Nova Biotechnol Chim (2023) 22(1): e1344 DOI: 10.34135/nbc.1344 1 Nova Biotechnologica et Chimica Review Health risks associated with the chronic consumption of energy drinks in children and adolescents Katlego Sharon Mphahlele1, Nosiphiwe Patience Ngqwala1, Oscar Agbor Ambang1, C. Sunitha Srinivas1 and Roman Tandlich1,2, 1 Faculty of Pharmacy, Rhodes University, Grahamstown 6140, South Africa 2 Faculty of Health Sciences, Technical University of Liberec, Studentská 2, Liberec 46117, Czech Republic  Corresponding author: r.tandlich@ru.ac.za Article info Article history: Received: 2nd January 2022 Accepted: 30th September 2022 Keywords: Adverse effects Advertising Alcohol Caffeine Regulations Taurine Abstract Energy drinks (EDs) have been available at the global market for almost 100 years and today, they are advertised as ’tools’ boost energy, enhance physical performance and mental alertness. Some of the main chemical components in EDs include caffeine, ginseng, and taurine. The market and consumption of these beverages is growing exponentially, and this is becoming a public health problem due to the adverse effects associated with these drinks. The main objective of this article is to review important ingredients in popular EDs in South Africa and look at their molecular mechanisms of action and interaction with other compounds within the body. At the same time, the authors aim to review the global consumption pattern of EDs among children and adolescents. Finally, this review article will provide an overview the health risks associated with EDs consumption. A literature review was conducted using scholarly databases. Keywords such as energy drinks, adverse effects, advertising, alcohol, caffeine, taurine, and regulations were used. Despite the claims of having significant benefits to mental and physical stamina, long-term consumption of EDs could have detrimental public health implications; and could result in increasing rates of the central nervous system disorders and the cardiovascular complications. A knowledge gap exists on how the lack of education impacts the decision of consumers of EDs and the parental guidance provided to children and adolescents in relation to the consumption of these beverages in South Africa. To address the issue of excessive ED consumption, communities need to be made aware of the harmful effects of these beverages through health education and implementing strict regulatory measures through policy. © University of SS. Cyril and Methodius in Trnava Introduction Energy drinks (EDs) have been available at the global market for almost 100 years and today, they are advertised as ’tools’ boost energy, enhance physical performance and mental alertness. According to several reports, EDs are one of the most popular supplement commodities in the United States second only multivitamins (Froiland et al. 2004; Hoffman 2010; Campbell et al. 2013). EDs have not only appealed to the adult population but to children and adolescents too, as we have seen an increase in the consumption rate within these population groups. In 2015 and focusing on mailto:r.tandlich@ru.ac.za.sk Nova Biotechnol Chim (2023) 22(1): e1344 2 the patterns of the ED consumption, the European Food Safety Authority commissioned survey-based research in 16 of the EU countries (European Food Safety Authority 2015). Among the adult population and the adolescent age groups (10 – 18 years old), as well as in the below-ten-year-old children, the results indicated that (< 10 years old) demographic 30 % of adults, 68 % of adolescents and 18 % of children were consuming EDs (European Food Safety Authority 2015). Correlating results were observed in a survey study conducted in 43 high schools in Ontario, which revealed that in a student population of 23,610; 73.6 % were reported to be consumers of EDs (Reid et al. 2015). In the recent years, novel findings have been published in scientific literature on the ED consumption and the related health effects. Some of the most concerning, and potentially damaging public health ones, include the increased probability and risks from childhood obesity, the increased probability in the rise of early onset cardiovascular pathophysiological conditions, suicidal ideation, and tendency, as well as impaired cognitive function in children (Usman and Jawaid 2012; Kammerer et al. 2014; Park et al. 2016). In addition to these health risks, aggressive behaviour and mood disorders were reported in a study and linked to caffeine consumption in 15 – 16 years olds (Soós et al. 2021). Due to their potential effect of enhancing physical performance, EDs have become increasingly appealing and popular to sport athletes. The distinction between EDs and sports drinks (SD) must be noted and clearly defined. EDs and SDs are two different types of supplement beverages with their own specific performance enhancement claims and nutritional compositions. SDs are targeted at individuals who play sports (athletes) or engage in high-performance activities. Their aim is to provide hydration and electrolyte replenishment to the body with the intent to support it during a high-performance activity (Campbell et al. 2013). Carbohydrates are one of the molecules found in both EDs and SDs in different estimated quantities of around 12 g and 3 g respectively, this compound is the body’s primary source of energy. EDs commonly contain caffeine as the main active ingredient, along with other ingredients such as ginseng, B vitamins, taurine, sugar, guarana, carnitine, green tea extracts and ginkgo biloba, which all have significant physiological effects on the body (Heckman et al. 2010). The observed exponential growth of ED consumption has become a great health concern towards nutrition and dietary inadequacies; some of the factors promoting this growth is the rise of the food processing industry, targeted advertising, and the absence of independent regulatory bodies (Higgins et al. 2010). EDs entered the mainstream beverage industry first in the early 1960s and since then have grown exponentially into a multi-billion-dollar industry. Bailey et al. (2014) carried out a study, using data from 160 countries, which showed that the annual consumption of EDs was greater than 5.8 billion litres. In the United States alone, sales in 2015 were reported to be $13.4 billion, with the major ED companies at the helm of the market in terms of sales and advertising (Richter 2014). The aggressive growth of the EDs market is fuelled by advertising. One of the marketing strategies used to gain massive exposure is through providing financial support to well-known sports teams and sponsoring major events, such as sports competitions and music festivals as (MacKnight 2020; Erdmann et al. 2021). The regulation of EDs, including health information and content labelling is different across countries and the absence of strict and consistent regulatory principles fuels the aggressive marketing of these beverages (Higgins et al. 2010). A knowledge gap exists on how the lack of education impacts the decision of consumers of EDs and the parental guidance provided to children and adolescents in relation to the consumption of these beverages in South Africa. This review article seeks to highlight the health risks associated with the chronic consumption of EDs in children and adolescents. Furthermore, interventions that can address and reduce the excessive consumption of these beverages will be discussed. Experimental A systematic literature review was conducted using the following databases: Cochrane Library, EBSCO host, Google Scholar, PubMed, Scopus, and ScienceDirect to search for relevant literature Nova Biotechnol Chim (2023) 22(1): e1344 3 published from 1980 to 2022. Only 9 publications were selected before the year 2005, 6 publications were selected between the year 2005 and 2009, the rest of the publications are from 2010 to 2022. We did not exclude articles based upon a date of publication due to lack of scientific research and literature in this area. Keywords such as adverse effects, advertising, alcohol, caffeine, taurine, and regulations were used. Furthermore, five different EDs were bought, together with Cola drink 1 and Cola drink 2. The ingredients of these beverages as shown on the packaging labels were analysed and compared, particularly looking at the amounts of caffeine, taurine, and sucrose in each of them. Using Google search, we looked at the quantity of caffeine found in brewed coffee, expresso, decaf coffee, ice tea, and green tea. Results and Discussion EDs are a rapidly growing market globally. They are popular among children, adolescents, and young adults. Various drinks were analysed based on their labelled content; the emphasis was particularly placed on the amount of caffeine, taurine, and sugar in each of them. Table 1. A list of popular energy drinks in South Africa with the main ingredients (based on label analysis). Energy Drinks & Soft Drinks Caffeine content [mg.100 mL-1] Taurine concentration [%] Sugar content [g.100 mL-1] 1. ED brand 1 32 Not stated 6.0 2. ED brand 2 26 Not stated 3.5 3. ED brand 3 32 0.4 11 (sucrose) 4. ED brand 4 30 0.4 3.7 5. ED brand 5 32 0.4 Sugar free (contains sucralose) 6. Cola drink 1 34 0 10.6 7. Cola drink 2 37.6 0 40 Table 1. above shows some of the popular EDs consumed in South Africa which are namely ED brand 1, ED brand 2, ED brand 3, ED brand 4, and ED brand 5. ED brands 1 and 2 are locally produced and owned. The average caffeine content of the listed EDs is 32 mg.100 mL-1. An interesting observation made from the table is that the quantity of caffeine in Cola drinks 1 and 2 which are 34 mg.100 mL-1and 37.6 mg.100 mL-1 respectively. This is greater than that of the EDs. The sugar content varies between the EDs and Colas, with Cola drink 2 containing more sugar (40 g.100.mL-1) than any one of the beverages. Perhaps more research is needed to investigate the impacts of cola in comparison with those of EDs, particularly looking at their caffeine content and the composition with other included ingredients. All the listed EDs have taurine concentration of 0.4 %, except of ED brand 1 having zero taurine content. Recently, ED brand 1 launched a new ED flavour which includes wormwood extracts as one of the ingredients. Wormwood, scientifically called Artemisia absinthium L., is known to have “anti- bacterial, anti-oxidant, anti-malarial, anti- inflammatory, anti-depressant and hepatoprotective pharmacological activities amongst others” (Ahamad et al. 2019; Batiha et al. 2020). The long- term use of wormwood has been reported to cause neurotoxic effects and mental disorder called “absinthism”. These psychoactive and neurotoxic effects are due to the high concentrations of thujone which is a chemical substance found in A. absinthium and is known to be an antagonist of gamma-aminobutyric acid-a (GABAA) receptor (Lachenmeier 2010; Batiha et al. 2020). The impacts of A. absinthium, particularly thujone in combination with caffeine and other chemical substances found in EDs still needs to be investigated. Table 2. A list of different coffee and tea with their caffeine content. Coffee and Tea (4-ounce) Caffeine [mg] 1. Brewed coffee 45.4 2. Expresso 240.4 3. Decaf - coffee 0.0 – 3.0 4. Iced Tea 12.5 5. Green Tea 9.0 Nova Biotechnol Chim (2023) 22(1): e1344 2 Table 2. A list of different coffee and tea with their caffeine contentabove shows the different caffeine quantities that were measured in coffee and tea that have been reported in literature. The concentrations of caffeine in brewed coffee and expresso are higher in values vs. the concentrations in EDs listed in Table 1. Brewed coffee and expresso are made from coffee beans which contain caffeine, tannin, proteins, lipids, and carbohydrates (Sharma 2020). Although EDs and coffee/expresso contain a similar compound “caffeine” as the main ingredient, what sets them apart are the added ingredients, which exhibit different mechanisms and effects in the body. Tea contains four substances known to have a stimulating effect on the brain, which are caffeine, theophylline, theobromine, and L-theanine. Like caffeine, theophylline and theobromine belong to a class of xanthines, and they both have physiological effects. However, the amounts found in a cup of tea are so small that the impact on the body can be considered negligible (Gunnars 2022). According to the 2012 guidelines issued by the UK’s Children Food Trust, it was recommended that children should avoid the consumption of food or drinks that contain caffeine, such as tea, coffee, cola, and other drinks (Children’s Food Trust 2012). Review of biochemical mechanism of action of the main ED ingredients Caffeine Caffeine is an alkaloid compound of the methylxanthine class, with its pharmacological mechanism of action including stimulation of the central nervous system (CNS) (Petre 2020). This class of drug is used clinically as a CNS stimulant, diuretic, bronchodilator, and cardiotonic. There is some evidence in biochemical and pharmacological literature that xanthines block or antagonize adenosine receptors in the human body (Bruns et al. 1980). Adenosine is a neurotransmitter that causes the brain to relax which decreases the nerve cell activity and leads to drowsiness and tiredness (Petre 2020). The formation of adenosine depends on the rate of ATP synthesis and breakdown (Bruns et al. 1980). Caffeine and adenosine have a similar molecular structure (Fig. 1), and therefore, the nerve cell recognizes caffeine as adenosine. The resulting binding causes the caffeine molecule to serve as an antagonist to the pharmacological activity of adenosine, which in turn leads to speeding up the nerve cell activity. The intracellular concentration of adenosine molecules rises as a consequence of the blockade of the receptors, thus activates noradrenaline neurons. The pituitary gland detects the cell activity and releases hormones that will activate the adrenal gland and therefore produce catecholamines (Brain et al. 2007). Caffeine blocks the activity of adenosine to open the brain’s blood vessels, which leads to constriction and decrease in cerebral blood flow (Nehlig et al. 1992). Therefore, some headache medicines contain a combination of aspirin and caffeine. (Brain et al. 2007). An experimental study conducted by Conlay et al. (1997) showed how caffeine can change the adenosine plasma level in rats that were exposed to 0.1 % caffeine. Their adenosine plasma concentration increased from 0.32 ± 0.5 μM to 3.17 ± 0.30 μM when compared to the control group. Fig. 1. Chemical structures of caffeine and adenosine illustrating the similarity of their molecular structure. Generated using Chemdraw software application. Experimental studies have demonstrated that caffeine consumption influences the cardiovascular system in that it acutely increases blood pressure, circulating concentrations of noradrenaline, inhibits ischemic preconditioning and impairs endothelium dependent vasodilation (Nawrot et al. 2003; Riksen et al. 2009; Turnbull et al. 2017). A high intake of EDs can make the veins firm which will contribute to heart disease. The commonly reported conditions are heart palpitations, increased heart rate, 4 Nova Biotechnol Chim (2023) 22(1): e1344 3 hypertension, chest pain, and dysrhythmias (Turnbull et al. 2017). An experimental research study found an association between myocardial infarction and ED consumption in healthy 17- and 19-year-old boys (Rath 2012). Molecules of caffeine function as inhibitors of the adenosine receptors, which results in the enhancement of angiotensin II, epinephrine, and catecholamines. The increased production of angiotensin causes the rise in systolic blood pressure, whilst the increased level of catecholamines, particularly epinephrine elevates the heart rate. The study conducted by Alsunni (2015) showed that there is generally an increase in the heart rate and the blood pressure in human arteries once a patient has consumed a caffeinated drink. This is linked to the above mechanisms. Moreover, caffeine acts as a weak non-selective phosphodiesterase (PDE) inhibitor, whereas the cyclic-AMP (cAMP) is catalysed by the cAMP- dependent phosphodiesterase (PDE3) and this process leads to the change in concentration of cAMP inside the cell. The inhibition of this enzyme leads to the increase of cAMP concentration inside the cell, and this results in the increase of cardiac inotropy, chronotropy, and dromotropy (Klabunde et al. 2020). Caffeine is rapidly absorbed in the gut, reaching nearly 100 % bioavailability in the body and peak plasma concentration within 30 – 120 min. It is metabolized largely by cytochrome P-450 and specifically by the CYP 1A2 isozyme (Babu et al. 2008). The major metabolites of caffeine are 3,7-dimethylxanthine (systematic name), which is trivially known as theobromine, and 1,3-dimethylxanthine (systematic name), which is trivially known as theophylline. Both compounds/metabolites complement the pharmacological effect of caffeine, while also being biologically active in the human body in their own right (Chen et al. 2017). Caffeine elimination follows non-linear pharmacokinetics that is based on the Michaelis-Menten kinetics equation. The caffeine half-life falls inside the interval from 3 to 6 h (Babu et al. 2008). Taurine Taurine has the systematic chemical name of 2-aminoethane-sulphonic acid (C2H7NO3S). It is a β-amino acid, and its concentration is high in the heart and the skeletal muscles, as well as in other tissues, with the normal plasma concentration of 44 ± 8 μmol.L-1. Although it falls under the group of amino acids, it does not take part in the formation of proteins (Schaffer et al. 2010). Taurine is a by-product of cysteine and methionine. It contains a sulfonate group and not a carboxyl group. This is how it differs from other amino acids hence it is considered as an amino sulfonic acid. The main route of taurine biosynthesis is illustrated below in Fig. 2 (Vitvitsky et al. 2011). In that figure, the molecule of the amino acid cysteine is converted into cysteinesulfinate by the action of cysteine dioxygenase. The next step in the pathway is catalysed by the cysteinesulfinic acid decarboxylase, with the reactant being cysteine sulfonate and the product being hypotaurine (Vitvitsky et al. 2011). As a result of this enzymatic reaction sequence, the final step occurs when hypotaurine undergoes oxidation to form taurine (Vitvitsky et al. 2011). When it comes to additional biochemical effects in the human body, taurine is an organic osmolyte that regulates cell volume and is involved in modulating free calcium concentration inside the cell. This amino sulfonic acid is found throughout the body but does not form components of proteins. It is found mostly in the pupil, heart, brain, retina, muscle tissue, and the heart (Ripps et al. 2012). Taurine has an influence on the homeostasis of calcium within the cell through the pathway of Na+/Ca2+ exchanger. It decreases glutamate- induced [Ca2+]i accumulation in the cells by preventing the intracellular uptake of Ca2+ and the molecular mechanism of this is the reverse mode of the Na+/Ca2+ exchanger (Wu and Prentice 2010). Literature suggests that taurine also influences the metabolism of energy in cardiac tissue and its deficiency leads to an impairment of the respiratory chain (Schaffer et al. 2016). Fig. 2 above outlines the main steps of how taurine is formed: 1) Cysteine is catalyzed by the enzyme cysteine dioxygenase and oxidized into cysteine sulfinate; 2) Cysteinesulfinate decarboxylase 5 Nova Biotechnol Chim (2023) 22(1): e1344 2 catalyzes cysteine sulfinate to form hypotaurine; 3) Hypotaurine is oxidized to taurine, catalyzed by hypotaurine dehydrogenase. There can be another branch of hypotaurine synthesis, in which cysteamine is converted to hypotaurine by the ADO enzyme activity (Vitvitsky et al. 2011). Fig. 2. A diagram illustrating the biosynthesis of Taurine. Generated using Chemdraw software application (based on the article by Vitvitsky et al., 2011). In addition, taurine has a molecular structure similar to gamma-aminobutyric acid (GABA) illustrated in Fig. 3, and binds to GABA receptors where it potentiates GABA-ergic effects in the body (Reyes-Haro et al. 2014). Usually, when drugs interact with the GABA receptor, they potentiate an anxiolytic effect, therefore it is possible that taurine may have the same effect as well. Dombovy-Johnson (2010) suggests that when taurine is combined with caffeine it may increase caffeine stimulant activity by interacting synergistically. This finding is supported by research done on the sleep-wake activity of the combination of taurine and caffeine on Drosophila melanogaster, a species of fruit fly. The results have shown that caffeine increases locomotive activity and decreases sleep duration, whereas taurine decreases locomotive activity and increases sleep time. When taurine was added to caffeine it resulted in an inhibition of sleep with a greater effect than when caffeine was administered alone (Lin 2010). This could be a result of the fact that taurine is known to influence the metabolism of energy. Literature suggests that taurine deficiency- mediated defects lead to a reduction in ATP generation by impairing energy metabolism (Schaffer et al. 2016). Therefore, when the ratio of NADH(+H+)/NAD+ is elevated, the resulting action leads to the inhibition of key dehydrogenases such as those in the Kreb’s cycle and they include “α-ketoglutarate dehydrogenase, isocitrate dehydrogenase and citrate synthase” (Schaffer and Kim 2018). Fig. 3. Chemical structures of GABA and Taurine illustrating similar molecular structure. Generated using Chemdraw software application. Cuttitta et al. (2013) investigated the role of taurine in the cardiovascular system. In the study, GABA was identified as the major inhibitory neurotransmitter responsible for the regulation of the heart. This neurotransmitter is found in the peripheral tissues as well as the CNS. The study was conducted on rabbits, and it was reported that GABA can suppress the release of noradrenaline which may lead to the regulation of vascular tone (Schaffer and Kim 2018). The selective permeability of the blood brain barrier restricts this inhibitory neurotransmitter from penetrating. 1 2 3 6 Nova Biotechnol Chim (2023) 22(1): e1344 3 Alternatively, taurine has more permeability than GABA, therefore there is no concentration change in the brain following IV administration of GABA. The study also indicated that IV administration of taurine exhibited a significant decrease in systolic blood pressure in an experiment that was performed on conscious adult rats. Furthermore, it has been proven using an aortic ring preparation that taurine can act as a vasodilator. Taurine as a neuromodulator protects the CNS and reduces seizure episodes by agonizing the GABAA receptors which are found on the muscularis of the cerebral blood vessels and the aorta (Cuttitta et al. 2013). There are similar reports that have been published by Chan et al. (2013) and L’Amoreaux et al. (2010) in recent years. In Japan, taurine has been approved to treat congestive heart failure. The chronic administration of taurine reduces the action of noradrenaline and angiotensin II, which decreases myocardial performance. Taurine can decrease catecholamine overflow through the alteration in Ca2+ transport, thus leading to the reduction of noradrenaline activity (Schaffer and Kim 2018). The therapeutic window period of taurine is at least 8 hours. This was proven in a study conducted by Sun et al. (2012) on experimental stroke in rats however, data is still lacking on the oral administration of taurine in humans. The NH2 group in the covalent structure of taurine can undergo the Maillard-type reactions (Elzoghby et al. 2015). Carbonyl groups are found in many primary metabolites in the human body and examples of those molecules include glucopyranose and CH3COH. Furthermore, it has been illustrated that taurine-glucose reaction results in an antioxidant effect and there is a likelihood of hindering taurine effect against protein modification when it reacts with acetaldehyde (Ogasawara et al. 1994). Carbohydrates Carbohydrates or sugars [Cn(H2O)n] are molecular compounds that are the major source of metabolic energy in humans and mammals. The carbohydrate content of the human diet is usually derived from fructose corn syrup, glucose, and sucrose (Alsunni 2015). Lactose can also play a role here. As listed on the packaging labels, most EDs contain sugar in the form of sucrose. The World Health Organization (WHO) has decreased the suggested amount of sugar that should be taken daily from 10 % to 5%, this is about 25 g of sugar per day. The sugar content in the EDs falls within the recommended amount. The consumption of high sugar content for a long period is a risk factor for obesity which subsequently leads to diabetes. There is a strong link between the Body Mass Index (BMI), diabetes and insulin resistance. In obese individuals, the building-up of insulin resistance is influenced by the increase in quantity of free fatty acids, cytokines, hormones, and other substances involved in the development of insulin resistance (Al-Goblan et al. 2014). An in vivo study that was performed on rodents showed that a high chronic consumption of fructose will result in obesity, high blood pressure, type 2 diabetes, hepatic and extrahepatic insulin resistance. In addition, the high intake of fructose can cause dyslipidemia and impair hepatic insulin sensitivity (Tappy and Lê 2010). Therefore, the high usage of EDs is an attribute that elevates the chances of developing type 2 diabetes and obesity (Alsunni 2015). Although the summary molecular formulas of fructose and glucose are the same (C6H12O6), their metabolism and absorption pathways have some differences. Fructose absorption takes place in the gut via the GLUT-5 transporter facilitated diffusion (Goran et al. 2013), whereas glucose absorption is mediated by the SGLT1 co-transport mechanism. Scientific reports in the literature have indicated that molecules of fructofuranose, does not trigger the secretion of insulin and leptin hormones (Bray et al. 2004) instead, it is believed that it directly adds to weight gain and increases energy intake (Goran et al. 2013). Ragsdale et al. (2010) conducted a study which reported that there is an increase in blood sugar level after the consumption of EDs; and this can be explained by the study performed by Lee et al. (2005) which demonstrated that caffeine consumption leads to decrease in insulin sensitivity. Alcohol and energy drinks The trend of mixing EDs with alcohol is no longer seen as an abnormality, but more of a common 7 Nova Biotechnol Chim (2023) 22(1): e1344 2 practice. Both alcohol and EDs have a diuretic and dehydrating effect therefore, they may decrease the body’s capability to metabolize alcohol (Ferré and O’Brien 2011). Caffeine and alcohol combinations The underlying molecular mechanism of the interaction between alcohol and caffeine is unknown however, it is known that both can alter the neurotransmission of adenosine. In a review carried out by Ferré and O’Brien (2011) it is suggested that during alcohol consumption, caffeine blocks the adenosine Al receptors and thus opposes the undesirable effects of alcohol. In addition, the interaction of dopamine D2 and adenosine A2A receptors can increase the effect of alcohol-induced dopamine release, and this can occur through the blockade of adenosine A2A receptors by caffeine. Li et al. (2014) demonstrated that some EDs can increase or decrease the activity of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). The degradation happens when alcohol is ingested and broken down into acetaldehyde (toxic compound) by alcohol dehydrogenase and further metabolized to acetate (less active by-product) by aldehyde dehydrogenase (U.S. Department of Health & Human Services 2007). An increase in the activity of these enzymes results in rapid metabolization of ethanol or acetaldehyde (Li et al. 2014). Another study by Wang et al. (2016) selected 20 ED beverages to assess their effect on ethanol and acetaldehyde levels in the blood; literature supporting this study suggests that EDs increase the activity of alcohol dehydrogenase, leading to the increased toxic effects of alcohol in the body. Similar findings were reported by Rutledge et al. (2012). These cases highlight the dangers of mixing alcohol with EDs. The effects of carbon dioxide on alcohol absorption There is evidence suggesting that carbonation, or addition of CO2 to EDs, may increase the alcohol absorption rate, which will overall lead to toxicity (Attila and Çakir 2011; Velazquez et al. 2012). It has been hypothesized that the gas released into the gastric lumen by carbonated beverages causes distension of the stomach, which ultimately elevates the rates of gastric emptying. This is believed to have effects on alcohol absorption rates (Roberts and Robinson 2007). There have been many speculations on carbonation and its effect on alcohol absorption rate therefore, further research needs to be conducted in this aspect of study. The effects of carbon dioxide on the mucosal blood flow were looked at in a study conducted by Siński et al. (2003) whereby the research was investigating if the gastric mucosal blood flow (GMBF) can be influenced by the stimulation of the central chemoreceptors in rats. The experiment was conducted in a hypercapnic-hyperoxic atmosphere with the following chemical components in it and with the following volume fractions present (%, v/v): CO2 (10 %), N2 (40 %), and O2 (50 %). The application of this gas mixture resulted in the activation of the central chemoreceptors which in turn resulted in the decrease of the GMBF. Findings from another research study by Sherwood et al. (2015) supported Dean’s theory of gastric CO2 ventilation and proved the hypothesis that, hypercapnia stimulates gastric CO2 production and ventilation, thus rendering the “gastroesophageal dysfunction”. Health risks associated with chronic consumption of energy drinks among youth Central nervous system effects Despite having significant benefits for mental and physical stamina of some or all the above- mentioned ED components, chronic consumption can be potentially dangerous to the CNS. Caffeinism is a pathophysiological condition which results from consuming excessive amount of caffeine of extended periods for time i.e., it is a medical condition which results from chronic abuse of caffeine by an individual. The condition presents itself in the CNS and periphery in the form of anxiety, psychomotor alterations, sleep disturbances, mood disturbances, and the like. Research has shown that abstaining from caffeine causes withdrawal syndrome as a result of prior over-consumption and dependence on the 8 Nova Biotechnol Chim (2023) 22(1): e1344 3 substance. The withdrawal symptoms include headaches, nausea, vomiting, diarrhea, facial flushes, muscle twitching, restlessness, and cardiac arrhythmias. At the same time, caffeinism can only be clinically diagnosed with blood tests. These symptoms can present themselves as quickly as 24 h from prior ingestion however, it has been reported that reintroducing caffeine into the body alleviates these symptoms within an hour of consumption (Doering et al. 2017). A long-term solution may be to gradually wear off caffeine until the individual is no longer dependent on it, or alternatively switch to a caffeine-free product. If an individual consumes a caffeine dose equal to or above 200 mg, they may develop the symptoms of caffeine toxicity (Alsunni 2015). The most common CNS side effects reported include anxiety, tremors, confusion, irritability, psychosis, agitation, seizures, and altered mental status (Rath 2012; Alsunni 2015). In addition, excessive chronic consumption of caffeine stimulates a “pro- nociceptive state of cortical hyperexcitability that can trigger or intensify headaches” (Espinosa et al. 2017). Caffeine induces four psychiatric disorders that are recognized by the Diagnostic and Statistical Manual of Mental Disorders (DSM). This is a diagnostic guideline used by psychiatrists and clinicians to diagnose psychiatric illnesses, namely “caffeine intoxication, caffeine-induced sleep disorder, caffeine-related disorder, and caffeine-induced anxiety disorder” (Bedi et al. 2014). Park et al. (2016) sought out to study the association between ED consumption and mood disorders in Korean adolescents. Their findings revealed that ED consumption was statistically significantly linked to sleep problems, extreme stress, “suicidal ideation and a higher risk of suicide attempt” (Park et al. 2016). Depending on subjective sensitivity, ED consumption has been linked to events of memory loss, anxiety, and certain types of sleep disorder (Daly et al. 1983; Nehlig et al. 1992). This has consequentially translated to fatigue during class hours, resulting in behavioural problems and lower academic performance (Dikici et al. 2013). The study by Park et al. (2016) also suggested a positive association between the consumption of EDs, soft drinks, and fast-food products. Adolescents who consumed EDs and fast-food products for 5 or more days a week were shown to be more susceptible to mental health risks and mood disorders. However, the study results did not indicate that there was a directional causality between ED consumption and mental illness. Further to this point, it can be inferred that stress, anxiety, and sleep disorders could be seen as pathophysiological states that would encourage an adolescent to consume EDs to resume a level of ‘functionality’. Thus, a reverse causality is equally plausible. A cross-sectional study was conducted at a primary school in Iceland, whereby a population-based survey was carried out with 11,267 boys and girls aged between 10 – 12 years participating (Visram et al. 2016). In this study, the percentage of boys and girls who reported to have consumed EDs daily were 7 % and 3 %, respectively. Some of the symptoms that were experienced and communicated were headaches, stomach-aches, and insomnia. There is currently not enough scientific information on the risks associated with the chronic consumption of EDs by children aged under 12 years, thus more research needs to be done in this age group. Dikici et al. (2013) described a case report of a healthy adult male who was rushed to the emergency ward with epileptic seizure and ischemic stroke. This incident occurred following the consumption of three 250 mL EDs with alcohol by the patient. There was no history of epilepsy in the patient or his family. Another case report of an 18-year-old male patient was described by Hernandez-Huerta et al. (2017) where the patient on admission presented with a psychotic episode after consuming 6 cans of EDs per day for 7 days. He did not have a history of any psychotic disorders, although his paternal family had a history of undefined mental disease. These case reports suggest that excessive consumption of caffeinated drinks may induce seizures and psychotic disorders. Cardiovascular system effects According to WHO, cardio-vascular diseases (CVDs) are the leading cause of global deaths with an estimation of 31 % deaths claimed globally in 2016. The chronic consumption of high-caffeinated beverages is a major concern due to effects they have on the cerebrovascular system. Caffeine is 9 Nova Biotechnol Chim (2023) 22(1): e1344 2 a sympathomimetic, thus its ingestion causes vasoconstriction and elevates blood pressure, the extent to which is dependent on the dose of caffeine, dosage form (capsule or liquid), and subjective sensitivity (Grasser et al. 2016). Doerner et al. (2015) studied the effect of ED consumption on myocardial contractility and their investigations found that there was an increased contractility of the left ventricle an hour after ingestion of caffeine and taurine mixture. In addition, observed an increase in diastolic pressure when caffeine was consumed alone. Other such studies have confirmed the blood pressure elevating effect of caffeinated drinks, and all account conclude that ED consumption is directly associated with, at the very least, acute increases in blood pressure (Cavka et al. 2015). Nowak et al. (2018) on the other hand, reported a statistically significant increase in the diastolic blood pressure based on the results of a study on 68 young adolescents. With dependence being a very possible outcome of consistent use of and tolerance to caffeinated EDs, it is possible for EDs to become a dangerous dietary addition that in the long term, may potentiate events such as early onset hypertension and other cardiovascular illnesses such as tachycardia. Cannon et al. (2001) wrote up and published a case report on the health outcomes of a 25-year-old Australian woman, who developed intractable ventricular fibrillation, a condition where the heart quivers in beat rather than in rhythm, caused by a combination of their consumption of a “natural energy” guarana health drink and the underlying pre-existing mitral valve prolapse. The case was already studied by other authors, but it is mentioned here against due to its clinical significance (Doering et al. 2017). The patient was discovered to have consumed a 55 mL squirt bottle of an ED with guarana and ginseng, and it was confirmed that she had no other sources of dietary caffeine apart from tea. During her autopsy, toxicologists detected caffeine in her aortic blood at a concentration of 19 mg.L-1, the equivalent of 15 – 20 cups of coffee and the link had been made to the natural ED consumed as it contained 10 g.L-1of caffeine. Despite the patient having a pre-existing cardiac condition, the levels of caffeine in her blood including the post-mortem results, indicated the extremely high concentrations of caffeine from the consumed ED which potentiated a fatal cardiac arrhythmia (Cannon et al. 2001). Another case report of a 13-year-old female who was consuming EDs every day for two consecutive weeks was described by Mangi et al. (2017). The patient was presented to the hospital with chest pains, palpitations and her QT interval was prolonged. A genetic test was performed which confirmed that she had a long QT syndrome (LQTS). This is a condition where the heart’s electronic system is disordered and takes a long to recharge after each heartbeat, resulting in a QT interval longer than normal. This disorder occurs when there is a defect in the ion channels and can lead to a potentially life-threatening cardiac arrhythmia. Regulations and advertising legislation for caffeinated beverages in South Africa The market for EDs in South Africa has been rising rapidly, with an estimated increase of 2 to 3 L per capita between the years 2009 and 2014 (Stacey et al. 2017). Advertising is one of the driving factors that influences consumption and spikes the volume of sales. Stacey et al. (2017) studied the consumption of EDs and the influence of marketing in South Africa. Their findings revealed that there is minimal scientific research on the advertisement and the consumption of caffeinated beverages in South Africa. The government introduced a sugar tax on soft drinks with the aim to reduce their consumption. This proposal was published in 2016 and came into effect on the 1st of April 2018; where some manufacturers replaced the sugar with artificial sweeteners (Zero sugar drinks), some reduced the sugar whilst others remained the same. The Minister of Health has amended the regulations of soft drinks, and the legislation that has been put into place requires manufacturers to display the following messages on the label of the container with capital letters of a height not less than 3.0 mm (South Africa. Department of Health 2018): i) “High caffeine content”; ii) “Not recommended for children under 12 years of age, pregnant women, persons sensitive to caffeine and not to be consumed as a mixture with alcohol beverages”. The manufacturers are also required to state the amount of caffeine in mg/serving size and mg/100 mL. The executive director of the BevSA 10 Nova Biotechnol Chim (2023) 22(1): e1344 3 declared that all their members have signed a marketing code that prevents the marketing to children younger than 12 years as regulated (South Africa, Department of Health 2018). Although a marketing code has been signed, there still seems to be an aggressive marketing that attracts diverse children who are particularly below 12 years of age, tom. For example, one of the most popular EDs is highly marketed to events such as the X- games, wrestling (WWE) and other extreme sports which attract a large adolescent demographic. Suggested proposals for the public health management of ED consumption by children and adolescents in South Africa According to Curran and Marczinski (2017) seventy percent of children, as well as around 40 % of teenagers, consumed caffeine doses in excess of the 3 mg.kg-1.day. Such consumption levels can result in adverse caffeine effects just by consuming one ED together with other food sources. The results were calculated from an experiment where the following population groups; “5 – 12 years old (children), 13 – 19 years old (adolescents) and 20 – 24 years old (young men) had consumed a single retail unit of ED” (Curran and Marczinski 2017). These experimental results, along with the EDs- related scientific information mentioned in this article, show the seriousness of this (potential) health-related issues from the consumption of EDs. As a result, policy interventions are needed to protect the health of children and adolescents against EDs. Given that caffeine is a psychostimulant drug with proven adverse effects upon high consumption, its inclusion in soft drinks should be treated the same way as other drugs, such as alcohol. The fact that the packaging label states that ED is “Not recommended for children under 12” (Curran and Marczinski 2017), should propel the banning of its sales to children, and places such as schools and events organised for children should not allow EDs to be sold there. Stacey et al. (2017) studied the consumption of EDs and the influence of marketing in South Africa, their findings revealed that there is minimal scientific research on the advertisement and the consumption of caffeinated beverages in South Africa. They further concluded that viewers, who are exposed to TV channels that advertise EDs are likely to be consumers. How the viewers comprehend the message of the advertisement differs, especially when it comes to their (health) literacy levels. A child/South African citizen, who is proficient in English, will understand an advert about EDs very differently when compared to their counterparts, whose mother tongue or major medium of communication is not English. The same applies to parents or guardians; most of these adverts, including the packaging labels are written in English and the comprehension may differ in accordance with the English-proficiency level or mother tongue of the speaker. Therefore parents/guardians and their approach to their children ED consumption might differ. More focus should be placed on regulatory measures to update the ED packaging labels. Specifically speaking about EDs, the label should be designed and populated with information so that “all” children, who are 12 years or younger, including adolescents and parents/guardians, are able to understand the packaging label and avoid the negative side-effects of ED consumption. Considering the education disparities that some parts of the population in South Africa are subjected to, raises the potential challenge of the general and universal application of English as the language of the labels and medium to disseminate information about the ED health effects. This calls for more regulatory measures to be implemented to overcome such challenges. To address the challenges related to of the EDs consumption by children and adolescents, educational health programmes and campaigns targeted at children, adolescents, adults (particularly parents and guardians) need to be initiated and rolled out at school and community levels (especially the low- income parts of South Africa). Pamphlets and posters showing images of the harm caused by the chronic usage of EDs can be distributed near and around social places. Social media is one of the platforms that could be used to mostly reach adolescents with the ED-related public health campaigns. 11 Nova Biotechnol Chim (2023) 22(1): e1344 2 Conclusion In the current article, the authors sought to place a focus on some of the health risks associated with the chronic consumption of EDs in children and adolescents. Additionally, they propose interventions that can be implemented to address this issue. The exponential growth of the sales and consumption of EDs needs to be matched with strict regulatory measures to protect vulnerable population groups from the associated health risks. EDs are dangerous to the health of children and adolescents, therefore consumption of EDs by this age group should be targeted for urgent public health interventions. South Africa has one of the most unequal societies in the world and the country is still draped with inequalities inherited from the colonial times. Socio-economic factors therefore play an important in public health. Any intervention must be targeted for the local education and literacy levels have, as well as the links to the decision-making of consumers in relation to EDs. The parental guidance provided to children and adolescents in relation to the consumption of these beverages in South Africa. Conflict of Interest The authors declare that there is no conflict of interest. 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