The Dark Side of Energy Drinks: A Comprehensive Review of Their Impact on the Human Body

In recent years, the consumption of energy drinks by young adults and athletes has risen significantly, but concerns have been raised about the potential health risks associated with excessive consumption. These concerns include cardiovascular problems, nervous system disorders, and the potential for addiction. This review aims to examine the reported effects of acute or chronic abuse of energy drinks on human health. The analysis shows a significant prevalence of adverse effects, particularly on the cardiovascular and neurovegetative systems. In particular, the analysis identified nine cases of cardiac arrest, three of which were fatal. The aetiology of these adverse effects is attributed to the inherent neurostimulant properties of these beverages, of which caffeine is the predominant component. A comparison of documented effects in humans with experimental studies in animal models showed an overlap in results. This review highlights the need for greater rigour in the assessment of sudden cardiac death, particularly in young people, as legal substances such as energy drinks may be involved. We propose stricter limits on the consumption of these beverages than for caffeine, based on the evidence found and the data in the literature. This review also calls for the establishment of regulations governing the consumption of these products in view of their potential impact on human health.


Introduction
The Food and Drug Administration (FDA) defines energy drinks (EDs) as "a class of products in liquid form that typically contains caffeine, with or without other added ingredients."They typically contain large amounts of caffeine, added sugars, other additives, and legal stimulants such as guarana, taurine, and L-carnitine.These legal stimulants can increase alertness, attention, and energy, as well as increasing blood pressure, heart rate, and breathing.These products are marketed as enhancers of mental acuity and physical performance [1,2].Prominent examples of energy drinks include Red Bull, Monster, NOS, Rockstar, Lucozade, Eastroc Super Drink, Bang Energy, and 5 Hour Energy [3,4], as described in Table 1.Adolescents gravitate towards these beverages to swiftly boost energy levels, enhance alertness, and increase scholastic or athletic performance.
Consequences of this consumption pattern have led to a rising incidence of young individuals seeking medical attention in emergency departments due to an array of adverse health outcomes, as documented in results section.Reports underscore that energy drinks have deleterious effects on a broad spectrum of bodily organs, culminating in mild adversities such as anxiety, gastrointestinal disturbances, dehydration, nervousness, and tachycardia, along with more severe outcomes like rhabdomyolysis, acute kidney injury (AKI), ventricular fibrillation, seizures, acute mania, and stroke.Furthermore, instances linking energy drink consumption to fatalities have been documented.
The rise of the energy drink market, particularly within the younger demographic, has caused a 70% escalation in caffeine ingestion among caffeine-consuming children and adolescents from 1977 to 2009 [1].Data sourced from the National Health and Nutrition Examination Survey spotlight an average caffeine intake of 61 mg daily for teenagers [5].While youth caffeine consumption has receded in recent decades, the utilisation of energy drinks has concurrently surged [5].
These beverages substantially differ in both caffeine content (ranging from 50 to 505 mg per can or bottle) and caffeine concentration (ranging from 2.5 to 171 mg per 28 mL).By comparison, a 170 g cup of brewed coffee contains caffeine concentrations varying between 77 and 150 mg [3].
As shown in Table 1, energy drinks are composed of a variety of ingredients, including taurine, ginseng, sugar, guarana, etc. tion, reaction time, and emotional state has sparked investigation, although conclusive evidence on combinatorial cognitive effects remains elusive.Seidl et al. conducted a double-blind, placebo-controlled trial administering caffeine, taurine, and glucuronolactone to the experimental group, yielding shorter motor reaction times and higher emotional well-being scores [14].While the study implied a positive cognitive impact, GABAergic, glycinergic, cholinergic, and adrenergic neurotransmitter system interactions were posited, acknowledging the caffeine factor [15].
Gluconolactone, an outcome of hepatic glucose metabolism, stands as a precursor for ascorbic acid synthesis.In the 1960s, Japanese researchers [16] directed attention toward its performance-amplifying attributes.A study demonstrated enhanced swimming endurance in laboratory rats following the direct intestinal injection of glucuronolactone, glucose, glycogen, and other agents, with the former group outperforming in two of three instances.The findings suggest that the equivalent human dose could range from 1 to 2 g of glucuronolactone, compared to 600 mg in a Red Bull can.Detoxifying potential may contribute to these results, as glucuronolactone supplementation may fortify the body's natural defences against carcinogens and tumour promoters [8].
Among the additional ingredients commonly found within energy drinks, carnitine, guarana, and the vitamin B complex should be mentioned.
Carnitine, comprising several compounds, including L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine [17], emerges as a derivative of an amino acid.It occurs naturally in numerous foods, particularly animal-derived foods, and is available in dietary supplement form.Carnitine synthesis transpires endogenously within the liver, kidneys, and brain from the amino acids, lysine and methionine [18,19].This compound plays a pivotal role in energy production, serving as an indispensable cofactor that facilitates the transport of long-chain fatty acids into mitochondria for oxidation, leading to adenosine triphosphate (ATP) energy generation [20,21].
Guarana (Paullinia cupana), a climbing plant native to the Amazon, has historically served as a stimulant and traditional medicine among Brazil's indigenous peoples [22].Guarana seeds notably surpass coffee beans in caffeine content, containing additional xanthine alkaloids such as theobromine and theophylline [23].This botanical additive enhances the caffeine content and stimulatory attributes of energy drinks (EDs), with its caffeine content being unlisted on product labels due to its status as an herbal supplement [24].
The aim of this review is to summarise all evidence on the adverse effects of energy drink consumption.

Materials and Methods
This systematic review follows the Preferred Reporting Items for Systematic Review (PRISMA) standards [26] (Figure 1).In the context of specific events, such as acute intoxication or preliminary reports of legal substances, we believe that case reports/studies and case series involving human subjects with medical reports can provide valuable evidence for systematic reviews.Therefore, descriptive observational study designs, including case series, individual case reports, and descriptive cross-sectional studies, were considered for inclusion in this review.We conducted a comprehensive literature search and critically appraised the collected studies.An electronic search was conducted using PubMed, Google Scholar and EBSCO search engines to identify peer-reviewed articles published between 5 January 2009 and 30 April 2023, using the search terms 'energy drink', 'Red Bull', 'Monster', 'taurine', 'adverse effects', 'arrhythmia', 'renal failure', 'death', 'gastrointestinal' in the title, abstract and keywords.Internet search engines such as Google were also used to find relevant information.In addition, the reference lists of all retrieved papers were reviewed and cross-referenced to identify additional relevant literature.Only English-language papers were included in this study.Data on each case were extracted, including age and sex of the case, brand of energy drink consumed (some brands were unknown), main pathologies, type of event and onset.Two or more independent reviewers screened titles and abstracts against the inclusion criteria for the review.The results of the search and study inclusion process were reported in detail in the final systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.In addition, case-control studies using animal models were included in the review to compare data from human case reports.The above search identified 458 articles, which were screened to exclude duplicates.The resulting reference lists were then screened for titles and abstracts, leaving 442 articles for further consideration.Non-English articles were excluded.The inclusion criteria were as follows: (1) original research articles and (2) case reports/series.These publications were carefully assessed, taking into account the main objectives of the review.Reviews and mini-reviews were not included in the qualitative synthesis but were used to check for missing articles.After this evaluation, 96 scientific papers remained.
Nutrients 2023, 15, 3922 9 of 30 the case, brand of energy drink consumed (some brands were unknown), main pathologies, type of event and onset.Two or more independent reviewers screened titles and abstracts against the inclusion criteria for the review.The results of the search and study inclusion process were reported in detail in the final systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines.In addition, case-control studies using animal models were included in the review to compare data from human case reports.The above search identified 458 articles, which were screened to exclude duplicates.The resulting reference lists were then screened for titles and abstracts, leaving 442 articles for further consideration.Non-English articles were excluded.The inclusion criteria were as follows: (1) original research articles and (2) case reports/series.These publications were carefully assessed, taking into account the main objectives of the review.Reviews and mini-reviews were not included in the qualitative synthesis but were used to check for missing articles.After this evaluation, 96 scientific papers remained.

Results
The papers in our study were divided in seven groups: cardiac effects (35 papers), gastrointestinal effects (12 papers), neurologic effects (18 papers), renal effects (7), gynaecological effects (2 papers), autoimmune and skin effects (2 papers).3, Table 4, Table 5, Table 6 and Table 7 show brief descriptions of these seven groups of studies, respectively.Furthermore, we incorporated case-control studies utilizing animal models (20 papers).

N/A
Increase consumption of filtered coffee from 2 to 5 cups a day and drink 3 to 4 rations of the Magnus Omnilife Products energy drink a day.After a few days, up to 10 daily portions of the energy drink (in addition to the five cups of filtered coffee per day).
Delusional ideas of grandeur, auditory hallucinations, and lacked awareness of disease manic syndrome.

Gorgulu et al., 2014 [78] 1 21/M ED + vodka N/A
Regularly consumed one or two energy drinks a day in order to be more energetic during his training, sometimes drank energy drink in combination with a small amount of vodka.
Hallucinations, disorganized behavior, excitation, persecution, mystic and grandious delusions.We evaluated a total of 86 cases (Figure 2).Most of the patients were young (median age, 30 years; range, 8 to 62 years).Slightly more men (66 patients, 76.7%) than women experienced an acute reaction and 35 of them (40.7%) had pathological remote anamnesis positive.
We evaluated a total of 86 cases (Figure 2).Most of the patients were young (median age, 30 years; range, 8 to 62 years).Slightly more men (66 patients, 76.7%) than women experienced an acute reaction and 35 of them (40.7%) had pathological remote anamnesis positive.
In addition, two cases of erythema have been reported in the scientific literature.One was in a man and the other in a woman.Neither had major pathologies.
There were at least two cases of death.In one case, there was sudden cardiac arrest and in the other case death due to ventricular fibrillation.One was a man and the other was a woman.Only one of them had a major pathology such as mitral valve prolapse.
Nine out of eight-six patients (10%) drank energy drinks with alcohol, one with cannabis, one (1%) with diet pills, one (1%) with another caffeinated drink, and five (6%) took several energy drinks.
In addition, two cases of erythema have been reported in the scientific literature.One was in a man and the other in a woman.Neither had major pathologies.
There were at least two cases of death.In one case, there was sudden cardiac arrest and in the other case death due to ventricular fibrillation.One was a man and the other was a woman.Only one of them had a major pathology such as mitral valve prolapse.
Nine out of eight-six patients (10%) drank energy drinks with alcohol, one with cannabis, one (1%) with diet pills, one (1%) with another caffeinated drink, and five (6%) took several energy drinks.

Discussion
Consumption of energy drinks has increased in recent years for several reasons [2].One of the main factors is the aggressive marketing and promotion of energy drinks by beverage companies, primarily targeting young adults and adolescents [101].This marketing often focuses on the energizing and stimulating effects of energy drinks and their association with extreme sports and other high-energy activities.Another reason for the increasing consumption of energy drinks is the belief that they can improve cognitive and physical performance.Many people consume energy drinks to boost their energy levels, improve focus and concentration, and enhance athletic performance.However, while energy drinks may provide some short-term benefits in these areas, their long-term effects on health and performance remain unclear [102].Finally, the increasing availability of energy drinks in grocery stores, petrol stations, and other retail outlets has also contributed to their increased consumption.Energy drinks are often promoted as a convenient and portable source of energy and stimulation, making them a popular choice for people who travel a lot or have busy lifestyles.However, the easy availability of energy

Discussion
Consumption of energy drinks has increased in recent years for several reasons [2].One of the main factors is the aggressive marketing and promotion of energy drinks by beverage companies, primarily targeting young adults and adolescents [101].This marketing often focuses on the energizing and stimulating effects of energy drinks and their association with extreme sports and other high-energy activities.Another reason for the increasing consumption of energy drinks is the belief that they can improve cognitive and physical performance.Many people consume energy drinks to boost their energy levels, improve focus and concentration, and enhance athletic performance.However, while energy drinks may provide some short-term benefits in these areas, their long-term effects on health and performance remain unclear [102].Finally, the increasing availability of energy drinks in grocery stores, petrol stations, and other retail outlets has also contributed to their increased consumption.Energy drinks are often promoted as a convenient and portable source of energy and stimulation, making them a popular choice for people who travel a lot or have busy lifestyles.However, the easy availability of energy drinks also means that they are more likely to be consumed in excess, which can increase the risk of negative side effects.
The main psychoactive substance in an energy drink is caffeine.They also contain other ingredients that are thought to increase energy and mental alertness, such as taurine, guarana, ginseng, vitamins, and others [101].
The effects of these drinks on the human body are not fully understood, which is why research into their negative effects has increased.

Effects on the Cardiovascular System
Effects on the cardiovascular system appear to be the most studied of all the side effects of these substances, due to their potentially fatal properties.The European Cardiac Arrhythmia Society (ECAS) has undertaken a critical review of the reported data on energy drinks, in particular on cardiovascular events and their possible cause-effect relationship, in order to provide recommendations on the safer use of these drinks [103].High consumption of these energy drinks is associated with an acute haemodynamic and adrenergic state [104], which increases glucose and norepinephrine levels.Supraventricular and ventricular arrhythmias, coronary vasospasm, ischaemia/myocardial infarction, atrial fibrillation, syncope, aortic dissection, cardiomyopathy, cardiac arrest, and sudden cardiac death have been reported in young and otherwise healthy patients [105][106][107][108] (Figure 8).We have found that the risk of cardiovascular outcomes is increased in individuals with pre-existing structural or inherited heart disease.In addition, the consumption of these beverages may lead to the diagnosis of heart disease of which the subjects were previously unaware.Adverse cardiovascular effects have also been found with the use of other substances, such as alcohol.Caffeine [109] has direct chronotropic and positive inotropic effects on the heart.At low concentrations, these effects appear to be due to increased release of catecholamines (epinephrine and norepinephrine) as a result of antagonism of presynaptic receptors for adenosine.At higher concentrations (>10 µM), caffeine can directly increase calcium uptake by increasing cyclic AMP due to inhibition of phosphodiesterase.At very high concentrations (>100 µM) it reduces calcium sequestration by the sarcoplasmic reticulum.At high doses, it induces vascular smooth muscle contraction, except in cerebral vessels.Habitual coffee consumption generally increases peripheral vascular resistance and blood pressure slightly, probably through the release of catecholamines.Systolic and diastolic blood pressure increases by 0.8 mmHg and 0.5 mmHg, respectively, per 100 mg of caffeine.In particularly sensitive individuals, the consumption of a few cups of coffee may cause cardiac arrhythmias, but in most people, parenteral administration of high doses of coffee causes only tachycardia.The stimulation of cardiac RgR2 ryanodine receptors and concomitant inhibition of phosphodiesterase cause a cardio-stimulatory effect, but at high doses, this can cause arrhythmias, tachycardia, and ventricular fibrillation.The ability of caffeine to induce arrhythmias in individuals with atrioventricular conduction disorders or ectopic foci has not been conclusively demonstrated [110].The inotropic effect of caffeine is enhanced by the positive chronotropic effect of guarana, which contains caffeine, theobromine, and teofiline.
As mentioned above, nine cases of cardiac arrest associated with the consumption of high doses of these stimulants have been reported in literature.The primary triggering mechanism is the occurrence of cardiac arrhythmias such as ventricular fibrillation or the unmasking of previously unrecognised channelopathies.Of the nine cases mentioned above, six required intensive cardiopulmonary resuscitation and no cardiac abnormalities were found in these patients during follow-up visits in the following months, while the other three individuals died (sudden cardiac arrest, STEMI, ventricular fibrillation), but we couldn't find any available information on their autopsy data in the literature.

Effects on the Neurological System
The consumption of energy drinks containing caffeine and other substances may also have effects on the central nervous system, such as seizures, cerebral vasculopathy and manic psychosis.Studies have shown that these ingredients overstimulate the adrenergic system, leading to hyperglycaemia, hypokalemia, leukocytosis, and metabolic acidosis.The psychostimulant effects of caffeine are evident at low doses.

Effects on the Neurological System
The consumption of energy drinks containing caffeine and other substances ma have effects on the central nervous system, such as seizures, cerebral vasculopath manic psychosis.Studies have shown that these ingredients overstimulate the adre system, leading to hyperglycaemia, hypokalemia, leukocytosis, and metabolic aci The psychostimulant effects of caffeine are evident at low doses.
Caffeine enhances dopamine-related behaviour by inhibiting adenosine receptors and increasing transmission via dopamine D2 receptors.Lorist and Tops used an echoencephalograph (EEG) to highlight the alpha wavelength of the brain ( power).They found that caffeine intake increased left frontal activation compared right, suggesting that dopamine function may be linked to fatigue, with caffeine red fatigue.Doses of less than 500 mg result in increased alertness, increased spe thoughts and speech, decreased fatigue and reduced sleep.Higher doses may restlessness, anxiety, insomnia, tremors, and, in cases of acute toxicity, seizures th not respond to antiepileptic drugs [112] (Figure 9).The ingestion of caffeine at very (pharmacological) doses has been associated with the possible occurrence of seizu animal models, intraperitoneal administration of caffeine produces convu associated with electroencephalography.In humans, seizures have been reported aft overdose or ingestion of drug preparations.The consumption of energy drinks has associated with the occurrence of seizures, both in patients with known epilepsy a those without a history of epilepsy [113].This may be due to the high caffeine cont energy drinks.
At normal average doses of caffeine in humans, caffeine acts as an adenosine rec antagonist with equal affinity for A1 and A2A receptors.When administered ac caffeine acts dominantly on A1 receptors (as ambient adenosine activates them chronic use of caffeine leads to the tolerance of A1 receptors.Caffeine then has neg effects on the A1 receptor and dominant effects on A2A receptors.The endocannabi endogenous ligands of the cannabinoid receptors, are synthesised as needed in res to increased neuronal excitation and activate the presynaptic CB1 receptor, redu levels of cyclic AMP (cAMP) released and decrease neurotransmitter release.Ca increases neurotransmitter release by removing the inhibitory control of acetylchol the hippocampus and prefrontal cortex, regulating the opening of potassium cha mediated by A1 receptors and increasing the firing rate of A2A receptors in the str dendritic spines of neurons.This inhibits glutamatergic thalamocortical neuro Caffeine enhances dopamine-related behaviour by inhibiting adenosine A2A receptors and increasing transmission via dopamine D2 receptors.Lorist and Tops [111] used an echoencephalograph (EEG) to highlight the alpha wavelength of the brain (alpha power).They found that caffeine intake increased left frontal activation compared to the right, suggesting that dopamine function may be linked to fatigue, with caffeine reducing fatigue.Doses of less than 500 mg result in increased alertness, increased speed of thoughts and speech, decreased fatigue and reduced sleep.Higher doses may cause restlessness, anxiety, insomnia, tremors, and, in cases of acute toxicity, seizures that do not respond to antiepileptic drugs [112] (Figure 9).The ingestion of caffeine at very high (pharmacological) doses has been associated with the possible occurrence of seizures.In animal models, intraperitoneal administration of caffeine produces convulsions associated with electroencephalography.In humans, seizures have been reported after the overdose or ingestion of drug preparations.The consumption of energy drinks has been associated with the occurrence of seizures, both in patients with known epilepsy and in those without a history of epilepsy [113].This may be due to the high caffeine content of energy drinks.
At normal average doses of caffeine in humans, caffeine acts as an adenosine receptor antagonist with equal affinity for A1 and A2A receptors.When administered acutely, caffeine acts dominantly on A1 receptors (as ambient adenosine activates them).The chronic use of caffeine leads to the tolerance of A1 receptors.Caffeine then has negligible effects on the A1 receptor and dominant effects on A2A receptors.The endocannabinoids, endogenous ligands of the cannabinoid receptors, are synthesised as needed in response to increased neuronal excitation and activate the presynaptic CB1 receptor, reduce the levels of cyclic AMP (cAMP) released and decrease neurotransmitter release.Caffeine increases neurotransmitter release by removing the inhibitory control of acetylcholine in the hippocampus and prefrontal cortex, regulating the opening of potassium channels mediated by A1 receptors and increasing the firing rate of A2A receptors in the striatum dendritic spines of neurons.This inhibits glutamatergic thalamocortical neurons by inducing cell activation and stimulating the adenylate cyclase pathway.Caffeine blocks A2A receptors and reduces the stimulatory effects of adenosine on cAMP.Caffeine can reduce the inhibition on striatal dopamine transmission by reducing the activity of striatal neurons and causing the disinhibition of thalamo-cortical projection neurons.The activation of A2A receptors leads to cAMP production, and the activation of D2 receptors reduces cAMP production and causes an inverse regulation of the activity of cAMP-dependent protein kinase (PKA) [114].As caffeine mimics the effect of dopamine on striatopallidal neurons, it causes a progressive sensitisation of cannabinoid CB1 receptors, which control GABAergic inhibitory postsynaptic currents (IPSCs) [115].The caffeine blockade of A2A receptors reduces the activation of cAMP-PKA pathways, resulting in increased glutamate release, the activation of mGlu5 metabotropic receptors, and endocannabinoid release.The blockade of adenosine A2A receptors in the striatum has been linked to the psychoactive properties of caffeine.There is also evidence that a specific genetic polymorphism of the adenosine A2A receptor influences habitual caffeine consumption in humans [116].
activation of A2A receptors leads to cAMP production, and the activation of D2 recep reduces cAMP production and causes an inverse regulation of the activity of cA dependent protein kinase (PKA) [114].As caffeine mimics the effect of dopamin striatopallidal neurons, it causes a progressive sensitisation of cannabinoid CB1 recep which control GABAergic inhibitory postsynaptic currents (IPSCs) [115].The caff blockade of A2A receptors reduces the activation of cAMP-PKA pathways, resultin increased glutamate release, the activation of mGlu5 metabotropic receptors, endocannabinoid release.The blockade of adenosine A2A receptors in the striatum been linked to the psychoactive properties of caffeine.There is also evidence that a sp genetic polymorphism of the adenosine A2A receptor influences habitual caff consumption in humans [116].
Richard and Smith [117] recently reviewed the literature on the chronic mental h effects of energy drinks.They concluded that while the acute effects of energy drink mood appear to be positive, chronic consumption is associated with stress, anxiety depression.Taurine is a molecule that crosses the blood-brain barrier and binds to G receptors.It can mimic the effects of GABA and glycine, resulting in an anticonvu effect that has a stabilising effect on membranes inside and outside the cell.

Effects on the Gastrointestinal and Renal System
These drinks can also lead to the development of gastrointestinal and renal disor Some authors describe cases of acute hepatitis, acute pancreatitis, and renal failure acute kidney injury (AKI).As mentioned above, all energy drinks contain high dos caffeine, taurine, sugar, and vitamins.A megadose of vitamin B3 (niacin) is assoc with hepatotoxicity.Niacin hepatotoxicity is thought to be a dose-dependent, dir toxic response.Vitamin B3 is associated with cellular metabolism and flushing hepatotoxicity at pharmacological doses.Hepatotoxicity manifests as a mild elevatio liver enzymes (ALT/AST), hepatic steatosis, hepatic necrosis, and, in rare cases, failure.The lowest dose of vitamin B3 known to cause hepatotoxicity, as reported i literature, is 1 g/day [31] (Figure 10).However, the main cause of AKI was most l taurine, which is used as a dietary supplement by athletes to enhance performance.Richard and Smith [117] recently reviewed the literature on the chronic mental health effects of energy drinks.They concluded that while the acute effects of energy drinks on mood appear to be positive, chronic consumption is associated with stress, anxiety, and depression.Taurine is a molecule that crosses the blood-brain barrier and binds to GABA receptors.It can mimic the effects of GABA and glycine, resulting in an anticonvulsant effect that has a stabilising effect on membranes inside and outside the cell.

Effects on the Gastrointestinal and Renal System
These drinks can also lead to the development of gastrointestinal and renal disorders.Some authors describe cases of acute hepatitis, acute pancreatitis, and renal failure with acute kidney injury (AKI).As mentioned above, all energy drinks contain high doses of caffeine, taurine, sugar, and vitamins.A megadose of vitamin B3 (niacin) is associated with hepatotoxicity.Niacin hepatotoxicity is thought to be a dose-dependent, directly toxic response.Vitamin B3 is associated with cellular metabolism and flushing and hepatotoxicity at pharmacological doses.Hepatotoxicity manifests as a mild elevation of liver enzymes (ALT/AST), hepatic steatosis, hepatic necrosis, and, in rare cases, liver failure.The lowest dose of vitamin B3 known to cause hepatotoxicity, as reported in the literature, is 1 g/day [31] (Figure 10).However, the main cause of AKI was most likely taurine, which is used as a dietary supplement by athletes to enhance performance.
Caffeine promotes digestion by stimulating salivation and gastric juice production due to the presence of synergistic substances acting on H2 receptors.Caffeine is also known to relax the gastroesophageal sphincter, which prevents the stomach contents from rising into the oesophagus.In addition to its renal effects, caffeine is a weak diuretic.This effect may be associated with an increase in glomerular filtration and a decrease in tubular sodium reabsorption (Figure 11).There are also GABA receptors in the gastrointestinal tract.These are located in the peripheral autonomic nervous system and are involved in acid secretion and the protection of the gastric mucosa from injury and motility.In the stomach, taurine accumulates in the parietal cells of the gastric glands.Taurine-containing cells are found in the myenteric plexus and submucosal plexus of the enteric nervous system.The taurinergic neurons in the muscle layer of the gastrointestinal tract and the gastrointestinal tract may be involved in gastrointestinal motility and endocrine cell functions [118].
Caffeine promotes digestion by stimulating salivation and gastric juice pro due to the presence of synergistic substances acting on H2 receptors.Caffein known to relax the gastroesophageal sphincter, which prevents the stomach conte rising into the oesophagus.In addition to its renal effects, caffeine is a weak diure effect may be associated with an increase in glomerular filtration and a decrease in sodium reabsorption (Figure 11).There are also GABA receptors in the gastroi tract.These are located in the peripheral autonomic nervous system and are inv acid secretion and the protection of the gastric mucosa from injury and motilit stomach, taurine accumulates in the parietal cells of the gastric glands.Taurine-co cells are found in the myenteric plexus and submucosal plexus of the enteric system.The taurinergic neurons in the muscle layer of the gastrointestinal tract gastrointestinal tract may be involved in gastrointestinal motility and endoc functions [118].

Other Effects
Finally, there are rare cases of obstetric, dermatological, and auto complications that are difficult to explain or whose association with energy drin not seem to be reliable and well explained.Regarding autoimmune a complications, some authors are convinced that there are underlying mechan Caffeine promotes digestion by stimulating salivation and gastric juice produ due to the presence of synergistic substances acting on H2 receptors.Caffeine is known to relax the gastroesophageal sphincter, which prevents the stomach contents rising into the oesophagus.In addition to its renal effects, caffeine is a weak diuretic.effect may be associated with an increase in glomerular filtration and a decrease in tub sodium reabsorption (Figure 11).There are also GABA receptors in the gastrointes tract.These are located in the peripheral autonomic nervous system and are involv acid secretion and the protection of the gastric mucosa from injury and motility.In stomach, taurine accumulates in the parietal cells of the gastric glands.Taurine-contai cells are found in the myenteric plexus and submucosal plexus of the enteric ner system.The taurinergic neurons in the muscle layer of the gastrointestinal tract and gastrointestinal tract may be involved in gastrointestinal motility and endocrine functions [118].

Other Effects
Finally, there are rare cases of obstetric, dermatological, and autoimm complications that are difficult to explain or whose association with energy drinks not seem to be reliable and well explained.Regarding autoimmune and complications, some authors are convinced that there are underlying mechanism

Other Effects
Finally, there are rare cases of obstetric, dermatological, and autoimmune complications that are difficult to explain or whose association with energy drinks does not seem to be reliable and well explained.Regarding autoimmune and skin complications, some authors are convinced that there are underlying mechanisms of hypersensitivity to synthetic taurine, which may be slightly different from natural taurine [119].Although the authors have not been able to elucidate the mechanism of anaphylaxis, they suggest that the additives used to stabilise the amino acids, such as sulphites, butylated hydroxyanisole, butylated hydroxytoluene, and olysorbate emulsifier, may be the cause of the symptoms [120].There is also no clear association with energy drinks in obstetric complications.We reported two cases of such complications.In the first case, we had neonatal hyperinsulinism due to isolated high maternal sugar intake, an event that has never been reported in the literature.In the second case, we had menorrhagia due to secondary VKD (acquired vitamin K deficiency) after consumption of high-energy drinks.There is no evidence in the literature of ingredients in energy drinks that might correlate with the development of VKD.

Experimental Studies on Animal Models
The adverse health effects have also been studied by various research groups using animals as an experimental model.The summarised results of these studies, outlined below, have shown effects similar to those observed in humans, with alterations affecting various organs or systems.
Salih et al. [121] used rabbits as an animal model to observe the histopathological effects of energy drinks (EDs) on various organs, including the brain, liver, kidneys, and heart.Their findings suggest a direct correlation between tissue damage and the dose administered.At higher doses, they observed renal vascular congestion, the bleeding of interstitial tissue, focal atrophy, and the degeneration of the lining epithelium of the proximal and distal convoluted tubules.Nieradko Iwanicka and colleagues [122] studied the effects of the ad libitum consumption of energy drinks in mice on memory, body weight and laboratory parameters.After 30 days of the experiment, the researchers observed weight gain in male mice, an increase in serum transaminases and cholesterol concentration, but no memory-related changes.Similar results were found by Sadowska [123], who studied the effects of energy drink consumption in 30 mice and highlighted three main consequences: reduced body weight gain despite increased energy expenditure, suggesting an increased catabolic rate in the animals studied; reduced peri-intestinal fat deposition and increased accumulation of peri-cardiac adipose tissue, which may act as a source of chemokines and cytokines with pro-inflammatory properties.Finally, energy drink consumption led to an increase in blood glucose concentration, most likely due to metabolic changes leading to increased lipolysis and the development of insulin resistance.
Rasheed and colleagues [124] investigated the effects of energy drinks on renal tubules using albino rats as an experimental animal model.Their research showed histopathological changes in renal tubular cells, such as increased tubular vacuolisation, in rats exposed to energy drinks.According to the researchers, this adverse effect is due to inhibition of the A2A adenosine receptor, resulting in increased oxidative stress and production of inflammatory stimuli.
Abonar et al. [125], Rehman et al. [126], and Haroun et al. [127] investigated the effect of energy drinks on the pancreas of adult male albino rats.They performed histological, immunohistochemical and biochemical studies that revealed alterations in pancreatic cytoarchitecture.Specifically, damage to the pancreatic acini and islets of Langerhans was observed, accompanied by an increase in collagen deposition in the pancreatic parenchyma, a decrease in serum insulin levels, and an increase in blood glucose levels.There was also an increase in TNF-a, NO, and malondialdehyde levels, indicating a global negative effect on both exocrine and endocrine functions of the gland.Kassab et al. [128] also studied the effects of energy drinks on the salivary glands of thirty adult albino rats and observed parenchymal changes, including cytoplasmic vacuolisation, pyknotic nuclei and abundant collagen fibre deposition, resulting in the displacement of striated muscle fibres.However, these pathological changes in the glands were found to be transient upon cessation of the substance.
Possible adverse effects of caffeine and taurine on cardiac electrophysiology were investigated using twenty-five rabbits as an animal model [129].The hearts of animals perfused with caffeine and taurine showed shortened repolarisation times and refractory periods on the ECG trace, followed by ventricular arrhythmias, confirming the potential arrhythmogenic effect of these substances.In another study, Demirel et al. [130] investigated the effects of the combined consumption of energy drinks and alcohol on the myocardium and skeletal muscle system.In particular, the study highlighted damage to the cardiac and endothelial cytoarchitecture, as well as an increased tendency towards anaerobic cellular respiration in skeletal muscle tissue, resulting in increased lactate formation.Diaz et al. [131] also investigated the effects of these two substances in combination.In their experimental study of rats exposed to the substances for 90 days, changes in the temporal cortex and hippocampus were analysed.The results show an inflammatory response associated with oxidative stress, local gliosis, and increased levels of IL-1, TNF-1, iNOS, reactive oxygen species, lipid peroxidation, and nitric oxide.In addition, at the neurological level, Ulenius [132] and colleagues demonstrated that the combination of caffeine and taurine enhances the stimulant properties of ethanol on the locomotor system, a phenomenon previously associated with substance dependence and associated with increased dopamine levels and reward circuits.Ugwuja [133] conducted experiments to assess the biochemical effects of energy drinks alone or in combination with alcohol on albino rats.The study showed changes in total white blood cell count, plasma potassium, calcium, renal function, liver enzymes, and plasma triglycerides.Krahe et al. [134] also analysed the effects of combined energy drink and alcohol consumption.Overall, animals treated with alcohol and energy drinks showed increased locomotor activity and increased anxiety levels in the open field test.They also showed an early loss of the righting reflex and poorer motor coordination in the rotarod test.These effects on righting reflex and motor coordination were associated with the over-activation of cerebellar GABAA receptors.The data also show that exposure to alcohol in combination with energy drinks prolongs the duration of motor impairment and ataxia in adolescent mice.This ability to prolong the effects of alcohol may explain why this group performed worse in the righting reflex loss test after cumulative administration of alcohol and energy drinks compared to animals receiving alcohol alone.Reis et al. [135] investigated the effects of 14 days of energy drink consumption alone or in combination with ethanol on oxidative stress parameters, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and the lipid peroxidation marker malondialdehyde (MDA) in 40-day "adolescent" mice.The ethanol-treated group showed a significant increase in SOD and GSH-Px activity in brain tissue compared with the control group.The elevated MDA levels observed in rats co-exposed to energy drinks and ethanol, as well as those exposed to energy drinks alone, may be a consequence of increased free radical formation and altered cellular antioxidant defence status.Liver histopathology results show that energy drinks may induce liver damage, and the combined effect of ethanol and energy drinks may cause more significant damage than either substance alone, as indicated by increased MDA levels.A histopathological examination of brain tissue did not show any treatment-related abnormalities, possibly due to the short duration of the experiment.
Nasi and colleagues [136] investigated the possible negative effect of energy drinks on the gastrointestinal tract by administering different substances to rats for five consecutive days.They did not observe any acute lesions in the gastrointestinal tract, but they did observe an eosinophilic infiltration in the intestinal mucosa.This histopathological change was also observed in rats treated with caffeine alone, suggesting that this inflammatory effect is a direct consequence of this substance, which is also present in energy drinks.
[137] investigated the effects of eight weeks of energy drink consumption on the female reproductive system, specifically analysing follicular ovarian reserve and anti-Müllerian hormone levels in the blood.They found a significant decrease in both parameters.Instead, Oyelowo et al. [138] focused on the biochemical effects of both natural and artificial energy drinks on testicular tissue after 28 consecutive days of consumption in pubertal male rats.Their results showed negative effects of energy drink consumption, whether natural or artificial, on male reproductive functions, including decreased testosterone steroidogenesis in Leydig cells, changes in gonadotropin synthesis, and disruption of sperm homeostasis.
Al-Basher et al. [139] conducted a study on the effects of perinatal exposure to caffeinebased energy drinks on the liver, kidneys, brain, locomotor activity, and anxiety in newborn mice.Pregnant mice received 2.5 or 5 mL of energy drinks from the first day of pregnancy until 15 days after birth.Perinatal exposure to energy drinks resulted in a significant increase in lipid peroxidation (MDA) and a decrease in antioxidant defences in the liver, kidneys, brain, cerebellum, and medulla oblongata of newborn mice on days 21 and 35 after birth.Energy drinks also induced various histological alterations, including vacuolation and lipid infiltration of hepatocytes, developing degenerated glomeruli and dilated interstitial spaces in the renal cortex, pyknosis and chromatolysis of cerebral and medullary neurons, and degenerated and abnormal Purkinje cells in the cerebellum.In addition, energy drinks increased locomotor activity and induced anxiety-like behaviour in newborn mice.
Posokhov et al. [140] investigated the effects of two months of energy drink consumption on red blood cell membranes.They used the fluorescent probe O1O (2-(2 -OH-phenyl)-5-phenyl-1,3-oxazole), which localises to the area of glycerol backbones, carbonyl groups of phospholipids, and hydrocarbon chains of phospholipids (near carbonyl groups) in the bilayer.The consumption of energy drinks was associated with increased fluorescence intensity in erythrocyte suspensions compared to control animals.The observed change in probe fluorescence is attributed to an increase in the viscosity of the probe environment within the membrane.Using the fluorescent probe O1O, it was shown that the long-term oral administration of caffeine-based energy drinks to rats caused an increase in membrane viscosity (resulting in reduced fluidity) in red blood cells.

Conclusions
This extensive literature review includes a large number of research studies on the potentially fatal health effects of both acute and chronic abuse of these substances.These consequences include cardiac arrhythmias, neurological and behavioural changes, acute organ inflammation (including the liver, stomach, pancreas, and kidneys) and even cases of rare dermatitis or autoimmune disorders.Furthermore, although based on a limited case pool, it is noteworthy that there is a marked disparity in the literature between cases of cardiac arrest requiring intensive cardiopulmonary resuscitation (nine cases) and documented deaths (three cases) resulting from energy drink abuse.These statistics suggest a plausible under-reporting of deaths associated with these substances, particularly among frequent users such as adolescents and athletes.Consequently, in the investigation of sudden cardiac death in young people, the role of the pathologist in meticulously collecting anamnestic and circumstantial data from the deceased, recognising the potential involvement of non-illicit substances such as energy drinks, becomes crucial [141].
The results of experimental studies in animal models echo the findings of the review, demonstrating acute and chronic effects consistent with observations in humans.
Although individual components have been shown to be safe [142], excessive consumption, especially among adolescents, often leads to potential adverse effects on human health.As shown in this review, these effects can vary, particularly regarding the cardiovascular and cerebral systems.It would therefore be important to consider the introduction of precise limits on the consumption of these drinks.As caffeine is the most representative ingredient in terms of composition, it is first necessary to consider the upper limits of safe caffeine intake.Most cans of energy drinks (250 mL) contain 50 to 150 mg of caffeine, while the EFSA upper safe intake limit for adults is up to 400 mg per day (about 5.7 mg/kg bw per day for a 70 kg adult), with a single dose not exceeding 200 mg [143].In fact, no health concerns regarding acute toxicity, bone status, cardiovascular health, cancer risk, or male fertility have been raised by other agencies in previous assessments at this level of habitual caffeine consumption.The FDA (Food and Drug Administration) estimates that toxic effects, such as seizures, may be observed following the rapid consumption of about 1200 mg of caffeine, or about 0.15 tablespoons of pure caffeine [144].For pregnant or breastfeeding women, the safe daily intake of caffeine is halved from 400 mg to 200 mg, or about half a can.Finally, for children and adolescents, it is important to accentuate that neither EFSA nor the FDA have indicated a safe limit, suggesting that these substances should be avoided altogether, as further emphasised by the American Academy of Pediatrics due to possible long-term negative effects on behavioural disorders.Therefore, based on our observations and those found in the literature, we suggest that the daily intake of energy drinks should not only not exceed the safety limits for caffeine established by European and American regulatory authorities, but should be even lower.Indeed, these drinks also contain other neurostimulants, the effects of which are not fully understood.Furthermore, as this review points out, there are cases in the literature of people with no known medical conditions who have suffered acute cardiac events after consuming just a few 250 mL cans of these drinks.Given that the concentration of caffeine in these drinks is between 50 and 150 mg per can (250 mL), we recommend no more than one can at a time and two cans per day to remain within an acceptable safety limit.We also believe that it is necessary to clearly state the daily intake limit for products containing high levels of caffeine (such as 'Demon Energy Shot', which contains 200 mg of caffeine in 60 mL of product), given the potential risk of acute caffeine intoxication [145].
In addition, the sale and consumption of these drinks in minors should be regulated as, although they are legal substances, their long-term effects are not yet known and may lead to psychiatric pathologies or the aggravation of cardiac conduction disorders.Increased public education on the potential risks associated with the misuse of energy drinks is warranted to enable individuals to make informed decisions regarding consumption.
Furthermore, extensive research is needed to elucidate the long-term effects of energy drink consumption on human health.

Figure 1 .
Figure 1.Our review strategy following PRISMA standards.

Figure 1 .
Figure 1.Our review strategy following PRISMA standards.

Figure 2 .
Figure 2. Different outcomes in our review.

Figure 2 .
Figure 2. Different outcomes in our review.

Figure 3 .
Figure 3. Cardiac outcomes in our review.

Figure 4 .
Figure 4. Neurologic outcomes in our review.

Figure 3 .
Figure 3. Cardiac outcomes in our review.

Figure 3 .
Figure 3. Cardiac outcomes in our review.

Figure 4 .
Figure 4. Neurologic outcomes in our review.

Figure 4 .
Figure 4. Neurologic outcomes in our review.

Figure 5 .
Figure 5. Gastrointestinal outcomes in our review.

Figure 6 .
Figure 6.Renal outcomes in our review.

Figure 5 .
Figure 5. Gastrointestinal outcomes in our review.

Figure 5 .
Figure 5. Gastrointestinal outcomes in our review.

Figure 6 .
Figure 6.Renal outcomes in our review.

Figure 6 .
Figure 6.Renal outcomes in our review.

Figure 7 .
Figure 7.The different types of energy drinks used in our review.
Type of Energy Drink InvolvedPercentage of brand of Energy Drink involved

Figure 7 .
Figure 7.The different types of energy drinks used in our review.

Figure 8 .
Figure 8. Pathological effects of energy drinks on cardiac tissue.

Figure 9 .
Figure 9. Pathological effects of energy drinks on cerebral tissues.

Figure 9 .
Figure 9. Pathological effects of energy drinks on cerebral tissues.

Figure 10 .
Figure 10.Pathological effects of Energy Drinks on gastrointestinal tissues.

Figure 11 .
Figure 11.Pathological effects of energy drinks on renal tissue.

Figure 10 .
Figure 10.Pathological effects of Energy Drinks on gastrointestinal tissues.

Figure 10 .
Figure 10.Pathological effects of Energy Drinks on gastrointestinal tissues.

Figure 11 .
Figure 11.Pathological effects of energy drinks on renal tissue.

Figure 11 .
Figure 11.Pathological effects of energy drinks on renal tissue.

Table 2 .
The results of our review on cardiac side effects.

Table 3 .
The results of our review on gastrointestinal side effects.

Table 4 .
The results of our review on neurological side effects.
the dose did not produce the desired effect.One week later, three shots over 15 min.Transient psychotic
Ingestion of several cans (about 6) of Red Bull together with coffee in the 4 h before onset.

Table 5 .
The results of our review on renal side effects.

Table 6 .
The results of our review on gynaecological side effects.

Table 7 .
The results of our review on autoimmune and skin side effects.