular levels of cyclic adenosine monophosphate (cAMP). This rise in plays a pivotal role in longitudinal bone growth. Changes in this carti­
cAMP sets off a series of actions that eventually result in the suppression lage due to various conditions have been associated with Longitudinal
of cell cycle progression, a defining characteristic of cell proliferation. Bone Growth Inhibition (LBGI), leading to growth issues. Dietary factors
Additionally, caffeine’s ability to inhibit adenosine-mediated cell are known to influence the development and progression of both oste­
growth signaling, particularly that of the A2A subtype, adds to its oarthritis and LBGI. Notably, there is substantial evidence highlighting
antiproliferative effects. Caffeine administration significantly decreased the adverse effects of caffeine consumption on hyaline cartilage which
cell viability and proliferation rates. This cell cycle arrest caused by has been highlighted, Fig. 8(e) [93].
coffee in the G2/M phase and the activation of apoptotic pathways were
both thought to be responsible for this antiproliferative impact, at least 5.6. Neurodegenerative diseases
in part by the polyphenol content [82]. Induction of pro-apoptotic
autophagy in human hepatocellular carcinoma via AMPK pathway is The two most common neurodegenerative diseases are Alzheimer’s
also studied [83]. Through cell cycle arrest and death, caffeine treat­ and Parkinson’s, both of which has no cure [48,94]. Caffeine has neu­
ment was shown in this study to inhibit the proliferation of liver cancer roprotective effects and can play a preventive role against the devel­
cells. In a scientific report, the main focus was on presenting findings opment of these diseases. Habitual caffeine consumption can lower the
that primarily dealt with the protective benefits of coffee and its readily risk of Alzheimer’s diseases [23]. Research shows that 3 to 5 cups of
available individual compounds in the context of gastrointestinal and coffee per day reduces the risk of Alzheimer’s diseases [94]. Alzheimer’s
liver cancer development, Fig. 8(c) [84]. It’s significant to note that the is characterized by the accumulation of misfolded β-amyloid (Aβ) pla­
antiproliferative effects of caffeine were mediated by the down­ ques [95]. Based on animal studies, caffeine has the ability to lower
regulation of important cell cycle regulatory proteins. β-amyloid levels in the plasma by reducing the beta and gamma secre­
tase levels in the hippocampus, which are responsible for the deposition
5.4. Cardiovascular effects of β-amyloids [94]. Furthermore, another study has shown that caffeine
is able to inhibit the peptide aggregation of amyloids as well by inter­
The scientific data presented by Danielle et al. indicates that caffeine acting with the aromatic phenylalanine residues of the peptides [96].
exerts cardiovascular effects by eliciting a rapid increase in blood Caffeine interacts with the peptides via hydrogen bonds and forms a
pressure [85]. By promoting the production of catecholamines like hydrophobic environment around the peptides, thereby physically
adrenaline and norepinephrine, which increase heart rate and contrac­ blocking the peptides from interacting with one another [97]. This is one
tility while narrowing blood arteries. Numerous investigations have possible mechanism through which caffeine prevents Alzheimer’s dis­
supported the hypertensive effects of caffeine, including those by eases. In addition, caffeine also improves the memory of patients who
Noordzij et al. [86] and Nurminen et al. [87]. Caffeine can affect are already suffering with the disease [95]. Fig. 8(f) [98] highlights
vascular reactivity by encouraging either vasodilation or vasoconstric­ various neuroprotective mechanisms of caffeine.
tion. It has been shown in studies by Battram et al. that caffeine increases The risk of Parkinson’s disease is also found to be decreased with
endothelium-dependent vasodilation in certain arteries, indicating a caffeine consumption [94]. Epidemiological studies reveal that
role in enhancing vascular function [85]. Regular consumption of consuming 3 to 4 cups of coffee daily can decrease the risk of Parkinson’s
moderate amounts of caffeine, such as 2–3 cups of coffee or tea per day, disease [48]. This is further supported by a recent case control study
seems to be safe for individuals with various cardiovascular conditions which showed that among at-risk population (gene-carriers), those who
and may have potential benefits, including a positive impact on diabetes consumed caffeine had a lower risk of developing the disease [99].
mellitus, atherosclerosis, heart failure, arrhythmia, and overall mortal­ Parkinson’s disease is characterized by the progressive loss of dopami­
ity. However, it is advisable to steer clear of consuming high doses of nergic neurons [48]. Caffeine improves the activity of the dopaminergic
caffeine, especially in the form of energy drinks. Fig. 8(d) [88] provides system by blocking the adenosine A2A receptor which stimulates the

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V.S. Reddy et al. European Journal of Medicinal Chemistry Reports 10 (2024) 100138

release of dopamine [7]. Moreover, not only is caffeine found to prevent flowchart illustrating the effects of caffeine and the potential mecha­
the onset of Parkinson’s disease, it is also believed to help in decreasing nisms by which it mitigates alcoholic liver disease (ALD), liver fibrosis,
the symptoms associated with the disease. For instance, caffeine con­ and NAFLD.
sumption can decelerate decline in motor skills in patients with Par­
kinson’s disease [48]. Noting the mechanism and therapeutic potential 5.9. Wound healing
of caffeine in managing Parkinson’s Disease, United States Food and
Drug Administration (FDA) recently approved the use of istradefylline Smaller wounds and cuts have traditionally been treated with coffee
(an A2A receptor antagonist) for the treatment of Parkinson’s Disease in powder. Diegelmann et al. looked into caffeine’s ability to enhance
2019. This is noteworthy given that istradefylline is the first collagen production, an important step in wound healing. Collagen is
non-dopaminergic drug to be approved in the last two years and this essential for wound closure since it gives recovering tissues structural
approval could lead the way for more innovations and development of stability. Additionally, caffeine increases the activity of fibroblasts, the
A2A receptor antagonist, including caffeine, as therapeutic drugs for the cells that create collagen and other elements of the extracellular matrix.
treatment of Parkinson’s Disease. According to research by Jimenez et al., increased fibroblast activity
Furthermore, given caffeine’s neuroprotective effect, there is a pos­ may speed up wound closure by suppressing pro-inflammatory mole­
sibility that it can protect against adverse effects of certain anti-seizure cules [21,108], caffeine also contributes to the decrease of inflammation
drugs used for newborns [100]. For instance, phenobarbital is one such and promotes an environment that’s better for wound healing. When a
common drug that is used to treat seizures, but it is also found to induce wound is healing, pain and discomfort are frequent concerns [109]. Due
neurodegeneration in the developing brain of newborns. A recent to caffeine’s possible analgesic effects, a more pleasant recovery time
experiment conducted on rats, showed that by co-treating newborns may result. The vasoconstrictive effects of caffeine may improve
with the drug and caffeine, this neurotoxic effect can be reduced [100]. microcirculation, potentially enhancing the supply of nutrients and ox­
ygen to the wound site. Enhancing blood flow is necessary for effective
5.7. Metabolic effect wound healing [110]. An article highlighted the wound healing poten­
tial of caffeine, which is further visualized in Fig. 8(h) [111].
Caffeine consumption is associated with a reduction in body weight
and weight gain [24]. Weight regulation is determined by energy bal­ 6. Caffeine and nanotechnology
ance, which consists of two components: Energy Intake and Energy
Expenditure. Caffeine works by increasing systemic catecholamine 6.1. Usage of caffeine for therapeutic purposes
levels through which it increases basal metabolic rate. This will lead to
an increase in energy expenditure and promote weight reduction. Caffeine can be administered as a medicine for various therapeutic
Another study conducted in mice revealed mechanism through which purposes. It has been used to treat a wide variety of clinical diseases,
caffeine can promote weight reduction [101]. This study showed that including Parkinson’s, atopic dermatitis, minimal brain dysfunction in
central or peripheral caffeine administration in diet-induced obesity children and apnea in newborns [112]. Caffeine is also extensively used
mice suppressed appetite, increased energy expenditure and reduced in combination with other types of drugs. For instance, caffeine can be
their body weight. Caffeine is able to do so by inhibiting the hypotha­ combined with analgesic drugs and the addition of caffeine to these
lamic adenosine receptors found in the paraventricular nucleus (PVN) drugs improves their pain-relieving effects. Likewise, combination of
oxytocin neurons [101]. Given caffeine’s positive effect on weight caffeine with ergotamine is also used to treat migraine headaches. In the
reduction, it can be used as an effective means to treat obesity. past years, caffeine has been examined to be used as treatment for
Furthermore, obesity related conditions are believed to be a various cancer types. Studies reveal that caffeine may have possible
contributing factor to the increase in incidence of non-alcoholic fatty anti-cancer effects [113]. Recent studies show that caffeine is able to
liver disease (NAFLD), which is caused by the excessive fat deposition in affect cell cycle and DNA repair by inhibiting two DNA damage response
liver cells. There are several studies indicating that caffeine can kinases, namely Ataxia-telangiectasia mutated (ATM) and Ataxia tel­
ameliorate hepatic steatosis by promoting oxidation and reducing fatty angiectasia and Rad3-related protein (ATR). Through this, caffeine is
acid synthesis [49]. Hence, caffeine can possibly protect against obesity able to selectively make cancer cells sensitive to DNA damaging agents
induced NAFLD as well. Caffeine is shown to increase insulin resistance and potentially eliminate various tumor cells [114].
and glucose levels in those with diabetes. Hence, increasing caffeine
consumption as a means to prevent Type II Diabetes is not recommended 6.2. Drug delivery methods
till proper research is done [102,103].
Drug delivery refers to the process of administering a particular drug
5.8. Hepatoprotective in humans or animals. There are various types of drug delivery tech­
niques: Oral, Inhalation, Through skin absorption and through intrave­
According to recent studies, caffeine may help prevent the buildup of nous injections. Drug delivery systems are developed to regulate the
fat in the liver, which is a defining characteristic of non-alcoholic fatty location and rate at which a particular drug is released in the body to
liver disease (NAFLD). Caffeine was found to have an effect on hepatic achieve the desired therapeutic effect [115]. The most effective drug
fat accumulation [104], which highlighted its potential to prevent the delivery system will be one that allows for rapid absorption of the drug
onset of NAFLD. The anti-inflammatory effects of caffeine are particu­ but with minimum side effects. One common way to reduce side effects
larly relevant to liver function. Caffeine can reduce pro-inflammatory without compromising on the therapeutic effect of the drug is to
molecules, which help in hepatoprotective benefits. In studies like the administer it locally (to a specific part of the body), then systemically (to
one by Arauz et al. [105], this decrease of inflammation is explained. the entire body). However, non-specificity of drug action is one of the
The antioxidant properties of caffeine may potentially be important major limitations of drug delivery systems. It is important that the drugs
for liver protection. Caffeine can help safeguard the liver from injury by are designed to have greater target specificity [116].
scavenging free radicals and reducing oxidative stress. According to Nanotechnology has played in key role in improving medications
some studies, caffeine consumption may cause high liver enzymes, such that are able to target diseases more effectively and accurately with
as alanine transaminase (ALT) and aspartate transaminase (AST), which minimal side effects. Recent advances in this field, especially in drug
are indicators of healthy liver function [49]. It has also been investigated delivery have led to the development of nanoscale drugs and delivery
if caffeine can reduce the development of liver fibrosis, a significant systems. Drugs sizes are reduced to nanometer range which increases
contributor to chronic liver disorders [106]. Fig. 8(g) [107]provides a their surface area. This helps to improve solubility and bioavailability of

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V.S. Reddy et al. European Journal of Medicinal Chemistry Reports 10 (2024) 100138

drugs which allows for the therapeutic effect to be experienced more Nanoparticles can also be used to facilitate drug delivery. Caffeine is
quickly. Nano-scale drug delivery vehicles are also being developed to used in several cosmetic products like anti-cellulite creams where
overcome biological barriers [117–120]. Examples of such delivery ve­ caffeine and its derivatives are the main ingredients [123]. Nano­
hicles used in oral drug delivery are shown in Fig. 9. particles of poly NIPAM that were copolymerized with acrylic acid (poly
(NIPAM-co-AAc)) were found to be potential carriers that can be used
for transdermal delivery of caffeine for dermatological and cosmetic
6.3. Nano delivery of caffeine agents.

Nano-vesicular systems are one way through which drugs can be 7. Conclusion
delivered to specific cells without any major side effects. Recently, re­
searchers have found that non-ionic vesicles obtained from Span 80 Caffeine, either naturally or synthetically derived, is being widely
(Sorbitan monooleate), can be used as an effective delivery system for consumed in the world, although the main source and the amount
caffeine. This can be a better alternative to the commonly used lipo­ consumed varies in different countries. The safety of caffeine has been a
somes as it has favorable physiochemical properties such as high subject of much debate over the course of many years. However, both
membrane fluidity. For instance, osteosarcoma (malignant tumor in human and animal studies conducted support that caffeine is safe as long
bone) has generally poor prognosis. Caffeine-potentiated chemotherapy as it is consumed in moderation [24]. Certain regulatory agencies
for this tumor using this nano delivery system demonstrated significant recommend that adults should not consume more than 450 mg of
anti-tumor effects and only minor adverse side effects [121]. Although caffeine per day. Moreover, emerging research shows that caffeine does
this was conducted on an animal model, it shows potential prominence have potential benefits on human health. It is proven to have significant
to be used clinically for osteosarcoma therapy [121]. Furthermore, nano implication in glaucoma management and is associated with alleviating
emulsions is another drug delivery method that can be used to deliver the risks for different diseases like Parkinson’s, Alzheimer’s, atopic
caffeine [113]. Nano emulsions are one of the most promising methods dermatitis, apnea and Type II Diabetes. However, it must be taken into
used for transdermal drug delivery as it is able to increase the skin consideration that association does not mean causation. Hence, further
permeation and bioavailability of drug. studies have to be conducted to prove the beneficial effects of caffeine
Studies have shown that caffeine is able to protect against ultraviolet and its role in the prevention of diseases.
B radiation induced skin carcinogenesis. Given that caffeine is highly Furthermore, the majority of caffeine studies focus on adults, with
hydrophilic, it has poor skin retention and is unable to permeate through limited research available on the impact of caffeine on children and
the lipophilic barrier of the outermost skin layer efficiently. Hence for adolescents [14]. Children and adolescents may be more susceptible and
efficient transdermal delivery, water in oil nano emulsion formulations sensitive to the negative effects of caffeine compared to adults. Given
of caffeine can be used as carriers [113]. A recent study also proved that that they are also increasingly consuming caffeine - containing bever­
optimal microemulsion formulations can also be used as topical nano ages and food, it is imperative that proper research is also conducted to
carriers for caffeine delivery [122]. The results from the study showed investigate the effects on both children and adults. Nevertheless, while
that microemulsions were able to enhance skin retention and improve current evidence does not warrant recommending caffeine for disease
therapeutic effect of caffeine on skin tumor. Hence, this shows that prevention, it is safe for consumers to take caffeine moderately since it
micro emulsions might be a promising topical vehicle for drug delivery poses no significant health risks.
of caffeine.

Fig. 9. Various nanocarriers used for drug delivery applications.

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V.S. Reddy et al. European Journal of Medicinal Chemistry Reports 10 (2024) 100138

Food-Based Dietary Guidelines (FBDG) typically take a cautious [15] International Coffee Organization (ICO), Word Coffee Consumption [Internet],
Int Coffee Organ, 2021 (August):1, [Link]
stance towards products containing caffeine due to potential risks,
[16] T.M. McLellan, J.A. Caldwell, H.R. Lieberman, A Review of Caffeine’s Effects on
especially for specific sub-groups. While concerns about the impact of Cognitive, Physical and Occupational Performance, vol. 71, Neurosci Biobehav
caffeine on human health, such as the risk of cancer and cardiovascular Rev [Internet, 2016, pp. 294–312, [Link]
diseases, have persisted over time, it’s worth noting that there is a neubiorev.2016.09.001.
[17] D. Turnbull, J.V. Rodricks, G.F. Mariano, F. Chowdhury, Caffeine and
growing body of evidence suggesting potential health benefits as well. Cardiovascular Health, vol. 89, Regul Toxicol Pharmacol, 2017, pp. 165–185,
With ongoing advancements in caffeine research and emerging findings, [Link] [Internet].
we can anticipate future revisions of FBDG worldwide to incorporate [18] P. Nawrot, S. Jordan, J. Eastwood, J. Rotstein, A. Hugenholtz, M. Feeley, Effects
of caffeine on human health, Food Addit. Contam. 20 (1) (2003) 1–30.
changes related to caffeine. These adjustments may serve as a frame­ [19] P. Banerjee, Z. Ali, B. Levine, D.R. Fowler, Fatal caffeine intoxication: a series of
work for future nutrition policies and programs that could positively eight cases from 1999 to 2009, J. Forensic Sci. 59 (3) (2014) 865–868.
influence public health. [20] D. Mrizak, F. B’chir, M. Jaidane, M.J. Arnaud, S. Saguem, Effects of change in
smoking habits on bladder cancer incidence in Tunisia, Health (Irvine Calif) 3
(10) (2011) 613–619.
CRediT authorship contribution statement [21] Котлер Ф, No TitleМаркетинг По Котлеру, 2008, p. 282.
[22] R.M. van Dam, F.B. Hu, W.C. Willett, Coffee, caffeine, and health, N. Engl. J. Med.
383 (4) (2020) 369–378.
Vundrala Sumedha Reddy: Writing – original draft, Visualization, [23] E.G. de Mejia, M.V. Ramirez-Mares, Impact of caffeine and coffee on our health
Project administration, Methodology, Investigation, Formal analysis, [Internet], Trends Endocrinol. Metabol. 25 (10) (2014) 489–492, [Link]
Data curation, Conceptualization. S. Shiva: Writing – original draft, 10.1016/[Link].2014.07.003.
[24] A. Roberts, Caffeine: an Evaluation of the Safety Database, Nutraceuticals Effic
Investigation, Formal analysis, Data curation, Conceptualization. Sri­
Saf Toxic, 2016, pp. 417–434.
nidhi Manikantan: Writing – original draft, Investigation, Conceptu­ [25] J.F. Young, G. Tognoni, S. Garattini, After Oral Doses, 1982, pp. 98–106.
alization. Seeram Ramakrishna: Writing – review & editing, [26] A. Zulli, R.M. Smith, P. Kubatka, J. Novak, Y. Uehara, H. Loftus, et al., Caffeine
and cardiovascular diseases: critical review of current research, Eur. J. Nutr. 55
Resources, Project administration, Formal analysis, Conceptualization.
(4) (2016) 1331–1343.
[27] W. Chemistry, S. Riegelman, P. October, Accepted C. Of Caffeine and its
Declaration of competing interest Metabolites in Man1 Observations, Society, 1983.
[28] Mandal BA, Robertson S, Sc B. Ca eine Pharmacology. :1–4..
[29] H.G. Mandel, Update on caffeine consumption, disposition and action, Food
The authors declare that they have no known competing financial Chem. Toxicol. 40 (9) (2002) 1231–1234.
interests or personal relationships that could have appeared to influence [30] A. Nehlig, J.L. Daval, G. Debry, Caffeine and the central nervous system:
mechanisms of action, Brain Res. Rev. 17 (2) (1992) 139–170.
the work reported in this paper.
[31] S. Cappelletti, P. Daria, G. Sani, M. Aromatario, Caffeine: cognitive and physical
performance enhancer or psychoactive drug? Curr. Neuropharmacol. 13 (1)
Data availability (2014) 71–88.
[32] D.G. Cook, J.L. Peacock, C. Feyerabend, I.M. Carey, M.J. Jarvis, H.R. Anderson, et
al., Relation of caffeine intake and blood caffeine concentrations during
No data was used for the research described in the article. pregnancy to fetal growth: prospective population based study, Br. Med. J. 313
(7069) (1996) 1358–1362.
Acknowledgments [33] S.H. Francis, K.R. Sekhar, H. Ke, J.D. Corbin, Inhibition of cyclic nucleotide
phosphodiesterases by methylxanthines and related compounds, Handb. Exp.
Pharmacol. 200 (2011) 93–133.
V.S.R. would like to acknowledge the support given by the NUS [34] B. Marx, É. Scuvée, J. Scuvée-Moreau, V. Seutin, F. Jouret, Mécanismes de l’effet
Research Scholarship (GRSUR5000003 RES SCH PhD SERIS IS) during diurétique de la caféine, M-S (Med. Sci.) 32 (5) (2016) 485–490.
[35] J.C. Vázquez, O. Martin de la Torre, J. López Palomé, D. Redolar-Ripoll, Effects of
the period of study. caffeine consumption on attention deficit hyperactivity disorder (ADHD)
treatment: a systematic review of animal studies, Nutrients 14 (4) (2022).
References [36] A.G. Franke, G. Koller, D. Krause, L. Proebstl, F. Kamp, O. Pogarell, et al., Just
“like coffee” or neuroenhancement by stimulants? Front. Public Health 9 (June)
(2021) 1–9.
[1] T. Roehrs, T. Roth, Caffeine: sleep and daytime sleepiness, Sleep Med. Rev. 12 (2)
[37] A.A. Souza, R.S. Silva, T.F. Silva, R.L. Tavares, A.S. Silva, Influence of different
(2008) 153–162.
doses of coffee on post-exercise blood pressure response, Am. J. Cardiovasc. Dis.
[2] N. Weitermann, The Effects of Caffeine on the Mortality Rates and Abnormalities
[Internet 6 (4) (2016) 146–152. [Link]
in Zebrafish Embryos, 2016.
[Link]?artid=PMC5218846.
[3] Sfetcu N. Health & Drugs..
[38] D.P. Healy, R.E. Polk, L. Kanawati, D.T. Rock, M.L. Mooney, Interaction between
[4] M. Heckmann, J. Weil, E. Gonzalez de Mejia, Caffeine (1, 3, 7-trimethylxanthine)
oral ciprofloxacin and caffeine in normal volunteers, Antimicrob. Agents
in foods: a comprehensive review on consumption, functionality, safety, and
Chemother. 33 (4) (1989) 474–478.
regulatory matters, J. Food Sci. 75 (2010) 77–87.
[39] A. Woziwodzka, M. Krychowiak-Maśnicka, G. Gołuński, A. Łosiewska,
[5] Allen AB. Differentiation of Synthetic and Natural Caffeine Changes in Cocoa
A. Borowik, D. Wyrzykowski, et al., New life of an old drug: caffeine as a
Tannins during Processing..
modulator of antibacterial activity of commonly used antibiotics,
[6] J. Jiang, P. Trundle, J. Ren, Y.-L. Cheng, C.-Y. Lee, Y.-L. Huang, et al., We are
Pharmaceuticals 15 (7) (2022) 1–17.
IntechOpen , the world ’ s leading publisher of Open Access books Built by
[40] C. Esimone, F. Okoye, C. Nworu, C. Agubata, In vitro interaction between caffeine
scientists , for scientists TOP 1 % [Internet], Intech 34 (8) (2010) 57–67, https://
and some penicillin antibiotics against Staphylococcus aureus, Trop. J.
[Link]/10.1007/s12559-021-09926-6%0A.
Pharmaceut. Res. 7 (2) (2008) 969–974.
[7] M.M. Lorist, M. Tops, Caffeine, fatigue, and cognition, Brain Cognit. 53 (1) (2003)
[41] M. Cooper, M. Safran, M. Eberhardt, Caffeine consumption among adults on
82–94.
benzodiazepine therapy: United States 1988-1994, Psychol. Rep. 95 (1) (2004)
[8] K. Wojciechowska, M. Zun, D. Dwornicka, K. Swiader, R. Kasperek, E. Poleszak,
183–191.
Physical properties and caffeine release from creams prepared with different oils,
[42] S. Hägg, O. Spigset, T. Mjörndal, R. Dahlqvist, Effect of caffeine on clozapine
Curr. Issues Pharm. Med. Sci. 27 (4) (2014) 224–228.
pharmacokinetics in healthy volunteers, Br. J. Clin. Pharmacol. 49 (1) (2000)
[9] &NA; caffeine for the sustainment of mental task performance: formulations for
59–63.
military operations, Nutr. Today 37 (2002) 26–27.
[43] Y.W. Lai, S.M. Huang, Tea consumption affects the absorption of levothyroxine,
[10] W.K. Michael, N.M. David, S.A. Bright, A.A. John, O. Gloria, Quantitative
Front. Endocrinol. 13 (September) (2022) 1–7.
estimation of the caffeine content in some energy drinks on the Ghanaian market,
[44] A. Yartsev, C. Peisah, Caffeine-clozapine interaction associated with severe
Int. J. Nutr. Metab. 10 (3) (2018) 16–22.
toxicity and multiorgan system failure: a case report, BMC Psychiatr. 21 (1)
[11] A. Baratloo, A. Rouhipour, M.M. Forouzanfar, S. Safari, M. Amiri, A. Negida, The
(2021) 1–5.
role of caffeine in pain management: a brief literature review, Anesthesiol. Pain
[45] S. Zafar, A. Ali, M.M. Ashraf, J.A. Khan, B. Aslam, R.D. Naseer, Alteration in
Med. 6 (3) (2016).
disposition kinetics of warfarin mediated by caffeine in healthy male albino
[12] C. Tavares, R.K. Sakata, Caffeine in the treatment of pain, Rev. Bras. Anestesiol.
rabbits, J. Anim. Plant Sci. 29 (1) (2019) 158–165.
[Internet] 62 (3) (2012) 387–401, [Link]
[46] J.L. Temple, C. Bernard, S.E. Lipshultz, J.D. Czachor, J.A. Westphal, M.A. Mestre,
70139-3.
The safety of ingested caffeine: a comprehensive review, Front. Psychiatr. 8 (May)
[13] A.A. Alsunni, Energy drink consumption: beneficial and adverse health effects,
(2017) 1–19.
Int. J. Health Sci. 9 (4) (2015) 468–474.
[47] Z. He, C. Zhu, H. Huang, L. Liu, L. Wang, L. Chen, et al., Prenatal caffeine
[14] C. Doepker, H.R. Lieberman, A.P. Smith, J.D. Peck, A. El-Sohemy, B.T. Welsh,
exposure-induced adrenal developmental abnormality in male offspring rats and
Caffeine: friend or foe? Annu. Rev. Food Sci. Technol. 7 (2016) 117–137.

12
V.S. Reddy et al. European Journal of Medicinal Chemistry Reports 10 (2024) 100138

its possible intrauterine programming mechanisms, Toxicol. Res. 5 (2) (2016) [77] E.-Y. Choi, J.-Y. Jang, Y.-O. Cho, Coffee intake can promote activity of
388–398. antioxidant enzymes with increasing MDA level and decreasing HDL-cholesterol
[48] M.H.K. Roshan, A. Tambo, N.P. Pace, Potential role of caffeine in the treatment of in physically trained rats, Nutr. Res. Prac. 4 (4) (2010) 283.
Parkinson’s disease, Open Neurol. J. 10 (1) (2016) 42–58. [78] B. Jasiewicz, A. Sierakowska, N. Wandyszewska, B. Warżajtis, U. Rychlewska,
[49] S.J. Zhang, Y.F. Li, G.E. Wang, R.R. Tan, B. Tsoi, G.W. Mao, et al., Caffeine R. Wawrzyniak, et al., Antioxidant properties of thio-caffeine derivatives:
ameliorates high energy diet-induced hepatic steatosis: sirtuin 3 acts as a bridge identification of the newly synthesized 8-[(pyrrolidin-1-ylcarbonothioyl)sulfanyl]
in the lipid metabolism pathway, Food Funct. 6 (8) (2015) 2578–2587. caffeine as antioxidant and highly potent cytoprotective agent, Bioorg. Med.
[50] T.P.R. Gonçalves, A.G. Parreira, V.S. Zanuncio dos S, K. de S. Farias, DB da Silva, Chem. Lett 26 (16) (2016) 3994–3998.
S. Lima Lar dos, Antibacterial and antioxidant properties of flowers from Tecoma [79] N.M. Wedick, A.M. Brennan, Q. Sun, F.B. Hu, C.S. Mantzoros, R.M. Van Dam,
stans (L.) Juss. ex Kunth (Bignoniaceae), South Afr. J. Bot. 144 (2022 Jan 1) Effects of caffeinated and decaffeinated coffee on biological risk factors for type 2
156–165. diabetes: a randomized controlled trial, Nutr J [Internet 10 (1) (2011) 93. htt
[51] D. Wikoff, B.T. Welsh, R. Henderson, G.P. Brorby, J. Britt, E. Myers, et al., p://[Link]/content/10/1/93.
Systematic review of the potential adverse effects of caffeine consumption in [80] D.J. Alperet, S.A. Rebello, E.Y.H. Khoo, Z. Tay, S.S.Y. Seah, B.C. Tai, et al., The
healthy adults, pregnant women, adolescents, and children, Food Chem. Toxicol. effect of coffee consumption on insulin sensitivity and other biological risk factors
[Internet] 109 (2017) 585–648, [Link] for type 2 diabetes: a randomized placebo-controlled trial, Am. J. Clin. Nutr.
[52] Amalia Yunia Rahmawati. 済無No Title No Title No Title. 2020. 1–23 p.. [Internet 111 (2) (2020) 448–458, [Link]
[53] L.A. Da Silva, R.A. Pereira, J.A. Túrmina, Kerppers II, R. Osiecki, L.R. Altimari, et [81] B. Srivastava, S. Sen, S. Bhakta, K. Sen, Effect of caffeine on the possible
al., Sulfonylurea induction of caffeine-enhanced insulin secretion and reduction amelioration of diabetic neuropathy: a spectroscopic study, Spectrochim. Acta
of glycemic levels in diabetic rats, Pharm. Biol. 52 (8) (2014) 956–960. Part A Mol Biomol Spectrosc [Internet] 264 (2022) 120322, [Link]
[54] R. Bakker, E.A.P. Steegers, A. Obradov, H. Raat, A. Hofman, V.W.V. Jaddoe, 10.1016/[Link].2021.120322.
Maternal caffeine intake from coffee and tea, fetal growth, and the risks of [82] Yangguang Ou, Rachael E. Wilson, Sgw, 乳鼠心肌提取 HHS public access, Annu.
adverse birth outcomes: the Generation R Study, Am. J. Clin. Nutr. [Internet] 91 Rev. Anal. Chem. 11 (1) (2018) 509–533.
(6) (2010) 1691–1698, [Link] [83] S. Sun, X. Liu, X. Wei, S. Zhang, W. Wang, Diallyl trisulfide induces pro-apoptotic
[55] J.W. Daly, D. Shi, O. Nikodijevic, K.A. Jacobson, The role of adenosine receptors autophagy via the AMPK/SIRT1 signalling pathway in human hepatocellular
in the central action of caffeine, Caffeine Behav. Curr. Views Res. Trends Curr. carcinoma HepG2 cell line, Food Nutr. Res. 67 (5) (2023) 1–8.
Views Res. Trends 7 (2) (2020) 1–31. [84] G.R. Romualdo, A.B. Rocha, M. Vinken, B. Cogliati, F.S. Moreno, M.A.G. Chaves,
[56] D. Echeverri, F.R. Montes, M. Cabrera, A. Galán, A. Prieto, Caffeine’s vascular et al., Drinking for protection? Epidemiological and experimental evidence on the
mechanisms of action, Int. J. Vasc. Med. 2010 (2010). beneficial effects of coffee or major coffee compounds against gastrointestinal and
[57] Mwendwa, 乳鼠心肌提取 HHS public access, Physiol. Behav. 176 (3) (2019) liver carcinogenesis, Food Res. Int. [Internet] 123 (April) (2019) 567–589,
139–148. [Link]
[58] T. Tazzeo, G. Bates, H.N. Roman, A.M. Lauzon, M.D. Khasnis, M. Eto, et al., [85] D.S. Battram, T.E. Graham, E.A. Richter, F. Dela, The effect of caffeine on glucose
Caffeine relaxes smooth muscle through actin depolymerization, Am. J. Physiol. kinetics in humans-influence of adrenaline, J. Physiol. 569 (1) (2005) 347–355.
Lung Cell Mol. Physiol. 303 (4) (2012) 334–342. [86] M. Noordzij, C.S.P.M. Uiterwaal, L.R. Arends, F.J. Kok, D.E. Grobbee, J.
[59] A. Nehlig, Effects of coffee on the gastro-intestinal tract: a narrative review and M. Geleijnse, Blood pressure response to chronic intake of coffee and caffeine: a
literature update, Nutrients 14 (2) (2022) 1–31. meta-analysis of randomized controlled trials, J. Hypertens. 23 (5) (2005)
[60] R.P. Barcelos, F.D. Lima, N.R. Carvalho, G. Bresciani, L.F. Royes, Caffeine effects 921–928.
on systemic metabolism, oxidative-inflammatory pathways, and exercise [87] M.L. Nurminen, L. Niittynen, R. Korpela, H. Vapaatalo, Coffee, caffeine and blood
performance, Nutr. Res. [Internet 80 (2020) 1–17, [Link] pressure: a critical review, Eur. J. Clin. Nutr. 53 (11) (1999) 831–839.
nutres.2020.05.005. [88] A. Voskoboinik, Y. Koh, P.M. Kistler, Cardiovascular effects of caffeinated
[61] L.H.B. Ferreira, S.C. Forbes, M.P. Barros, A.C. Smolarek, A. Enes, A.H. Lancha- beverages, Trends Cardiovasc. Med. [Internet] 29 (6) (2019) 345–350, https://
Junior, et al., High doses of caffeine increase muscle strength and calcium release [Link]/10.1016/[Link].2018.09.019.
in the plasma of recreationally trained men, Nutrients 14 (22) (2022) 1–11. [89] H. Hallström, H. Melhus, A. Glynn, L. Lind, A.C. Syvänen, K. Michalsson, Coffee
[62] World Health Organization, The World Health Organization Report 2002: consumption and CYP1A2 genotype in relation to bone mineral density of the
Reducing Risks, Promoting Healthy Life, WHO Libr Cat Publ Data, 2002, p. 232. proximal femur in elderly men and women: a cohort study, Nutr. Metab. 7 (2010)
[63] T.S. Hinds, W.L. West, E.M. Knight, B.F. Harland, The effect of caffeine on 1–9.
pregnancy outcome variables, Nutr. Rev. 54 (7) (1996) 203–207. [90] H. Hallström, A. Wolk, A. Glynn, K. Michaëlsson, Coffee, tea and caffeine
[64] W. Kalow, B.-K. Tang, Use of caffeine metabolite ratios to explore CYP1A2 and consumption in relation to osteoporotic fracture risk in a cohort of Swedish
xanthine oxidase activities, Clin. Pharmacol. Ther. 50 (5–1) (1991) 508–519. women, Osteoporos. Int. 17 (7) (2006) 1055–1064.
[65] I.S. Santos, C.G. Victora, S. Huttly, J.B. Carvalhal, Caffeine intake and low birth [91] H.C. Chang, C.F. Hsieh, Y.C. Lin, D.M. Tantoh, P.C. Ko, Y.Y. Kung, et al., Does
weight: a population-based case-control study, Am. J. Epidemiol. 147 (7) (1998) coffee drinking have beneficial effects on bone health of Taiwanese adults? A
620–627. longitudinal study, BMC Publ. Health 18 (1) (2018) 1–10.
[66] L.M. Grosso, M.B. Bracken, Caffeine metabolism, genetics, and perinatal [92] J. Grgic, E.T. Trexler, B. Lazinica, Z. Pedisic, Effects of caffeine intake on strength
outcomes: a review of exposure assessment considerations during pregnancy, and power, Sports Med. 28 (2) (2018) 104–125.
Ann. Epidemiol. 15 (6) (2005) 460–466. [93] M. Guillán-Fresco, E. Franco-Trepat, A. Alonso-Pérez, A. Jorge-Mora, M. López-
[67] I. Ibrahim, J.A. Ayariga, J. Xu, R.K. Boakai, O.S. Ajayi, J. Owusu-Kwarteng, Fagúndez, A. Pazos-Pérez, et al., Caffeine, a risk factor for osteoarthritis and
A comparative study of skimmed milk and cassava flour on the viability of freeze- longitudinal bone growth inhibition, J. Clin. Med. 9 (4) (2020) 1–14.
dried lactic acid bacteria as starter cultures for yogurt fermentation, Foods 12 (6) [94] A. Perez, T. Li, The rationale of using coffee and melatonin as an alternative
(2023) 1207. treatment for Alzheimer’s disease, J. Alzheimer’s Dis. Park. 6 (1) (2016) 1–5.
[68] V. Sengpiel, E. Elind, J. Bacelis, S. Nilsson, J. Grove, R. Myhre, et al., Maternal [95] E. Anggreani, L. Cy, Nutrition and dietetics (IJFS) ISSN : 2326-3350
caffeine intake during pregnancy is associated with birth weight but not with neuroprotective effect of chlorogenic acids against alzheimer ’ s disease CGAs
gestational length: results from a large prospective observational cohort study, composition in coffee and the effect of processing on total cgas content
BMC Med. 11 (1) (2013) 42 [Internet], [Link] bioavailabili, Int. J. Food Sci. 6 (2017) 330–337.
015/11/42. [96] B. Sharma, S. Paul, Action of caffeine as an amyloid inhibitor in the aggregation
[69] J. Rhee, R. Kim, Y. Kim, M. Tam, Y. Lai, N.N. Keum, et al., Maternal caffeine of Aβ16-22 peptides, J. Phys. Chem. B 120 (34) (2016) 9019–9033.
consumption during pregnancy and risk of low birth weight: a dose-response [97] B. Sharma, S. Kalita, A. Paul, B. Mandal, S. Paul, The role of caffeine as an
meta-analysis of observational studies, PLoS One 10 (7) (2015) 1–18. inhibitor in the aggregation of amyloid forming peptides: a unified molecular
[70] X. Weng, R. Odouli, D.K. Li, Maternal caffeine consumption during pregnancy and dynamics simulation and experimental study, RSC Adv. [Internet] 6 (82) (2016),
the risk of miscarriage: a prospective cohort study, Am. J. Obstet. Gynecol. 198 [Link] 78548–58.
(3) (2008) 279.e1–279.e8. [98] X. Zhou, L. Zhang, The neuroprotective effects of moderate and regular caffeine
[71] L. Fenster, B. Eskenazi, G.C. Windham, S.H. Swan, Caffeine consumption during consumption in Alzheimer’s disease, Oxid. Med. Cell. Longev. (2021) 2021.
pregnancy and fetal growth, Am. J. Publ. Health 81 (4) (1991) 458–461. [99] L.L. Sokol, M.J. Young, A.J. Espay, R.B. Postuma, Cautionary optimism: caffeine
[72] G. Retardation, P. Birth, Am. J. Nurs. J Am Diet Assoc. 94 (12) (1994) 1443. and Parkinson’s disease risk, J. Clin. Mov. Disord. [Internet] 3 (1) (2016) 10–12,
[73] R.M. Carr, A. Oranu, V. Khungar, Pengse Po, Erin Delaney, Howard Gamper, [Link]
Miklos Szanti-Kis, Speight Lee, LiWei Tu, Andrey Kosolapov, E. James Petersson, [100] S. Endesfelder, U. Weichelt, C. Schiller, M. Sifringer, I. Bendix, C. Bührer, Caffeine
Ya-Ming Hou, Cd, 乳鼠心肌提取 HHS public access, Physiol. Behav. 176 (1) protects against anticonvulsant-induced neurotoxicity in the developing rat brain,
(2016) 139–148. Neurotox. Res. 32 (3) (2017) 460–472.
[74] J.C. Konje, J.E. Cade, Maternal caffeine intake during pregnancy and risk of fetal [101] L. Wu, J. Meng, Q. Shen, Y. Zhang, S. Pan, Z. Chen, et al., Caffeine inhibits
growth restriction: a large prospective observational study, Br. Med. J. 337 hypothalamic A 1 R to excite oxytocin neuron and ameliorate dietary obesity in
(7682) (2008) 1334–1338. mice, Nat. Commun. 8 (May) (2017).
[75] T.S. de Medeiros, J.R. Bernardi, M.L. de Brito, V.L. Bosa, M.Z. Goldani, C.H. da [102] C.F. Chen, S.H. Chen, R.F. Chen, K.F. Liu, Y.R. Kuo, C.K. Wang, et al.,
Silva, Caffeine intake during pregnancy in different intrauterine environments A multifunctional polyethylene glycol/triethoxysilane-modified polyurethane
and its association with infant anthropometric measurements at 3 and 6 Months foam dressing with high absorbency and antiadhesion properties promotes
of age, Matern. Child Health J. 21 (6) (2017) 1297–1307. diabetic wound healing, Int. J. Mol. Sci. 24 (15) (2023).
[76] H. Djati Utomo, Reducing copper toxicity by drinking coffee, WIT Trans. Ecol. [103] I. Paiva, L. Cellai, C. Meriaux, L. Poncelet, O. Nebie, J.M. Saliou, et al., Caffeine
Environ. 110 (April 2008) (2008) 199–207. intake exerts dual genome-wide effects on hippocampal metabolism and learning-
dependent transcription, J. Clin. Invest. 132 (12) (2022).

13
V.S. Reddy et al. European Journal of Medicinal Chemistry Reports 10 (2024) 100138

[104] D. Papandreou, E. Andreou, Role of diet on non-alcoholic fatty liver disease: an [116] P. Viswanathan, Y. Muralidaran, G. Ragavan, Challenges in oral drug delivery: a
updated narrative review, World J. Hepatol. 7 (3) (2015) 575–582. nano-based strategy to overcome, Nanostruct. Oral. Med. (December) (2017)
[105] J. Arauz, N. Zarco, J. Segovia, M. Shibayama, V. Tsutsumi, P. Muriel, Caffeine 173–201.
prevents experimental liver fibrosis by blocking the expression of TGF-β, Eur. J. [117] J. Wang, Q. Ni, Y. Wang, Y. Zhang, H. He, D. Gao, et al., Nanoscale drug delivery
Gastroenterol. Hepatol. 26 (2) (2014) 164–173. systems for controllable drug behaviors by multi-stage barrier penetration
[106] Morris, et al., 基因的改变NIH public access, et al. 2012, Gerontology 61 (6) [Internet]. 2021, J. Contr. Release 331 (May 2020), [Link]
(2012) 515–525, 2015. jconrel.2020.08.045, 282–95.
[107] L. Shan, F. Wang, D. Zhai, X. Meng, J. Liu, X. Lv, Caffeine in liver diseases: [118] M.J. Mitchell, M.M. Billingsley, R.M. Haley, M.E. Wechsler, N.A. Peppas,
pharmacology and toxicology, Front. Pharmacol. 13 (October) (2022) 1–13. R. Langer, Engineering precision nanoparticles for drug delivery [Internet], Nat.
[108] N. Namviriyachote, V. Lipipun, Y. Akkhawattanangkul, P. Charoonrut, G. Rev. Drug Discov. 20 (2) (2021) 101–124, [Link]
C. Ritthidej, Development of polyurethane foam dressing containing silver and 0090-8.
asiaticoside for healing of dermal wound, Asian J. Pharm. Sci. [Internet] 14 (1) [119] J.A. Finbloom, F. Sousa, M.M. Stevens, T.A. Desai, Engineering the drug carrier
(2019) 63–77, [Link] biointerface to overcome biological barriers to drug delivery, Adv. Drug Deliv.
[109] S.G. Shim, D.W. Jun, E.K. Kim, W.K. Saeed, K.N. Lee, H.L. Lee, et al., Caffeine Rev. 167 (2020) 89–108.
attenuates liver fibrosis via defective adhesion of hepatic stellate cells in cirrhotic [120] J. Torres, N. Dhas, M. Longhi, M.C. García, Overcoming biological barriers with
model, J. Gastroenterol. Hepatol. 28 (12) (2013) 1877–1884. block copolymers-based self-assembled nanocarriers. Recent advances in delivery
[110] O. Pınar, F. Yangılar, P. Oğuzhan, F. Yangılar, Pullulan : production and usage in of anticancer therapeutics, Front. Pharmacol. 11 (November) (2020) 1–15.
food ındustry, African J. Food Sci. Technol. 4 (3) (2013) 57–63. [121] H. Nakata, T. Miyazaki, T. Iwasaki, A. Nakamura, T. Kidani, K. Sakayama, et al.,
[111] Clinical research, Clinical trials, Aust. Life Sci. 5 (4) (2008) 2021. Development of tumor-specific caffeine-potentiated chemotherapy using a novel
[112] A. Carlsson, L. Werko, Clinical pharmacology, Nord. Med. 67 (150 ml) (1962) drug delivery system with Span 80 nano-vesicles, Oncol. Rep. 33 (4) (2015)
5–7. 1593–1598.
[113] F. Shakeel, W. Ramadan, Transdermal delivery of anticancer drug caffeine from [122] H. Ma, M. Yu, M. Lei, F. Tan, N. Li, A novel topical targeting system of caffeine
water-in-oil nanoemulsions, Colloids Surf. B Biointerfaces 75 (1) (2010) 356–362. microemulsion for inhibiting UVB-induced skin tumor: characterization,
[114] M. Andrs, D. Muthna, M. Rezacova, M. Seifrtova, P. Siman, J. Korabecny, et al., optimization, and evaluation, AAPS PharmSciTech 16 (4) (2015) 905–913.
Novel caffeine derivatives with antiproliferative activity, RSC Adv. 6 (39) (2016) [123] N.H. Abu Samah, C.M. Heard, Enhanced in vitro transdermal delivery of caffeine
32534–32539. using a temperature- and pH-sensitive nanogel, poly(NIPAM-co-AAc), Int. J.
[115] NIH. Drug, Delivery Systems: Getting Drugs to Their Targets in a Controlled Pharm. 453 (2) (2013) 630–640, [Link]
Manner [Internet], National Institute of Biomedical Imaging and Bioengineering. [Internet].
October, 2016. October):1. [Link]
e-topics/drug-delivery-systems-getting-drugs-their-targets-controlled-manner.

14