Neurological Complication of Energy Drinks (ED) & Caffeinated Beverages in Young Adults: A Review

An assortment of caffeine, guarana, taurine, ginseng, vitamins, herbs, sugar, and other chemicals make up vitality drinks. Energy drinks are non-alcoholic beverages that include caffeine, amino acids, botanicals, and vitamins. While energy drinks are advertised as a means to alleviate tiredness and enhance both physical and mental abilities, regular intake of these beverages has been associated with adverse health effects.¹ Energy drinks, sometimes referred to as EDs, are beverages that include caffeine and a range of other substances such as guarana, taurine, ginseng, vitamins, herbal supplements, and sugar. These drugs are advertised as increasing energy levels, enhancing athletic performance, and improving concentration, reaction speed, attentiveness, emotions, and metabolism, while simultaneously reducing physical and mental stress. They are motivated to become healthy, enhance athletic performance, improve focus, enhance cognitive functions, regulate emotions, and boost metabolism while reducing stress in the body and mind. The use of energy drinks has seen a significant surge in the last twenty years, especially among teenagers and young people. Energy drinks are heavily promoted with the assertion that they provide a surge of energy to enhance both physical and cognitive abilities. Energy drinks (EDs) are distinct from sports drinks, since the latter are specifically designed to be consumed during physical activity.² Energy drinks are a kind of liquid beverage that usually include caffeine, and may or may not have additional nutritional supplements added to them. The first energy beverage made its debut in the United States in 1949 under the brand name "Dr. Enuf". Energy drinks first appeared in 1987 in Europe, but it wasn't until 1997 when Red Bull hit the market that they really took off. Afterwards, several brands have been introduced on a worldwide basis, leading to a substantial development of the energy drink business.  An important public health problem is on young people incorporating alcohol into beverages, especially during social gatherings or dances. Adolescents often consume alcohol mixed with illicit drugs such as amphetamines and marijuana. Energy products, namely energy drinks, are increasingly being used worldwide, notably by young adults aged 20 to 39. Young folks and active people are particularly inclined to use alcohol due to its remarkable effects, the sense of camaraderie it fosters among friends, and a lack of awareness about the associated risks. The primary public health issue pertains to the disparity in alcohol use disorders among adolescents, particularly in relation to social activities like dancing. Young people sometimes confuse ED with illicit stimulants like amphetamines and cannabis.³ Around 12.5 billion USD was the overall value of the US energy drink market in 2012. Not only that, but the market grew substantially, by 56% from 2006 to 2012. Energy drink use in sixteen EU member states was the subject of a 2011 study by the European Food Safety Authority (EFSA). The study revealed that individuals between the ages of 10 and 18 had the greatest reported rate of consumption, with a prevalence of 68%. In comparison, adults over the age of 18 had a consumption rate of 30%, while children under the age of 10 had a rate of 18%. Young individuals in the UK were shown to have a higher use of energy drinks compared to their peers in other European Union nations, with an average of 3.1 liters per month compared to 2.1 liters. The expanding market for caffeinated energy drinks (CEDs) has raised concerns over excessive caffeine use and associated negative consequences, especially among the youth. The use of energy drinks may lead to increased blood pressure, dehydration, irregular heart rhythms, insomnia, and anxiety. Additionally, it can worsen the symptoms of cardiac problems, diabetes, and anxiety disorders, and interact negatively with prescribed medications.⁴

Basic Pharmacology of Caffeine and Other Common Ingredients in Energy Drinks

Caffeine

The caffeine content is a common thread throughout all the various erectile dysfunction drugs. More than sixty varieties of coffee plants, namely the methylxanthine-containing coffea Arabica form, provide caffeine in their uncooked berries. Caffeine may also be found in cocoa, kola nuts, and tea.  Energy drinks are specifically formulated to provide the consumer with an increase in energy levels via a mix of stimulants and substances that enhance energy. Caffeine is the primary component found in the majority of energy drinks. The majority of products available on the market include substantial quantities of glucose, although a few brands provide artificially sweetened alternatives.⁵ The exact safe limits of caffeine consumption have not yet been established. However, available research indicates that the maximum recommended daily intake of caffeine ranges from 2.5 mg/kg/day to 6 mg/kg/day for children, 100 mg/day for adolescents, and up to 400 mg/day for adults. After being consumed, caffeine is quickly absorbed (within 30-60 minutes) from the digestive system.⁶ Caffeine reaches all of the body's tissues rapidly after absorption in the small intestine, which takes around an hour. There is caffeine in every physiological fluid, including saliva and CSF fluid. It is soluble in water and lipids and may easily cross the blood-brain barrier. Caffeine has a stimulating effect on several organ systems in adults. As an example, you may notice an increase in your temperature, heart rate, blood pressure, speech rate, motor activity, alertness, gastric secretion, and urine output. Acute psychosis and rhabdomyolysis may occur in those who consume too much coffee. Deaths caused by coffee poisoning do occur, however rarely. The lethal dose of caffeine in rats was found to be between 200 and 400 mg/kg.⁷ In 2009, an instance of cardiac arrest resulting from the use of energy drinks containing caffeine was documented. The patient's electrocardiograms showed evidence of acute myocardial ischemia, which is most likely due to coronary vasospasm triggered by coffee. The cause of such coronary events is thought to include increased platelet aggregation and reduced endothelial functioning.

Pharmacological And Physiological Effects of Caffeine:

The intestines rapidly and fully absorb caffeine; 99% of it is absorbed within 45 minutes after intake. Oral dosing leads to peak plasma concentrations between 15 to 120 minutes. The primary disparity at now might be attributed to changes in the digestive system and the accessibility of alternative food sources, such as dietary fibre. Inhaling caffeine does not seem to have any immediate impact on the mind. It originates from the first sound judgment and is encountered in a system characterized by a single-chamber open model. It is derived from the first sound judgment and is intriguing due to its utilization of an open-source framework. The biological decay rate of caffeine is 3.5 to 6 hours. Physiological effects manifest within a time frame of less than 1 hour. Infants do not metabolize caffeine, resulting in a half-life of around 4 days.⁸ The liver is the primary location where caffeine is metabolized. Metabolic rates differ across different breeds. The half-life is shorter in individuals who smoke, but longer in pregnant women and women who use oral contraceptives. The cytochrome (CYP) P450 oxidase system is mainly responsible for the metabolism of caffeine. The metabolic process described comprises the enzymatic conversion of caffeine into three dimethylxanthines by the CYP1A2 isoenzyme. These three dimethylxanthines, namely paraxanthine (72%), theobromine (20%), and theophylline (8%), each have distinct effects on the body:

• • • • Paraxanthine: Increases lipolysis and increases plasma glycerol and free fatty acid content.
      • Theobromine: Dilates blood vessels and increases urine output. Theobromine is also an important alkaloid found in cocoa beans
      • Theophylline: Relaxes bronchial smooth muscles and is used in the treatment of asthma. However, the therapeutic effects of theophylline are many times greater than those achieved through caffeine metabolism

The kidneys expel these compounds after further metabolism. Individuals with liver dysfunction have the ability to retain caffeine in their systems, hence extending its half-life. Caffeine functions as an antagonist of adenosine receptors, inhibiting the binding of naturally occurring adenosine to these receptors. Hence, caffeine has the ability to eradicate temporary tiredness, thereby preserving or reinstating wakefulness. Furthermore, coffee seems to amplify the effects of dopamine by counteracting adenosine's inhibitory influence on dopamine receptors. Research indicates that the release of dopamine in the nucleus accumbent shell may serve as a distinct neuropharmacological mechanism for the development of caffeine addiction. The increase in activity of the adenosine system during prolonged caffeine administration seems to be caused by neurochemical processes that contribute to caffeine withdrawal problems. This process leads to heightened functional sensitivity to adenosine in individuals who do not respond to caffeine, and it is believed to have a crucial role in the behavioural and physiological effects caused by caffeine withdrawal.⁹

2. Guarana

Guarana is obtained from the seeds of Paullinia cupana, a plant native to South America that is renowned for its stimulating effects. Guarana is rich in caffeine (4%-8%), theobromine, theophylline, and has a high concentration of tannins. It also includes tiny levels of saponins and flavonoids. Guarana use boosts energy levels, improves physical performance, and facilitates weight reduction. The primary cause of these effects is mostly linked to the elevated levels of caffeine.  Additionally, the caffeine content shown here is on top of the caffeine content for energy drinks. Hence, the caffeine content of the drink could be more than what's listed in the ingredients. In addition, it is absorbed at a slower rate in the gastrointestinal system, resulting in a more prolonged impact compared to caffeine derived from coffee beans. Currently, it is believed that Guarana does not have any negative consequences, other for the possibility of caffeine poisoning.¹⁰

3. Ginseng (Panax ginseng)

Ginseng is a plant extract that is well known for its purported properties as a stimulant and aphrodisiac. Caffeine is included in energy drinks in quantities that are below the average daily consumption, and there have been no documented instances of it posing a risk. Ginseng has several notable drug interactions, which might have clinical ramifications depending on the amount of ginseng ingested and the dose and frequency of the interacting medications. Ginseng poisoning may present with several symptoms including diarrhoea, vaginal bleeding, headache, vertigo, hypertension, rashes, insomnia, irritability, Stevens-Johnson syndrome, and agranulocytosis.5 Some of these symptoms may be linked to contaminants, such as phenylbutazone and aminopyrine, that are used in the manufacturing process.¹¹

4. L-Carnitine

This amino acid plays a crucial part in the β-oxidation pathway of fatty acids. It improves the process of breaking down fat and increases the ability to sustain physical activity. At elevated levels, it may induce symptoms such as nausea, vomiting, stomach discomfort, and diarrhoea. There have been reports indicating that it may increase the frequency of seizures in individuals with a seizure condition.

5. Taurine

Taurine is a naturally occurring compound in humans that has a role in regulating the activity of nerve cells, stabilizing cell membranes, producing bile salts, and removing some foreign substances from the body. The daily consumption of taurine in humans is believed to range from 40 to 400 mg. Certain energy drinks exceed the recommended daily allowance of taurine by almost 10-fold. Taurine, similar to coffee, has a physiological influence on the levels of calcium in muscles, which may lead to vasospasm.

6. Additional ingredients

Supplements that are believed to increase energy, alertness, and cognitive skills are also included, along with amino acids, vitamins, herbs, and others. The quantity of these additional compounds differs substantially across various ED kinds. Some Ed supplements include L-carnitine, inositol, milk thistle, ginkgo biloba (ginkgo), acai berry, L-theanine, and creatine. They have properties that make them bioactive. Few studies have examined the potential interactions between caffeine and the other active ingredients in energy drinks, despite the abundance of literature on the effects of caffeine abuse.¹²

a. B Vitamins and “energy blend”

These components are present in significant quantities, which raises the probability of adverse effects. Energy drinks (EDs) often include a mixture of B vitamins and a "energy blend". The B vitamins included substantial amounts of vitamin B12 (cyanocobalamin), B9 (folic acid), B6 (pyridoxine), and vitamin B3 (niacin), while the enzymes consisted of amylase, protease, cellulase, and lactase.

Folic acid is essential for the creation of DNA, red blood cells, and the development of cells. The National Academy of Sciences recommends that people should not consume more than 1000 μg of folic acid per day. Administration of dosages over 15,000 μg per day may result in gastrointestinal disturbances, sleep disturbances, dermatological responses, and epileptic seizures.

Vitamin B12 has a role in the metabolism of nucleic acids, the production of RBCs and the creation and repair of myelin. Even when consumed in high quantities, it has little harm.

Vitamin B6 plays a crucial role in the metabolism of heme, nucleic acids, lipids, carbohydrates, and amino acids. Toxicity arises from the use of excessive amounts of vitamin B6, often exceeding 500 mg per day.¹³

d. Sugar

A typical component found in most energy drinks is a carbohydrate source, such as glucose, sucrose, maltodextrin, ribose, or fructose. Carbohydrate content in energy drinks ranges from zero to sixty-seven grams per 240 millilitre serving. The normal serving size is twenty-five to thirty grams. The carbohydrate content in the average ED is often greater, ranging from 11% to 12%. Consuming drinks with carbohydrate concentrations over 10% has been shown to slow down the process of emptying the stomach and lead to an increase in gastrointestinal discomfort. According to the American College of Sports Medicine (ACSM), it is recommended to consume 0.7 grams per kilogram of body weight every hour during activity. Moreover, the elevated sugar concentration in caffeinated energy drinks is comparable to that of other carbonated beverages and is recognized to be a factor in obesity and changes to tooth enamel. The majority of EDs often have a pH level that falls within the acidic range, namely between pH 3 and pH 4. Demineralization of enamel is associated with a low pH. Energy drinks (EDs) commonly include citric acid, which has a high erosive effect. This is because it continues to demineralize the enamel even after the pH has been lowered. Consequently, it is important to educate patients about the possible harmful consequences of regularly consuming such drinks.¹⁴

f. Preservatives and synthetic dyes found in energy drinks

Energy drinks include both active ingredients and other chemicals that are added to them to make them last longer and look better.

Perhaps those who are dependent on alcohol seek out highly caffeinated drinks to help them cope with the after-effects of a night out on the town, or maybe the common habit of mixing energy drinks with alcohol is to blame for the association between the two. Hence, it is highly recommended to implement inclusive educational initiatives targeting young individuals, with a specific emphasis on the possible health consequences of EDs, alcohol use, and the concurrent use of both substances. These programs should aim to enhance their capacity to effectively regulate and control their drinking behaviours. Consuming a significant amount of alcohol prolongs the time it takes for caffeine to be eliminated from the body and reduces its rate of elimination.¹⁵ The long-term effects of using alcohol remain uncertain and unrecorded. it is important to note that other factors in the diet may also contribute to calorie intake, including sugary beverages.

1.Endothelial Function: Numerous well-designed studies have demonstrated that vascular endothelial function in healthy young adults is temporarily impaired when resting, but returns to normal after a few hours of exposure to caffeine and other energy drink components (typically consumed in less than 5 minutes). A measure of the health of the blood vessels is endothelial function. Chronic inflammation, reduced vascular reactivity, increased thrombosis, poor adhesion, and vasoconstriction are all symptoms of abnormal endothelial cell function, sometimes referred to as "endothelial dysfunction," which also speeds up the course of illness. The short-term effects of alcohol on endothelial function show a decline, while the long-term implications of alcohol use are poorly understood.¹⁶

2.Hemodynamics: Norepinephrine levels increased by 74% in a following investigation of alcohol-consuming young people. An increase in blood flow to skeletal muscles, an acceleration of the heart rate, and a rise in blood pressure are all effects of norepinephrine. The majority of healthy individuals usually experience an increase in systolic blood pressure of 6 to 10 mmHg, diastolic blood pressure of 3 to 6 mmHg, and mean arterial pressure of 3 to 7 mmHg within 1 to 2 hours after ingesting alcohol. Add up all the times. If you're already dealing with heart issues, this change might be quite concerning. Keep in mind that drinking too much caffeine (from soda, tea, coffee, or energy drinks) might cause your blood pressure and heart rate to increase.¹⁷

3.Electrocardiographic Abnormalities and Dysrhythmias: The corrected QT (QTc) interval in healthy individuals increases by 22 to 25 ms even 1 to 2 hours after alcohol use. Even in otherwise healthy people, alcohol use may cause supraventricular arrhythmias, most notably atrial fibrillation. Even healthy people who drink a lot of energy drinks quickly might develop arrhythmias in their ventricles, such as ventricular tachycardia or ventricular fibrillation. According to reports, sudden cardiac death is mostly attributed to energy expenditure, particularly during physical activity. It is important to consider that in many situations, there are factors that might complicate the analysis, such as the presence of other cardiovascular issues (such as drug or alcohol use), hereditary factors, and intense physical activity. As a result, it is not possible to solely assign a cause-and-effect link to alcohol intake alone. Nevertheless, instances of abrupt mortality in young, fit individuals without any apparent connection to alcohol use have been documented.¹⁸

4.Gastrointestinal: According to reports from the emergency department, around 6% of patients who consume alcohol have gastrointestinal upset, which may disrupt the vomiting effects of caffeine. Reports indicate that two patients, who were considered to have liver illness, experienced the development of liver disease and jaundice as a result of consuming large quantities of alcohol. It is worth noting that one of the patients had previously had a liver transplantation procedure.

5.Renal: Energy drinks intake has been linked to the development of chronic renal failure, rhabdomyolysis, and metabolic acidosis. Consuming highly caffeinated drinks may significantly impact renal function. Caffeine, the primary component in these beverages, acts as a diuretic, which results in an increased output of urine. The diuretic action of this substance results in increased fluid excretion from the body, potentially causing dehydration if insufficient fluid intake occurs. Dehydration exerts strain on the kidneys and may result in renal complications.  Furthermore, many energy drinks are abundant in sugar and other ingredients. Excessive consumption of sugar may result in obesity and metabolic syndrome, both of which are linked to kidney damage. In addition, several additives included in the beverage, such as taurine and guarana, have also been associated with renal failure.^19,20

6.Psychiatric: Psychiatric illnesses have been documented as a consequence of using alcoholic drinks. Adolescents and young adults who use alcohol are at a higher risk of developing anxiety, irritability, depression, and insomnia compared to those who consume caffeine. Furthermore, individuals who consume alcohol are more prone to participating in hazardous activities, such as reckless driving (e.g. exceeding speed limits and neglecting to wear a seatbelt), engaging in risky sexual behaviour, smoking, using marijuana, experimenting with psychedelic drugs, using cocaine, engaging in excessive alcohol consumption, using other illegal substances, combining alcohol with other substances, and neglecting to take prescribed stimulant medications. The use of energy drinks has the ability to trigger the onset of other types of drug dependency. Mixing alcohol with energy drinks is common, and when compared to other drinkers, teens who do this consume more alcohol and act more disruptively.²¹

7. Neurological:  Symptoms of caffeine intoxication often manifest when individuals consume dosages equal to or above 200 mg. The symptoms include anxiety, sleeplessness, gastrointestinal disturbance, muscular spasms, restlessness, and episodes of unflagging energy. Furthermore, consuming high amounts of caffeine is linked to both acute and chronic daily headaches due to its potential to stimulate a state of cortical hyperexcitability that promotes pain sensitivity.  An study including individuals aged 15 to 16 years revealed a robust association between the use of caffeine and both aggressive behaviour and conduct issues. Multiple data indicate that energy drinks may be a contributing factor to the occurrence of ischemic stroke and the development of epileptic seizures. Individuals who use more than 300 mg of caffeine per day may have hallucinations. The elevated amounts of cortisol that occur after consuming coffee may account for this phenomenon. Cortisol amplifies the physiological impacts of stress, leading to an increased inclination for individuals to have hallucinations.²² Multiple case reports and research conducted by the National Poison Data System have shown negative neurological consequences linked to the excessive intake of energy drinks. These conditions include epileptic seizures, reversible cerebral vasoconstriction, and intracerebral bleeding.

Effects Of Caffeine on The Central Nervous System: 

The primary and evident impact of caffeine is heightened wakefulness. At higher doses, it activates the CNS, first with the cortex and then the medulla, before finally stimulating the spinal cord. The effects of this substance begin within one hour and last for a duration of three to four hours. Indeed, a little level of cortical stimulation is beneficial for enhancing clarity and critical thinking. Multiple studies have shown a correlation between the ingestion of caffeine and heightened levels of wakefulness, particularly during nighttime driving. The effects of caffeine become apparent within 1 hour and last for a duration of 3 to 4 hours. Research indicates a correlation between caffeine use and a reduced likelihood of developing several neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease.^23,24 Side effects may be caused by consuming about 150 to 250 mg of caffeine, which is equivalent to drinking 1 to 2 cups of coffee. Nevertheless, the correlation between coffee use and brain injury remains ambiguous. Excessive use of caffeine might lead to the development of headaches. Abruptly discontinuing the use of caffeine might result in the onset of a headache. Caffeine is used in several over-the-counter (OTC) drugs as well as migraine and headache remedies. An excessive amount of caffeine may lead to hyperesthesia, restlessness, and other symptoms. A similar scenario might be seen when there is an excessive intake of caffeine. Symptoms of a caffeine overdose include confusion and hallucinations. In addition, an excessive dosage might lead to fatality due to seizures.

Neurodegenerative Diseases:

• Neurodegenerative illnesses refer to a diverse range of issues that affect the development and functioning of the central or peripheral nervous system. The functioning of neurons, synapses, glial cells, and their interconnected systems is impacted. Typically, the presence of abnormal proteins or their deposits outside of cells (known as plaques) in neurons and glial cells in the brain and spinal cord indicates harm to the human brain. The classification of neurodegenerative illnesses is determined based on several factors, including symptoms, the specific area of the brain affected, the impact on different types of cells, alterations in proteins, and the underlying cause. Individuals afflicted with these conditions have movement abnormalities, such as excessive or reduced movement, impaired functioning of the cerebellum, and difficulties with both upper and lower body movements. Additionally, they may also suffer from cognitive deterioration, dementia, and heightened challenges in mental decision-making.  The brain regions that are impacted exhibit indications of atrophy and/or impairments in metabolic activity.^25,26
• Neurological and psychological problems affect millions of individuals globally. Annually, stroke claims the lives of about six million individuals, while dementia afflicts 7.7 million new instances.
• Stroke: Stroke is a pathological condition characterized by the development of anomalies in the blood arteries that provide blood to the brain. This leads to abrupt malfunction in certain areas of the brain, resulting in different neurological impairments such as impaired awareness, paralysis on one side of the body, and/or speech difficulties.

• Ischemic Stroke: Approximately 13-15 million individuals globally have a stroke annually, resulting in the death of over 5 million individuals. Ischemic strokes account for about 85% of all strokes. An ischemic stroke is characterized by a reduction in cerebral blood flow. It may occur as a consequence of thrombotic or embolic occurrences. On the other hand, in embolic events, blood flow is obstructed because of a clot that has traveled from another location and is now blocking the blood vessels. It exerts its effects across the whole body, primarily targeting the heart and cerebrovascular system. Various forms of ischemic stroke may be identified based on the affected artery, such as middle cerebral artery infarction, anterior cerebral artery infarction, vertebrobasilar infarction, cerebellar infarction, and lacunar infarction. Consequently, the therapy for a specific ischemic stroke varies based on the region of the brain that the damaged artery serves. Brain necrosis in the damaged region leads to visual impairments in motor skills and cognition. Common symptoms include facial, lingual, or muscular weakness, speech difficulties, vision impairment.²⁷

• Parkinson’s Disease:  Parkinson's disease is a progressive and degenerative condition that impacts over 6 million individuals globally. The condition presents with both motor and non-motor symptoms. Physical manifestations include restlessness, often affecting one side of the limbs but sometimes including the head, mouth, and tongue as well. Other symptoms include bradykinesia, postural instability, and stiffness. Self-mobility diminishes, facial expression fades, blinking frequency reduces, thirst is unpleasant and leads to asphyxiation. In addition, there are limitations on the range of motion of the hand, as well as on the time it takes for the hand to cool down and transition between different movements. Individuals afflicted with Parkinson's disease may undergo episodes of excessive eating or social isolation.²⁸

Cardiovascular Effect:

Various studies have shown an increase in heart rate and arterial blood pressure after the use of energy beverages. The observed findings were attributed to the ergogenic effects of the caffeine included in the energy drink. Moreover, the excessive use of energy drinks has been shown to induce significant cardiac symptoms, such as ventricular arrhythmias, ST segment elevation, and QT prolongation. Furthermore, two robust adolescent males, aged 14 and 16, had atrial fibrillation after the use of high-energy drinks. Energy drink usage has recently been associated with myocardial infarction in adolescent males aged 17 and 19 who are in good health. Research has shown that the use of energy drinks has negative effects on endothelial function and promotes platelet activity by causing platelet aggregation via the action of arachidonic acid in healthy young people. Recent findings have shown a connection between excessive intake of energy drinks and the widening of arteries, the development of aneurysms, as well as the tearing and bursting of big arteries.^29-32

Table-2- Effect Of Energy Drinks on Various Organs