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SUMMARY - Submission on Review of Liquor Control Act 1988 (WA) Provided by: Red Bull Australia Pty Ltd Contact: Zac Rich, Corporate & Regulatory Affairs Manager ([email protected]; 02 9023 2892) Date: 25 February, 2012 1. CONTEXT This submission provides the Committee with some insights into the non-alcoholic energy drink category. Having been established in 1987 in Austria, Red Bull is now available in 165 countries. As the global energy drink manufacturer, we look to develop cooperative relationships with regulators. This includes the federal, state, and territory governments of Australia where Red Bull has been sold for 13 years. Like soda water, lemonade, cola, fruit juices and other mixers, some consumers choose to mix energy drinks with alcohol. To that end, we draw the Committee’s attention to the most recent research in the area of non-alcoholic energy drinks mixed with alcohol (AmED). For the Committee’s benefit, copies of the research are appended to this submission. 2. KEY FACTS 1 Energy drinks represent less than one per cent of beverage sales in licensed venues in Australia.1 A standard 250mL can of energy drink contains a maximum of 80mg of caffeine. This is equivalent to a cup of instant coffee. All energy drinks in Australia are stringently regulated by Food Standard 2.6.4 (Formulated Caffeinated Beverages). This limits the amount of caffeine, imposes mandatory advisory statements, and requires caffeine content to be disclosed.2 When 30mL of alcohol is mixed with a standard 250mL can of energy drink, the alcoholic content is equivalent to approximately five per cent. This equates to a beer. A 2012 study of over 6,000 Dutch students by Utrecht University compared those that consumed AmED versus those that drank alcohol alone. The results show that consuming AmED does not increase overall alcohol consumption and/or alcohol-related consequences: on a night out, students consumed less alcohol overall when mixing with energy drink, versus drinking alcohol alone. This resulted in fewer alcohol related consequences.3 Both the Scientific Committee on Food (SCF) in 2003 and the European Food Safety Authority (EFSA) in 2009 addressed the issue of possible interactions between AmED in their corresponding opinions. The SCF 2003 opinion concluded that ‘there is no confirmation of a causal relationship between the reported effects of the consumption of alcohol and the consumption of energy drinks’ containing taurine and glucuronolactone. The 2009 EFSA opinion agreed with the considerations of the SCF and stated that ‘it is unlikely that glucuronolactone would have any interaction with caffeine, taurine, alcohol or the effects of exercise.’ A 2012 literature review this conclusion. The review found that there was little evidence that energy drinks altered intoxication levels. It also found no evidence that mixing energy drinks and alcohol increased consumption levels.4 The 2012 findings of the UK Government’s Committee on Toxicity concluded that the current balance of evidence does not support a harmful toxicological or behavioural interaction between caffeine and alcohol.5 BarScan Energy Category Report 2012 By comparison, the US does not have an equivalent standard. Red Bull (and other major manufacturers) maintain a global formula and always disclose caffeine content. Other US manufacturers to not adhere to the same standards. 3 de Haan L, de Haan HA, Olivier B, Verster JC, Alcohol mixed with energy drinks: methodology and design of the Utrecht Student Survey, International Journal of General Medicine, 2012: 5 889–898 4 Joris C Verster, Christoph Aufricht, Chris Alford “Energy drinks mixed with alcohol: misconceptions, myths and facts” (International Journal of Medicine, 2012, Volume 5) at 187. 5 Committee on Toxicity of Chemical in Food, Consumer Products and the Environment, “COS Statement on the interaction of caffeine and alcohol and their combined effects on health and behaviour” (December 2012). 2 SUBMISSION BY RED BULL AUSTRALIA TO THE REVIEW OF THE LIQUOR CONTROL ACT 1988 Introduction Red Bull is a non-alcoholic energy drink that has enjoyed a successful history since its inception in Austria in 1987. It is available in 165 countries and has been available in Australia for 13 years. As a market leader in the non-alcoholic energy drink sector, Red Bull cooperates with scientific, regulatory and health bodies internationally and in Australia. Red Bull assisted Food Standards Australia and New Zealand to develop Standard 2.6.4, which is considered one of the most stringent standards in the world. Background to energy drinks in Australia In Australia, all ingredients in a standard 250 mL energy drink are clearly labelled, including caffeine content (80mg) which is equivalent to a cup of instant coffee, in addition to a maximum daily consumption recommendation. This is in stark contrast with the United States where there is no regulation on caffeine content in these products or any requirement for energy drink manufacturers to list ingredients or provide advisory statements on its products. While Red Bull (and other major manufacturers) maintains the same formula in Australia and the United States, there are a number of rogue products in the US that do not observe comparable limits or disclose caffeine content. A significant portion of the negative debate and commentary surrounding energy drinks emanates from the United States and has been generated by outlier products. In response, Red Bull has invested significant resources to assist regulators and other industry representatives to access the latest information and science available to clarify these key issues. Alcohol and Energy Drinks In any discussion about the sale of energy drinks in licenced premises in Western Australia, it is important for the Committee to have an understanding of the context of energy drink sales. According to figures provided by BarScan, energy drinks comprise less than one per cent of overall sales over the bar nationally. BarScan sources primary sales information from cash registers in more than 950 bars and 330 liquor venues across Australia and tracks more than 60 million beverage serves across licenced premises each year. Like other non-alcoholic mixers, some consumers chose to mix energy drinks with alcohol. When a 250mL can of energy drink is mixed with 30mL of alcohol, the concentration of alcohol is approximately 5 per cent which is equivalent to beer. In licenced venues in which Red Bull is available, the product is sold for approximately $6 per can. Patrons purchasing a vodka and can of Red Bull will pay $12-$15. This fits within the premium pricing range and is the approximate equivalent of two vodka and lemonades. The premium price position of an energy drink purchased with alcohol does provide a price disincentive for over consumption. Research and Science Red Bull has long believed and remains firm in its view that sound policy and regulation must be underpinned by evidence-based research. Following negative publicity and concerns about the use of energy drinks as a mixer, a number of research papers and studies have been conducted to examine this issue further. Copies of this research are attached to this submission. Both the Scientific Committee on Food (SCF) in 2003 and European Food Safety Authority (EFSA) in 2009 addressed the issue of mixing alcohol and energy drinks in their corresponding opinions. The SCF concluded that “there is no confirmation of a causal relationship between the reported effects of the consumption of alcohol and/or drugs and the consumption of energy drink” containing taurine and glucuronolactone. In 2009, EFSA agreed with the conclusions from the SCF. Both SCF and EFSA in their respective opinions do not support the assumption of any combined effect or interaction between alcohol and energy drinks. There have also been concerns raised that mixing energy drinks with alcohol could result in the subjective perception by consumer that he/she is less intoxicated than if alcohol was consumed on its own. There is also concern raised that people would consume more alcohol when mixed with energy drinks compared with the consumption of alcohol beverages on their own. These concerns/views are not supported by science. For example, Energy Drinks Mixed with Alcohol, Misconceptions, Myths and Facts (Verster et al) is a scientific review which concludes that there is no consistent evidence that energy drinks alter the perceived level of intoxication of people who mix energy drinks with alcohol and there is no evidence that co-consumption of energy drinks causes increased alcohol consumption. In addition, a recent study Effects of Consuming Alcohol Mixed with Energy Drinks versus Consuming Alcohol Only (de Haan et al) of more than 6,000 Dutch students comparing those who consumed alcohol mixed with energy drinks compared with those that drank alcohol alone, provides scientific evidence that mixing energy drinks with alcohol does not increase overall alcohol consumption and/or alcohol-related consequences. “The study also shows clearly that mixing alcohol with energy drinks does not increase the likelihood of potentially dangerous activities or serious negative consequences, such as driving while intoxicated, being injured, or getting involved in a flight, unplanned sexual activity, or taking foolish risks” Furthermore, the UK Government’s Committee on Toxicity’s Statement on the Interaction of Caffeine and Alcohol and their Effects on Health and Behaviour has concluded that the current balance of evidence does not support a harmful toxicological or behavioural interaction between caffeine and alcohol. “A number of studies have suggested that caffeine can reduce the outward effects of alcohol, especially on reaction times, but other investigations have failed to support this. The evidence that perceptions of alcohol intoxication are modified by caffeine is conflicting. Overall, the range of methods used in reported studies prevents firm conclusions on whether caffeine counteracts the short-term effects of alcohol on brain function.” WA liquor licensing landscape Western Australia has the strictest liquor licensing regime across Australia with regard to energy drink restrictions and it appears that regulatory authorities are taking a precautionary approach as evidenced by a study of recent liquor applications (Public Interest Applications). Red Bull is aware that despite there being no clear scientific basis to do so, and despite the limited amount of energy drinks being sold in licenced premises, the WA Police in conjunction with the Department of Health often object to energy drinks being supplied or sold in new liquor licence applications, as well as applications to renew Extended Trading Permits. Consequently, applicants — many of which could be considered low risk in terms of incidents of anti-social behaviour — volunteer in their applications not to sell energy drinks to avoid objections from these two agencies and the subsequent extension of time required to obtain a liquor licence. While WA Police and the Department of Health may argue that there has been a reduction in antisocial behaviour as a consequence of the current restrictions there is no conclusive evidence to defend this position. Indeed, there may be other factors which can be attributed to this outcome. What is clearly lacking in the debate is the absence of empirical data that demonstrates the efficacy of the bans and restrictions placed on energy drinks as they apply to community safety outcomes in Western Australia. Red Bull believes that, given the absence of such data, the Committee has a role to provide clear guidance on the issue of restrictions to deliver a balanced approach on this matter. For example, external agencies currently are able to influence unfairly liquor licence applications outcomes, particularly in regard to low risk venues such as small bars. Recommendations To assist the Committee, Red Bull respectfully makes the following recommendations: 1. Given the available scientific evidence, the current restrictions and bans on energy drinks in venues across WA should be removed. 2. Restrictions on the sale of energy drinks for new liquor applications, for example low risk venues, such as small bars, should not be imposed. 3. That policy and regulation must be underpinned by robust evidence-based research. Submitted by: Zac Rich Regulatory Affairs Manager – Australia and New Zealand Red Bull Australia [email protected] 02 9023 2892 25 February 2013 Enclosures 1. 2. 3. 4. 5. 6. 7. 8. Scientific Committee on Food (SCF) in 2003 European Food Safety Authority (EFSA) in 2009 Energy Drinks mixed with alcohol; misconceptions, myths and facts – Verster et al The effects of energy drink in combination with alcohol on performance and subjective awareness – Alford et al Effects of consuming alcohol mixed with energy drinks versus consuming alcohol only on overall consumption and negative alcohol related consequences – de Haan et al Committee on Toxicity – CoT Statement on the interaction of caffeine and alcohol and their combined effects on health and benaviour Committee on Toxicity – Cot Statement on the interaction of caffeine and alcohol and their combined effects on health and behaviour – Lay Summary BarScan Energy Category Report – October 2012 EUROPEAN COMMISSION HEALTH & CONSUMER PROTECTION DIRECTORATE-GENERAL Directorate C - Scientific Opinions C2 - Management of scientific committees II; scientific co-operation and networks Scientific Committee on Food SCF/CS/PLEN/ENDRINKS/16 Final Opinion of the Scientific Committee on Food on Additional information on “energy” drinks (expressed on 5 March 2003) Rue de la Loi 200, B- 1049 Bruxelles/Wetstraat 200, B-1049 Brussel- Belgium-Office: G-1 01/242 Telephone: direct line (+32-2) 29 84698, swithboard 299.11.11 Fax: (+32-2) 2994891 http://europa.eu.int/comm/food/fs/sc/scf Opinion on Additional information on “energy” drinks Terms of reference The Committee is asked to review additional information submitted on energy drinks and indicate if the conclusions in its opinion of 21 January 1999 need to be modified. Background The SCF opinion of 1999 The Committee adopted an opinion on so-called “energy” drinks in 1999, which evaluated the safety of caffeine, taurine and D-glucurono-g-lactone as constituents of “energy” drinks (SCF, 1999). For caffeine, it was concluded that the contribution of “energy” drinks to overall caffeine intake was not a matter of concern for non-pregnant adults. For children who do not normally consume much tea or coffee, and who might substitute “energy” drinks for cola or other soft drinks, consumption of “energy” drinks might represent an increase in daily caffeine exposure compared with their previous intake. The Committee considered that this could result in transient behavioural changes, such as increased arousal, irritability, nervousness or anxiety. For pregnant adults, the Committee concluded that while intakes of caffeine up to 300mg/day appeared to be safe, the question of possible effects on pregnancy and the offspring at regular intakes above 300mg/day remained open. This suggested that moderation of caffeine intake, from whatever source, was advisable during pregnancy. For taurine and glucuronolactone, the Committee was unable to conclude that the safety-in-use of these constituents in the concentration ranges reported for "energy" drinks had been adequately established. Further studies would be required to establish upper safe levels for daily intake of taurine and glucuronolactone. The Committee noted that possible interactions of constituents of "energy" drinks have not been well studied and considered that possible interactions between caffeine, taurine and alcohol may warrant investigation in humans, particularly under conditions of exercise and consequent dehydration through sweating. Submission of further data Since the publication of its 1999 opinion, four further submissions of data have been received from one manufacturer of “energy” drinks (Red Bull GmbH, 2000, 2001, 2002a,b). These comprised: - a 13-week oral toxicity study in the mouse on Red Bull® given in the drinking water a 13-week oral gavage study in rats on taurine; 1 - a 13-week oral gavage study in rats on glucuronolactone; a review of other toxicology studies on taurine and glucuronolactone; information on the use of taurine in human medicine; an evaluation of the possibility of interactions between taurine, caffeine and glucuronolactone; an evaluation of the possibility of interactions between taurine and alcohol and caffeine and alcohol; results from a survey of the consumption of “energy” drinks in Austria and derived new exposure estimates; remarks on the SCF opinion of 1999. The Committee was also asked by the petitioner to take into account published reports and statements from the Australian New Zealand Food Authority (ANZFA, 2000) and the UK Food Standards Agency (FSA, 2001a). Other relevant developments in the EU The Committee also noted other developments in the EU since its last opinion in 1999: · · · · · The Agence Française de Sécurité Sanitaire des Aliments, reviewed the 13-week mouse oral toxicity study on Red Bull®, concluding that authorisation of the use of various substances in “energy” drinks was not acceptable since harmlessness at the concentrations recommended by the petitioner had not been demonstrated (AFSSA, 2001). The UK Committee on Toxicity published a statement on the reproductive effects of caffeine in the context of intakes from all food sources, including “energy” drinks (COT, 2001). It drew similar conclusions to those in the 1999 SCF opinion, commenting that caffeine intakes above 300 mg/day show a plausible association with low birth weight and spontaneous abortion. Based on this, the UK Food Standards Agency issued advice for pregnant women that they should limit their intake of caffeine to less than the equivalent of four average cups of coffee a day; the estimated “energy” drink equivalent to this was 4 cans a day (FSA, 2001b). A review of the health effects of “energy” drinks (stimulant drinks), commissioned by the Minister of State at the Department of Health and Children in the Republic of Ireland, has been published (Stimulant Drinks Committee, 2002). It made a number of recommendations covering labelling, concerns about marketing and promotion, further research needs, and advice to pregnant women, and cautioning against both consumption by children under 16 years of age and consumption in association with sport or exercise. A number of EU Member States have raised concerns about “energy” drinks in response to anecdotal cases of acute symptoms requiring medical attention in young people consuming “energy” drinks, in most cases in conjunction with alcohol and/or drugs used socially. A meeting of EU Member States in February 2002 to discuss perceived safety issues around “energy” drinks, concluded that the Commission should not take any action, but noted that new data had been submitted to the SCF and the position should be reconsidered once a new SCF opinion became available (FSA, 2 2002). An amendment to the EC labelling directive (EC, 2000) was agreed, to come into effect by July 2004, requiring that beverages, other than those based on coffee or tea, containing more than 150 mg caffeine/l should be labelled “high caffeine content” and the exact amount present indicated on the label (EC, 2002). Intake data The Committee noted that in its earlier opinion it used a figure of 500 ml of “energy” drink as the “likely consumption on any one day by regular consumers” (SCF, 1999). Two new surveys of intake of “energy” drinks have become available, one from Austria (Red Bull GmbH, 2001) and one from Ireland (Stimulant Drinks Committee, 2002). Details of these surveys are given in Annex 1. For this evaluation, the Committee has chosen from the new data mean chronic, high chronic and acute consumption estimates for regular consumers, as shown in Table 1. The estimate for acute consumption of 750 ml/day would give intakes of 240 mg caffeine/day, 3000 mg taurine/day and 1800 mg/day glucuronolactone, assuming the “energy” drinks contained maximum levels of 320, 4000 and 2400 mg/l of caffeine, taurine and glucuronolactone respectively. Table 1: Intake estimates used by the Committee Consumption Mean chronic High chronic Acute No. of 250ml cans/day 0.5 1.4 3.0 ml/day 125 350 750 Note that for acute consumption the Committee used 3 cans/day as a reasonable high consumption, this amount being higher than the 90th percentile recorded in the Austrian survey (2.6 cans/day) and being the average reported in the Irish survey for the most number of cans consumed in a single session. The Committee was aware that amounts up to 8-12 cans/day were reported by a few extreme consumers in both surveys. Toxicological studies A 13-week mouse oral toxicity study on Red Bullâ (RCC, 2000) and 13-week rat oral toxicity and toxicokinetic studies on taurine (WIL, 2001a) and on glucuronolactone (WIL, 2001b) have been submitted. The key findings in these new studies are summarised and discussed below, in the context of data reviewed previously by the Committee (SCF, 1999). Details of the studies are given in Annex 2. 13-week mouse oral toxicity study on Red Bullâ Mice were given Red Bullâ (RB) either undiluted or as a mixture with tap water at concentrations of 0, 33, 50 or 100% in the drinking water ad libitum for 13 weeks from 6 weeks of age (RCC, 2000). There were significant reductions in body weight in all treated groups, most likely attributable to observed reductions in food intake. Considerable dose-related increases in water/fluid intake, ranging from 27% to 115% compared with controls, were seen in all treated groups. These were not unexpected, 3 given the proportions of tap water replaced by RB, a fluid of much higher osmolarity. Many of the statistically significant findings in haematology, clinical chemistry and urinalysis, which were seen mainly in the 100% RB groups, are almost certainly attributable to the increased fluid intakes and glucose loading from the sucrose in RB. Disturbances in fluid balance would not be expected to occur in humans consuming “energy” drinks as part of their normal diet. Due to the effects on body weight, an overall no-observed-adverse-effect level (NOAEL) cannot be determined from this study. Neither does this study provide any useful data for the safety assessment of the individual constituents, caffeine, taurine or glucuronolactone, since the mode of administration did not allow very high amounts of the individual constituents to be consumed by the mice (see Annex 2). Studies on taurine The new toxicokinetic data on taurine in rats (WIL, 2001a), showing ready bioavailability and peak plasma levels one hour after oral administration, are in accordance with findings from the limited published data on humans. Human studies showed significant increases in plasma taurine 90 minutes after consumption of a taurine-rich meal with levels declining to background within 180-270 minutes (Trautwein and Hayes, 1995). These results also corroborate those from an unpublished human study by Taisho Pharmaceuticals, using radiolabelled taurine, which showed peak serum levels at 1-2 hours after oral administration, declining by 7 hours (Watanabe, cited in Red Bull GmbH, 2001). Other human data suggest that taurine is absorbed orally via an active transport mechanism in the gut wall (Ahlman et al., 1993, 1995a,b). The possible accumulation of taurine has also been investigated. The new rat toxicokinetic study only sampled on study days 0 and 90 but the results did not indicate any accumulation (WIL, 2001a). On the other hand, Trautwein and Hayes (1995) concluded, from a study in which 400 mg taurine was given daily for 7 days to humans, that there was accumulation of taurine in the plasma and a slight increase in whole blood taurine levels. In the new 13-week oral toxicity study, rats were given taurine at doses of 0, 300, 600 and 1000 mg/kg bw/day, dissolved in deionised water, orally by gavage once daily for 13 weeks from 6 weeks of age (WIL, 2001a). There were no persistent effects on body weight or food consumption and no histopathological changes in organs or tissues in any dose group. However, there were dose-related behavioural changes in both sexes of all three dosed groups. These were persistent increased activity most noticeable 1 hour after dosing, occasional chewing of limbs, and a possible decrement in motor performance on a rotarod. These findings, together with the toxicokinetic data, showing peak plasma levels at 1 hour, and the lack of increased locomotor activity when measured some hours after dosing, suggest that taurine may have exhibited an acute, central pharmacological effect in this study. Taurine is known to be present at high concentrations in the brain where it acts as a neuromodulator (see later). Previous sub-chronic studies on rats, reviewed earlier by the Committee (SCF, 1999), mostly involving administration of taurine in the drinking water or by intraperitoneal injection have, if anything, reported unchanged or reduced activity, though one study did report enhanced exploratory activity. The results of the new sub-chronic study show that 1000 mg/kg bw/day is a clear 4 effect level for behavioural changes while the lower doses of 300 and 600 mg/kg bw/day are marginal effect levels in males but clear effect levels in females. Thus, a NOAEL for behavioural effects in rats has not been established. Of the other studies on taurine mentioned by the petitioner (Red Bull® GmbH, 2001), all have been reviewed previously by the Committee (SCF, 1999), with the exception of a developmental toxicity study by Yamada et al. (1981), which showed no adverse effects, either prenatally or postnatally, from gavage administration of taurine at 300, 1000 or 3000 mg/kg bw/day to rats on days 7-17 of gestation. The submission (Red Bull GmbH, 2001) also included an extensive review of the clinical use of taurine in humans in conditions including diabetes, epilepsy, congestive heart failure, hypertension, liver disease and cystic fibrosis, concluding that “No adverse health effects attributable to taurine have been reported in more than 30 clinical investigations reported over a period of 30 years. In many cases taurine has proved medically beneficial.” The Committee was aware of these studies at the time of its earlier opinion (SCF, 1999). Studies on glucuronolactone The new toxicokinetic data on glucuronolactone in rats, showing bioavailability and lack of accumulation, with peak plasma levels 1-2 hours after oral administration (WIL, 2001b), are in accordance with findings from the limited published data on humans. In the new 13-week toxicity study, rats were given glucuronolactone at doses of 0, 300, 600 and 1000 mg/kg bw/day, dissolved in deionised water, orally by gavage once daily for 13 weeks from 6 weeks of age (WIL, 2001b). There were no significant, treatmentrelated effects, apart from vacuolation and inflammatory changes localised to the papilla of the kidney in females at 600 and 1000 mg/kg/day, with a NOAEL of 300 mg/kg bw/day. The petitioner has commented that the occurrence of the lesions only in females may be related to the higher acidity and osmolality of urine in the female rat and went on to comment that the osmolality of human urine is considerably less than that of the Sprague-Dawley rat. However, in the Committee’s view, the mechanistic cause of the kidney lesions remains unclear. The submission (Red Bull GmbH, 2001) reviewed some additional studies on glucuronolactone, including a study on growing hamsters (Di Filippo and Blumenthal, 1972) that had not previously been seen by the Committee. The previous SCF opinion specifically commented that there were no studies in mammalian species that included administration of high doses of glucuronolactone to growing animals, and that knowledge of the influence, if any, of high doses of glucuronolactone on blood glucose homeostasis and metabolic pathways involving glucose would be relevant for risk assessment in relation to children and diabetics (SCF, 1999). The purpose of the 28-day hamster study was to investigate whether glucuronolactone could prevent experimental cholelithiasis when given in the drinking water at doses up to 5.25%, equivalent to an intake of approximately 500 mg/kg bw/day. There were no clinical signs of toxicity and body weights in treated groups were comparable to controls. 5 Potential for interactions between constituents of “energy” drinks The petitioner submitted an evaluation by an outside expert, based on the existing literature, which discussed the possibility of interactions between caffeine, taurine and glucuronolactone (Red Bull GmbH, 2002a). The evaluation considered the fate of the compounds in the body (toxicokinetics) and their known effects (toxicodynamics). There are extensive data on the toxicokinetics of caffeine and taurine but less information on glucuronolactone. Consideration of the chemical nature of the three parent compounds and their metabolites, and the fact that differing processes are involved in their absorption, distribution, metabolism and excretion did not, in the expert’s view, raise any a priori reasons to expect any toxicokinetic interactions, even at high intakes of any one constituent. This was supported by known physiology and citation of existing studies. The physiological handling and lack of toxicological effects of glucuronolactone (other than on the female rat kidney - see above) did not, in the expert’s view, raise any a priori reasons to expect toxicodynamic interactions from this constituent. Caffeine and taurine, on the other hand, each affect the functioning of the central nervous system, kidneys and heart, thus there is a need to consider the potential for toxicodynamic interactions between these two constituents. Data relevant to these possible interactions are discussed below. Some of the data on caffeine derives from in vitro studies using high concentrations that would not be achieved in vivo following ingestion. For example, caffeine mobilises calcium, decreasing intracellular calcium concentrations (Otun et al., 1991), but only at in vitro concentrations that are around 200-fold higher than the plasma/tissue concentrations that would be achieved after consuming 160 mg of caffeine as a single dose, say, from 0.5 l of “energy” drink (Red Bull GmbH, 2002a). Nevertheless it should be noted that calcium disturbances (reduced blood levels) were seen in the mouse study on Red Bullâ. Central nervous system Caffeine is a central nervous system stimulant whereas taurine generally act as an inhibitory neuromodulator. Caffeine exerts stimulatory effects by blocking the inhibitory action of adenosine at its binding sites, with subsequent increases in the levels in some brain regions of several neurotransmitters, including adrenaline, noradrenaline, tryptophan and dopamine (Schlosberg, 1984; Hadfield and Milio, 1989; Kirch et al., 1990; Hughes 1996; Dager et al., 1999; Schuckit, 2000). It also modulates the effects of GABA and serotonin (Kaplan et al., 1992; Nehlig, 1999). Taurine, on the other hand, depresses the activity of excitable membranes in the brain (Iida and Hikichi, 1976; Huxtable, 1992). Centrally, taurine acts as an agonist of the more sedating glycine receptors and inhibits the more excitatory actions of NMDA receptors and glycine neurotransmitter function (De Saint et al., 2001; Font et al., 2001). It therefore could modulate the excitatory actions of some other amino acids (Saransaari and Oja, 1999, 2000). 6 While these data may appear to indicate that if there were any interaction, taurine might reduce caffeine-mediated excitation, the Committee noted that caffeine and taurine act on different receptors and moreover, in the rat study on taurine (see earlier), there was a stimulatory action on locomotor activity 1 hour after administration in all treated groups. Kidney Both caffeine and taurine can have short-term diuretic actions, causing loss of body water and sodium. Taurine acts via inhibition of central release of the anti-diuretic hormone, vasopressin (Hussy, 2001). Caffeine does not inhibit vasopressin release but has a direct action on kidney tubule functions, such as ionic reabsorption and renal perfusion, probably via adenosine receptor blockade (Daly, 1993). A high dose of taurine in the drinking water, equivalent to about 1500 mg/kg bw, was required to elicit diuresis and natriuresis in rats (Mozaffari and Schaffer, 2001), whereas 1g or more intravenously over 15 minutes (about 15 mg/kg bw) was sufficient in sensitive humans with liver cirrhosis and ascites (Gentile et al., 1994). Bearing in mind that taurine is rapidly absorbed across the gut via an active transport mechanism, the diuretic effects in normal subjects with an acute consumption of 750 ml of “energy” drink containing 3g of taurine are difficult to predict. The Committee noted that since caffeine and taurine act via different mechanisms, any diuretic effects could be additive. Cardiovascular system Caffeine can increase heart rate, force of contraction of heart muscle and blood pressure. Taurine, on the other hand, depresses the activity of excitable membranes in the heart (Huxtable, 1992). Caffeine enhances catecholamine synthesis and release from adrenal cells in vitro, probably related to its effects on intracellular calcium (Matsumura et al., 2000; McKenzie and Marley, 2002). Numerous in vivo studies have shown oral caffeine at doses of 6 mg/kg bw or more increases plasma catecholamine concentrations, especially adrenaline, in a dose-related manner during exercise (Bangsbo et al., 1992; Van Soeren et al., 1993; Anderson and Hickey, 1994; Graham and Spriet, 1995; Jackman et al., 1996; Kamimori et al., 2000), though one study giving 8.8 mg/kg in an “energy” drink found no increase (Wemple et al., 1997). The acute consumption estimate for “energy” drinks of 750 ml is equivalent to a caffeine intake of 4 mg/kg bw for a 60 kg adult. There is no evidence that taurine increases catecholamine release; if anything it has an inhibitory effect on excessive sympathetic activity in rat models of hypertension, with reduction of plasma catecholamines (Yamamoto et al., 1985; Sato et al., 1987; Trachtman et al., 1989). Neither does taurine given alone have any effect on heart rate or blood pressure in rats or humans (Mozaffari and Schaffer, 2001; Gentile et al., 1994). Both taurine and caffeine influence the activity of angiotensin II, an endogenously formed substance that raises arterial blood pressure and reduces the excretion of sodium and water by the kidney, but their action on angiotensin II is in opposite directions. In vivo caffeine augments the action of angiotensin II on the kidney and may raise plasma renin levels (Ohnishi et al., 1987; Holycross and Jackson, 1992; Brown et al., 1993; 7 Tseng et al., 1993), whereas taurine attenuates the effects of circulating angiotensin II (Schaffer et al., 2000). In view of the above data, the Committee considered that if there are any cardiovascular interactions between caffeine and taurine, taurine might reduce the cardiovascular effects of caffeine. Potential for interactions between constituents of “energy” drinks and alcohol In its earlier opinion (SCF, 1999), the Committee commented on the lack of research on the effects of “energy” drinks in combination with alcohol and/or fluid loss during exercise. The petitioner commented that there would be serious ethical problems in conducting research to study directly the combined effects of high blood alcohol concentrations with exercise, dehydration and consumption of “energy” drinks in humans. The petitioner therefore submitted an evaluation by an outside expert (Red Bull GmbH, 2002b), based on the existing literature, which discussed the possibility of interactions between alcohol and taurine or caffeine, including consideration of whether sweating and dehydration might predispose to additional effects. The expert (Red Bull GmbH, 2002b) considered the acknowledged health risks in situations of fluid and electrolyte loss through excessive sweating, pointing out that when more than 7% of body water is lost or hyponatraemia (blood sodium below 135 mEq/l) occurs, symptoms such as lung congestion, confusion, disorientation, muscle weakness, loss of coordination, headache, nausea and vomiting can occur, and that in extreme situations these can progress to cardio-respiratory arrest and death. Taurine and alcohol Studies on the effect of co-administration of alcohol and taurine on behaviour have used different routes of administration of alcohol, varying doses, and differ in the order in which taurine and alcohol were administered (Ferko, 1987). The results were inconsistent and showed little or no clinical interaction (Aragon et al., 1992; Boggan et al., 1978; Ferko and Bobyock, 1987). Taurine has antagonistic activity to alcohol in several situations, including ethanol-induced sleep time (McBroom et al., 1986; Ferko, 1987), effects of acute ethanol on memory (Vohra and Hui, 2000), and alcohol-induced liver and gastric mucosal damage (Timbrell et al., 1995; Xieyonglixiao et al., 1998). These effects are possibly mediated through taurine’s facilitation of the activity of the liver enzyme, aldehyde dehydrogenase, which metabolises alcohol, thereby reducing blood levels of alcohol (Messiha, 1979; Theofanopoulos et al., 1998a,b). In contrast, intraventricular coadministration of alcohol and taurine may increase the sedating effects of alcohol in mice and rats (Ferko, 1987; Mattucci-Schiavone and Ferko, 1985; Yarbrough et al., 1981), a situation in which taurine’s influence on aldehyde dehydrogenase in the liver would not be evident. Alcohol intoxication or hypo-osmotic stress cause release of endogenous taurine in several areas of the brain (Lallemand et al., 1998,200: Quertemont et al., 2000; Ward et al., 2000; Guizouarn et al., 2000), but the significance, if any, of this observation for exogenous taurine is unclear. These co-administration studies indicate that some alcohol-taurine interactions are possible, including protective ones, but the effects are neither marked nor consistent. 8 Both taurine (Gentile et al., 1994) and alcohol centrally inhibit the release of the antidiuretic hormone, vasopressin, and the Committee considered that they could act additively to increase water and sodium loss from the body in the short-term. Caffeine and alcohol The widely held belief that caffeine can antagonise the depressant effects of alcohol and drugs is generally supported by the extensive literature on this subject. Both animal and human studies indicate a modest, antagonistic effect of caffeine on the effects of alcohol, but the effects are usually only seen with simpler tasks and at lower blood alcohol concentrations (Moskowitz and Burns, 1971; Osborne and Rogers, 1983; Kerr et al., 1991; Liguori et al., 1997; Kerr and Hindmarch, 1998; Liguori and Robinson, 2001; Warburton et al., 2001). In humans, for example, the antagonistic activity of caffeine has been shown in driving-related tasks of tracking, divided attention and some aspects of reaction time after 2-5 standard alcoholic drinks. Most of the studies show the effects of caffeine are dose-dependent and that caffeine does not affect blood alcohol concentrations. Other studies have shown little if any ability of caffeine to antagonise the psychomotor effects of alcohol (Newman and Newman, 1956; Forney and Hughes, 1965; Mushill, 1979; Nuotto et al., 1982) and some have even raised the possibility that caffeine might enhance the effects of alcohol, especially during the early phase of drinking where some stimulatory properties of alcohol predominate (Hughes and Forney, 1961; Lowe, 1981; Osborne and Rogers, 1983; Dews, 1984). The majority of studies suggest that caffeine would not exacerbate the adverse effects of alcohol and at lower blood alcohol levels caffeine may improve performance. Human case reports The Committee was aware of a number of anecdotal reports of acute, adverse effects in young persons consuming “energy” drinks, usually together with alcohol and/or drugs used socially, such as ecstasy and amphetamines. The effects mentioned included, tremors, seizures, drowsiness, muscle weakness, dizziness, nervousness, tachycardia, palpitations, nausea, vomiting, headache, bronchospasm and hyperventilation. One case of myocardial infarction in a 23-year-old playing football (Rallis, 2001) and one case of sudden unexplained adult death syndrome, possibly resulting from cardiac dysrhythmia, in an 18-year old playing basketball (Stimulant Drinks Committee, 2002) have also been reported. The Committee had very little information about any of these cases and was not aware that any had been written up in the medical literature. The co-consumption of alcohol and/or drugs noted in most of these cases makes interpretation particularly difficult. Thus, there is no confirmation of any causal relationship between the reported effects and the consumption of “energy” drinks. Under these circumstances, the reports can only be noted. 9 Conclusions Taurine In its previous opinion on “energy” drinks, the SCF commented as follows on taurine (SCF, 1999): “Toxicological studies did not reveal any indication for a genotoxic, carcinogenic or teratogenic potential of taurine. However, there is no adequate study on chronic toxicity/carcinogenicity. Investigation of subacute/subchronic toxicity has also been fragmentary. Overall, the available data are insufficient to establish an upper safe level for daily intake of taurine.” The new 13-week study in rats provided further useful information in that it showed no significant changes in pathological measures, but it did show the occurrence of significant behavioural effects (increased activity and self-chewing), and possibly impaired motor performance, which could be mediated via a pharmacological action on the central nervous system. In view of this the Committee is of the opinion that focused neurological studies are now needed. The Committee concluded that these effects should be taken into account in human risk assessment, noting that behavioural effects were observed at the lowest dose tested of 300 mg/kg bw/day. This effect level is 36-fold above the estimated human intake of taurine (8.3 mg/kg bw for a 60 kg adult) at the mean chronic daily intake for “energy” drinks, and 6-fold above the more relevant estimate for acute intake (50 mg/kg bw for a 60 kg adult). The absence of a NOAEL for these effects precludes the setting of an upper safe level for daily intake of taurine. The Committee’s reservations are expressed in the context of an estimated acute intake of taurine of up to 3000 mg/day from consumption of “energy” drinks, compared with the highest estimated intake of taurine from naturally occurring sources in the diet of 400 mg/day. Glucuronolactone In its previous opinion on “energy” drinks, the SCF commented as follows on glucuronolactone (SCF, 1999): “Human metabolic considerations indicate the body is likely to handle small quantities of glucuronolactone without any problems. However, the intake of glucuronolactone from consumption of some "energy" drinks is possibly as much as two orders of magnitude greater than that from the rest of the diet. There is very little information available for risk assessment of glucuronolactone at such intakes. While there is no indication from the available data that there is any risk to health from consumption of high amounts of glucuronolactone, there is a lack of scientific evidence to support the safety of glucuronolactone present in beverages at concentrations that may result in intakes as much as two orders of magnitude greater than that obtained from the rest of the diet. As was the case with taurine, there is insufficient information on which to set an upper safe level for daily intake of glucuronolactone.” 10 The new 13-week study provided useful information indicating that in rats, there were no adverse effects except on the kidney. The NOAEL for these effects was 300 mg/kg bw, which is around 20-fold above the estimate of high chronic intake of glucuronolactone of 14 mg/kg bw/day for a 60 kg adult. The hamster study and the new 13-week rat study both provided information showing no effects on body weight gain in growing animals. However, the 1999 opinion also pointed out that rodents may not be an appropriate model for man since they can metabolise exogenous glucuronolactone to vitamin C whereas primates, including man, do not possess this metabolic pathway. The Committee therefore reiterates its earlier conclusion (SCF, 1999) that there is a lack of scientific evidence to support the safety of glucuronolactone present in beverages at concentrations that may result in intakes several-fold higher than that usually obtained from the rest of the diet. Due to the lack of relevant data it is not possible to set an upper safe level for daily intake of glucuronolactone. The Committee’s reservations are expressed in the context of an estimated high chronic intake of glucuronolactone of 840 mg/day and an acute intake of up to 1800 mg/day from consumption of “energy” drinks, compared with the estimated intake of glucuronolactone from naturally occurring sources in the diet of 1-2 mg/day. Caffeine The Committee’s earlier opinion on caffeine (SCF, 1999) remains unchanged (see “Background”). Interactions between constituents of energy drinks, alcohol and exercise The Committee considers it unlikely that glucuronolactone would have any interaction with caffeine, taurine, alcohol or the effects of exercise. The Committee concluded that consideration of the potential for interactions between caffeine and taurine has not ruled out the possibility of stimulatory effects from both substances at the level of the central nervous system. At the cardiovascular level, if there are any interactions between caffeine and taurine, taurine might reduce the cardiovascular effects of caffeine. The main area for likely additive interactions is in the diuretic actions of caffeine and taurine, which could be further enhanced by ingestion of alcohol. This, coupled with loss of body fluids via sweating on exercise, could, theoretically, result in short-term dehydration. While the Committee notes that some of the anecdotally reported symptoms in humans are compatible with loss of body water and sodium, it is also apparent that they may equally well be related to the intake of high amounts of alcohol and/or drugs reported in many of these cases. It is therefore not possible to draw definitive conclusions about effects in humans. 11 References Agence Française de Sécurité Sanitaire des Aliments, Avis relatif à l’évaluation de l’emploi de diverses substances nutritives et de caféine dans une boisson présentée comme « énergisante ». 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The survey was conducted in 2001 on 8500 Austrians aged 15 years and over. Forty-two percent of the sample consumed “energy” drinks at least occasionally and 12% were regular users. The 1007 regular users were further questioned in detail about their consumption habits. “Energy” drink consumers were more often male (55% of consumers, 59% of regular users) than female and were also largely in the age range 1530 years (46% of consumers, 61% of regular users). Chronic consumption Regular users were asked to recall the number of cans of “energy” drink they had consumed the previous week (7 day recall - 7DR), the number of cans they usually drank in one week (food frequency questionnaire - FFQ), and the number of cans they had consumed in the previous 24 hours (24-hour recall - 24HR). From these, estimates of both mean and high consumption may be made. The statistical distribution of intake was very skewed with a large number of “small” consumers and a few “extreme” consumers. There was good consistency between the estimates obtained using the three different indicators (7DR, FFQ and 24HR) for the mean daily quantities consumed by regular users, as shown in Table 1. Table 1: Mean daily chronic consumption of “energy” drink by regular users Indicator 7DR FFQ 24HR No. of 250 ml cans/day 0.45 0.47 0.52* * Including consumers and non-consumers on that day 20 Intakes by high consumers are shown in Table 2. Again there was good agreement between the two indicators. Note that the 24HR data cannot be used for this estimate. Table 2: High chronic consumption of “energy” drink by regular users* Indicator 7DR FFQ No. of 250 ml cans 90th percentile 7/week = 1/day 6/week = 0.9/day No. of 250 ml cans 95th percentile 10/week = 1.4/day 10/week = 1.4/day * N = 1007 regular users Acute consumption Acute intakes are shown in Table 3. Regular users were asked both about the maximum amount of “energy” drinks they had ever consumed at one time and for their 24HR. The first question could lead to biased answers and the so the 24HR figures are shown below as these are considered more likely to be accurate. Table 3: Acute consumption of “energy” drink by regular users Indicator 24HR No. of 250 ml cans/day Mean 1.7 No. of 250 ml cans/day 90th percentile 2.6 Irish survey The review commissioned in Ireland (Stimulant Drinks Committee, 2002) included information on consumption of “energy” drinks, as part of a market research survey conducted during July 2001, using face-to-face interviews with 625 people in the Republic of Ireland and 635 people in Northern Ireland, aged 11-35 years. In Northern Ireland and Republic of Ireland respectively, 51% and 37% of participants reported ‘ever’ consuming “energy” drinks and 10% and 11% reported consuming “energy” drinks frequently. Among ‘ever’ consumers, average consumption was 3 (250 ml) cans/week and for the 95th percentile consumers it was 8 cans/week. The most number of cans consumed in a single session among ‘ever’ consumers averaged approximately 3 cans, rising to 8 cans among the highest consumers; the comparable figure for 11-14 year-olds was approximately 2 cans. These results are similar to those obtained in the Austrian survey. 21 ANNEX 2 Details of toxicological studies submitted on Red Bullâ, taurine and glucuronolactone 13-week mouse oral toxicity study on Red Bullâ Groups of 20 mice/sex/dose were given Red Bullâ either undiluted or as a mixture with tap water at concentrations of 0, 33, 50 or 100% in the drinking water ad libitum for 13 weeks from 6 weeks of age. The study (RCC, 2000) was conducted in compliance with Good Laboratory Practice (GLP) regulations and conforming to 1981 OECD Guidelines (OECD, 1981). Mean intakes of Red Bullâ (RB) during the study period were equivalent to 89, 145 and 427 g/kg bw/day and 126, 188 and 520 g/kg bw/day in 33, 50 and 100% RB male and female groups respectively. Intakes of the individual constituents of interest were as shown in Table 5: Table 1: Intakes of caffeine, taurine and glucuronolactone Percentage RB in drinking water 33 50 100 Caffeine mg/kg bw/day Male Female Taurine mg/kg bw/day Male Female 27 44 131 342 554 1625 39 58 159 483 720 1989 Glucuronolactone mg/kg bw/day Male Female 205 333 981 290 432 1194 The significant findings were a reduction in mean body weight in all groups receiving RB compared with controls. Terminal body weights were significantly reduced by 11%, 12% and 15% in males and 8%, 6% and 12% in females in 33, 50 and 100% RB groups respectively. Food intake was transiently reduced at the start of the study in the 33 and 50% RB groups and during most of the study, by around 9%, in both sexes given 100% RB. Water/fluid consumption was significantly higher in all treated groups compared with controls throughout the study. Average differences from controls were +40%, +48% and +115% in males and + 27%, +27% and + 67% in females, in 33, 50 and 100% RB groups respectively. There were statistically significant increases in blood glucose in females given 33 or 50 % RB and in both sexes at 100% RB. Other significant findings were decreases in mean corpuscular haemoglobin concentration, platelet count and reticulocyte count in males receiving 100% RB. Creatinine was reduced in 100% RB females. Alkaline phosphatase levels were raised in 100% RB males. Calcium was reduced in 50% RB males and 100% RB males and females. Sodium was reduced in 100% RB males and chloride increased in 100% RB females. Total protein and absolute albumin concentrations were reduced in 22 100% RB males and females. The urine of 100% RB males had increased specific gravity and osmolality. Both absolute and relative weights of the inguinal fat pad were reduced in all treated male groups, suggesting the reductions in body weight may have been attributable to a reduced proportion of body fat. There were no treatment-related macroscopical or microscopical findings, apart from a reduction in liver centrilobular fat vacuolation in 100% RB males. 13-week rat oral toxicity study on taurine Groups of 20 rats/sex/dose were given taurine at doses of 0, 300, 600 and 1000 mg/kg bw/day, dissolved in deionised water, orally by gavage once daily for 13 weeks from 6 weeks of age (WIL, 2001a). The study was conducted in compliance with GLP regulations and to a protocol in accordance with US Food and Drug Administration Redbook II Guidelines (FDA, 1993). In a concurrent toxicokinetic study on separate animals, 12 animals/sex/dose were given the same dosages as in the main toxicology study and blood samples taken from 3 animals/sex/dose, at time 0 (immediately prior to dosing), 1, 2, 4, 8 and 24 hours following dosing on days 0 and 90 of the study, for estimation of plasma taurine levels. Blood samples were collected from concurrent controls (6 animals/sex) on the same days at 0, 2 and 8 hours following dosing with vehicle. There were no treatment-related deaths and only transient higher body weight gains in some treated groups. Food consumption was unaffected by treatment. There were some statistically significant differences in haematological and clinical chemistry parameters measured at 4, 8 and 13 weeks between treated and control groups, but the differences were small and none were seemingly treatment-related. There was a dose-related reduction in urinary pH in both sexes, which was probably attributable to the presence of acidic taurine in the urine. Small but significant reductions in absolute and relative thyroid/parathyroid gland weights in males at 1000 mg/kg and in females at 300, 600 and 1000 mg/kg were attributable to control values that were relatively high compared with laboratory historical controls and concurrent controls in the glucuronolactone study (see later). Because of the differences in thyroid weights at necropsy, serum TSH and T4 were measured. The only finding was a significant reduction in TSH levels in 600 mg/kg males at 4 weeks. There were no treatment-related gross or microscopic findings in any organs or tissues, including the thyroid. Clinical observations were performed on all animals at the time of dosing and about 1 hour after dosing. Significant behavioural changes were observed 1 hour after dosing. Table 6 shows the results of the 1-hour observations over the 13 weeks of the study. 23 Table 2: Clinical observations (Total occurrences/No. of animals) 1 hour after dosing with taurine Dose (mg/kg bw/day) Number of animals Observations Increased activity Chewing of forelimb(s) Chewing of hindlimb(s) Chewing of cage Hyper-reactive to touch 0 20 Males 300 600 20 20 1000 20 1/1 0/0 0/0 0/0 0/0 5/4 0/0 0/0 0/0 0/0 11/8 3/3 1/1 1/1 1/1 4/4 2/2 0/0 0/0 0/0 0 20 Females 300 600 20 20 1000 20 3/2 0/0 0/0 0/0 0/0 36/10 3/2 1/1 0/0 0/0 62/16 11/7 2/2 2/2 0/0 29/10 3/3 2/2 1/1 0/0 Increased activity was recorded in all treated groups compared with controls, particularly in females. The increase in frequency and number of animals exhibiting this behaviour was similar in 300 and 600 mg/kg males and females and greatest in the 1000 mg/kg groups. The frequency was similar in the first and last months of the study showing that tolerance did not develop over time. Chewing on forelimbs and hindlimbs was also seen in a few animals among 600 and 1000 mg/kg males and in all groups of treated females. The frequency was highest among 1000 mg/kg females. These findings were followed up in a functional observation battery conducted at 6 and 12 weeks on control and 1000 mg/kg groups. There were occasional observations in the treated group, mostly in females, of greater alertness in the home cage, cage biting, higher arousal in the open field, more energetic reactions to approach, touch and startle response stimuli and jumping, biting or attacking in response to tail pinch. However, all but one of these behaviours was seen in only single animals and none of the differences were statistically significant. Impaired performance on the rotarod was seen in both sexes of the 1000 mg/kg group; the mean length of time they remained on the rotarod compared with controls was reduced by 49% and 52% in males and females respectively at 6 weeks and by 24% and 18% in males and females respectively at 12 weeks. Due to high variability within groups, none of these reductions were statistically significant. In a 60 minute test for locomotor activity run on individual animals at 6 and 12 weeks, a significant reduction in mean ambulatory activity and a non-significant reduction in mean total activity were seen in 1000 mg/kg males at 6 weeks. There were no effects in males at 12 weeks or in females at 6 or 12 weeks. In the toxicokinetic study, plasma taurine levels increased in a dose-related manner, reaching peak Cmax values at around 1 hour after dosing and generally returning to baseline values by 24 hours. Plasma taurine levels 2 hours after dosing were 21-51% of the values measured at one hour. Initial half-life was less than 1 hour and terminal halflife ranged from 8.7 to 40 hours. Plasma concentrations 24 hours after dosing were comparable with control values both on study day 0 and on day 90. Area under the plasma-time concentration curve (AUC) values were similar on study days 0 and 90. Both Cmax and AUC were proportional to dose. This study showed that taurine is readily bioavailable following oral administration and that it does not accumulate. 24 13-week rat oral toxicity study on glucuronolactone Groups of 20 rats/sex/dose were given D-glucuronolactone at doses were 0, 300, 600 and 1000 mg/kg bw/day, dissolved in deionised water, orally by gavage once daily for 13 weeks from 6 weeks of age (WIL, 2001b). The study was conducted in an almost identical manner to the study on taurine described above, in compliance with GLP regulations and to a protocol in accordance with FDA Redbook II Guidelines (FDA, 1993). In this study no functional observation battery was performed. A concurrent toxicokinetic study on separate animals was conducted to the same protocol as described earlier for the taurine study. There were no deaths and only transiently higher body weight gains in some treated groups. There were no significant effects on food consumption, apart from higher food consumption in 300, 600 and 1000 mg/kg females in week 10-11. There were some statistically significant differences in haematological and clinical chemistry parameters measured at 4, 8 and 13 weeks between treated and control groups, but the differences were small and none were seemingly treatment-related. In urinalysis, the only significant differences were in males: an increase in total volume at 600 mg/kg, a lower specific gravity at 600 and 1000 mg/kg and a lower pH at 1000 mg/kg at 13 weeks. There were no significant effects on organ weights, but histopathological changes were found in the kidneys of females in the 600 and 1000 mg/kg groups. These changes included cytoplasmic vacuolation, and inflammatory changes. Cytoplasmic vacuolation was present in 50% of all groups including controls but the incidence of mild as opposed to minimal change was dose-related (1/20, 1/20, 5/20, 8/20 in control, 300, 600 and 1000 mg/kg groups). No inflammatory changes were seen in the controls or 300 mg/kg group, but they were seen in 2/20 females in the 600 mg/kg group and in 3/20 females in the 1000 mg/kg group. Although inflammatory changes are typically seen in the presence of mineralisation, calculi or crystaluria, none of these types of change were observed, neither was there any evidence of urinary bladder irritation. No treatment related effects were seen in the kidneys of males. In the toxicokinetic study, plasma glucuronolactone levels increased in a dose-related manner, reaching peak Cmax values at around 1-4 hours on study day 0 and at 1 hour on study day 90. The half-life ranged from 0.89 to 3.9 hours. AUC values were similar on study days 0 and 90. Both Cmax and AUC were proportional to dose. These results show that glucuronolactone is bioavailable following oral administration and that it does not accumulate. 25 The EFSA Journal (2009) 935, 1-31 SCIENTIFIC OPINION The use of taurine and D-glucurono-γ-lactone as constituents of the so-called “energy” drinks 1 Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food (Question No EFSA-Q-2007-113) Adopted on 15 January 2009 PANEL MEMBERS F. Aguilar, U.R. Charrondiere, B. Dusemund, P. Galtier, J. Gilbert, D.M. Gott, S. Grilli, R. Guertler, G.E.N. Kass, J. Koenig, C. Lambré, J-C. Larsen, J-C. Leblanc, A. Mortensen, D. Parent-Massin, I. Pratt, I.M.C.M. Rietjens, I. Stankovic, P. Tobback, T. Verguieva, R.A. Woutersen. SUMMARY Following a request from the Commission, the Scientific Panel on Food Additives and Nutrient Sources added to Food (ANS) has been asked to evaluate the safety-in-use of taurine and D-glucurono-γ-lactone as constituents of the so-called “energy” drinks. In the present opinion the Panel evaluates the safety of taurine and D-glucurono-γ-lactone as individual ingredients of so-called “energy” drinks based on the new studies provided by the petitioner. The Panel does not evaluate the safety of “energy” drinks as such. Taurine and D-glucurono-γ-lactone are constituents of the so-called “energy” drinks, but they also occur at much lower levels as natural ingredients in food, and they are also normal human metabolites. Previous Scientific Committee on Food (SCF) Opinions have summarized safety studies of taurine and D-glucurono-γ-lactone, but the safety-in-use of these 1 For citation purposes: Scientific Opinion of the Panel on Food Additives and Nutrient Sources added to Food on a request from the Commission on the use of taurine and D-glucurono-γ-lactone as constituents of the socalled “energy” drinks. The EFSA Journal (2009) 935, 1-31. © European Food Safety Authority, 2009 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks two ingredients at the levels of exposure expected from their use in “energy” drinks could not be established at that time. In the absence of new chronic and acute exposure data, the exposures used in this opinion are based on the data reported by the SCF in 2003, i.e. a daily mean chronic consumption of 0.5 cans per person and a high chronic exposure at the 95th percentile of 1.4 cans per regular consumer. The Panel notes that actual exposure data on “energy” drink consumption, especially for adolescents and young adults, may need to be collected. Based on the assumption that a can contains 250 mL and 4000 mg/L taurine and 2400 mg/L D-glucurono-γlactone, the SCF calculated that these values result in a mean daily exposure to 500 mg taurine (8.3 mg taurine/kg bw/day for a 60 kg person) and 300 mg D-glucurono-γ-lactone (5.0 mg D-glucurono-γ-lactone/kg bw/day for a 60 kg person). The 95th percentile exposure of regular users would amount to 1400 mg taurine/day (23.3 mg/kg bw/day for a 60 kg person) and 840 mg D-glucurono-γ-lactone /day (14 mg/kg bw/day for a 60 kg person). If it is assumed that this amount of chronic consumption is relevant to occasional exposure of children of 25 kg body weight, then their exposure (on a body weight basis) would be about 2.5 times higher than that for adults (60-65 kg body weight). It must be emphasized that these estimates relate to chronic exposures by average and high consuming adults, and would not reflect the occasional and sporadic exposure that might occur in children. If the frequency of exposure for children would be 2.5 times lower than for adults, then the average chronic exposure for children, on a body weight basis, would be the same as for adults. If children were to consume the adult intake of 0.5 and 1.4 cans per person only once per week, then the average chronic exposure to “energy” drinks and their constituents for children, on a body weight basis, would be one third of that for adults. These estimates for the daily exposure to taurine and D-glucurono-γ-lactone from “energy” drinks are higher than the estimated mean daily exposure to taurine from omnivore diets which was estimated to be at most 400 mg/day, and that of D-glucurono-γ-lactone from naturally occurring sources in the diet estimated to amount to 1-2 mg/day. The SCF Opinion of 2003 used 3 cans/day as a reasonable high (acute) consumption, this amount being higher than the 90th percentile recorded in the Austrian survey (2.6 cans/day) and being the average reported in the Irish survey for the highest number of cans consumed in a single session. The SCF also indicated that it was aware that amounts of up to 8-12 cans/day were reported by a few extreme consumers in both surveys, which would result in an intake of 4800-7200 mg D-glucurono-γ-lactone and 8000-12000 mg taurine per day, equivalent to 80120 mg D-glucurono-γ-lactone/kg bw/day and 133-200 mg taurine/kg bw/day for a 60 kg person. The SCF Opinion of 2003 and the recent BfR Opinion mention a number of anecdotal and case reports of acute, adverse effects, including fatalities, in individuals consuming “energy” drinks, containing caffeine, taurine and D-glucurono-γ-lactone. In these cases “energy” drinks had either been consumed in very high amounts (1420 mL), in combination with physical exercise, or more frequently together with alcohol. The Panel considers that it is possible that the effects reported in recent publications by Iyadurai and Chung, Nagajothi et al. and Terlizzi et al. could be due to the well known side effects of high caffeine intake, while the assumption of a causal relationship with taurine intake is lacking scientific evidence. Taurine Upon oral exposure taurine is readily bioavailable in the systemic circulation. The Panel concludes that new ADME data support the contention that oral exposure to taurine was not The EFSA Journal (2009) 935, 2-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks increasing taurine levels in the brain, because in rat studies, brain taurine levels did not increase after dosage. The SCF already concluded in 1999 that toxicological studies did not reveal any indication for a genotoxic, teratogenic or carcinogenic potential of taurine. It can be concluded that the NOAEL derived from a new 13-week oral neurotoxicity study in male and female rats including functional observational battery and locomotor activity tests, confirmed the NOAEL established in the prior 13-week study, described already by the SCF in 2003, of 1000 mg taurine/kg bw/day, and provided evidence for a NOAEL of 1500 mg taurine/kg bw/day for behavioural effects. The results of this study were sufficient to address the concerns raised previously, notably the observation of increased activity and possible decrements in motor skills on the rotarod. The NOAEL of at least 1000 mg/kg bw/day for pathological changes is respectively 120-fold higher than the estimated mean and 43-fold higher than the estimated 95th percentile exposure to taurine from “energy” drinks only, when calculated for a 60 kg person. Given that taurine is a natural body constituent, the Panel concludes that these margins of safety are sufficiently large to conclude that exposure to taurine at the levels mentioned above is not of safety concern. D-glucurono-γ-lactone The SCF already concluded that the available data indicate that D-glucurono-γ-lactone administered orally to humans is rapidly absorbed, metabolised and excreted as glucaric acid, xylitol and L-xylulose. Animals, such as rodents, which can synthesise vitamin C endogenously do so from glucuronic acid and such animals can also convert exogenously administered D-glucurono-γ-lactone into vitamin C. However, primates, including man, and guinea pigs do not possess this metabolic pathway. The SCF concluded that for this reason, the rodent may be an inappropriate model for man in the study of the effects of D-glucuronoγ-lactone. The Panel concludes that data in the literature indicate that synthesis of vitamin C is only a minor pathway of D-glucurono-γ-lactone metabolism in the rat and of limited relevance to the safety assessment of exogenous D-glucurono-γ-lactone. In 2003 the SCF evaluated a 13-week oral toxicity rat study with D-glucurono-γ-lactone and concluded that the cause of the kidney lesions remained unclear. The petitioner has now provided data from a new 13-week oral (gavage versus drinking water) toxicity study of D-glucurono-γ-lactone in rats, with specific focus on the kidneys. This study used the same rat strain as the previous study reported in the SCF Opinion of 2003. Extensive urinalysis and histopathological examinations demonstrated no treatment-related effects. Based on the results of this study, the NOAEL for daily oral administration of Dglucurono-γ-lactone in rats was 1000 mg/kg bw/day, the highest dose tested. Toxicological studies on the genotoxic, teratogenic or carcinogenic potential of D-glucuronoγ-lactone were not available. However, D-glucurono-γ-lactone is a normal human metabolite formed from glucose and there are no structural alerts for mutagenicity or carcinogenicity. At physiological pH it is in equilibrium with glucoronic acid, its immediate precursor. Dglucurono-γ-lactone and its hydrolysis product glucuronic acid are endogenous metabolites in humans and other mammals, they occur naturally in several dietary sources and are readily metabolized to innocuous products and excreted. Furthermore, in the high dose 13-week rat studies there was no evidence of any effect on the gonads which might indicate the need for reproductive toxicity studies. The EFSA Journal (2009) 935, 3-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks The NOAEL for D-glucurono-γ-lactone of 1000 mg/kg bw/day is 200-fold higher than the estimated mean and 71-fold higher than the estimated 95th percentile exposure to Dglucurono-γ-lactone from “energy” drinks only, when calculated for a 60 kg person. Given the fact that D-glucurono-γ-lactone is a natural body constituent the Panel concludes that these margins of safety are sufficiently large to conclude that exposure to D-glucurono-γlactone at the levels mentioned above is not of safety concern. Overall, the Panel concludes that the exposure to taurine and D-glucurono-γ-lactone at the levels currently used in “energy” drinks and mentioned in the present opinion is not of safety concern. The ANS Panel agrees with the considerations of the SCF Opinion from 2003 on the fact that it is unlikely that D-glucurono-γ-lactone would have any interaction with caffeine, taurine, alcohol or the effects of exercise. The Panel also concludes, based on the new data available, that additive interactions between taurine and caffeine on diuretic effects are unlikely. Other interactions between taurine and caffeine were not investigated. Key words: Taurine, CAS No. 107-35-7, D-glucurono-γ-lactone, CAS No. 32449-92-6, “energy” drinks. The EFSA Journal (2009) 935, 4-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks TABLE OF CONTENTS Panel Members .........................................................................................................................................1 Summary ..................................................................................................................................................1 Background as provided by the Commission...........................................................................................6 Terms of reference as provided by the Commission ................................................................................7 Acknowledgements ..................................................................................................................................7 Assessment ...............................................................................................................................................8 1. Technical data ................................................................................................................................8 1.1. Chemistry..................................................................................................................................8 1.2. Manufacturing Process..............................................................................................................9 1.3. Specifications............................................................................................................................9 1.4. Methods of analysis in foods ....................................................................................................9 1.5. Reaction and fate in foods, stability..........................................................................................9 1.6. Case of need and use levels ......................................................................................................9 1.7. Exposure .................................................................................................................................10 1.8. Existing authorisations and evaluations..................................................................................11 2. Biological and toxicological data.................................................................................................12 2.1. Absorption, distribution, metabolism and excretion ...............................................................12 2.2. Toxicological data...................................................................................................................14 2.2.1. Acute oral toxicity....................................................................................................14 2.2.2. Short-term and sub-chronic toxicity ........................................................................14 2.2.3. Reproductive and developmental toxicity................................................................17 2.2.4. Mutagenicity ............................................................................................................17 2.2.5. Carcinogenicity and long-term studies ....................................................................18 2.2.6. Human data ..............................................................................................................18 3. Discussion ....................................................................................................................................20 Conclusions and Recommendations.......................................................................................................23 Documentation provided to EFSA .........................................................................................................23 References ..............................................................................................................................................23 Glossary / Abbreviations ........................................................................................................................31 The EFSA Journal (2009) 935, 5-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks BACKGROUND AS PROVIDED BY THE COMMISSION On 21 January 1999 the Scientific Committee on Food (SCF) expressed an opinion on caffeine, taurine and D-glucurono-γ-lactone as constituents of the so-called “energy” drinks. For taurine and D-glucurono-γ-lactone, the SCF was unable to conclude that the safety-in-use of taurine and D-glucurono-γ-lactone in the concentration ranges reported for these constituents in “energy” drinks had been adequately established. It indicated that further studies would be required to establish upper safe levels for daily intake of taurine and Dglucurono-γ-lactone. In 2002, following the submission of new information by a manufacturer of “energy” drinks and the publication of reports and statements on the issue by the Australian New Zealand Food Safety Authority and the UK Food Standard Agency, the SCF was asked by the Commission to indicate if the conclusions of its opinion of 1999 needed to be revised. On 5 March 2003, the SCF expressed an opinion on additional information on “energy” drinks. Concerning taurine, the SCF indicated that the new 13-week study in rats provided further useful information and that it showed no significant changes in pathological measures, but it did show the occurrence of significant behavioural effects (increased activity and selfchewing), and possibly impaired motor performance, which could be mediated via a pharmacological action on the central nervous system. In view of this, the SCF was of the opinion that focused neurological studies were needed. The SCF concluded that these effects should be taken into account in human risk assessment, noting that behavioural effects were observed at the lowest dose tested of 300 mg/kg bw/day. This effect level is 36-fold above the estimated human intake of taurine (8.3 mg/kg bw/day for a 60 kg adult) at the mean chronic daily intake for “energy” drinks, and 6-fold above the more relevant estimate for acute intake (50 mg/kg bw/day for a 60 kg adult). The absence of a NOAEL for these effects precludes the setting of an upper safe level for daily intake of taurine. The SCF’s reservations were expressed in the context of an estimated acute intake of taurine up to 3000 mg/day from consumption of “energy” drinks, compared with the highest estimated intake of taurine from naturally occurring sources in the diet of 400 mg/day. Concerning D-glucurono-γ-lactone, the new 13-week study provided useful information indicating that in rats there were no adverse effects except on the kidney. The NOAEL for these effects was 300 mg/kg bw/day, which is around 20-fold above the estimate of high chronic intake of D-glucurono-γ-lactone of 14 mg/kg bw/day for a 60 kg adult. The hamster study and the new 13-week rat study both provided information showing no effects on body weight gain in growing animals. However, the 1999 Opinion also pointed out that rodents may not be an appropriate model for man since they can metabolise exogenous glucuronolactone to vitamin C whereas primates including man do not possess this metabolic pathway. The SCF therefore reiterated its earlier conclusion (SCF, 1999) that there is lack of evidence to support the safety of D-glucurono-γ-lactone present in beverages at concentrations that may result in intakes several-fold higher than that usually obtained from the rest of the diet. Due to the lack of relevant data, it was not possible to set an upper safe level for daily intake of D-glucurono-γ-lactone. The SCF’s reservations were expressed in the context of an estimated high chronic intake of D-glucurono-γ-lactone of 840 mg/day and an acute intake of up to 1800 mg/day from consumption of “energy” drinks, compared with the estimated intake of D-glucurono-γ-lactone from naturally occurring sources in the diet of 1-2 mg/day. The EFSA Journal (2009) 935, 6-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks Following these opinions, and taking into account the remarks made by the SCF, a manufacturer of “energy” drinks has submitted new data on the safety-in-use of taurine and D-glucorono-γ-lactone as constituents of the so-called “energy” drinks. TERMS OF REFERENCE AS PROVIDED BY THE COMMISSION In accordance with Article 29 (1) (a) of Regulation (EC) No 178/2002, the European Commission asks the European Food Safety Authority to: - review the data submitted on the safety-in-use of taurine and D-glucurono-γ-lactone as constituents of the so-called “energy” drinks - consider, if appropriate, to provide a scientific opinion on the safety-in-use of taurine and D-glucurono-γ-lactone as constituents of the so-called “energy” drinks. ACKNOWLEDGEMENTS The European Food Safety Authority wishes to thank the members of the Working Group B on Food Additives and Nutrient Sources for the preparation of this opinion: D. Boskou, U.R. Charrondiere, B. Dusemund, D. Gott, T. Hallas-Møller, K.F.A.M. Hulshof, J. König, D. Parent-Massin, I.M.C.M. Rietjens, G.J.A. Speijers, P. Tobback, T. Verguieva, R.A. Woutersen. The EFSA Journal (2009) 935, 7-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks ASSESSMENT In the present opinion the Panel evaluates the safety of taurine and D-glucurono-γ-lactone as individual ingredients of the so-called “energy” drinks based on the new toxicological studies provided by the petitioner. The Panel does not evaluate the safety of “energy” drinks as such. 1. Technical data 1.1. Chemistry Taurine Taurine (CAS No. 107-35-7) occurs naturally in food, especially in seafood and meat, and it is a normal metabolite in humans. It is a metabolic product of sulphur-containing amino acids, and it is mainly biosynthesised from cysteine in the liver (SCF, 1999). Its molecular weight is 125.15 g/mol, the molecular formula is C2H7NO3S and the structural formula is as shown: D-glucurono-γ -lactone D-glucurono-γ-lactone (CAS No. 32449-92-6) is a normal human metabolite formed from glucose. At physiological pH it is in equilibrium with glucuronic acid, its immediate precursor (see figure below). Glucuronic acid occurs in plants, mainly in gums, but as it is in polymeric combination with other carbohydrates it is not readily available. Glucuronic acid is also an important constituent of fibrous and connective tissues in all animals (SCF, 1999). The molecular weight of D-glucurono-γ-lactone is 176.12 g/mol, the molecular formula is C6H8O6 and the structural formula is as shown: O O O HO OH HO O + H2O OH HO D-glucurono-γ-lactone OH HOOC OH D-glucuronic acid The EFSA Journal (2009) 935, 8-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks 1.2. Manufacturing Process The petitioner provided adequate information on the production process of taurine, retrieved from supplier information describing the general principle of the process. Taurine can be made from monoethanolamine and sulphuric acid as the starting materials or from ethylene oxide and sodium hydrogen sulphate as the starting materials. The crude production is followed by purification steps. The petitioner provided adequate information on the production process of D-glucurono-γlactone, retrieved from supplier information describing the general principle of the process. D-glucurono-γ-lactone is made from nitric acid and starch as the starting materials. The crude production is followed by purification steps. 1.3. Specifications The petitioner indicated that taurine used in “energy” drinks complies with US pharmacopoeia specifications (US Pharmacopeia, 2005). Purity is not less than 98.5 %. The petitioner provided the following specifications for D-glucurono-γ-lactone and indicated that the methods for determining these specifications meet the requirements of several pharmacopoeias or regulations describing testing methods. D-glucurono-γ-lactone is a white crystalline powder and its purity is not less than 98.5 %. Impurities identified by HPLC include glucuronic acid <0.19%, other identified constituents each at <0.05 % and in total <0.15% and unknown constituents each at <0.05 % in total <0.15 %. Melting range is 170176 oC, its appearance in solution is clear and colourless, the acidity of a 10% solution in water is 3.7-4.1, the loss on drying is <0.2%, heavy metals are present at <0.001% (10 mg/kg), arsenic at <2 mg/kg, iron at < 2 mg/kg, copper at < 2 mg/kg, chloride at <100 mg/kg, ammonia at < 200 mg/kg and sulphate at < 100 mg/kg. Specifications for microbial purity were also provided by the petitioner. 1.4. Methods of analysis in foods The petitioner indicated that taurine can be determined in “energy” drinks after derivatization with dabsylchloride by HLPC with UV detection, and that D-glucurono-γ-lactone can be quantified in “energy” drinks by HPLC without derivatization. 1.5. Reaction and fate in foods, stability The petitioner indicates that samples of “energy” drinks were stored at 20 0C for 24 months and tested at defined time-points for the levels of taurine and D-glucurono-γ-lactone. Based on the results obtained it could be concluded that taurine and D-glucurono-γ-lactone in the “energy” drink were stable during these 24 months of storage at 20 0C. 1.6. Case of need and use levels According to the petitioner taurine and D-glucurono-γ-lactone are to be used as constituents of so-called “energy” drinks together with caffeine. The EFSA Journal (2009) 935, 9-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks A submission from the Austrian National Food Authority (1996) included a list of the content of 32 “energy” drinks taken from a published review of drinks on the Austrian market. Some “energy” drinks did not contain taurine. In those drinks in which taurine was present and its concentration declared, one contained 300 mg/L, one 2000 mg/L and 11 contained 4000 mg/L. For the exposure estimates done in 2003 the SCF assumed that the “energy” drinks contained maximum levels of 4000 mg/L taurine and 2400 mg/L of D-glucurono-γ-lactone (SCF, 2003). 1.7. Exposure No new data on exposure were available to the Panel. In 2003 the SCF established a mean chronic consumption of 0.5 cans per person per day (250 mL per can) (SCF, 2003). High chronic exposure was estimated by the SCF to be 1.4 cans per person per day. This figure was based on the 95th percentile exposure of regular users, a group which represents 12% of the total population. Based on the assumption that a can contains 250 mL and 4000 mg/L taurine and 2400 mg/L D-glucurono-γ-lactone the SCF calculated that these values result in a mean daily exposure to 500 mg taurine (8.3 mg taurine/kg bw/day for a 60 kg person) and 300 mg D-glucurono-γlactone (5.0 mg D-glucurono-γ-lactone /kg bw/day for a 60 kg person). The 95th percentile exposure to regular users would amount to 1400 mg taurine/day (23.3 mg/kg bw/day for a 60 kg person) and 840 mg D-glucurono-γ-lactone /day (14 mg/kg bw/day for a 60 kg person). The mean daily exposure to taurine from omnivore diets was determined to be around 58 mg (range from 9 to 372 mg) and to be low or negligible from a strict vegetarian diet (Rana and Sanders, 1986). In another study, taurine exposure was estimated to be generally less than 200 mg/day, even in individuals eating a high meat diet (Laidlaw et al., 1990). And in another study, taurine consumption was estimated to vary between 40 and 400 mg/day (Hayes and Trautwein, 1994). The SCF Opinion mentioned an estimated exposure to D-glucurono-γ-lactone from naturally occurring sources in the diet of 1-2 mg/day (SCF, 2003). The SCF also concluded that “Human metabolic considerations indicate the body is likely to handle small quantities of glucuronolactone without any problems. However, the exposure to glucuronolactone resulting from consumption of “energy” drinks is possibly as much as two orders of magnitude greater than that from the rest of the diet.” The mean exposure to D-glucurono-γ-lactone would be 300 mg/day, and at the 95th percentile exposure would be 840 mg/day. The chronic exposures by average and high adult consumers have been estimated by the SCF (2003) to be 0.5 and 1.4 cans per person per day. The petitioner indicates that if it was assumed that this level of chronic consumption is relevant to occasional exposure of children of 25 kg body weight (about 6 to 7 years of age), then their exposure (on a body weight basis) would be about 2.5 times higher than that of adults (60-65 kg body weight). The petitioner emphasizes that these estimates relate to chronic exposures by average and high consuming adults, and would not reflect the occasional and sporadic exposure that might occur in children. If the frequency of exposure of children would be 2.5 times lower than in adults, then the average chronic exposure of children, on a body weight basis, would be the same as for adults. If children were to consume the adult intake of 0.5 and 1.4 cans per person only once per week, then the average chronic exposure of children, on a body weight basis, would be one third of that in adults. The EFSA Journal (2009) 935, 10-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks The SCF Opinion (2003) used 3 cans/day as a reasonable high (acute) consumption, this amount being higher than the 90th percentile recorded in the Austrian survey (2.6 cans/day) and being the average reported in the Irish survey for the most number of cans consumed in a single session. The SCF also indicated that it was aware that amounts up to 8-12 cans/day, were reported by a few extreme consumers in both surveys, which would result in an intake of 4800-7200 mg D-glucurono-γ-lactone and 8000-12000 mg of taurine per day, equivalent to 80 - 120 mg D-glucurono-γ-lactone/kg bw/day and 133-200 mg taurine/kg bw/day. 1.8. Existing authorisations and evaluations In 1999, the SCF adopted an opinion on so-called “energy” drinks, which evaluated the safety of caffeine, taurine and D-glucurono-γ-lactone as constituents of “energy” drinks (SCF, 1999). The SCF (1999) concluded that toxicological studies did not reveal any indication for a genotoxic, teratogenic or carcinogenic potential of taurine. At that time, the SCF was unable to conclude that the safety-in-use of taurine and glucuronolactone in the concentration ranges reported for "energy" drinks had been adequately established. The SCF commented that “there is insufficient information on which to set an upper safe level for daily intake of these constituents.” In 2001, the Agence Française de Sécurité Sanitaire des Aliments (AFSSA), reviewed a 13week mouse oral toxicity study on “energy” drinks, concluding that authorisation of the use of various substances in “energy” drinks was not acceptable since harmlessness at the concentrations recommended by the petitioner had not been demonstrated (AFSSA, 2001). The AFSSA reiterated the same conclusions in three subsequent opinions (AFSSA, 2003, 2006a, 2006b). In 2003 the SCF was asked to review additional information submitted on “energy” drinks and indicate if the conclusions in its opinion of 21 January 1999 needed to be modified. The SCF was also asked by the petitioner to take into account published reports and statements from the Australian New Zealand Food Authority (ANZFA, 2000) and the UK Food Standards Agency (FSA, 2001; 2002). The SCF (2003) concluded the following on taurine: “The new 13-week study in rats provided further useful information in that it showed no significant changes in pathological measures, but it did show the occurrence of significant behavioural effects (increased activity and self-chewing), and possibly impaired motor performance, which could be mediated via a pharmacological action on the central nervous system. In view of this, the Committee is of the opinion that focused neurological studies are now needed and that the effects reported in a 13-week study should be taken into account in human risk assessment, noting that behavioural effects were observed at the lowest dose tested of 300 mg/kg bw/day. This effect level is 36-fold above the estimated human intake of taurine (8.3 mg/kg bw/d for a 60 kg adult) at the mean chronic daily intake for “energy” drinks, and 6-fold above the more relevant estimate for acute intake (50 mg/kg bw/d for a 60 kg adult). The absence of a NOAEL for these effects precludes the setting of an upper safe level for daily intake of taurine. The Committee’s reservations are expressed in the context of an estimated acute intake of taurine of up to 3000 mg/day from consumption of “energy” drinks, compared with the highest estimated intake of taurine from naturally occurring sources in the diet of 400 mg/day.” The EFSA Journal (2009) 935, 11-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks The SCF (2003) concluded the following on glucurono-γ-lactone: “The new 13-week study provided useful information indicating that in rats, there were no adverse effects except on the kidney. The NOAEL for these effects was 300 mg/kg bw/d, which is around 20-fold above the estimate of high chronic intake of glucuronolactone of 14 mg/kg bw/d for a 60 kg adult. The hamster study and the new 13week rat study both provided information showing no effects on body weight gain in growing animals. However, the 1999 Opinion also pointed out that rodents may not be an appropriate model for man since they can metabolise exogenous glucuronolactone to vitamin C whereas primates, including man, do not possess this metabolic pathway. The Committee therefore reiterates its earlier conclusion (SCF, 1999) that there is a lack of scientific evidence to support the safety of glucuronolactone present in beverages at concentrations that may result in intakes several-fold higher than that usually obtained from the rest of the diet. Due to the lack of relevant data it is not possible to set an upper safe level for daily intake of glucuronolactone. The Committee’s reservations are expressed in the context of an estimated high chronic intake of glucuronolactone of 840 mg/day and an acute intake of up to 1800 mg/day from consumption of “energy” drinks, compared with the estimated intake of glucuronolactone from naturally occurring sources in the diet of 1-2 mg/day.” In 2005, a statement was expressed by the EFSA Scientific Panel on food additives, flavourings, processing aids and materials in contact with food (AFC) on studies designed to investigate the safety-in-use of taurine and D-glucurono-γ-lactone in "energy" drinks (EFSA, 2005). 2. Biological and toxicological data Previous SCF Opinions have summarized safety studies of taurine and D-glucurono-γ -lactone (SCF, 1999; SCF, 2003) and a previous EFSA Statement from the AFC Panel commented on studies designed to further investigate the safety-in-use of taurine and D-glucurono-γ-lactone in “energy” drinks (EFSA, 2005). The present opinion only describes in detail those studies that were submitted after the publication of the SCF Opinion in 2003 and the EFSA Statement in 2005. 2.1. Absorption, distribution, metabolism and excretion Taurine The SCF Opinion already concluded that new toxicokinetic data submitted at that time on taurine in rats showing ready bioavailability and peak plasma levels one hour after oral administration are in accordance with findings from the limited published data for humans (SCF, 2003). Human studies showed significant increases in plasma taurine 90 minutes after consumption of a taurine-rich meal with levels declining to background within 180-270 minutes (Trautwein and Hayes, 1995). The SCF indicates that these results also corroborate those from an unpublished human study using radiolabelled taurine, which showed peak serum levels at 1-2 hours after oral administration, declining by 7 hours (SCF, 2003). Other The EFSA Journal (2009) 935, 12-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks human data suggest that taurine is absorbed orally via an active transport mechanism in the gut wall (Ahlman et al., 1993; 1995a, b). Results from a new study on absorption, tissue distribution, metabolism and elimination of taurine given orally to rats were provided by the petitioner. In this study (Sved et al., 2007) three biodisposition studies with taurine were performed in male and female adult rats at dosages of 30 and 300 mg/kg bw. A single dose of 14C taurine was rapidly absorbed, distributed to tissues and excreted unchanged in the urine. Elimination of radioactivity from intracellular pools was slow. Pre-treatment of animals for 14 days with unlabelled taurine did not significantly affect the fate of 14C taurine. Daily administration of unlabelled taurine for 14 days did not result in an increase in total taurine in the brain. It was concluded that the data indicated that exogenous taurine rapidly equilibrates with endogenous body pools and that any excess is rapidly eliminated by the kidneys. Based on these data which revealed that brain taurine levels did not increase after dosing, the petitioner concluded that the possibility that taurine may exhibit acute, central pharmacological effects mediated by an action on the central nervous system was scientifically improbable. D-glucurono-γ-lactone The SCF (1999) already concluded that the available data indicate that when D-glucurono-γlactone is administered orally to humans it is rapidly absorbed, metabolised and excreted as glucaric acid, xylitol and L-xylulose. The SCF Opinion of 2003 stated that the toxicokinetic data on D-glucurono-γ-lactone in rats, showing bioavailability and lack of accumulation, with peak plasma levels 1-2 hours after oral administration, were in accordance with findings from the limited published data on humans (SCF, 2003). Animals, such as rodents, which can synthesise vitamin C endogenously do so from glucuronic acid and such animals can also convert exogenously administered D-glucurono-γlactone into vitamin C (SCF, 1999). However, primates, including man, and guinea pigs do not possess this metabolic pathway. The SCF concluded that for this reason, the rodent may be an inappropriate model for man in the study of the effects of D-glucurono-γ-lactone. In 2003, the SCF reiterated the 1999 Opinion that rodents may not be an appropriate model for humans since they can metabolise exogenous D-glucurono-γ-lactone to vitamin C whereas guinea pigs and primates, including humans, do not possess this metabolic pathway. However, the petitioner indicates that synthesis of vitamin C is only a minor pathway of Dglucurono-γ-lactone metabolism in the rat and argues that, although of nutritional importance, it is of limited relevance to the safety assessment of exogenous D-glucurono-γ-lactone. This is supported by more recent literature data demonstrating that D-glucurono-γ-lactone is predominantly metabolised in rats via the pentose pathway and that the flux through the pathway that results in synthesis of ascorbic acid from D-glucurono-γ-lactone is relatively small (Kondo et al., 2006; Linster and Van Schaftingen, 2007). The EFSA Journal (2009) 935, 13-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks 2.2. Toxicological data 2.2.1. Acute oral toxicity In an acute toxicity study of taurine in Wistar rats, a 50% taurine suspension in 1.0% carboxymethylcellulose (CMC) solution was administered in a volume of 10 mL/kg bw. No dead animals were observed during the observation period of 14 days, and the authors indicate that this suggests that the LD50 value of taurine is higher than 7000 mg/kg bw upon oral administration (Kihara et al., 1991). 2.2.2. Short-term and sub-chronic toxicity Taurine In 2003 the SCF evaluated a newly submitted 13-week rat study with taurine at dose levels of 0, 300, 600 and 1000 mg/kg bw/day which showed no significant changes in pathological measures, but did show the occurrence of significant behavioural effects (increased activity and self-injury such as self-chewing), and possibly impaired motor performance, which could have been mediated via a pharmacological action on the central nervous system. In view of this, the SCF was of the opinion that focused neurological studies were needed. The absence of a NOAEL for these effects precluded the setting of an upper safe level for daily exposure to taurine. The petitioner argued that there had been bias in the original study observations and the EFSA Working Group (EFSA, 2005) agreed that the observations reported in this study on certain behavioural patterns of the animals had not been well described in the original submission and could be discounted since there was no evidence of self-injury. However, the EFSA Working Group also concluded that, even combined with the expert analyses provided, this information was insufficient in itself to address all the concerns raised previously, notably the observation on increased activity and possible decrements in motor skills on the rotarod. Therefore, the petitioner has now provided data from a specifically-designed, new 13-week oral (gavage and drinking water) neurotoxicity study of taurine in male and female rats which was performed according to FDA and OECD principles of Good Laboratory Practice. The objective of this study was to evaluate any potential neurotoxic effects of taurine when administered to rats for 13 weeks either by gavage or by way of drinking water, and to address the reliability of observations noted in the previous 13-week taurine toxicity study. Beginning in the second week of the acclimatization period, all animals (180 males and 180 females) were tested twice in the functional observational battery (FOB) and locomotor activity paradigms. After initial evaluations, outliers in locomotor activity were eliminated from the study. The remaining animals were randomized based on their performance on the rotarod test. Finally, the mean and standard deviation of the locomotor activity results were analyzed to ensure that group means and variances were approximately equal before initiation of dosing, thereby minimizing subsequent skewing of these data. Potential functional deficits were assessed using a FOB and a measure of spontaneous locomotor activity. This study was conducted in a “blinded” manner, in which the actual dose level for each group (gavage and drinking water) were unknown to the personnel conducting the study, in order to remove human bias from all aspects of the study. The EFSA Journal (2009) 935, 14-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks Taurine in the vehicle, deionized water, was administered orally by gavage once daily for 13 weeks to 2 groups of 20 male and 20 female Cr1:CD(SD) rats at dose levels of 600 and 1000 mg/kg bw/day. In addition taurine was administered ad libitum in drinking water for 13 weeks to 2 groups of 20 male and 20 female Cr1:CD(SD) rats at target dose levels of 1000 and 1500 mg/kg bw/day (actual mean taurine intake levels obtained with drinking water were 1095 and 1117 mg/kg bw/day for the males and females respectively in the low dose group and 1647 and 1656 mg/kg bw/day for the males and females respectively in the high dose group). Concurrent control groups received the vehicle by gavage and drinking water respectively, on comparable regimes. Clinical examinations were performed daily and detailed physical examinations were performed weekly. These examinations were conducted “blinded” with respect to treatment. Individual body weights and water consumption were recorded twice weekly and food consumption was recorded weekly. Functional observational battery and locomotor activity data were recorded for all animals prior to the initiation of dose administration and during study weeks 0, 6 and 12. Complete necropsies were conducted on all animals, and selected tissues and organs were collected at the scheduled necropsy. The results indicated that there were no test-article-related deaths, clinical findings or macroscopic findings. No test-article-related effects were observed on body weights or food consumption. Some differences were observed in water consumption when rats were supplied taurine ad libitum in the drinking water. Increases in water consumption in the 1000 and 1500 mg/kg bw/day group males were noted only for study days 0 to 3 and/or 3 to 7 (both in g/animal/day and g/kg bw/day). The petitioner indicates that these differences were considered test-article-related, but not considered adverse effects and that they occurred temporarily and were considered to reflect adaptation to the osmotic property of the test article. There were no test-article-related effects on FOB parameters (home cage, handling, open field, sensory, neuromuscular and physiological observations). Locomotor activity counts (total and ambulatory) and patterns were unaffected by test article administration. Based on these results the petitioner concluded that the oral administration of taurine at dose levels of 600 and 1000 mg/kg bw/day was well tolerated by male and female rats and did not result in any behavioural changes. The Panel concluded that this study confirmed the NOAEL derived from the earlier study which included histopathology (1000 mg/kg bw/day – the highest dose tested). In addition, it provided evidence of a NOAEL of 1500 mg/kg bw/day (actual level approximately 1650 mg/kg bw/day) for behavioural effects. D-glucurono-γ-lactone For D-glucurono-γ-lactone the SCF concluded that the 13-week study in Crl:CD(SD) rats showed that there were no significant, treatment-related effects, “apart from vacuolisation and inflammatory changes localised to the papilla of the kidney in females at 600 and 1000 mg/kg bw/day, with a NOAEL of 300 mg/kg bw/day” (SCF, 2003). The study reported cytoplasmic vacuolation in 6/20 and 4/20 males in the control and 1000 mg/kg bw/day groups respectively and in 11/20, 9/20, 11/20 and 11/20 females in the control, 300, 600 and 1000 mg/kg bw/day groups respectively. The incidence was not increased by treatment. The lesions were described as mild (grade 2) rather than minimal (grade 1) in 1/20 and 0/20 males in the control and 1000 mg/kg bw/day groups and in 1/20, 1/20, 5/20 and 8/20 females in the control, 300, 600 and 1000 mg/kg bw/day groups respectively. Therefore the data indicated that there was a slight dose-related increase in severity in the treated females in comparison to the treated males. However the petitioner noted that for all rats used in the The EFSA Journal (2009) 935, 15-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks study, a range of other effects in the kidneys were reported, such as inflammatory changes, nephropathy, pyelitis, indicative of renal problems. The petitioner argued that the occurrence of the renal observations were incidental, related to background lesions usually occurring in this rat strain. The SCF concluded that the cause of the kidney lesions remained unclear. The petitioner also indicated that the occurrence of the lesions only in females may be related to the higher acidity and osmolality of urine in the female rat and went on to comment that the osmolality of human urine is considered less than of the Sprague-Dawley rat. However, the SCF stated that in their view the mechanistic cause of the kidney lesions remains unclear (SCF, 2003). In a statement (EFSA, 2005) the Working Group on Additives of the AFC Panel noted that the guinea pig might be a better model for human, in terms of its metabolism of D-glucuronoγ-lactone. But they expressed considerable reservations about a study on D-glucurono-γlactone in guinea pigs as proposed by the petitioner. The Working Group particularly noted that the proposed study in guinea pigs with D-glucurono-γ-lactone in drinking water could be difficult to perform (e.g. mortality) and interpret (e.g. lack of extensive background data on this species), and that in view of these potential difficulties, consideration should be given to whether this study could be justified on animal welfare grounds. The Working Group suggested that a more productive strategy might be to undertake mechanistic studies to support the hypothesis put forward by the petitioner that the rat kidney effects were not relevant for human risk assessment. The petitioner has now provided data from a new 13-week oral (gavage versus drinking water) toxicity study of D-glucurono-γ-lactone in the Crl:CD(SD) rat strain, with specific focus on the kidneys. This study used the same rat strain as the previous study reported in the SCF Opinion of 2003 and was performed according to FDA and OECD principles of Good Laboratory Practice. In this new study, D-glucurono-γ-lactone was administered orally by gavage once daily for 13 consecutive weeks to 4 groups of Cr1:CD(SD) rats at dose levels of 0, 300, 600 and 1000 mg/kg bw/day. In addition D-glucurono-γ-lactone was administered ad libitum in drinking water for 13 weeks to another 4 groups of Cr1:CD(SD) rats at target dose levels of 0, 300, 600 and 1000 mg/kg bw/day. Each group consisted of 20 males and 20 females. Actual mean D-glucurono-γ-lactone intake levels obtained in the drinking water groups were 311 and 322 mg/kg bw/day for the males and females respectively in the low dose group, 598 and 635 mg/kg bw/day for the males and females respectively in the mid dose group and 980 and 1066 mg/kg bw/day for the males and females respectively in the high dose group. Concurrent control groups of 20 males and 20 females received the vehicle by gavage and drinking water respectively on comparable regimens. Clinical examinations were performed daily, and detailed physical examinations were performed weekly. Individual body weights and water consumption were recorded twice weekly. Serum chemistry evaluations were performed on all animals prior to the initiation of dose administration (study week 2), during study weeks 4 and 8, and at the scheduled necropsy (study week 13) and at time-points during 0 to 6 hours and 6 to 24 hours after dose administration from the gavage groups during study weeks 4, 8 and 13. Urine samples were collected from the drinking water groups on the same schedule (same time of day). Complete necropsies were conducted on all animals, and selected organs were weighed at the scheduled necropsy. Selected tissues were examined microscopically from all animals. Results revealed no test article-related deaths. There were no effects on clinical observations, food or water consumption, body weights, clinical pathology parameters, organ weights or clinical chemistry parameters representing renal function. Extensive urinalysis demonstrated no The EFSA Journal (2009) 935, 16-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks treatment related effects, and no differences between gavage and drinking water groups. There were no test article-related macroscopic or microscopic findings. Histopathological examinations revealed focal inflammation in the kidneys in a few male and female animals, scattered among the groups, including controls. The petitioner indicates that inflammation was observed in only a small number of animals at each dose level, that it was unilateral and not treatment-related and that these background lesions are typical for this strain of rats. There were no compound-related observations of vacuolization of the cells lining the collecting tubules. The petitioner also indicated that a greater number of rats in this new study had healthy kidneys in comparison to the first study. There were no differences between the gavage and drinking water groups. There was no significant incidence of cytoplasmic vacuolization in any groups. The petitioner also indicated that in light of the difference between the two studies the slides have been carefully reassessed, and that cytoplasmic vacuolization has been confirmed not to be present. The petitioner also stated that the pathologist who undertook the histopathological examination has indicated that the effect in the previous study was most likely a preparation artifact which was exacerbated by the generally poor health status of the kidneys in the rats at that time. Vacuolisation of renal collecting tubules may arise as an artifact using normal fixation techniques. The petitioner concluded that based on the results of this and the previous study, the NOAEL for daily oral administration of D-glucurono-γ-lactone to rats was 1000 mg/kg bw/day, the highest dose tested in both studies. The Panel agrees with this NOAEL derived from the recent 13-week rat study which was performed under GLP. 2.2.3. Reproductive and developmental toxicity The SCF already concluded in 1999 that toxicological studies did not reveal any indication for a teratogenic potential of taurine (SCF, 1999). Studies on reproductive and developmental toxicity for D-glucurono-γ-lactone were not available. However the petitioner indicates that this substance and its hydrolysis product glucuronic acid are endogenous metabolites in humans and other mammals, that they occur naturally in several dietary sources and are readily metabolized to innocuous products and excreted. Furthermore there were no effects on the gonads in the 13-week rat studies. Therefore the Panel concluded that there was no need for reproductive toxicity studies. There are no new studies available. 2.2.4. Mutagenicity The SCF already concluded that toxicological studies did not reveal any indication for a genotoxic potential of taurine (SCF, 1999). In a study on the antimutagenic activity of lactones in Escherichia coli, D-glucurono-γlactone was reported to be not mutagenic to E. coli strains WP2 and WPs (Kuroda et al., 1986). There are no new studies available. The EFSA Journal (2009) 935, 17-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks 2.2.5. Carcinogenicity and long-term studies The SCF already concluded that toxicological studies did not reveal any indication for a carcinogenic potential of taurine (SCF, 1999). But the SCF also indicated that there is no adequate chronic toxicity/carcinogenicity study for taurine. Long term studies on D-glucurono-γ-lactone were not available. However this substance and its hydrolysis product glucuronic acid are endogenous metabolites in humans and other mammals, they occur naturally in several dietary sources and are readily metabolized to innocuous products and excreted. Furthermore, there was no evidence of any putative preneoplastic or hyperplastic lesions in the 13-week rat studies, which might indicate the need for a long term carcinogenicity study. 2.2.6. Human data Available human data from the use of taurine in human medicine do not give any indication of safety concerns (Franconi et al., 1995; Takahashi and Nakane, 1978; Fukuyama and Ochiai, 1982; Airaksinen et al., 1980; Mantovani and DeVibo, 1979; Marchesi et al., 1975; Mutani et al., 1975; Azuma et al., 1983a; 1983b; 1985; 1992; 1994; Fujita et al., 1987; Yamori et al., 1996; Krøll and Lund, 1966; Yamamoto et al., 1994; Gentile et al., 1994; Matsuyama et al., 1983; Podda et al., 1990; Kimura et al., 1992; Obinata et al., 1996; Durelli et al., 1982; 1983; Nyland et al., 1989; Kopple et al., 1990; Thompson 1988; Darling et al., 1985; Carrasco et al., 1990; Belli et al., 1987; Colombo et al., 1988; Smith et al., 1991; De Curtis et al., 1992; Skopnik et al., 1991; Colombo et al., 1990). In these separate studies taurine has been administered, mostly by oral ingestion on a daily basis for periods up to one year, and with daily doses generally in the 3-6 g range, to a large number of patients (adults, children and even infants) suffering from a wide variety of serious diseases. Taurine has also been administered parenterally at a daily dose of 0.64 g for 20 months or by intravenous administration at daily doses of 12 g for 15 days and 18 g for 60 days. Although the principal aim of these clinical studies was not to evaluate potential adverse effects of chronic administration of taurine it is apparent that these doses produced no adverse health effects. Such information has revealed that oral daily ingestion of taurine doses in the 3-6 g range for periods up to one year, did not produce adverse health effects. The SCF Opinion of 2003 refers to a number of anecdotal reports of acute, adverse effects in young persons consuming “energy” drinks, containing caffeine, taurine and D-glucurono-γlactone, usually together with alcohol and/or ‘social drugs’, such as ecstasy and amphetamines. The adverse effects reported included tremors, seizures, drowsiness, muscle weakness, dizziness, nervousness, tachycardia, palpitations, nausea, vomiting, headache, bronchospasm, hyperventilation and also myocardial infarction and sudden unexplained death possibly resulting from cardiac dysrhythmia (SCF, 2003). The SCF already concluded the following: “The co-consumption of alcohol and/or drugs noted in most of these cases makes interpretation of effects due to the “energy” drinks particularly difficult. Thus there is no confirmation of any causal relationship between the reported effects and the consumption of “energy” drinks. Under these circumstances, the reports can only be noted”. New human data on the assessment of “energy” drinks have been compiled in a recent BfR Opinion (BfR, 2008) reporting recent Swedish and American studies (Lehtihet et al., 2006; Wiklund et al., 2004; Steinke et al., 2007; American Heart Association; 2007; Iyadurai and Chung; 2007). In a Swedish publication possible adverse reactions of “energy” drinks The EFSA Journal (2009) 935, 18-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks including three cases of death are discussed, focussing on a potential contributing role of taurine associated with its known effects e.g. in osmoregulation and on the cardiovascular system. The three fatalities occurred after “energy” drinks had been consumed in combination with alcohol, whereby the forensic examinations including autopsy yielded negative results concerning medicaments and drugs, values between 0.59 and 0.87 parts per thousand of ethanol in blood samples, but no clear causes of death. In a further case, severe adverse effects arose after consumption of an “energy” drink in combination with physical efforts: A 31-yearold regularly trained man consumed 750 mL of an “energy” drink while taking part in a 3,000 m competition. He developed a poor general condition with a rhabdomyolysis and acute kidney failure with tubular necrosis diagnosed one week after the competition (Lehtihet et al., 2006). Two new cases of “energy” drink-related tachycardias, in one individual associated with orthostatic intolerance, were reported by other authors (Nagajothi et al., 2008; Terlizzi et al., 2008). In the Terlizzi study, consumption was reported to amount to 4 to 5 cans of “energy drinks” a day. In addition, cases of four patients who suffered generalised cerebral seizures after consuming a high dose of “energy” drinks, without there being any reports of parallel alcohol consumption were reported (Iyadurai and Chung, 2007). Overall, the results also raised the issue of combination effects and possible interactions between, amongst others, taurine and alcohol, between taurine and caffeine and between taurine and D-glucurono-γ-lactone. The SCF Opinion already evaluated the possibility of interactions between taurine, caffeine and D-glucurono-γ-lactone and considered it unlikely that D-glucurono-γ-lactone would have any interaction with caffeine and taurine. The SCF concluded (2003) “that consideration of the potential for interactions between caffeine and taurine has not ruled out the possibility of stimulatory effects from both substances at the levels of the central nervous system”. The SCF also noted that “since caffeine and taurine act via different mechanisms, any diuretic effects could be additive” and that “Both taurine (Gentile et al., 1994) and alcohol centrally inhibit the release of the antidiuretic hormone, vasopressin and the Committee considered that they could act additively to increase water and sodium loss from the body in the short-term”. New data have recently been published (Riesenhuber et al., 2006) describing results from a study investigating the possible additive diuretic effects of caffeine and taurine in a cross-over design in which 12 healthy male volunteers each received four different test drinks (750 mL of “energy” drink containing 240 mg caffeine and 3 g taurine, the three other test drinks that lacked caffeine, taurine or both). Effects on urinary output, urinary osmolarity and natriuresis were compared by mixed model analyses. Urinary output and natriuresis increased significantly with caffeine alone and in the caffeine-taurine group. This study demonstrated that the diuretic potential and natriuretic effects of the tested “energy” drinks were largely mediated by caffeine and that there were no additive interactions between taurine and caffeine. The petitioner concluded that this study does not support the possibility of interactions between taurine and caffeine. To investigate possible cardiovascular effects of the combined exposure to caffeine and taurine with “energy” drinks an orientational study was conducted in healthy volunteers with low blood pressure (8 women, 7 men, average age of 26 years) in a state of physical rest (Steinke et al., 2007; American Heart Association, 2007). The test persons had abstained from caffeine for 48 h before the start of the study and throughout the study period. After an initial examination during which blood pressure and heart rate were measured and an ECG was The EFSA Journal (2009) 935, 19-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks carried out, each participant consumed 500 mL of “energy” drink containing a total of 80 mg caffeine and 1000 mg taurine. The examinations were repeated at intervals of up to 4 hours. On each of the following five days the participants again drank 500 mL and on the seventh day the procedure of the first day was repeated. Four hours after consumption of the beverage, systolic blood pressure had increased by 7.9 % (day one) or 9.6 % (day seven) and heart rate had been raised by 7.8 % (day one) or 11 % (day seven). Over the duration of the study this means an increase of blood pressure by 10 mm Hg and of heart rates of 5 to 7 beats per minute. No habituation could be determined following several days exposure since the effects were slightly enhanced on the seventh day. Until the submission of further findings the researchers recommended that patients with high blood pressure or cardiac diseases and corresponding medication should refrain from consuming “energy” drinks because of a possible health risk. 3. Discussion In the absence of new chronic and acute exposure data, the exposure assessment is based on the data reported by SCF (2003), i.e. a daily mean chronic consumption of 0.5 cans per person and a high chronic exposure at the 95th percentile of 1.4 cans per regular consumer. The Panel notes that actual exposure data on “energy” drink consumption, especially for adolescents and young adults, may need to be collected. These estimates for the daily exposure to taurine (mean 500 mg/day; 95th percentile 1400 mg/day) or D-glucurono-γ-lactone (mean 300 mg/day; 95th percentile 840 mg/day) from “energy” drinks are higher than the estimated mean daily exposure to taurine from omnivore diets which was estimated to be at most 400 mg/day and that of D-glucurono-γ-lactone from naturally occurring sources in the diet estimated to amount to 1-2 mg/day (SCF, 2003). The Panel concludes that assuming that children were to consume within the adult intake range of 0.5 and 1.4 cans per person only once per week, then the average chronic exposure of children to “energy” drinks and their constituents, on a body weight basis, would be one third of that in adults. The SCF Opinion (2003) used 3 cans/day as a reasonable high (acute) consumption, this amount being higher than the 90th percentile recorded in the Austrian survey (2.6 cans/day) and being the average reported in the Irish survey for the most number of cans consumed in a single session. The SCF also indicated that it was aware that amounts of up to 8-12 cans/day were reported by a few extreme consumers in both surveys. Taurine Results from a new study on absorption, tissue distribution, metabolism and elimination of taurine given orally to rats were provided by the petitioner (Sved et al., 2007). The Panel concludes that these new ADME data support the contention that oral exposure to taurine was not increasing taurine levels in the brain. In 2003 the SCF evaluated a 13-week rat oral toxicity study of taurine and concluded that focused neurological studies were needed and that the absence of a NOAEL for these effects precluded the setting of an upper safe level for daily exposure to taurine. The EFSA Journal (2009) 935, 20-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks The Panel evaluated a new 13-week oral rat toxicity and neurotoxicity study in male and female rats which included FOB and locomotor activity tests. The new study confirmed the NOAEL of 1000 mg/kg bw/day for pathological changes established in the earlier 13-week study described already by the SCF in 2003 and provided evidence for a NOAEL of 1500 mg/kg bw/day for behavioural effects. The results of this study were sufficient to address the concerns raised previously, notably the observation of increased activity and possible decrements in motor skills on the rotarod. The NOAEL of at least 1000 mg/kg bw/day for pathological changes is 120-fold higher than the estimated mean and 43-fold higher than the estimated 95th percentile exposure to taurine from “energy” drinks only, when calculated for a 60 kg person. Given that taurine is a natural body constituent, the Panel concludes that these margins of safety are sufficiently large to conclude that exposure to taurine at the levels mentioned above is not of safety concern. D-glucurono-γ-lactone In 2003 the SCF evaluated a 13-week rat oral toxicity study with D-glucurono-γ-lactone and concluded that the cause of the kidney lesions remained unclear. The petitioner has now provided data from a new 13-week oral (gavage versus drinking water) toxicity study of D-glucurono-γ-lactone in rats, with specific focus on the kidneys. This study used the same rat strain as the previous study reported in the SCF Opinion of 2003. Extensive urinalysis and histopathological examinations demonstrated no treatment-related effects. Based on the results of this study, the NOAEL for daily oral administration of Dglucurono-γ-lactone was 1000 mg/kg bw/day, the highest dose tested. Toxicological studies on genotoxic, teratogenic or carcinogenic potential of D-glucurono-γlactone were not available. However, D-glucurono-γ-lactone is a normal human metabolite formed from glucose and there are no structural alerts for mutagenicity or carcinogenicity. At physiological pH it is in equilibrium with glucuronic acid, its immediate precursor. Dglucurono-γ-lactone and its hydrolysis product glucuronic acid are endogenous metabolites in humans and other mammals, they occur naturally in several dietary sources and are readily metabolized to innocuous products and excreted. Furthermore there was no evidence of any effect on the gonads in the high dose 13-week studies which might indicate the need for reproductive toxicity studies. The NOAEL for D-glucurono-γ-lactone of 1000 mg/kg bw/day is 200-fold higher than the estimated mean and 71-fold higher than the estimated 95th percentile exposure to Dglucurono-γ-lactone from “energy” drinks only, when calculated for a 60 kg person. Given the fact that D-glucurono-γ-lactone is a natural body constituent the Panel concludes that these margins of safety are sufficiently large to conclude that exposure to D-glucurono-γlactone at the levels mentioned above is not of safety concern. Combined exposure The SCF Opinion of 2003 and the recent BfR Opinion (BfR, 2008) mention a number of anecdotal and case reports of acute, adverse effects, including fatalities, in individuals consuming “energy” drinks, containing caffeine, taurine and D-glucurono-γ-lactone. In these cases, “energy” drinks had either been consumed in very high amounts (1420 mL), in combination with physical exercise or more frequently together with alcohol. The SCF The EFSA Journal (2009) 935, 21-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks Opinion of 2003 also takes into account that drugs, such as ecstasy and amphetamines may have been involved. The effects mentioned included tremors, seizures, drowsiness, muscle weakness, dizziness, nervousness, tachycardia, palpitations, nausea, vomiting, headache, bronchospasm, hyperventilation and also myocardial infarction and sudden unexplained death possibly resulting from cardiac dysrhythmia (SCF, 2003; BfR, 2008; Lehtihet et al., 2006; Iyadurai and Chung; 2007, Nagajothi et al., 2008; Terlizzi et al., 2008). The SCF concluded the following: “The co-consumption of alcohol and/or drugs noted in most of these cases makes interpretation particularly difficult. Thus there is no confirmation of any causal relationship between the reported effects and the consumption of “energy” drinks. Under these circumstances, the reports can only be noted”. With regard to some actual reports (e.g. Iyadurai and Chung; 2007, Nagajothi et al., 2008; Terlizzi et al., 2008) the Panel considers that it is possible that the effects could be due to the well known side effects of high caffeine intake, while the assumption of a causal relationship with taurine intake is lacking scientific evidence. These results also raised the issue of combination effects and possible interactions between, amongst others, taurine and alcohol, between taurine and caffeine and between taurine and Dglucurono-γ-lactone. The SCF Opinion (SCF, 2003) already evaluated the possibility of interactions between taurine, caffeine and D-glucurono-γ-lactone and considered it unlikely that D-glucurono-γlactone would have any interaction with caffeine and taurine. The SCF concluded “that consideration of the potential for interactions between caffeine and taurine has not ruled out the possibility of stimulatory effects from both substances at the level of the central nervous system”. Results from a new study provided by the petitioner (Sved et al., 2007) revealed that brain taurine levels did not increase after dosing. The Panel concludes that these new ADME data support the contention that oral exposure to taurine was not increasing taurine levels in the brain and that this largely rules out the possibility of stimulatory effects from taurine at the level of the central nervous system. The SCF (2003) also noted that “since caffeine and taurine act via different mechanisms, any diuretic effects could be additive” and that “Both taurine (Gentile et al., 1994) and alcohol centrally inhibit the release of the antidiuretic hormone, vasopressin and the Committee considered that they could act additively to increase water and sodium loss from the body in the short-term”. New data have recently been published (Riesenhuber et al., 2006) describing results demonstrating that the diuretic potential and natriuretic effects of the tested “energy” drinks were largely mediated by caffeine and that there were no additive interactions between taurine and caffeine. The Panel concludes that the diuretic potential and natriuretic effects of “energy” drinks may be largely mediated by caffeine and not by taurine. In a recent study, possible cardiovascular effects of the combined exposure to caffeine and taurine with “energy” drinks were investigated (Steinke et al., 2007; American Heart Association, 2007). Four hours after consumption of 500 mL of “energy” drink containing a total of 80 mg caffeine and 1000 mg taurine, systolic blood pressure had increased by 7.9 % (day one) or 9.6 % (day seven) and heart rate had been raised by 7.8 % (day one) or 11 % (day seven). Over the duration of the study this means an increase of blood pressure by 10 mm Hg and of heart rates of 5 to 7 beats per minute. Until the submission of further findings the researchers recommended that patients with high blood pressure or cardiac diseases and corresponding medication should refrain from consuming “energy” drinks because of a The EFSA Journal (2009) 935, 22-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks possible health risk. The Panel notes that the studies were not designed to show whether the effects were due to caffeine or taurine. Overall, the ANS Panel concludes that the diuretic potential and natriuretic effects of the tested “energy” drinks are largely mediated by caffeine. Other interactions between taurine and caffeine were not investigated. CONCLUSIONS AND RECOMMENDATIONS In the present opinion the Panel evaluates the safety of taurine and D-glucurono-γ-lactone as individual ingredients of the so-called “energy” drinks based on the new studies provided by the petitioner. The Panel does not evaluate the safety of “energy” drinks as such. In the absence of new chronic and acute exposure data, the exposure is based on the data reported by the SCF in 2003. The Panel concluded that actual exposure data on “energy” drink consumption, especially for adolescents and young adults, may need to be collected. The Panel concludes that the exposure to taurine and D-glucurono-γ-lactone at the levels presently used in “energy” drinks and mentioned above is not of safety concern. The ANS Panel agrees with the considerations of the SCF Opinion from 2003 that it is unlikely that glucurono-γ-lactone would have any interaction with caffeine, taurine, alcohol or the effects of exercise. The Panel also concludes, based on the new data available, that additive interactions between taurine and caffeine on diuretic effects are unlikely. Other interactions between taurine and caffeine were not investigated. DOCUMENTATION PROVIDED TO EFSA 1. Kroes R. and Renwick, A.G. Summary report regarding the safety in Use of Taurine and D-glucuronolactone as constituents of “energy” drinks. 2. Final report. A 13-week oral (gavage and drinking water) neurotoxicity study of taurine in male and female rats (WIL-42306). Submitted by Red Bull GmbH. 3. Final report. 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Smith LJ, Lacaille F, Lepage G, Ronco N, Lamarre A, Roy CC, 1991. Taurine decreases fecal fatty acid and sterol excretion in cystic fibrosis. A randomized double-blind trial. Am J Dis Child. 145(12), 1401-1404. Steinke L, Kalus JS, Dhanapal V, Lanfear DE, Berlie HD, 2007. Abstract 3661: “Energy drink” consumption causes increases in blood pressure and heart rate. Circulation 116, II_831. Sved DW, Godsey JL, Ledyard SL, Mahoney AP, Stetson PL, Ho S, Myers NR, Resnis P, Renwick AG, 2007. Absorption, tissue distribution, metabolism and elimination of taurine given orally to rats. Amino Acids 32, 459-466. Takahashi R, Nakane Y, 1978. Clinical trial of taurine in epilepsy. In: Barbeau A, Huxtable RJ (eds.). Taurine and Neurological Disorders. Raven Press, New York, pp. 375-385. Terlizzi R, Rocchi C, Serra M, Solieri L, Cortelli P, 2008. Reversible postural tachycardia syndrome due to inadvertent overuse of Red Bull. Clin. Auton. Res. 18, 221-223. Thompson GN, 1988. Excessive fecal taurine loss predisposes to taurine deficiency in cystic fibrosis. J. Pediatr. Gastroenterol Nutr. 7(2), 214-219. Trautwein EA and Hayes KC, 1995. Plasma and whole blood taurine concentrations respond differently to taurine supplementation (humans) and depletion (cats). Z. Ernährungswiss 34, 137-142. United States Pharmacopoeia 29 - National Formulary 24, 2005. Taurine-USP Monographs, page 2058. Wiklund U, Öström M, Messner T, Holmgren P, 2004. Do energy drinks affect the heart rhythm? Europace, Suppl. 6, 68. The EFSA Journal (2009) 935, 29-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks Yamamoto S, Ohmoto K, Ideguchi S, Yamamoto R, Mitsui Y, Shimabara M, Iguchi Y, Ohumi T, Takatori K, 1994. Painful muscle cramps in liver cirrhosis and effects of oral taurine administration. Nippon Shokakibyo Gakkai Zasshi. 91(7), 1205-1209. Yamori Y, Nara Y, Ikeda K, Mizushima S, 1996. Is taurine a preventive nutrional factor of cardiovascular diseases or just a biological marker of nutrition? Adv. Exp. Med. Biol. 403, 623-629. The EFSA Journal (2009) 935, 30-31 The use of taurine and D-glucurono-γlactone as constituents of the so-called “energy” drinks GLOSSARY / ABBREVIATIONS ADME Absorption, Distribution, Metabolism, Excretion AFSSA Agence Française de Sécurité Sanitaire des Aliments ANZFA Australia New Zealand Food Authority BfR Federal Institute for Risk Assessment CMC Carboxymethylcellulose EFSA European Food Safety Authority FSA Food Standards Agency HPLC High performance liquid chromatography NOAEL No Observable Adverse Effect Level SCF Scientific Committee on Food The EFSA Journal (2009) 935, 31-31 International Journal of General Medicine Dovepress open access to scientific and medical research R eview Open Access Full Text Article Energy drinks mixed with alcohol: misconceptions, myths, and facts This article was published in the following Dove Press journal: International Journal of General Medicine 1 March 2012 Number of times this article has been viewed Joris C Verster 1 Christoph Aufricht 2 Chris Alford 3 1 Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Utrecht, The Netherlands; 2Medical University of Vienna, Department of Pediatrics and Adolescent Medicine, Währinger Gürtel, Wien, Austria; 3University of the West of England, Psychology Department, Faculty of Health and Life Sciences, Frenchay Campus, Coldharbour Lane, Bristol, UK Background: Whilst energy drinks improve performance and feelings of alertness, recent articles suggest that energy drink consumption combined with alcohol may reduce perception of alcohol intoxication, or lead to increased alcohol or drug use. This review discusses the available scientific evidence on the effects of mixing energy drinks with alcohol. Methods: A literature search was performed using the keywords “energy drink and Red Bull®” and consulting Medline/Pubmed, PsycINFO, and Embase. Results: There is little evidence that energy drinks antagonize the behavioral effects of alcohol, and there is no consistent evidence that energy drinks alter the perceived level of intoxication of people who mix energy drinks with alcohol. No clinically relevant cardiovascular or other adverse effects have been reported for healthy subjects combining energy drinks with alcohol, although there are no long-term investigations currently available. Finally, whilst several surveys have shown associations, there is no direct evidence that coadministration of energy drinks increases alcohol consumption, or initiates drug and alcohol dependence or abuse. Conclusion: Although some reports suggest that energy drinks lead to reduced awareness of intoxication and increased alcohol consumption, a review of the available literature shows that these views are not supported by direct or reliable scientific evidence. A personality with higher levels of risk-taking behavior may be the primary reason for increased alcohol and drug abuse per se. The coconsumption of energy drinks being one of the many expressions of that type of lifestyle and personality. Keywords: energy drink and Red Bull®, Red Bull®, alcohol, intoxication, caffeine, masking Introduction Correspondence: Joris C Verster Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands Tel +31 03 0253 6909 Email [email protected] submit your manuscript | www.dovepress.com Dovepress http://dx.doi.org/10.2147/IJGM.S29313 Although energy drinks comprise only 1% of the total soft drink market, these products are becoming increasingly popular.1 The market leader, Red Bull® Energy Drink is available in over 160 countries and, although some local sales restrictions may apply, energy drinks are not banned in any country. The most important functional ingredient of energy drinks is caffeine. Table 1 lists some of the well known energy drink brands, and their caffeine content. It is evident from Table 1 that popular energy drinks such as Red Bull (250 mL, 8.4 oz) contain a similar amount of caffeine (ie, 80 mg) to that present in one regular cup of coffee (240 mL, 8 oz).2,3 However, less popular brands may have a higher caffeine content. Caffeine does not have adverse effects for the general population of healthy adults if they limit caffeine intake to 400 mg per day.4 Various experimental studies have examined the behavioral effects of energy drinks when consumed alone. Most studies have shown that energy drink consumption can significantly improve cognitive International Journal of General Medicine 2012:5 187–198 187 © 2012 Verster et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Dovepress Verster et al Table 1 Caffeine content of some well known energy drinks2,3 Red bull Monster Rockstar Full throttle No fear Amp SoBe Tab energy Cola Coffee Tea Bottle/can mL (oz) Caffeine mg/100 mL (mg/oz) Total caffeine mg (range) 250 (8.4) 473 (16) 473 (16) 473 (16) 473 (16) 250 (8.4) 250 (8.4) 311 (10.5) 355 (12) 237 (8) 237 (8) 32 (9.6) 34 (10) 34 (10) 30 (9) 37 (10.9) 30 (8.9) 32 (9.5) 31 (9.1) 11 (3.3) 36 (10.6) 17 (5) 80 160 160 144 174 75 79 95 40 (30–60) 85 (65–120) 40 (20–90) and psychomotor functioning5–10 and driving ability,10–12 preexercise consumption can significantly improve endurance and physical performance,7,13–15 and whilst some studies have reported small changes in heart rate or blood pressure, no clinically relevant adverse cardiovascular effects have been reported after normal use of energy drinks in healthy volunteers,7,16–21 although there is currently a lack of longterm data. Health regulatory authorities across the world have concluded that energy drinks are safe to consume, although some authorities have expressed concerns about the potential health risks associated with mixing alcohol and caffeine. It should also be noted that there are anecdotal and case reports of acute adverse effects, including fatalities, in individuals consuming energy drinks combined with alcohol, but no confirmation of any causal relationship between the reported effects and the consumption of energy drinks.22 Research and media attention has recently been drawn to alcohol mixed with energy drinks (AmED). In this context, it has been suggested that AmED consumption may reduce the perception of alcohol intoxication or that coconsumption may lead to increased alcohol consumption. This paper aims to review and put into perspective the current scientific evidence on the combined use of energy drinks and alcohol. Methods A literature search was performed (updated December 1, 2011) using the keywords “energy drink” and “Red Bull”, consulting Medline/Pubmed, PsycINFO, and Embase for clinical trials and surveys examining the effects of energy drinks consumed together with alcohol. Cross-references were checked for additional research papers. This literature search yielded 23 research articles that were included in this review. 188 submit your manuscript | www.dovepress.com Dovepress Results Most people consume energy drinks only occasionally (eg, less than 6% of college students consume energy drinks daily).23 Surveys among students reveal that they consume energy drinks to counteract sleepiness, to enhance energy and concentration,24 or because they simply like it.25 Reasons given for consuming energy drinks combined with alcohol include “during partying”,24 to celebrate,26 because they like the taste,26 to hide the flavor of alcohol,27 or to get drunk.26 However, only 2% of all students (and 15% of those who combined alcohol with energy drinks) indicated they did so in an attempt to be able to drink more and not feel as drunk.27 Surveys among students have found that 6%–44% report consumption of AmED.24–32 Price et al interviewed 72 regular consumers of energy drinks about their past week and lifetime energy drink and alcohol intake, applying the timeline follow-back approach.33 Thirteen percent of past-week alcohol consumption sessions involved the co-use of energy drinks. Analysis of survey data revealed that students who consume AmED were significantly more often young white males.27,31,34 Taken together, these surveys suggest that a relative minority of students occasionally consume AmED. Do energy drinks antagonize alcohol-induced performance impairment? Seven studies examined the possible antagonizing effects of energy drinks on alcohol-induced performance impairment, including both recovery from physical exercise and cognitive testing.16,35–40 The results of these studies are summarized in Table 2. A significant limitation of two of these studies36,37 is that alcohol was not tested alone, so it cannot be determined if the effects caused by AmED are actually the same as when administering alcohol alone. Ferreira et al failed to find significant differences on a variety of physical performance and recovery parameters.16 The statistical analysis reported by Marczinski et al, based on significant changes from baseline, found that some aspects of cognitive performance were poorer for alcohol alone compared with the energy drink, placebo, or AmED groups, but not for all tests.38 In a second study, Marczinski et al did not find any significant difference between impairment on information processing and motor coordination tasks between AmED and alcohol only.39 Ferreira et al also failed to show differences between alcohol and AmED,35 whilst Alford et al showed improvement with AmED in one test, but not others, compared with alcohol.40 Therefore, there is mixed evidence that energy drink consumption antagonizes some performance effects International Journal of General Medicine 2012:5 International Journal of General Medicine 2012:5 12 healthy volunteers received lower dose, 14 higher alcohol dose, both also receiving energy drink or water control, or alcohol + energy drink in a mixed, blind design with random allocation Double-blind, crossover trial to examine heart rate variability and ECG changes in 10 healthy volunteers Ferreira et al35 submit your manuscript | www.dovepress.com Dovepress Double-blind, placebo-controlled study in18 healthy volunteers Marczinski et al39 Placebo, energy drink (3.57 g/kg), alcohol (0.65 g/kg), AmED Placebo, energy drink, alcohol (0.072%–0.089% BrAC), AmED (0.07%–0.08% BrAC) AmED (6% alcohol by volume), energy drink alone, and a noncaffeinated placebo drink Alcohol or AmED in a rising dose (0.046% and 0.087% BrAC) 3 cans (750 mL) of energy drink alone or in combination with alcohol (vodka, 0.4 g/kg body weight) or no drink at all Abbreviations: BrAC, breath alcohol concentration; AmED, alcohol mixed with energy drink; ECG, electrocardiogram. Double-blind, placebo-controlled, between subjects comparison in 56 healthy volunteers, divided into four groups Double-blind, placebo-controlled study in two groups of 10 healthy volunteers Alford et al40 Marczinski et al38 Double-blind, placebo-controlled trial in 27 healthy females Curry and Stasio36 Wiklund et al37 Alcohol (1.0 g/kg), energy drink (3.57 mL/kg body weight), and their combination Double-blind crossover trial in 14 healthy volunteers Ferreira et al16 Alcohol (0.6 and 1.0 g/kg); energy drink, or same volume water (3.57 mL/kg body weight) Dosing Subjects and design Reference Subjects performed a maximal bicycle ergometer exercise for 30 minutes. Postexercise recovery in heart rate and heart rate variability was slower after energy drink and alcohol than after exercise alone. No clinically significant arrhythmias or ECG changes were observed AmED significantly impaired neuropsychological function (in particular visuospatial and language skills), whereas the energy drink alone nonsignificantly improved performance (in particular attention scores) Reaction time and memory were impaired by both alcohol and AmED, although Stroop performance was improved for AmED compared with alcohol suggesting partial antagonism. No significant difference in breath alcohol concentration between alcohol and AmED Compared with alcohol, coadministration of energy drink counteracted some but not all performance impairment. No significant difference in breath alcohol concentration between alcohol and AmED Compared with alcohol, AmED did not significantly alter performance on tests of information processing and motor coordination No significant difference on maximal effort test (cycle ergometer) or recovery for a number of physiological and biochemical parameters between alcohol alone, and alcohol administered in combination with energy drink Breath alcohol concentration, visual reaction time, and grooved peg-board reported as not showing differences between alcohol alone and AmED Findings highlighted by authors Table 2 Studies examining potential antagonizing effects of energy drinks on alcohol-induced performance impairment No evidence of energy drink antagonizing effects of alcohol Possible antagonism of alcohol seen in three out of four performance tests for AmED compared with alcohol alone Possible antagonism of alcohol seen in one out of three tests for AmED compared with alcohol alone Alcohol alone not tested, therefore no comparison can be made between alcohol and AmED Alcohol alone not tested, therefore no comparison can be made between alcohol and AmED No evidence of energy drink antagonizing effects of alcohol No evidence of energy drink antagonizing effects of alcohol Comment Dovepress Energy drinks mixed with alcohol 189 Dovepress Verster et al caused by alcohol intoxication but not others. This suggests no consistent antagonism of alcohol-induced impairment by coconsumption of energy drinks. A recent double-blind, placebo-controlled study by Howland et al did not observe any significant differences on simulated driving, sustained attention, or reaction time between caffeinated and noncaffeinated beer (383 mg caffeine, peak breath alcohol concentration [BrAC] of 0.12%), suggesting no consistent antagonism of alcohol-induced impairment by coconsumption of caffeine.41 Do energy drinks change the drinker’s perception of intoxication? It has been claimed that people consume energy drinks because they presume it will counteract the impairing effects of alcohol. For example, O’Brien et al reported this for 15% of students who consumed AmED. 27 Few experimental studies actually examined the perception of intoxication after consuming AmED. One of the most cited studies in this context was performed by Ferreira et al, who evaluated breath alcohol concentration (0.04%–0.1% BrAC), psychomotor functioning, and subjective intoxication after administration of an energy drink, alcohol (vodka, 0.6 or 1.0 g/kg), or AmED.35 Twenty-six subjects participated in this randomized, controlled trial. Coadministration of energy drink did not affect breath alcohol concentration. Symptoms during intoxication were scored using the Bond and Lader 13-item somatic symptoms scale,42,43 extended with five additional items, giving 18 items in all. The paper revealed that alcohol and AmED similarly impaired psychomotor performance. The results section reports that AmED reduced the perception of headache, dry mouth, and impairment of motor coordination compared with alcohol alone. However, the appropriateness of using these symptoms as a measure of intoxication should be questioned, especially because most other symptoms, of which several are related to feelings of intoxication (eg, dizziness, speech, tiredness, vision, walking, wellbeing), did not show a significant reduction for AmED compared with alcohol alone. Consequently, the interpretation of these results as showing a reduction in perceived intoxication after AmED compared with alcohol alone cannot be taken as consistent and reliable on the basis of this single study. Alford et al found participants felt significantly impaired after alcohol (0.05%–0.09% BrAC) and significantly impaired by the higher compared with lower alcohol dose (4/5 scales), but no overall difference between alcohol alone and energy drink combined with alcohol.40 190 submit your manuscript | www.dovepress.com Dovepress Marczinski et al reported that alcohol alone (0.07–0.09 BrAC) significantly increased ratings of feeling the drink, liking the drink, impairment, and level of intoxication, whereas it reduced the rating of ability to drive.38 AmED showed no significant difference for these ratings. The abstract of this article implies that self-reported stimulation was increased for AmED compared with alcohol alone, and that this might contribute to a higher risk scenario. However, their data showed that subjective stimulation was significantly increased from baseline for both the alcohol and AmED groups. Unfortunately, in this paper, no direct statistical comparisons were made between the AmED and alcohol group. In a second study, Marczinski et al reported that consumption of AmED reduced mental fatigue and increased feelings of stimulation, when compared with consuming alcohol alone.39 No significant difference between AmED and alcohol alone was reported on subjective intoxication or ability to drive. Taken together, the results from these studies do not show a change in perceived intoxication on the majority of subjective scales, including intoxication and ability to drive, when alcohol is mixed with energy drink. Higher levels of alcohol have been compared with alcohol and caffeine in combination, though not using energy drinks. Howland et al investigated higher doses of alcohol comparing the effects of caffeinated beer versus noncaffeinated beer, and nonalcoholic beer in 127 nondependent, heavy episodic drinkers, aged 21–30 years.41 When a peak BrAC of 0.12% was achieved, there was no significant difference in estimated BrAC between caffeinated and noncaffeinated beer, indicating that caffeine (a total dose of 383 mg on average) did not mask the alcohol intoxication effects, and thereby supporting the majority of findings observed with energy drinks. Do energy drinks enhance alcohol consumption? Given the stimulant effects of caffeine-containing energy drinks, it has been suggested that when consumed together with alcohol, energy drinks would increase alcohol ingestion. Although no experimental data are available, several surveys examined the coconsumption of energy drinks and alcohol.27–34,44–48 The design and results of these studies, which are nearly all from the US, are summarized in Table 3. In addition to the conclusions drawn by the respective authors, Table 3 also includes our interpretation of the data in the comment column. Arria et al conducted a 3-year longitudinal study aiming to examine illicit drug use patterns among college students (the 2003 College Life Study).49 Annually, they interviewed International Journal of General Medicine 2012:5 International Journal of General Medicine 2012:5 Jock identity (mediated by masculine norms and risk-taking behavior) was positively related to energy drink consumption (without alcohol) AmED consumption was associated with significantly increased heavy episodic drinking, episodes of weekly drunkenness, and alcohol-related consequences 795 undergraduate students 4271 college students; 697 AmED (16%); 2189 alcohol alone (52%); 1351 nondrinkers (32%); between-subject comparison 1060 college students; 264 energy drink users; 796 nonusers; between-subject comparison Miller44 US O’Brien et al27 US Arria et al28 US Attila and Cakir30 439 Turkish students; Turkey between-subject comparison Frequency of energy drink consumption was positively associated with marijuana use, sexual risk-taking, fighting, not wearing a seat belt, risk-taking, smoking, drinking, alcohol problems, and illicit prescription drug use 602 undergraduate students Miller34 US Those who consume energy drinks are more likely to smoke and drink alcoholic beverages. 40% of current users report mixing energy drinks with alcohol Compared with nonusers of energy drinks, energy drink users had a heavier alcohol consumption pattern, and were more likely to have used other drugs. Year 2 energy drink consumption correlated significantly with year 3 nonmedical use of prescription stimulants and analgesics, but not other drugs Findings highlighted by authors Subjects and design Reference Consumption of energy drinks is quite common among students. Their knowledge of ingredients and potential health hazards is low Energy drink users tend to have greater involvement in alcohol and other drug use Risk-taking behavior partly mediates the relationship between jock identity and AmED consumption With AmED consumption students are at increased risk for alcohol-related consequences (also after adjustment for the amount of alcohol consumed) Energy drink consumption is closely associated with a problem behavior syndrome Authors’ conclusion Table 3 Surveys and on-premise studies that examined the relationship between alcohol and energy drink consumption submit your manuscript | www.dovepress.com Dovepress (Continued) • The authors show that those who consume more alcohol experience more alcohol-related consequences • The authors do not provide evidence that during the days of heavy episodic drinking or reported drunkenness alcohol was mixed with energy drinks • No evidence of a causal relationship between energy drink and alcohol consumption is provided • Only a relative minority (16%) mixed alcohol with energy drinks • The study was designed for another purpose, and those with past experience of illicit and/or prescription drugs were oversampled • The difference between alcohol consumption of energy drink users and nonusers is statistically significant but of no clinical relevance (6.0 versus 4.7 drinks per drinking day); similarly for the past year count of drug use (1.5 versus 1.0 occasions) • It is not determined whether energy drinks and alcohol were consumed together or alone • Prescription and illicit drug use was measured using a binary (yes or no) scale • No evidence of a causal relationship between energy drink and alcohol consumption is provided • Only 15.2% of current users reported that the main reason to consume energy drinks is to mix with alcohol. Most students consumed energy drinks to feel energetic (24.2%), boost performance during exercise (21.4%), or because of its taste (17.0%) • No information on quantity of energy drink consumption was provided • No information was provided on whether alcohol and drugs were consumed together with energy drink or alone • No information was provided on whether alcohol-related consequences were experienced when alcohol was consumed together with energy drinks or alone • Energy drink consumption explains only a small part of the variance of ten domains of problem behavior that were examined (R2 = 0.23 or less) • The presented associations prove no causal relationship • No evidence of a causal relationship is provided Comment Dovepress Energy drinks mixed with alcohol 191 192 Dovepress submit your manuscript | www.dovepress.com 328 bar patrons: 180 alcohol only, n = 64 cola-caffeinated alcohol only, n = 10 AmED only; onpremise study 413 bar patrons For secondary analyses, see data references 29 and 45 Thombs et al45 US Arria et al46 US Rossheim and Thombs32 US 1097 fourth-year college students, 975 entered analyses (338 nonusers, 518 low-frequent users 1–51 times/year), 802 bar patrons (people who visit a bar and consume alcohol): 602 alcohol only, 45 AmED; onpremise study Thombs et al29 US Woolsey et al48 US 72 subjects, of which 10 consumed AmED and alcohol alone during the past week; within-subject comparison 401 student athletes: 165 alcohol only; 150 AmED; 194 energy drinks alone. Both within-group and between-subject comparison Subjects and design Price et al33 Canada Reference Table 3 (Continued) Comparing n = 69 alcohol mixed with regular cola, n = 24 alcohol mixed with diet cola, n = 19 AmED, and n = 147 alcohol only, n = 129 noncaffeinated mixers and alcohol. Those who mix alcohol with diet-cola have a significantly higher BrAC when leaving the bar. No significant difference between alcohol only and AmED was found Energy drink consumers consumed more alcohol (both quantity and frequency) and a significant association was reported between high-frequency energy drink users Cola-caffeinated alcoholic beverages consumers and AmED consumers leave the bar significantly more intoxicated than those who consume alcohol alone Weekly or daily energy drink consumption is strongly associated with alcohol dependence Reported risks associated with on premise AmED drinking may be reduced by greater attention given to other types of mixers, particularly diet cola Mixing alcohol with cola poses a similar level of risk for bar patrons to those associated with AmED consumption Combined users consumed significantly more alcohol and had riskier drinking habits than those who consume alcohol only. The combined use of alcohol and energy drinks may increase alcohol consumption, risk-taking behavior, and the chance of experiencing negative alcohol-related consequences Energy drink consumption by young adults at bars is a marker for elevated involvement in night-time risk-taking behavior Combined users consumed significantly more alcohol and had riskier drinking habits than those who consume alcohol only, and experience more negative alcohol-related consequences Patrons who consumed AmED were at three-fold increased risk of leaving the bar highly intoxicated (BrAC . 0.08%), and a four-fold increased risk of intending to drive upon leaving the bar district AmED consumption seems associated with increased alcohol ingestion Authors’ conclusion Subjects (10) consumed significantly more alcohol when mixed with energy drinks (8.6 drinks) when compared with consuming alcohol alone (4.7 drinks) Findings highlighted by authors • The survey fails to indicate whether or not energy drinks were consumed with alcohol, or separately. Hence, the authors do not rule out the possibility that energy drinks were consumed during the day. For example, to compensate for alcohol-related hangover effects • Mixing alcohol with caffeinated cola (22.5%) was more popular than mixing with energy drinks (6%) • No significant difference was found between alcohol only and AmED • Relatively low power (AmED group, n = 19) limits conclusions • Within-subject comparisons show that combined users (AmED, n = 150) report drinking significantly less (27%) alcohol when mixing alcohol with energy drinks (and 41% less on the heaviest drinking day) • Within-subject comparison provides much more reliable evidence than between-subject comparison. Nevertheless, authors do not discuss their within subject findings • No significant within-subject differences were found on the major risk-taking items • It was not verified if they indeed drove a car (no actual risk-taking was determined, only the intention to do so) • The quantity of energy drink consumption was not determined • No significant difference in AUDIT-C (alcoholic drink consumption) score between AmED and alcohol alone • BrAC difference between AmED (0.1%) and alcohol alone (0.08%) was equivalent to just one alcoholic drink • AmED group (n = 10) has insufficient power to draw reliable conclusions • Low sample size does not have sufficient power to draw any conclusion • Short time-frame (one week) Comment Verster et al Dovepress International Journal of General Medicine 2012:5 Dovepress International Journal of General Medicine 2012:5 Abbreviations: AmED, alcohol mixed with energy drink; US, United States; BrAC, breath alcohol concentration; AUDIT-C, Alcohol Use Disorders Identification Test, version C; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. • The number of subjects who consumed energy drinks was low (n = 24) and this limits conclusions • The data did not allow a within-subject comparison • A heavy drinking night that caused a hangover may not reflect a regular night of alcohol consumption Mixing with caffeinated beverages does not change overall alcohol consumption, nor does it affect next-day hangover severity 549 Dutch students, who reported on their latest hangover; between-subject comparison Penning et al47 The Netherlands Compared with nonconsumers, ED drinkers were predominantly male, non-Black, and young (18–29 years old), AmED drinkers white and young. Hazardous drinkers (AUDIT-C 4 or more) were four times more likely to consume energy drinks No significant difference was found in the number of alcoholic drinks consumed on the night before their latest hangover between those who consumed AmED and those who consumed alcohol alone 946 adults aged 18–92 years; between-subject comparison Berger et al31 US 119 high-frequent users (52+ times/year); between-subject comparison and having a DSM-IV diagnosis of alcohol dependence There are population differences between those who mixed alcohol with energy drinks and those who consume alcohol alone • The authors show that those who consume more alcohol (quantity and frequency) also consume more energy drinks. The correlation reported does not imply a cause-and-effect relationship • Those who consume more alcohol are more likely to meet the criteria of alcohol dependence • Only a minority of college students (10.1%) was classified as high-frequency energy drink consumers (52+ times/year) • No information on amount of alcohol consumed or AUDIT-C scores was provided • 6% mixed energy drinks with alcohol during the past year Energy drinks mixed with alcohol 1063 college students. To ensure a sufficient number of eligible subjects, those with past experience of illicit and/or prescription drugs were oversampled. An exploratory analysis of the data was performed comparing those who consume energy drinks and those who do not.28 Since the study was not set up for this purpose, only two questions about energy drink consumption were asked. These questions were “What types of caffeinated products do you consume?” and “Estimate the typical, minimum, and maximum number of caffeinated drinks you consume during a typical week”. Based on the first question, subjects were classified as energy drink users (n = 264) and those who do not consume energy drinks (n = 796). Energy drink consumers reported significantly more alcohol intake (both quantity and frequency). Illicit drug use was not significantly higher in energy drink consumers, nor was the use of medicinal drugs, except for prescription stimulants and analgesics. Subjects also completed the short form of the Zuckerman–Kuhlman Personality Questionnaire. Energy drink consumers scored significantly higher on the subscale of impulsive, sensation-seeking behavior. Unfortunately, the authors did not gather any specific data on whether energy drinks were mixed with alcohol or not. Also, prescription and illicit drug use was only measured using a binary (yes or no) scale. Recently, Arria et al published data from the fourth yearly interview of students participating in the 2003 College Life Study.46 In this interview, students estimated the types of energy drinks and the number of days and usual quantity of energy drinks they consumed during the previous 12 months. The statistical analysis showed an association between energy drink and alcohol consumption, and reported that those who “frequently” consume energy drinks ($52 days per year, ie, $1 per week; representing 10.1% of the sample) significantly more often met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for alcohol dependence. However, the survey also failed to indicate whether or not energy drinks were consumed together with alcohol, or separately. In fact, in both studies, the authors do not rule out the possibility that energy drinks were consumed separately during the day, or the day after to compensate for alcohol-related hangover effects.28,46 A survey among 4271 college students by O’Brien et al showed that consumption of AmED was associated with increased heavy episodic drinking (6.4 days versus 3.4 days in the past 30 days) and weekly drunkenness (1.4 days/week versus 0.73 days/week), and experiencing negative alcoholrelated consequences significantly more often.27 Again, this study also does not provide any evidence for a causal submit your manuscript | www.dovepress.com Dovepress 193 Verster et al r elationship, but does support the association that when people drink more alcohol they may also mix some of their alcohol with energy drinks. Price et al interviewed 10 regular energy drink users about their past week and lifetime energy drink and alcohol use.33 These 10 subjects consumed significantly more alcohol on the occasion that they also consumed energy drinks (8.4 versus 4.7 alcoholic consumptions, respectively). The authors acknowledge the small sample size and recommend additional research, but nevertheless conclude that using energy drinks is associated with increased alcohol consumption. Thombs et al examined energy drink and alcohol use in a naturalistic setting, ie, college bars, between 10.00 pm and 03.00 am.29 In a bar district, 802 subjects were interviewed about their alcohol use and energy drink consumption and performed a breath analysis test to estimate BrAC. Subjects also completed the shortened Alcohol Use Disorders Identification Test (AUDIT-C), a measure of quantity/ frequency of consumption, and were asked how likely it was that they would drive home by car at the end of their night out. Significant differences were observed between those who consumed alcohol only (n = 602) and those who mixed energy drinks with alcohol (n = 46); the differences included mean BrAC (0.08% versus 0.11%), alcohol consumed (95.3 g versus 152.2 g), and total hours of drinking (2.9 hours versus 3.9 hours) for these two groups, respectively. AUDIT-C scores did not significantly differ between the groups. Logistic regression analysis revealed that those who mixed alcohol and energy drinks were 3.32 times more likely to leave the bar intoxicated (BrAC $ 0.08%) and had a 4.26 times increased risk of intending to drive a car after leaving. The authors concluded that the latter suggests perception of alcohol-induced impairment is reduced when coconsumed with energy drinks. An alternative explanation may be that the groups already differed at baseline in alcohol consumption and risk perception. In a second study by Thombs et al, only 10 people reported consuming AmED.45 Therefore, the conclusions drawn based on the data from this small study should be interpreted with caution. Rossheim and Thombs then combined the data from both onpremise studies.32 Based on the combined data, they concluded that energy drink consumption was not associated with an increased risk of being intoxicated. Miller conducted a survey among 602 undergraduate students that indicated energy drink consumption was associated with problem behaviors, particularly among white students.34 Frequency of energy drink consumption was positively associated with marijuana use, smoking, drinking, 194 submit your manuscript | www.dovepress.com Dovepress Dovepress alcohol problems, illicit drug use, and risk-taking behavior. In a second survey among 795 undergraduate students, Miller confirmed that levels of conformity to masculine norms, risk-taking behavior, and sport-related (“jock”) identity significantly predicted the frequency of energy drink consumption.44 Berger et al reported ethnic and other differences between those who consume alcohol alone compared with energy drink users, or those who consume AmED.31 These differences were noted by the authors, who then suggest subgroup targeting for health information. However, they fail to point out that the observed increase in “hazardous drinking” for the AmED group may be accounted for by intergroup differences alone (eg, age, ethnicity), rather than to AmED consumption. A finding from several surveys has been that AmED consumption was associated with increased alcohol consumption.27,28,46 These surveys show that research comparing different groups (eg, those who combine alcohol with energy drinks and those who do not) is always difficult to interpret, and can yield potentially biased results because baseline and other characteristics of the groups have not been controlled for and may differ significantly. This potential bias can be prevented by conducting research using a withinsubject design, ie, comparing drinking occasions in the same subjects with and without energy drink consumption and using an appropriate sample size. This design was applied in a recent survey by Woolsey et al among athletes.48 When comparing drinking habits of those who drink alcohol only (n = 165) and those who mixed alcohol with energy drinks (n = 150) these researchers showed that those who consumed AmED drank alcohol significantly more often, drank more alcohol on single occasions, reported more heavy drinking episodes, and had consumed twice the amount of alcohol during the past year when compared with the group that never mixed alcohol with energy drinks. However, when looking at the group that combined energy drinks with alcohol, it was shown that on occasions when they did mix alcohol and energy drinks they consumed significantly less alcohol (6.28 drinks) when compared with occasions when they consumed alcohol without energy drinks (8.60 drinks) a reduction of 27%. Also, when reporting on the greatest number of alcoholic drinks consumed on a single occasion during the past year, the combined group reported significantly less alcohol consumption (10.83 drinks) when combining alcohol with energy drinks compared with a session of alcohol without energy drinks (18.23 drinks), ie, a reduction of 41%. Also, no significant within subject International Journal of General Medicine 2012:5 Dovepress d ifferences were found on the major risk-taking items “taking risks”, “being brave and daring”, and “being likely to fight”, whereas the statistically significant differences found for “acting aggressively” (2.46 versus 2.76) and “driving a motor vehicle” (1.57 versus 1.75) for alcohol versus AmED, respectively, reflect only small numerical differences and therefore have no clinical relevance. Unfortunately, the authors concluded their article with a discussion of the potential dangers of energy drinks and a call for action to protect the public, and disregarded their own findings showing that alcohol consumption within subjects was substantially reduced when mixing alcohol with energy drinks. Interestingly, recent onpremise studies reveal that the single focus on energy drinks as a mixer for alcohol may be unjustified and misplaced, because other caffeinated mixers such as cola beverages are more popular than energy drinks.29,32,45 They showed that mixing alcohol with caffeinated cola (22.5%) was much more popular than mixing with energy drinks (6%). Breathalyzer assessment on leaving the bar revealed that BrAC levels were similar in those who consumed alcohol mixed with cola (BrAC 0.108%) or consumed AmED (BrAC 0.106%), and somewhat higher than found in those who consumed alcohol only (BrAC 0.091%). A recent survey confirmed these findings among Dutch students, when reporting on their latest night out that caused a hangover.47 No difference in total alcohol consumption was found between those who consumed alcohol alone or AmED, whereas those who mixed alcohol with cola beverages consumed significantly more alcohol. In conclusion, the specific nature of the relationship between energy drink consumption and alcohol consumption, if any, cannot be established from these surveys. The fact that two things occur together (ie, the presented correlations in the surveys between energy drink and alcohol consumption) does not imply that one causes the other.50 More direct and reliable within-subject comparisons comparing occasions of alcohol intake both with and without energy drink consumption, such as performed by Woolsey et al,48 are necessary to establish if there is an actual difference, and to what extent energy drinks influence alcohol consumption, or not.50 Discussion Excessive and irresponsible consumption of alcoholic drinks has adverse effects on human health and behavior, but it should be clear that this is due to the alcohol, and not the mixer. When presenting their data, several authors fail to acknowledge that correlations between energy drink and International Journal of General Medicine 2012:5 Energy drinks mixed with alcohol alcohol consumption do not provide any cause-and-effect relationship.50,51 Instead, they describe the “high” risk of combined use of energy drinks and alcohol52 as “a growing problem”3 or “a new hazard for adolescents”,53 without providing supportive scientific evidence, or they simply copy the conclusions of other authors without having a closer look at the methodology of the surveys and the way the data were analyzed and presented.54 This way of presenting and interpreting scientific data may raise unsubstantiated concerns among consumers and parents about the use of energy drinks (alone or in combination with alcohol) and may actually trigger unjustified regulations in the absence of appropriate data. Some recent reviews have copied the conclusions of these authors, summarizing the data and its interpretation as offered by the authors that conducted these studies, draw unjustified conclusions, or present recommendations for legislation that are not supported by the available scientific data.53–55 However, other authors have commented on the current energy drink debate and disputed the conclusions drawn in these reviews.50,51,56 Other criticism focuses on the methodology and setup of previous studies, some of which were underpowered or were not specifically designed to examine the association between energy drink consumption and alcohol consumption.49 Given the limitations of these studies (summarized in Tables 2 and 3), Skeen and Glenn56 concluded that there is an “imaginary link between alcoholism and energy drinks”, and Verster and Alford50 concluded that the concerns about energy drinks are not justified by the currently available scientific data. But most importantly, when judging articles on energy drinks mixed with alcohol, it should be kept in mind that correlation does not mean causation.51 In fact, there are many alternative explanations. Several surveys compared groups of subjects who do and do not combine alcohol with energy drinks. As some surveys on energy drink consumption suggested, it is possible that the groups of subjects that were compared already differed at baseline regarding the level of risk-taking behavior and other personality traits.28,34,44,46,48 This may explain the observed differences in alcohol and drug use between the groups. People who are high risk-takers are more likely to exhibit life-style behaviors characterized by disinhibition and loss of moderation. These behaviors include increased frequency and amount of alcohol consumption, caffeine consumption, smoking, and recreational drug use, as well as gambling and engagement in risk-taking behavior.57,58 Being a high risk-taker may then be the cause of increased alcohol consumption. submit your manuscript | www.dovepress.com Dovepress 195 Dovepress Verster et al A significant association between levels of risk-taking behavior (measured as sensation-seeking, impulsivity, and related traits) has been reported for alcohol and drug use,59,60 as well as energy drinks.28,34,44,46,48 These surveys link the consumption of energy drinks with a risk-taking lifestyle that is already characterized by higher levels of alcohol consumption. In other words, a personality with higher levels of risk-taking behavior may be the primary reason for increased alcohol and drug abuse. The coconsumption of energy drinks is just one of the many expressions of such a lifestyle and personality. Given that energy drink companies often market their products by relating them to extreme sports and adventurous activities, it is understandable that individuals who are attracted to energy drinks more often have a higher risktaking profile. Seven main conclusions can be drawn from the available scientific literature: • There are currently insufficient properly controlled studies to draw any firm conclusions regarding the effects of energy drinks mixed with alcohol • A relative minority of students occasionally mix energy drinks with alcohol, and there is no evidence that energy drinks are consumed more than other caffeinated drinks (eg, colas) combined with alcohol • There is some evidence that energy drinks may antagonize some, but not all, aspects of alcohol-induced performance impairment • There is no consistent evidence that energy drinks alter the perceived level of intoxication of people who mix energy drinks with alcohol • Whilst there are associations between the levels of alcohol and energy drink consumption, there is no evidence that coconsumption of energy drinks causes increased alcohol consumption • There is no direct evidence that coconsumption of alcohol and energy drinks initiates drug and alcohol dependence or abuse • A personality with higher levels of risk-taking behavior may be the primary reason for increased alcohol and drug abuse. The coconsumption of energy drinks may be one of the many expressions of their lifestyle and personality type. These conclusions are drawn from the limited evidence available at this time. Hence, more and better research is needed. Properly controlled clinical studies, surveys, and prospective studies are required before definite conclusions can be drawn. In order to define the effects of an energy drink, 196 submit your manuscript | www.dovepress.com Dovepress such clinical studies must include sessions of administration of both energy drink or placebo drink (ie, an energy drink without the active ingredients) as well as alcohol alone, and whenever possible applying a within-subject design. Such designs are more complex but essential if the focus is on the effects of energy drinks on alcohol consumption. Until these data are available, interventions with the primary goal of reducing alcohol consumption and related problems should focus on the availability and consumption of alcohol per se. Disclosure Over the last 3 years, Joris Verster has received research funding from Takeda Pharmaceuticals, Deenox, and Red Bull GmbH, and done consultancy work for Takeda, Sepracor, Sanofi Aventis, Deenox, Red Bull GmbH, CBD, Trimbos Institute, and Transcept. Chris Alford has received funding from the UK Ministry of Defence, Red Bull GmbH, and Sanofi-Aventis. Christoph Aufricht has received research funding from the Austrian Science Fund, the European Community, Fresenius Medical Care, Baxter Healthcare, and Zytoprotec. References 1. Canadean Wisdom Database: Available at: http://www.canadean.com/ Products/Wisdom_Database.aspx. Accessed August 15, 2011. 2. International Food Information Council Foundation. IFIC Review: Caffeine and health: clarifying the controversies, 1998. 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Increased alcohol consumption, nonmedical prescription drug use, and illicit drug use are associated with energy drink consumption among college students. J Addict Med. 2010;4:74–80. 29. Thombs D, Rossheim M, Barnett T, Weiler R, Moorhouse M, Coleman B. Is there a misplaced focus on AmED? Associations between caffeine mixers and bar patron intoxication. Drug Alcohol Depend. 2010;116:31–36. 30. Attila S, Çakir B. Energy-drink consumption in college students and associate factors. Nutrition. 2011;27:316–322. 31. Berger LK, Fendrich M, Chen HY, Ar ria AM, Cisler RA. Sociodemographic correlates of energy drink consumption with and without alcohol: results of a community survey. Addict Behav. 2011;36: 516–519. 32. Rossheim ME, Thombs DL. Artificial sweeteners, caffeine, and alcohol intoxication in bar patrons. Alcohol Clin Exp Res. 2011;35: 1891–1896. International Journal of General Medicine 2012:5 Energy drinks mixed with alcohol 33. Price SR, Hilchey CA, Darredeau C, Fulton HG, Barrett SP. Energy drink co-administration is associated with increased reported alcohol ingestion. Drug Alcohol Rev. 2010;29:331–333. 34. Miller KE. Energy drinks, race, and problem behaviors among college students. J Adolesc Health. 2008;43:490–497. 35. Ferreira SE, de Mello MT, Pompéia S, de Souza-Formigoni MLO. Effects of energy drink ingestion on alcohol intoxication. Alcohol Clin Exp Res. 2006;30:598–605. 36. Curry K, Stasio MJ. The effects of energy drinks alone and in combination with alcohol on neuropsychological functioning. Hum Psychopharmacol. 2009;24:473–481. 37. Wiklund U, Karlsson M, Öström M, Messner T. Influence of energy drinks and alcohol on post-exercise heart rate recovery and heart rate variability. Clin Physiol Funct Imaging. 2009;29: 74–80. 38. Marczinski CA, Fillmore MT, Bardgett ME, Howard MA. Effects of energy drinks mixed with alcohol on behavioral control: risks for college students consuming trendy cocktails. Alcohol Clin Exp Res. 2011;35:1282–1292. 39. Marczinski CA, Fillmore MT, Henges AL, Ramsey MA, Young CR. Effects of energy drinks mixed with alcohol on information processing, motor coordination and subjective reports of intoxication. Exp Clin Psychopharmacol. 2011. [Epub ahead of print.] 40. Alford C, König J, Aufricht C, Verster JC. Proceedings of the 2010 Energy Drinks Symposium. Available at: http://benthamscience. com/open/toneuroppj/articles/V004/1TONEUROPPJ.pdf. Accessed January 22, 2012. 41. Howland J, Rohsenow DJ, Arnedt JT, et al. The acute effects of caffeinated versus non-caffeinated alcoholic beverage on driving performance and attention/reaction time. Addiction. 2010;106:335–341. 42. Bond AJ, Lader MH. Residual effects of hypnotics. Psychopharmacologia. 1972;25:117–132. 43. Greenwood MH, Lader MH, Kantameneni BD, Curzon G. The acute effects of oral (–)-tryptophan in human subjects. Br J Clin Pharmacol. 1975;2:165–172. 44. Miller KE. Wired: energy drinks, jock identity, masculine norms, and risk taking. J Am Coll Health. 2008;56:481–489. 45. Thombs D, O’Mara R, Tsukamoto M, et al. Event level analysis of energy drink consumption and alcohol intoxication in bar patrons. Addict Behav. 2010;35:325–330. 46. Arria AM, Caldeira KM, Kasperski SJ, Vincent KB, Griffiths RR, O’Grady KE. Energy drink consumption and increased risk for alcohol dependence. Alcohol Clin Exp Res. 2011;35:1–11. 47. Penning R, de Haan L, Verster JC. Caffeinated drinks, alcohol consumption, and hangover severity. The Open Neuropsychopharmacol J. 2011;4:36–39. 48. Woolsey C, Waigandt A, Beck NC. Athletes and energy drinks: reported risk-taking and consequences from the combined use of alcohol and energy drinks. J Appl Sport Psychol. 2010;22:65–71. 49. Arria AM, Caldeira KM, O’Grady KE, et al. Drug exposure opportunities and use patterns among college students: results from a longitudinal prospective cohort study. Subst Abus. 2008;29:19–38. 50. Verster JC, Alford C. Unjustified concerns about energy drinks. Curr Drug Abuse Rev. 2011;4:1–3. 51. Siegel S. The Four-Loko effect. Perspect Psychol Sci. 2011;6(4): 357–362. 52. Arria AM, O’Brien MC. The “high” risk of energy drinks. JAMA. 2011; 305:600–601. 53. Pennington N, Johnson M, Delaney E, Blankenship MB. Energy drinks: a new health hazard for adolescents. J Sch Nurs. 2010;26: 352–359. 54. Higgins JP, Tuttle TD, Higgins CL. Energy beverages: content and safety. Mayo Clin Proc. 2010;85:1033–1041. 55. Pennay A, Lubman DI, Miller P. Combining energy drinks with alcohol. A recipe for trouble? Aust Fam Phys. 2011;40:104–107. 56. Skeen MP, Glenn L. Imaginary link between alcoholism and energy drinks. Alcohol Clin Exp Res. 2011;35:1375–1376. submit your manuscript | www.dovepress.com Dovepress 197 Dovepress Verster et al 57. De Wit H. Impulsivity as a determinant and consequence of drug use: A review of underlying processes. Addict Biol. 2009;14:22–31. 58. Ohannessian CM, Hesselbrock VM. A finer examination of the role that negative affect plays in the relationship between paternal alcoholism and the onset of alcohol and marijuana use. J Stud Alcohol Drugs. 2009;70:400–408. 59. De Haan L, Kuerten Y, Kuipers E, van Laar MW, Olivier B, Verster JC. The RT-18: a new screening tool to assess young adult risk taking behavior. Int J Gen Med. 2011;4:575–584. 60. Hosier SG, Cox WM. Personality and motivational correlates of alcohol consumption and alcohol-related problems among excessive drinking university students. Addict Behav. 2011;36:87–94. Dovepress International Journal of General Medicine Publish your work in this journal The International Journal of General Medicine is an international, peer-reviewed open-access journal that focuses on general and internal medicine, pathogenesis, epidemiology, diagnosis, monitoring and treatment protocols. The journal is characterized by the rapid reporting of reviews, original research and clinical studies across all disease areas. A key focus is the elucidation of disease processes and management protocols resulting in improved outcomes for the patient.The manuscript management system is completely online and includes a very quick and fair peer-review system. Visit http://www.dovepress.com/ testimonials.php to read real quotes from published authors. Submit your manuscript here: http://www.dovepress.com/international-journal-of-general-medicine-journal 198 submit your manuscript | www.dovepress.com Dovepress International Journal of General Medicine 2012:5 Psychopharmacology (2012) 222:519–532 DOI 10.1007/s00213-012-2677-1 ORIGINAL INVESTIGATION The effects of energy drink in combination with alcohol on performance and subjective awareness Chris Alford & Jennifer Hamilton-Morris & Joris C. Verster Received: 30 August 2011 / Accepted: 22 February 2012 / Published online: 29 March 2012 # Springer-Verlag 2012 Abstract Rationale This study investigated the coadministration of an energy drink with alcohol to study the effects on subjective intoxication and objective performance. Objectives This study aims to evaluate the objective and subjective effects of alcohol versus placebo at two alcohol doses, alone and in combination with an energy drink, in a balanced order, placebo-controlled, double-blind design. Methods Two groups of ten healthy volunteers, mean (SD) age of 24 (6.5), participated in the study. One group consumed energy drink containing 80 mg of caffeine and the other consumed a placebo drink, with both receiving two alcohol doses (0.046 and 0.087% breathalyser alcohol concentration). Tests included breath alcohol assessment, objective measures of performance (reaction time, word memory and Stroop task) and subjective visual analogue mood scales. Results Participants showed significantly impaired reaction time and memory after alcohol compared to the no alcohol condition and had poorer memory after the higher alcohol dose. Stroop performance was improved with the energy drink plus alcohol combination compared to the placebo drink plus alcohol combination. Participants felt significant subjective dose-related impairment after alcohol compared C. Alford (*) : J. Hamilton-Morris Psychology Department, Faculty of Health and Life Sciences, University of the West of England, Frenchay Campus, Coldharbour Lane, Bristol BS16 1QY, UK e-mail: [email protected] J. C. Verster Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands to no alcohol. Neither breath alcohol concentration nor the subjective measures showed a significant difference between the energy drink and the placebo energy drink when combined with alcohol. Conclusions Subjective effects reflected awareness of alcohol intoxication and sensitivity to increasing alcohol dose. There were no overall significant group differences for subjective measures between energy drink and placebo groups in the presence of alcohol and no evidence that the energy drink masked the subjective effects of alcohol at either dose. Keywords Alcohol . Antagonism . Caffeine . Energy drink . Intoxication . Performance . Subjective awareness Introduction Energy drinks are sold in more than 160 countries, and sales are increasing. Energy drinks contain caffeine, taurine and carbohydrates in the form of sugars as principal ingredients (Heckman et al. 2010). They are popular with young people, and students report their use for a variety of reasons including to enhance memory and concentration or to counteract sleepiness (Malinauskas et al. 2007; O’Brien et al. 2008). Whilst a minority of students combine energy drinks with alcohol (Arria et al. 2010; Attila and Cakir 2010; Berger et al. 2010; Malinauskas et al. 2007; O’Brien et al. 2008; Oteri et al. 2007; Rossheim and Thombs 2011), this still represents a significant number and so they are becoming a popular mixer. Caffeine and alcohol are two of the oldest commonly consumed psychoactive compounds, and caffeinated drinks have been mixed with alcohol for many years. 520 There are some recent claims that energy drinks may mask the subjective effects of alcohol, and this may either lead people to drink more or that they may be unaware of how intoxicated they are (Arria et al. 2010; Arria and O’Brien 2011; O’Brien et al. 2008), although these views on masking have been challenged (Verster and Alford 2011) and an alternative explanation for enhanced intoxication with novel drink flavours has been offered by Siegel (2011). A brief review of the effects of caffeine and energy drinks alone and in combination with alcohol is provided in order to establish whether or not energy drinks appear different to other caffeinated drinks when mixed with alcohol. Mechanisms of action Folklore tells how caffeine has long been used as a stimulant to help maintain wakefulness, including helping monks with their nightly prayers, and early studies found that caffeine improved performance including the speed of response (Hollingworth 1912; Ritchie 1980; Schilling 1921). The primary action of caffeine as an adenosine inhibitor is well established, thus counteracting the actions of this inhibitory neurotransmitter and increasing the release of other neurotransmitters including noradrenaline and dopamine, producing a moderate stimulant and mood-enhancing effect. Blockade of the A2A receptor by caffeine inhibits the sleeppromoting effect with adenosine levels increasing across the hours of wakefulness (Davis et al. 2003; Ferré 2008; Huang et al. 2007; Landolt 2008; Sturgess et al. 2010). In contrast to caffeine, alcohol has long been found to have detrimental effects on both judgement and performance (Cohen et al. 1958; Wallgren and Barry 1970), with Miller (1992) concluding‚ ‘In general, alcohol has an adverse effect on cognitive performance’. Alcohol may have more complex effects than caffeine, with regions of the CNS affected differentially by dose (Rivers 1994) and with multiple actions including depressing the ion channel function controlled by the excitatory neurotransmitter glutamate at the NMDA receptor, inhibiting acetylcholine release and potentiating GABA resulting in impaired cognition, inability to form new memories and sedation (Braun 1996; McKim 1997). Alcohol has a wide spectrum of action within the CNS affecting many neurotransmitter systems including major neurotransmitters adenosine, dopamine, GABA, glutamate and serotonin. Interaction with the mesolimbic dopamine reward pathways may well contribute to the process of addiction and alcohol misuse (Lovinger 2008). The comparatively restricted action spectrum of caffeine, focused on adenosine inhibition, may account for its more limited misuse potential seen in caffeinism, although it is not recognized as a dependence-inducing substance (APA 1994). Psychopharmacology (2012) 222:519–532 Effects on subjective state and performance Alcohol impairs a wide range of psychomotor and cognitive tasks, slowing reaction times, impairing memory formation and increasing errors (Cameron et al. 2001; Hindmarch et al. 1991; Mackay et al. 2002; Maylor and Rabbitt 1993; Millar et al. 1995; Moskowitz et al. 1985; Ogden and Moskowitz 2004; Tiplady et al. 2009). The differential effects on regions of the CNS may be linked to lower doses affecting higher-level processing (Jääskeläinen et al. 1995) and genetic differences contribute to overall variation in sensitivity to alcohol (Tagawa et al. 2000). Koelega (1995) concluded that the effects on information processing and divided attention tasks are important because of their relevance to everyday life. Therefore, it is not surprising that alcohol impairs driving and driving-related skills (Holloway 1995; Starmer 1989; Verster et al. 2009). The dose–response curve linking blood alcohol level and relative probability of causing a driving accident has long been established and applied in setting legal limits for alcohol levels and driving (Borkenstein et al. 1964) with limits in Europe, US and UK currently set around 0.05–0.08% blood alcohol concentration (BAC) levels. Laboratory studies show that driving-related skills are significantly impaired at the 0.05% BAC level (Ogden and Moskowitz 2004). Alcohol intoxication has been linked to riskier sexual behaviour (Fromme et al. 1999), although there may problems with the use of retrospective accounts (Halpern-Fischer et al. 1996). Judgement may also be affected with people overestimating their abilities (Flanagan et al. 1983; Tiplady et al. 2004), including being able to deal with a potentially risky situation or acting on immediate short-term consequences rather than longer-term consequences (Farquhar et al. 2002). Specific to driving, alcohol may cause a ‘risky shift’, resulting in hitting the test bollards and failing the gap acceptance test (Alford and Starmer 1990, personal communication; Betts et al. 1984). In contrast to alcohol, the moderate stimulant effects of caffeine are associated with improved performance. Doses typically in the 100- to 200-mg dose range result in improved mood (Mumford et al. 1994), shorter reaction time and improved attention and vigilance (Frewer and Lader 1991; Koelega 1998; Nehlig et al. 1992; Robelin and Rogers 1998; Smit and Rogers 2000; Smith 2002; Van der Stelt and Snel 1998) in a dose-dependent way (Smith et al. 2005). However, significant effects are not always seen, which may be due to the limited effect size and possible ceiling effects in that it is harder to enhance performance in healthy young adults. There is also genetic variation in response to caffeine (Nehlig 2010) so that sampling will affect observed response. Caffeine and glucose are both contained in energy drinks, and studies have found improved performance when they are taken together. Both Adan and Serra-Grabulosa Psychopharmacology (2012) 222:519–532 (2011) and Scholey and Kennedy (2004) found faster speed of response with attentional tasks, as well as improved memory, with caffeine and glucose combined in comparison to the individual constituents, although significant changes in mood were not seen. Overnight withdrawal from caffeine can itself result in improved performance following morning caffeine: the caffeine reinstatement or withdrawal hypothesis (James 1997; James and Rogers 2005), although improvements in performance are still seen independently of this when additional caffeine is consumed after the usual caffeine intake (Christopher et al. 2005; Smith et al. 2005; Warburton 1995; Watson et al. 2002). Beneficial effects are more clearly seen when participants are sleep-deprived or fatigued (Alford 2009; Davis et al. 2003; Fagan et al. 1998; James 1997; James and Gregg 2004; Ker et al. 2010; Nehlig 2010; Rogers et al. 2005; Smith 2002; Swift and Tiplady 1988), with a recent review (Glade 2010) concluding that caffeine has a beneficial effect increasing energy availability and expenditure whilst decreasing the subjective effort linked to physical activity, enhancing physical, motor and cognitive ability including neuromuscular coordination, speeding and increasing accuracy of reactions, increasing concentration, focus and short-term memory and problem solving, increasing correct decision making, and increasing subjective feelings of alertness and energy (for physical performance, see Astorino and Roberson 2010; Sokmen et al. 2008). 521 or through proximal consumption of alcohol and caffeine such as dinner with alcohol followed by coffee. Given that caffeine is a weak stimulant and alcohol is a sedative, a predicted outcome would be that caffeine would antagonize the effects of alcohol, reducing both subjective and objective impairment. However, whilst some studies have shown antagonism (Hasenfratz et al. 1993), some others have found no effect (Nuotto et al. 1982) and yet others have shown that caffeine may even increase the impairing effects of alcohol (Oborne and Rogers 1983). A recent view is that caffeine can antagonise some, but not all, behavioural effects of alcohol (Azcona et al. 1995; Liguori and Robinson 2001; Marczinski and Fillmore 2006), although expectancy may be involved (Fillmore et al. 2002; Fillmore and VogelSprott 1995). Azcona et al. suggested that caffeine antagonism may more readily be seen in tasks where caffeine itself has a more positive effect on performance. An important safety-related aspect of psychopharmacological investigations is whether or not subjective awareness parallels objective impairment or behavioural toxicity (Hindmarch et al. 1992). Laboratory investigations have shown that caffeine and alcohol in combination do not alter the ‘high’ or perceived or actual BAC with caffeine levels up to around 400 mg and alcohol 0.012% BAC (Howland et al. 2010; Liguori and Robinson 2001; Rush et al. 1993). Energy drinks and alcohol Effects of energy drinks Since their introduction into Europe in the late 1980s, there has been interest in the performance-enhancing effects of energy drinks. Popular brands contain around 80 mg of caffeine per 250 ml which places them above colas but on a similar level to coffee, although some minority brands can contain higher doses as can other preparations of coffee (IFIC 1998; Reissig et al. 2009). Other key ingredients include taurine, carbohydrates in the form of sugars and glucoronolactone (a sugar metabolite) and B complex vitamins. Energy drink consumption has been shown to improve physical performance in several but not all studies (Alford et al. 2001; Hoffman 2010; Ivy et al. 2009; Klepacki 2010; Walsh et al. 2010). In addition, improvements have been shown for both psychomotor and cognitive functioning, as well as driving and driving-related skills (Alford et al. 2001; Gershon et al. 2009; Horne and Reyner 2001; Mets et al. 2010; Reyner and Horne 2002; Seidl et al. 2000; Smit et al. 2006). Caffeine and alcohol Caffeine and alcohol are commonly combined either through consumption of alcohol with caffeinated mixers including colas or energy drinks (Thombs et al. 2010a, b) Given the increasing popularity of energy drinks and that caffeine is a principal ingredient, it is logical to raise questions regarding their interaction with alcohol on both subjective and objective measures. A recent commentary claimed that individuals who combined energy drinks with alcohol underestimate their true level of impairment and that the drink combination could lead to engaging in risky behaviour, whilst others have claimed that these effects could have an increased accident risk (Arria and O’Brien 2011; Riesselmann et al. 1996). Currently, there are only a few studies investigating the combined effects of energy drink and alcohol compared to alcohol alone. Ferreira et al. (2004) investigated the effects on physical performance of alcohol (1.0 g/kg) and energy drink (3.57 ml/kg equivalent to a standard 250 ml can) alone and in combination. Whilst alcohol impaired maximal effort assessed using a cycle ergometer, no significant differences were found between alcohol alone and energy drink combined with alcohol. A recent study by Marczinski et al. (2011) compared the effects of alcohol alone to alcohol combined with energy drink at 0.06–0.07% breath alcohol concentration (BrAC). They found no differences in breath alcohol or level of impaired performance. They undertook over 20 individual subjective ratings, including perceived intoxication and ability to drive, which again found no 522 differences between alcohol and energy drink in combination with alcohol. However, the authors focused in on two subjective measures that failed to show significant effects with ANOVA but did show reduced mental fatigue and increased stimulation for the energy drink and alcohol combination compared to alcohol, but not against placebo for the latter, using paired comparisons. They interpreted this as potentially dangerous despite the lack of difference in a direct subjective measure of intoxication, as well as ability to drive. Several authors have recently claimed that energy drink when combined with alcohol produces a reduction in perceived intoxication or ‘masking’ of subjective awareness (Arria and O’Brien 2011), although this appears to be based on a single study which is, therefore, considered in some detail. Ferreira et al. (2006) compared the effects of two doses of alcohol (0.04–0.05 and 0.097–0.099% BrAC) assessed using two participant groups, when given alone and in combination with energy drink. Psychomotor performance was assessed (reaction time and grooved peg board) and found to be impaired with both alcohol alone and the alcohol and energy drink combination. An 18-item modified somatic symptom scale assessed subjective intoxication at 2 time points (18×2 scales). Dry mouth, headache, motor impairment and weakness (4), i.e. not all were typical alcohol impairment assessment scales, showed reduced perception for the alcohol energy drink combination compared to alcohol at 1 of the 2 time points (4/18×2) for alcohol doses combined. More scales, though including 2 from the above: dizziness, motor impairment, speech, tiredness, vision, walking, weakness and well-being (8), showed impairment with alcohol at more time points (10/18×2) that were not reduced for the alcohol and energy drink combination. However, the authors concluded that energy drink reduced the perception of alcohol impairment. Given the variability of results regarding the perception of impairment, further studies are required to clarify the effects of energy drink when combined with alcohol on the subjective perception of intoxication. The current study examined these effects with the use of both objective performance measures to establish impairment and subjective ratings to assess perceived impairment. Methods Design The present study investigated the effects of alcohol alone and in combination with an energy drink in a placebocontrolled, rising dose, double-blind design. There were two groups of participants with random allocation to Psychopharmacology (2012) 222:519–532 treatment. One group received energy drink and the other received placebo energy drink in a balanced order for both the alcohol and placebo alcohol treatments on two separate occasions. Participants Ten female and 10 male participants provided 2 mixed gender groups of 10 volunteers, with the mean age of 24.5 years and range of 19–33 years. Average weight was 70.7 kg; for these light to moderate social drinkers, range was 4–30 units, averaging 17 units per week (females 13.4, males 20.6), with daily caffeine of 350 mg. Prior to participation, the study was approved by a University of the West of England Ethics Committee and each participant signed an informed consent. All participants reported that they were in good health, not pregnant, taking illicit or social drugs, ‘over the counter’ or prescribed medication with the exception of the contraceptive pill. None reported adverse reactions to either alcohol, caffeine or energy drinks and all consumed weekly alcohol and had tried an energy drink at least once, but not on a regular basis. Assessments Breath alcohol concentration Alcometer readings were taken by the experimenter who kept their hand over the visual display so that participants were blind to their alcohol concentration readings. Subjective impairment was measured using the Bond and Lader (1974) 100-mm visual analogue scales (VAS) representing bipolar adjective pairs for the assessment of both alerting and sedating CNS drug effects with clearheaded– muzzy, clumsy–well coordinated, energetic–lethargic, drowsy–alert, and mentally slow–quick witted selected for analysis of alcohol-induced impairment. These scales have previously been used to assess both energy drinks and alcohol (Alford et al. 2001; Tiplady et al. 2004; Warburton et al. 2001). Critical flicker fusion threshold This was assessed by viewing four red-coloured light-emitting diodes set 1 cm apart in a square formation on a black background providing foveal fixation when viewed at 1 m. The diodes flickered on/off at a constantly varying rate of 1 Hz/s with participants pressing a response button at the point of perceiving either fusion or flicker for three ascending and descending repetitions using the psychophysical method of limits (Hindmarch et al. 1991). Choice reaction time Psychomotor speed was measured using a free standing box which comprised a touchsensitive home pad around which six equally spaced Psychopharmacology (2012) 222:519–532 response pads were situated at 150 mm from the home pad in a 120° arc with a red light-emitting signal diode positioned distal to each response pad. Participants were required to move their finger from the home pad to the appropriate pad as quickly and accurately as possible in response to illumination of one of the stimulus diodes which were lit in a random sequence over 20 trials (Hindmarch et al. 1991). Word memory Printed sheets each containing a vertical list of 30 words based on Pavio’s word lists balanced for concreteness, imagery and meaningfulness were used to assess memory (Paivio et al. 1968). Participants had 1 min to view and memorise the list, followed by a further minute to write down as many words as they could from the original list. Stroop cognitive interference task (Stroop) Participants were required to say out loud the colour of the ink, and not the printed word, whilst reading down each of 4 columns totalling 100 printed colour words. For example, with the word ‘RED’ printed in green ink, a correct response would be to say ‘green’, ignoring what the letters spelt (Stroop 1935). The time taken to complete the list and the number of errors was recorded. Equipment Critical flicker fusion (CFF) and choice reaction time (CRT) were tested using dedicated hardware supplied by Comstat Medical based on the Leeds psychomotor tester (Hindmarch et al. 1991). %BrAC was used to estimate %BAC using a Lion Alcometer SD-400, Lion Laboratories, Barry, UK. Treatments Alcohol was given as vodka (37.5% by volume) with amount adjusted for body weight using the formula adapted from McKim (1997) to achieve an estimated blood alcohol level of approximately 0.1% BAC divided across two drinks. The energy drink treatment comprised a standard can of Red Bull® Energy Drink (250 ml) containing 80 mg caffeine to which was added peppermint cordial and Robinson’s apple and black currant (no added sugar) concentrate to mask the flavour of the energy drink. The placebo comprised 250 ml soda water together with peppermint cordial and Robinson’s apple and black currant (no added sugar) concentrate with equal total volumes for alcohol and non-alcohol conditions. Supercook black/blue food colouring was added to help mask the presence of energy drink, with two drinks presented in each treatment condition in glasses after the rim was swabbed with alcohol to help further mask treatments. 523 Procedure An opportunity sample of potential participants completed screening questionnaires to assess health status, exclude nondrinkers, excessive drinkers, none or high caffeine users, or experience of an adverse reaction to test compounds, or those who may be pregnant. On test days, health status and the preceding night’s sleep was checked. They were asked to abstain from alcohol and caffeine from the preceding night, not drive to the university on test days, and have a light lunch an hour before testing which was undertaken in the psychology laboratories starting between 1 and 2 pm. A practice session, weighing, explanation of study procedures and random allocation to treatment group preceded testing on the first test day with test sessions averaging 2.5 h for the two test days which were separated by a week. Treatments were administered double-blind with the assistance of an additional experimenter who prepared the drinks. Participants were assessed three times on each test day, first at baseline then 45 min after starting the first drink, with 10 min for drinking, and similarly after the second with about an hour between drinks. The fixed test order, though different word lists, started with subjective VAS assessment, then breathalyser, followed by word list memory, Stroop, CFF, CRT and finally delayed memory recall all administered with standardised instructions. After completing the test sessions, participants were escorted home and later followed up to check they had not experienced any adverse reaction to treatment. Debriefing followed the final test day. Data handling All data were analysed blind. Raw data were collated and transcribed into Excel spreadsheets. The Comstat Medical equipment provided numerical values for ascending and descending CFF thresholds, resulting in an overall mean. Similarly, separate component means were given for CRT including recognition reaction time (RRT) representing elapsed time from stimulus signal onset to initiation of response when the finger is lifted from the home pad. Movement reaction time (MRT) is the time taken for the finger to be moved from the home pad to the target pad and total CRT is the sum of these two elements (RRT + MRT) combined. For word memory, the correct number recalled within the 60 s immediate or delayed recall period was entered. For the Stroop task, the number of errors and time taken to complete the task were recorded. The VAS scales assessing subjective impairment were scored by measuring the distance along the 100-mm line separating the adjective pairs (e.g. drowsy–alert) for each of the five adjectives. These values were also entered onto the results spreadsheet together with the alcometer readings which were manually recorded at each breath analysis session. 524 Psychopharmacology (2012) 222:519–532 Results Choice reaction time Statistical analysis Alcohol slowed total CRT, although differences failed to achieve significance for the main effects of alcohol and drink; the energy drink produced a trend (P<0.1) for faster responses compared to placebo. RRT showed a significant slowing after alcohol (F1,18 06.5, MSe00.00, P00.02) and trends for faster responses with the energy drink (P<0.1) and for an interaction between alcohol and drink (P<0.1), reflecting slower responses after the second alcohol drink compared to faster responses after alcohol placebo for both the energy drink and placebo energy drink groups combined. Means are plotted in Fig. 1. Data were analysed using SPSS V17 (SPSS 2010). Placebo baselines were compared for the energy drink and placebo energy drink groups with t tests. Neither subjective impairment measures nor performance measures produced significant contrasts, demonstrating the comparability of the two participant groups. To help standardise results between the two groups of participants (energy drink and placebo energy drink), as well as helping to control for variation between test days, baseline difference scores were calculated. These scores were then analysed using a three-factor 2 × 2 × 2 ANOVA (treatment group 2: energy drink and placebo energy drink; alcohol 2: alcohol and placebo alcohol; drinks 2: drink 1 and drink 2). Statistical significance was set at the 5% level (P<0.05 or better) to assess main effects and interactions. The analysis was, therefore, focused on assessing the overall effects of alcohol (alcohol vs placebo alcohol), increasing dose (drink 1 vs drink 2) and energy drink (energy drink vs placebo energy drink). A simple main effects analysis was additionally employed to specifically assess differences between alcohol and energy drink contrasted with alcohol and energy drink placebo. A summary table including means (SEM), together with associated P values and effect sizes, for both subjective and performance measures are included in Table 1. Word memory Similar effects were found for both immediate and delayed word memory recall. Alcohol markedly reduced the number of words recalled (immediate: F1,18 023.8, MSe012.3, P0 0.001; delayed: F1,18 023.9, MSe019.5, P00.001) and in a dose-dependent way (drinks—immediate: F 1,18 028.6, MSe 03.46, P 00.001; delayed: F1,18 022.0, MSe 07.52, P00.001), resulting in an alcohol × drink interaction reflecting the decrease in words recalled with increased alcohol compared to alcohol placebo (interaction—immediate: F1,18 015.8, MSe 06.57, P 00.001; delayed: F1,18 018.0, MSe013.0, P00.001). These highly significant effects for immediate recall are shown in Fig. 1. Stroop task Alcohol dose All participants produced zero BrAC at each baseline and for the placebo alcohol treatment. Mean BrAC after drink 1 was 0.046% BrAC and after drink 2 was 0.087% BrAC. The mean (SD) results for the energy drink group were 0.044 (0.01) and 0.081 (0.02)% BrAC and for the placebo energy drink group were 0.047 (0.01) and 0.094 (0.02)% BrAC after drinks 1 and 2, respectively. Differences between treatment groups were nonsignificant (t test), facilitating comparison between the two groups for alcohol versus placebo and between drinks 1 and 2, though noting highest breath alcohol levels were recorded after drink 2 for the placebo energy drink group. Performance tests Critical flicker fusion Whilst no significant main effects or interactions were found, the lowest thresholds were recorded in the alcohol condition for both groups, consistent with a sedative effect. Error rate was not significantly affected by alcohol overall, although the highest error scores were recorded after the second alcohol drink for the placebo energy drink group and with a trend for lower error scores in the energy drink group (P<0.1). Stroop completion time was faster with energy drink (F1,18 011.1, MSe00.035, P00.004) and unexpectedly faster still for alcohol combined with energy drink, resulting in a main effect for alcohol (F1,18 06.06, MSe00.03, P00.024), as well as a significant interaction between alcohol and treatment group (F1,18 04.59, MSe 00.03, P 00.046). Simple main effects analysis revealed that, in addition to completion time (F1,18 011.2, MSe00.05, P00.004), Stroop errors were also significantly reduced (F1,18 05.71, MSe03.68, P00.028) by alcohol combined with energy drink contrasted with the alcohol and energy drink placebo combination. Effect sizes (Cohen’s d) can be characterised as follows: small d00.2; medium d00.5; large d00.8 (Cohen 1992). Effect sizes of d≥0.2 were generally associated with statistically significant results, although both CRT overall and RRT produced effect sizes for energy drink contrasted with energy drink placebo of just over d00.2, reflecting faster responses after energy drink that approached significance (P00.06). 1.41 (0.07) 1.21 (0.04) ED EDPla ED EDPla ED EDPla ED EDPla RRT (s) Memory immediate recall (N) Memory delayed recall (N) Stroop errors (N) Stroop completion ED EDPla time (min) ED EDPla ED EDPla ED EDPla ED EDPla Clumsy (mm) Drowsy (mm) Energetic (mm) Mentally slow (mm) 37.5 (3.6) 43.0 (3.6) 55.1 (3.8) 45.3 (4.2) 36.1 (5.1) 43.5 (4.8) 38.3 (4.0) 37.5 (3.6) 68.0 (4.1) 63.5 (4.6) 10.85 (0.96) 12.45 (0.56) 12.65 (0.96) 13.05 (0.42) 0.345 (0.01) 0.313 (0.01) −0.25 (0.57) 0.34 (0.76) 0.43 (0.63) NS 0.78 (0.95) −0.26 (0.07) −0.02 (0.02) −0.23 (0.07) −0.02 (0.02) 12.4 (6.7) 5.1 (3.1) −13.3 (7.4) 8.7 (10.8) −1.8 (7.5) 0.4 (9.5) 9.8 (4.3) −3.5 (2.7) 31.5 (8.1) 2.4 (10.6) 24.0 (5.9) 17.4 (4.9) 14.8 (9.5) −0.9 (5.8) 16.3 (5.2) 6.4 (3.0) −32.9 (7.9) −17.5 (8.9) 0.30 (0.40) 1.80 (0.59) −0.40 (0.54) 1.00 (0.45) −21.0 (6.8) −13.7 (7.5) −8.2 (1.65) −9.3 (1.01) −2.7 (1.13) −2.2 (1.36) Alc, D2<D1 4.3 (3.2) −5.1 (1.5) −3.6 (3.3) −2.9 (4.4) −5.6 (9.9) −1.9 (5.3) −5.7 (6.4) −3.8 (8.5) 5.6 (7.8) 2.7 (6.4) 1.0 (7.3) 1.2 (3.1) −6.8 (6.6) −3.3 (4.1) 8.6 (5.9) 1.3 (8.0) −5.2 (7.2) −8.2 (2.4) Alc>Pla, 0.01 NS Alc, D2>D1 Alc>Pla, 0.05 Alc×Drink, 0.05 Alc>Pla, 0.001 Alc<Pla, 0.02 ED, Alc<Pla Alc×Treat, 0.05 −0.08 (0.05) Alc, 0.03 −0.02 (0.07) Alc<Pla 0.80 (0.51) NS 1.20 (0.36) Alc, D2<D1 Alc×Drink, 0.001 0.1 (0.85) Alc, 0.001 −1.1 (1.17) Alc<Pla −0.2 (6.1) −9.0 (4.6) −0.05 (0.03) 0.00 (0.01) 1.40 (0.58) 0.80 (0.33) −1.3 (1.74) −0.8 (0.79) Alc×Drink, 0.001 0.21 D2>D1, 0.05 0.08 NS 0.22 NS 0.38 D2>D1, 0.001 0.26 D2<D1, 0.03 0.20 NS 0.08 NS 0.38 D2<D1, 0.001 0.38 D2<D1, 0.001 0.8 (0.99) Alc, 0.001 0.1 (0.99) Alc<Pla −6.3 (1.27) −5.0 (0.82) −1.5 (0.79) −0.8 (1.38) 1.0 (1.11) −0.2 (0.57) 0.23 NS 0.15 NS 0.13 NS Treatment (ED vs EDPla) Alc+ED vs Alc+EDPla 0.15 Alc+ED<Alc +EDPla, 0.03 0.02 NS 0.00 NS 0.23 NS 0.22 NS 0.04 NS d 0.32 0.02 0.09 0.15 0.19 0.02 d 0.13 NS 0.06 NS 0.04 NS 0.11 NS EDPla, D2>D1 0.20 NS 0.02 Treat×Drink, 0.04 0.05 NS ED, D2<D1 0.07 NS 0.15 NS 0.08 NS 0.26 0.15 0.29 0.18 0.16 0.04 ED<EDPla, 0.004 0.31 Alc+ED<Alc 0.50 +EDPla, 0.004 0.07 NS 0.21 NS 0.20 NS 0.01 NS 0.03 NS 0.05 NS Drink (D1 vs D2) d 0.001 (0.01) 0.002 (0.01) −0.033 (0.02) −0.043 (0.02) Alc, 0.02 0.009 (0.01) 0.0189 (0.01) 0.004 (0.00) −0.002 (0.01) Alc>Pla 0.024 (0.03) −0.079 (0.05) −0.095 (0.06) NS 0.045 (0.02) 0.014 (0.02) 0.010 (0.04) −0.11 (0.46) −0.66 (0.47) Alcohol (Alc vs Pla) d Main effects, interactions, P values, effect sizes (Cohen’s d) Alc alcohol, AlcPla alcohol placebo, Alc+ED alcohol and energy drink combined, Alc+EDPla Alcohol and energy drink placebo combined, CFF critical flicker fusion, CRT total choice reaction time, D1 drink 1, D2 drink 2, ED energy drink, EDPla energy drink placebo, Pla placebo, RRT recognition reaction time, Treat treatment group, + increase in values compared to baseline, − decrease in values compared to baseline ED EDPla Clearheaded (mm) Subjective 0.75 (0.27) 0.60 (0.20) ED EDPla CRT (s) −0.59 (0.36) −0.20 (0.46) AlcPla D2 AlcPla D1 Alc D1 Alc D2 Alcohol placebo Alcohol 0.649 (0.05) −0.044 (0.04) 0.562 (0.02) 0.047 (0.03) ED EDPla 30.82 (0.48) 29.47 (0.68) Treatment group Baseline CFF (Hz) Performance Measure (units) Table 1 Baseline means (SEM) and post drink baseline differences—performance and subjective awareness measures for alcohol and energy drink alone, alcohol combined with energy drink and their respective placebo conditions Psychopharmacology (2012) 222:519–532 525 526 Psychopharmacology (2012) 222:519–532 placebo. Although with energy drink, improvements in reaction time approached significance. These results clearly show the overall performanceimpairing effects of alcohol in this study, which then provide a useful basis from which to evaluate the subjective perception of impairment. Subjective measures Fig. 1 Performance results—RRT and immediate memory recall, contrasting alcohol and energy drink alone, as well as in combination, and against their respective placebos In summary, alcohol significantly impaired both reaction time and memory performance. The Stroop task results were more complex. Whilst alcohol was associated with the most errors in the placebo energy drink group and completion time was faster after energy drink, the combination of energy drink and alcohol produced the fastest completion times, as well as reducing errors. Therefore, either trends or significant impairments were seen with alcohol for five out of seven variables derived from the four performance tests. The most significant effects were seen with memory, including a dose-related increase in impairment with alcohol. The effects of energy drink were relatively weak in overcoming the effects of alcohol so that only one (Stroop) out of four separate tests resulted in a significant improvement with energy drink, reflecting improved scores for alcohol and placebo alcohol combined, as well as alcohol combined with energy drink showing improvement when contrasted with alcohol and energy drink The subjective response to both energy drink and alcohol followed a consistent pattern for four of the five subjective measures. Energy drink with alcohol placebo was associated with participants feeling more clearheaded and energetic, whilst less clumsy and drowsy. However, energy drink combined with alcohol resulted in participants feeling least clearheaded and energetic, together with being most clumsy, drowsy and mentally slow, precluding the significant effects for the energy drink treatment group compared to the placebo energy drink group. The results for the placebo energy drink group generally fell within these levels, with alcohol again increasing subjective impairment relative to alcohol placebo, although compared to the lower dose, the higher dose was associated with feeling more energetic. The general pattern of subjective impairment after alcohol for both the energy drink and placebo energy drink groups are plotted in Fig. 2, showing dose–response effects for the clearheaded and clumsy descriptors. Statistical analysis supported the graphical presentations with alcohol producing significant increases in subjective impairment for feelings of being less clearheaded and more clumsy, drowsy and mentally slow (alcohol—clearheaded: F1,18 06.41, MSe0761, P00.02; clumsy: F1,18 024.7, MSe0 263, P00.001; drowsy: F1,18 04.40, MSe01193, P00.05; mentally slow: F1,18 08.20, MSe0148, P00.01). Significant dose-related increases in perceived impairment between drink 1 to drink 2 were seen for clearheaded (F1,18 05.47, MSe090.6, P00.03), clumsy (F1,18 014.9, MSe080.5, P0 0.001) and mentally slow (F1,18 04.61, MSe 077.4, P 0 0.046). Whilst there were no overall significant differences between the energy drink and placebo energy drink groups, feelings of being energetic were associated with a drink × treatment group interaction (F1,18 04.84, MSe0151, P0 0.04), as after the second drink, those in the energy drink group felt less energetic, whilst the placebo energy drink group felt more energetic. There was also an alcohol × drink interaction (F1,18 04.46, MSe090.8, P00.049) with perceived drowsiness increasing after the second drink with alcohol compared to placebo alcohol. Effect sizes of ≥0.2 were again generally associated with statistically significant contrasts, although increased feelings of being drowsy and mentally slow that were experienced after the alcohol and energy drink combination contrasted with alcohol and energy drink placebo with effect sizes of d>0.2 Psychopharmacology (2012) 222:519–532 Fig. 2 Subjective awareness—clearheaded and clumsy, contrasting alcohol and energy drink alone, as well as in combination, and against their respective placebos and associated P<0.1. Interestingly, the drink factor produced three significant contrasts between drink 1 and drink 2, although the associated effect sizes were d<0.2. The subjective assessment revealed significant increases in impairment for four out of five descriptors with alcohol for the combined treatment groups and increases from drink 1 to drink 2 for three descriptors, but no overall significant differences between the energy drink and placebo energy drink groups. Significant interactions reflected a doserelated increase in drowsiness after alcohol and a reduction in feeling energetic after the second drink for the energy drink treatment group. Discussion The performance tests showed the expected impairment after alcohol. With laboratory tests, significant impairment 527 is generally seen in 50% of studies at the 0.05% BAC and 90% at the 0.08% BAC (Moskowitz and Fiorentino 2000), and therefore, similar to the concentration recorded here for the combined treatment groups (0.046 and 0.087% BrAC). The similarity in BrAC between the energy drink and placebo energy drink group allowed between-group comparisons for both alcohol doses and alcohol versus placebo comparisons. Objective performance measures found statistically significant impairments with alcohol for both reaction time and memory, whilst CFF, which may be relatively insensitive to alcohol (Ogden and Moskowitz 2004), showed only trends for reduced flicker fusion thresholds with alcohol for both the energy drink and placebo energy drink groups. The results for Stroop performance were more complicated, with the greatest number of errors recorded at the higher dose for the placebo energy drink group, consistent with previous work reporting increased errors after alcohol (Tiplady et al. 2004, 2009). However, the combination of energy drink and alcohol significantly reduced completion time and errors, reflecting improved performance. Therefore, overall, alcohol was associated with impaired performance and greater impairment was seen at the higher dose for three out of four tasks. Whilst studies assessing the effects of energy drink in combination with alcohol are very limited, it was noted in the ‘Introduction’ that the addition of caffeine has either antagonised the effects of alcohol, had no effect, or further increased impairment (Azcona et al. 1995; Liguori and Robinson 2001; Marczinski and Fillmore 2006; Nuotto et al. 1982; Oborne and Rogers 1983). From examining the means or graphical plots for the current study, energy drink and alcohol, when compared to placebo energy drink with alcohol, showed lower levels of impairment at the higher dose with CFF, total reaction time and RRT and a reduction in Stroop errors and completion time. However, no reduction was seen with memory. These relative reductions in alcohol-induced impairment after coadministration of energy drink suggest at least some possible antagonism by caffeine or a combination of energy drink constituents. However, statistical evaluation only provided a trend (P00.06) for Stroop errors and a significant (P00.004) difference in completion time between the energy drink group and placebo energy drink group, although this may have been partially obscured by the combination of factors in the overall ANOVA. In comparison, the reduced simple main effects model demonstrated significant improvements for the alcohol and energy drink combination compared to alcohol and energy drink placebo for both Stroop errors (P00.028) and completion time (P00.004). The notable improvement in Stroop completion time seen here, also reflecting a reduction in errors, when alcohol was combined with energy drink may reflect an anomaly of the 528 Stroop assessment. Participants were asked to name the ink colour and ignore the printed word. There are different possible assessments that can be undertaken (Stroop 1935); for example, participants could have been asked to name the printed word and ignore the ink colour. By asking participants to name the ink colour and ignore the printed word, a reduction in focus or visual acuity as occurs with alcohol (Moskowitz et al. 1993) would aid perception and dominance of the ink colour as the printed letters became potentially more ambiguous. This would reduce the interference effect and possibly improve performance. However, greatest errors were seen after the higher dose of alcohol in the placebo energy drink group, though speed was not increased, supporting earlier findings of increased errors after alcohol (Starmer 1989; Tiplady et al. 2009). In contrast, Liguori and Robinson (2001) failed to find significant effects with either CFF or Stroop in their investigation of caffeine and alcohol. The results for word memory were stronger and more consistent with both immediate and delayed recall producing highly significant results (P00.001) for alcohol impairment and increase with the higher dose. There was no evidence of energy drink antagonism of alcohol impairment. The results with alcohol are generally in keeping with the literature as memory impairment is a robust and common feature of alcohol intoxication (Maylor and Rabbitt 1993) and provide further support for the results of the current study. Therefore, three out of four tests showed either trends (CFF) or significant impairment (reaction time, word memory) after alcohol, but no significant differences between the energy drink or placebo energy drink groups. One test (Stroop) showed a significant improvement in both completion time and errors after the alcohol and energy drink combination. The five scales selected from the Bond and Lader (1974) VAS scales were comprised of bipolar opposites (e.g. alert– drowsy), with the midpoint representing a neutral position. The scales are suitable for assessing both stimulant (e.g. more alerting) as well as sedative (e.g. increased drowsiness) effects and are, therefore, suitable for assessing both the individual and combined effects of caffeine-based energy drinks (stimulant) and alcohol (sedative), although noting that rising blood alcohol levels can be associated with feelings of increased activation (Rueger et al. 2009). The results showed significant and consistent increases in subjective impairment after alcohol for four out of five scales, although feelings of being energetic showed a dose-related reduction with alcohol in the energy drink group but contrasted with an increase after the second drink for the placebo energy drink group, precluding an overall effect of alcohol for the two groups combined. Dose-related increases in subjective impairment were reflected in significant increases for the Psychopharmacology (2012) 222:519–532 drinks factor with three of the five descriptors (less clearheaded, more clumsy and mentally slow), whilst a significant interaction between alcohol and drink reflected the increase in drowsiness after the second alcohol drink for both treatment groups combined. There was no evidence of antagonism of alcohol-induced subjective impairment by energy drink as there were no overall significant differences between the energy drink and placebo energy drink groups, nor specifically between the alcohol and energy drink combination compared to alcohol and energy drink placebo with simple main effects analysis. Although, as mentioned, feelings of energy were decreased for the energy drink group after the second drink compared to the placebo energy drink, reflecting a divergence in the perception of alcohol-induced sedation between groups. Overall, in comparison to the other treatment conditions, energy drink without alcohol consistently resulted in the least levels of sedation or greatest subjective stimulation for all but the mentally slow descriptor. In contrast, energy drink combined with alcohol produced the highest levels of subjective impairment and sedation including effect sizes of d≥0.2 for drowsy and mentally slow, although this may partially reflect differences between the two participant groups. What is clear is that the subjective perception of impairment was reliably and consistently seen after alcohol and that several descriptors were sensitive to the increase in dose. None of the descriptors showed overall significant differences between the energy drink combined with alcohol and alcohol alone. There was no evidence of a possible masking effect with energy drink, reducing the perception of intoxication; indeed, the mean trends were for the energy drink and alcohol combination to show greater levels of subjective impairment compared to alcohol alone, although differences were not statistically significant. These findings receive some support from the recent study by Marczinski et al. (2011) who compared the effects of alcohol alone and in combination with energy drink assessing breath alcohol, performance and subjective measures. They also found no significant differences between breath alcohol levels, performance and for subjective effects including intoxication and ability to drive with ANOVA. However, paired comparisons showed reduced subjective mental fatigue and increased stimulation for the alcohol and energy drink combination compared to alcohol alone. These 2 findings, out of over 20 individual ratings taken, are in contrast to the present study where mean values for energetic and mentally slow were not reduced with the alcohol and energy drink combination. These results clearly contrast with the only other currently published study directly comparing the effects of alcohol and energy drink alone and in combination on both psychomotor performance and subjective intoxication. The study of Psychopharmacology (2012) 222:519–532 Ferreira et al. (2006) interpreted the findings as demonstrating that energy drink reduced the perception of alcohol intoxication although they had more descriptors registering impairment with the energy drink and alcohol combination, as well as alcohol alone, than showed reduced impairment after coadministration of energy drink with alcohol. Therefore, their overall results were more in line with the findings of the present study. Other similarities between these two studies include the two alcohol levels. Further, the findings of significant objective performance impairment in both studies provided a suitable basis from which to assess subjective awareness of impairment. One difference between the studies was that, in the Ferreira study, one participant group received the lower alcohol dose and the other the higher dose, whilst in the present study, participant groups were split by energy drink and placebo energy drink. The sample size of 10 participants per group is a limitation with the present study through limiting power which may then impact on the number of statistically significant contrasts observed and requiring caution in interpreting these results. However, the results showed that the study was sufficiently powered to produce significant contrasts for all three factors analysed, i.e. alcohol compared to placebo alcohol, energy drink compared to placebo energy drink, and drink 1 compared to drink 2, as well as significant interactions between them. The inclusion of effect size values (Cohen’s d) found that, generally, effect sizes of d≥0.2, and therefore classified as at least ‘small’ (Cohen 1992), were associated with statistically significant effects, although improvements in reaction time after energy drink were associated with effect sizes of d≥0.2 but failed to achieve significance (P00.06). Similarly, increased feelings of drowsiness and being mentally slow for the alcohol and energy drink combination compared to alcohol also achieved the ‘small’ effect size threshold but failed to achieve significance (P<0.1). These might reflect sample size as well as between-group differences. Future studies might benefit from using a larger sample to increase power and a fully repeated-measures design to enable more sensitive comparisons between all four treatment combinations of alcohol, energy drink and their respective placebos, although repeated testing can itself impact on results. Indirect support for our findings comes from studies investigating the combined effect of caffeine and alcohol compared to alcohol alone, including higher alcohol and caffeine concentrations than investigated here, but also failing to find any difference in either BAC or perception of alcohol intoxication. These laboratory investigations have shown that caffeine and alcohol in combination do not alter the ‘high’ or perceived or actual BAC with caffeine levels up to around 400 mg and alcohol 0.012% BAC (Howland et al. 2010; Liguori and Robinson 2001; Rush et al. 1993). 529 In conclusion, the present study found that alcohol at doses of 0.046 to 0.087% BrAC impaired psychomotor and cognitive performance. The combination of energy drink with alcohol failed to show consistent differences from alcohol alone on several performance measures, although Stroop performance was improved. 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Br J Clin Pharmacol 54:400–406 International Journal of General Medicine Dovepress open access to scientific and medical research O riginal R esearch Open Access Full Text Article Effects of consuming alcohol mixed with energy drinks versus consuming alcohol only on overall alcohol consumption and negative alcohol-related consequences This article was published in the following Dove Press journal: International Journal of General Medicine 14 November 2012 Number of times this article has been viewed Lydia de Haan 1 Hein A de Haan 2,3 Job van der Palen 4,5 Berend Olivier 1 Joris C Verster 1 Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Utrecht, 2 Tactus Addiction Treatment, Deventer, 3Nijmegen Institute for Scientist-Practitioners in Addiction, Nijmegen, 4Medical School Twente, Medisch Spectrum Twente, Enschede, 5Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, The Netherlands 1 Background: The aim of this study was to examine differences in alcohol consumption and its consequences when consumed alone and when mixed with energy drinks. Methods: A survey was conducted among Dutch students at Utrecht University and the College of Utrecht. We collected data on alcohol consumption and alcohol-related consequences of alcohol consumed alone and/or alcohol mixed with energy drinks (AMED). The data were analyzed using a retrospective within-subject design, comparing occasions when subjects consumed AMED with those when they consumed alcohol only in the past 30 days. Results: A representative sample of 6002 students completed the survey, including 1239 who consumed AMED. Compared with consuming alcohol only, when consuming AMED, students consumed significantly fewer alcoholic drinks on an average drinking day (6.0 versus 5.4, respectively), and reported significantly fewer drinking days in the previous month (9.2 versus 1.4), significantly fewer days being drunk (1.9 versus 0.5), and significantly fewer occasions of consuming more than four (female)/five (male) alcoholic drinks (4.7 versus 0.9). The maximum number of mixed alcoholic drinks (4.5) in the previous month was significantly lower when compared with occasions when they consumed alcohol only (10.7). Accordingly, the mean duration of a drinking session was significantly shorter when mixing alcoholic drinks (4.0 versus 6.0 hours). Finally, when consuming AMED, significantly fewer alcohol-related consequences were reported (2.6) for the previous year, including driving a car while intoxicated, taking foolish risks, or being injured or hurt, as compared with alcohol-related consequences when consuming alcohol only (4.9). Conclusion: Mixing alcohol with energy drinks decreases overall alcohol consumption, and decreases the likelihood of experiencing negative alcohol-related consequences. Keywords: alcohol, energy drinks, AMED, alcohol consumption, consequences Introduction Correspondence: Joris C Verster Utrecht University, Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacology, Universiteitsweg 99, CG3584, Utrecht, The Netherlands Tel +313 0253 6909 Email [email protected] submit your manuscript | www.dovepress.com Dovepress http://dx.doi.org/10.2147/IJGM.S38020 Alcohol abuse is a major problem worldwide. It has been estimated that 42% of males and 20% of females in the US will experience an alcohol use disorder (abuse or dependence) during their lifetime, and approximately 12.5% of males and 5% of females meet the criteria for an alcohol use disorder in the previous year.1 Excessive alcohol consumption is ranked as the third leading cause of death in the US, and is also associated with marked functional impairment.1–3 According to the World Health Organization, 6.2% of all deaths worldwide are related to alcohol consumption, which makes it one of the leading causes of death.4 There is global concern about drinking International Journal of General Medicine 2012:5 953–960 953 © 2012 de Haan et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. de Haan et al trends among young people, particularly with regard to heavy episodic or “binge” drinking.5 For example, in the US, about 500,000 college students are injured every year due to drinking alcohol, with about 1700 of them dying annually due to extreme binge-drinking.6 During adolescence, several neural systems undergo alterations, and during maturation, some of these systems modulate sensitivity to a variety of the effects of alcohol, potentially increasing the propensity for relatively high levels of adolescent alcohol use. This might set the stage for later alcohol use disorders.7 Hence, it is important to study factors that may contribute to increased alcohol consumption among young adults. Concerns have been raised regarding the potential negative consequences of consumption of alcohol mixed with energy drinks (AMED). The relevant ingredient in this context is caffeine, of which most popular energy drinks contain 80 mg per 250 mL or 8.4 fl oz.8,9 The stimulant effect of caffeine is thought to counteract the sedative effect of alcohol, possibly leading to increased alcohol consumption and experiencing of more negative alcohol-related consequences. Only a few studies have investigated whether use of AMED is indeed associated with more alcohol consumption. O’Brien et al questioned 4271 college students, of whom 52% had consumed alcohol without mixing with energy drinks and 16.3% (N = 697) had consumed AMED in the previous 30 days, and concluded the AMED consumers to be at increased risk for alcohol-related consequences, even when adjusted for the amount of alcohol consumed.10 This conclusion was based on a between-subjects comparison of AMED consumers and alcohol-only consumers. A similar design was used by Arria et al, comparing college students who consumed energy drinks versus those who did not consume energy drinks in a 3-year longitudinal study. It was concluded that consumers of energy drinks tend to have a greater involvement in alcohol and drug use and have higher levels of sensation-seeking, compared with students who do not consume energy drinks.11 Other surveys reported similar significant correlations between energy drink and alcohol consumption, and reported that those who consume AMED generally consume more alcohol and experience more alcohol-related consequences than those who consume alcohol alone.12–15 These conclusions have raised concerns regarding AMED consumption. However, some researchers have questioned the methodology of these surveys and the interpretation of the results regarding designs used to research AMED consumption,8,16,17 and two studies did not find comparable results while using a between-groups design.18,19 Penning et al reported that those who consume AMED do not 954 submit your manuscript | www.dovepress.com Dovepress Dovepress consume more alcohol than those who consume alcohol only. Rossheim and Thombs found no significant relationship between AMED consumption and the chances of being intoxicated (ie, having a blood alcohol content . 0.08%). However, the main reason for criticism of existing surveys is that the majority of them have compared AMED consumers with those who consume alcohol only, using a betweengroups design. Unfortunately, by comparing an AMED group with an alcohol-only group, it is not possible to determine if there is any causal relationship between energy drink consumption and overall alcohol consumption. In other words, it cannot be established from a between-group comparison whether mixing alcohol with energy drinks had any influence on overall alcohol consumption. Also, between-group analyses introduce the influence of potential confounders, such as differences between groups regarding personality characteristics. To verify whether mixing alcohol with energy drinks increases overall alcohol consumption, studies using a within-subject design are needed. A within-subject comparison is essential to determine whether AMED groups consume more alcohol on occasions when they consume AMED compared with occasions when they consume alcohol only. Another important advantage of a within-subject design is that if a sufficient sample size is obtained, the actual response rate to the survey is of minor concern. As long as the sample that completed the survey reflects the basic demographics and characteristics of the general population, a large enough sample size with adequate power for the statistical analyses is sufficient to yield reliable research results. Nevertheless, it remains important to compare the demographic characteristics of the sample with those of the total population to ensure that the sample studied is representative of this population. Two studies have reported the results of a within-subject comparison.20,21 Price et al found that AMED consumption was associated with increased alcohol consumption, but their sample size of 10 subjects was too small to draw conclusions. A second within-subject comparison was presented by Woolsey et al. These authors only drew conclusions based on their between-group comparison (AMED versus alcohol-only groups), but together with the within-subject comparison (ie, within the AMED group) presented, important results were revealed, supporting the hypotheses that AMED and alcohol-only groups differ from each other in critical characteristics (eg, alcohol consumption when not mixing with energy drinks), and that within the AMED group, mixing alcohol with energy drinks does not increase overall alcohol consumption when compared with occasions on which they consume alcohol only. Woolsey et al found that International Journal of General Medicine 2012:5 Dovepress when mixing energy drinks with alcohol, AMED consumers drink significantly less alcohol than on occasions when they consume alcohol only (6.28 drinks versus 8.60 drinks, respectively). Because the within-subject comparison by Woolsey et al was performed in a relatively small sample of AMED consumers (n = 150), surveys with a larger sample size are needed to confirm these findings. Given the limitations of previous survey research on mixing energy drinks with alcohol, an extensive online survey was developed and conducted in The Netherlands. The aim of this survey was to examine alcohol consumption and its consequences when consumed alone or when mixed with energy drinks using a within-subject design. Given the current scientific evidence available, it was hypothesized that there is no difference in total alcohol consumption (frequency and quantity) and alcohol-related negative consequences when alcohol is consumed alone or when mixed with energy drinks. Materials and methods Sample All 70,000 students from the Utrecht University and the College of Utrecht were invited by email to complete an online survey on consumption of energy drinks and alcohol. Two teams approached students at the campuses, and distributed leaflets to remind them to complete the survey. The study protocol was reviewed by the Twente medical ethics committee, but no formal medical ethics approval needed to be obtained. Participation was anonymous and voluntary, and a prize draw was held among those who completed the survey. In total, 7158 students opened the link to the survey. After cleaning the data set the final dataset comprised 6002 students. For the analyses in this paper, data were used for the alcohol-only group (ie, those who only consumed alcohol, n = 3185), and the AMED-group (consisting of participants who consumed both alcohol only and AMED, n = 1239). Data concerning the group that consume both alcohol and energy drinks but never mix these and the group that do not consume alcohol will be discussed elsewhere. Survey outline After obtaining demographic data from the participants, questions were asked about alcohol use when consumed alone and when mixed with energy drinks. The consumption questions were standard ones investigating the subject´s consumption habits (frequency and quantity) considering the particular drink asked about, with a focus on the past 30 days, and adapted from the Quick Drinking Screen, which contains four consumption questions that have been shown International Journal of General Medicine 2012:5 Consuming alcohol mixed with energy drinks to be highly reliable and consistent when compared with the 12-month Timeline Follow Back method.22,23 Mixing was defined as consuming energy drinks within a time frame of 2 hours before or after drinking alcohol. The Dutch version of the Brief Young Adult Alcohol Consequences Questionnaire (BYAACQ) was included to study alcohol-related negative consequences.24 The BYAACQ consists of 24 possible consequences of alcohol consumption that can be answered by “yes” or “no”. The outcome score ranges from 0 to 24. The BYAACQ was completed for alcohol only and for mixing with energy drinks depending on the specific drinking behavior of the participant. In addition to the BYAACQ, two additional items were included to determine whether participants were injured or got into a fight after alcohol consumption (with or without mixing with energy drinks). A detailed description of the survey design and its questions can be found elsewhere.25 Furthermore, it should be taken into account that alcoholic drinks in The Netherlands, when obtained in a bar, pub, or restaurant, contain a standardized amount of alcohol. Data collection and statistical analyses The survey went online on June 6, 2011 and remained online for 10 days. Data were collected online via SurveyMonkey and analyzed using the Statistical Package for the Social Sciences version 18 (SPSS Inc, Chicago, IL). The mean, standard deviation, and frequency distribution was computed for alcohol consumption questions and BYAACQ scores for occasions on which subjects consumed AMED or alcohol only. Variables with a normal distribution were tested with the Student t-test. For nominal variables, a χ2-test was performed. To analyze within-subject differences within the AMED group (drinking AMED versus drinking alcohol only), a paired t-test was used for consumption questions, and intraclass correlations were calculated to look for interindividual correlations where appropriate. For the BYAACQ data, a McNemar test was performed on the single items, and a paired t-test and intraclass correlation on the BYAACQ total scores. All tests were two-tailed, and differences were regarded as significant at P , 0.05. Results Between-group comparisons The demographics of the participants are summarized in Table 1. The age and gender distribution of the sample obtained did not differ significantly from the total Utrecht student population.25 The alcohol-only group comprised 3185 subjects and the AMED group comprised 1239 subjects. submit your manuscript | www.dovepress.com Dovepress 955 Dovepress de Haan et al Table 1 Demographics of study participants Male/female ratio Age (years), mean (SD) Weight (kg), mean (SD) Height (m), mean (SD) Sorority/fraternity member Medication use Drug use Tobacco use Alcohol-only group (n = 3185) Alcohol mixed with energy drinks group (n = 1239) P value 32.5%/67.5% 22.1 (2.6) 68.9 (11.8) 1.75 (0.1) 20.6% 23.2% 22.0% 23.2% 39.1%/60.9% 21.5 (2.3) 70.4 (12.3) 1.76 (0.1) 22.8% 23.0% 38.3% 41.7% ,0.001 ,0.001 ,0.001 ,0.001 0.113 0.905 ,0.001 ,0.001 Abbreviation: SD, standard deviation. Between-group analyses showed that the groups differed significantly from each other on variables related to alcoholonly consumption, smoking, and drug use, as summarized in Tables 1 and 2. Between-group analyses also revealed a consistent pattern of significant differences on most variables, in that AMED consumption was greater than alcohol-only consumption, as summarized in Table 2. Within-subject analyses for AMED group To establish whether mixing energy drinks with alcohol has an impact on total alcohol consumption, withinsubject comparisons were performed for members of the AMED group (n = 1239), comparing occasions on which they consumed AMED with occasions on which they consumed alcohol only. The results of these comparisons are summarized in Figure 1. Intraclass correlations were calculated when appropriate to examine these within-subject comparisons further. The within-subject analyses revealed generally lower consumption of alcohol when combining alcohol with energy drinks. Compared with consuming alcohol only, when consuming AMED, students consumed significantly fewer alcoholic drinks (mean 6.0 ± 3.9 versus 5.4 ± 3.7, respectively; intraclass correlation 0.636, P # 0.001) during an average drinking session, and reported significantly fewer drinking days in the previous month (9.2 ± 6.4 versus 1.4 ± 1.8), significantly fewer days being drunk (1.9 ± 2.7 versus 0.5 ± 1.0), and significantly fewer occasions of consuming more than four (female)/five (male) alcoholic drinks (4.7 ± 4.7 versus 0.9 ± 1.7). Furthermore, compared with consuming alcohol only, when consuming AMED, students consumed significantly fewer maximum number of alcoholic drinks on a single occasion in the previous month (10.7 ± 6.8 versus 4.5 ± 5.7, respectively; intraclass correlation 0.185, P # 0.001). Accordingly, duration of alcohol consumption on this occasion was significantly shorter Table 2 Between-group comparison of those who consumed alcohol only and those who mixed alcohol with energy drinks with regard to their alcohol consumption on occasions when they consume alcohol only (without mixing with energy drinks) At what age did you first consume alcohol? At what age did you consume alcohol regularly? How many standard drinks do you usually have on one occasion? In the past 30 days, how many days did you drink alcohol? In the past 30 days, how many days did you get drunk? In the past 30 days, how many times did you have more than five (male)/four (female) alcoholic drinks on one occasion? In the past 30 days, what is the greatest number of alcoholic drinks you had on one occasion? On that occasion (previous question), how many hours did you consume alcohol? In the past 12 months, what was the greatest number of alcoholic drinks you consumed on one occasion? Total BYAACQ score for drinking alcohol only Alcohol-only group (n = 3185) Alcohol mixed with energy drinks group (n = 1239) P value 14.5 (2.0) 17.2 (1.9) 4.1 (3.1) 7.9 (6.3) 1.0 (1.9) 2.9 (3.9) 14.0 (1.9) 16.5 (1.7) 6.0 (3.9) 9.2 (6.4) 1.9 (2.7) 4.8 (4.8) ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 7.7 (6.0) 10.7 (6.7) ,0.001 5.1 (3.1) 6.0 (3.1) ,0.001 10.7 (7.1) 14.6 (7.9) ,0.001 3.1 (3.0) 4.9 (3.8) ,0.001 Abbreviation: BYAACQ, Brief Young Adult Alcohol Consequences Questionnaire. 956 submit your manuscript | www.dovepress.com Dovepress International Journal of General Medicine 2012:5 Dovepress Consuming alcohol mixed with energy drinks Alcohol only (AO) 12 10.7 Alcohol mixed with energy drinks (AMED) 9.2 9 6 6.0 6.0 5.4 4.7 3 1.4 4.5 4.0 1.9 0.5 0.9 0 Standard drinks Drinking days Days got drunk >4/5 drinks [occasion] [past month] [past month] [past month] Max drinks [past month] Drinking hours [max drinks past month] Figure 1 Means (SEM) for within-subjects analyses in the AMED group (n = 1189) on consumption questions for alcohol only and alcohol mixed with energy drinks. Notes: Questions are specifically asked for both conditions (consuming solely alcohol/consuming alcohol mixed with energy drinks). All differences are significant at the P , 0.001 level. Abbreviations: AMED, alcohol mixed with energy drinks; SEM, standard errors of the mean. when consuming AMED than when consuming alcohol only (4.0 ± 3.3 versus 6.0 ± 3.0 hours, respectively; intraclass correlation 0.301, P # 0.001). All differences between consuming AMED and alcohol only were examined using a paired t-test and are significant at the P , 0.001 level. Finally, the highest number of AMED consumptions on one occasion during the previous year was 4.8 ± 4.8. BYAACQ Confirmation of alcohol-related consequences after consuming AMED or alcohol only are summarized in Table 3. The within-subject comparisons show that when consuming AMED alcohol-related negative consequences are often experienced significantly less when compared with consuming alcohol only. The total BYAACQ score shows a reduction of 47% from 4.9 ± 3.8 for drinking alcohol only to 2.6 ± 3.5 for AMED (intraclass correlation 0.414, P # 0.001). For two items (numbers 18 and 22) no significant difference was found between the AMED and alcohol only occasions. None of the individual items showed an increased chance of experiencing an alcohol-related negative consequence on AMED occasions compared with drinking alcohol only. Discussion The results of this survey show that people who mix alcohol with energy drinks do not consume more alcohol when they consume AMED compared with occasions on which they consume alcohol only. In contrast, when consuming AMED, International Journal of General Medicine 2012:5 students reported consuming significantly fewer alcoholic drinks on average, having fewer drinking days in the past month, less days of being drunk in the past month, and fewer occasions of consuming more than 4–5 drinks in the past month, compared with consuming alcohol only. Further, when consuming AMED, the maximum number of alcoholic drinks on one occasion during the past month was significantly lower when compared with occasions on which only alcohol was consumed. In addition, no increase in alcoholrelated consequences was reported for occasions when they consumed AMED; this finding is of importance, considering that some authors have suggested otherwise.10–12,14 The current study shows clearly that mixing alcohol with energy drinks does not increase the likelihood of potentially dangerous activities or serious negative consequences, such as driving while intoxicated, being injured, or getting involved in a fight, unplanned sexual activity, or taking foolish risks. The within-subject analyses yield results that are comparable with those reported by Woolsey et al,20 and our current results also clearly show that mixing alcohol with energy drinks does not increase overall alcohol consumption, nor the likelihood of experiencing negative consequences. The large sample size and robust findings of the current study are supportive of this conclusion. The fact that mixing alcohol with energy drinks has no negative impact on overall alcohol consumption or its negative consequences should not be interpreted as suggesting that alcohol abuse does not exist among Dutch students. submit your manuscript | www.dovepress.com Dovepress 957 Dovepress de Haan et al Table 3 Within-subjects comparison in the AMED group (N = 1110) on BYAACQ items for occasions on which they consumed alcohol only compared with occasions on which they mixed alcohol with energy drinks Item 1 5 10 3 9 7 2 11 4 12 24 16 6 13 15 21 20 17 14 8 23 19 18 22 * * BYAACQ Within subject comparison I have had a hangover (headache, sick stomach) the morning after I had been drinking I have had less energy or felt tired because of my drinking I have felt very sick to my stomach or thrown up after drinking I’ve not been able to remember large stretches of time while drinking heavily While drinking, I have said or done embarrassing things I often have ended up drinking on nights when I had planned not to drink I have taken foolish risks when I have been drinking I have not gone to work or missed classes at school because of drinking, a hangover, or illness caused by drinking The quality of my work or school work has suffered because of my drinking When drinking, I have done impulsive things I regretted later I have found that I needed larger amounts of alcohol to feel any effect, or that I could no longer get high or drunk on the amount that used to get me high or drunk I have felt badly about myself because of my drinking My drinking has got me into sexual situations I later regretted I have been overweight because of drinking I have spent too much time drinking I have often found it difficult to limit how much I drink I have neglected my obligations to family, work, or school because of drinking My drinking has created problems between myself and my boyfriend/girlfriend/spouse, parents, or other near relatives I have woken up in an unexpected place after heavy drinking My physical appearance has been harmed by my drinking I have become very rude, obnoxious, or insulting after drinking I have driven a car when I knew I had too much to drink to drive safely I have felt like I needed a drink after I’d got up (that is, before breakfast) I have passed out from drinking Total BYAACQ score mean (SD) I have physically injured myself or others after drinking – separate to being in a fight I have got into a fight after drinking P value Alcohol-only Alcohol mixed with energy drinks 861 (77.6%) 522 (47.0%) ,0.001 697 (62.8%) 412 (37.1%) 393 (35.4%) 330 (29.7%) 220 (19.8%) 198 (17.8%) ,0.001 ,0.001 ,0.001 386 (34.8%) 308 (27.7%) 193 (17.4%) 114 (10.3%) ,0.001 ,0.001 300 (27.0%) 268 (24.1%) 169 (15.2%) 138 (12.4%) ,0.001 ,0.001 252 (22.7%) 117 (10.5%) ,0.001 219 (19.7%) 182 (16.4%) 114 (10.3%) 122 (11.0%) ,0.001 ,0.001 155 (14.0%) 152 (13.7%) 151 (13.6%) 121 (10.9%) 92 (8.3%) 86 (7.7%) 82 (7.4%) 68 (6.1%) 77 (6.9%) 62 (5.6%) 56 (5.0%) 62 (5.6%) ,0.001 ,0.001 ,0.001 ,0.001 ,0.001 0.002 79 (7.1%) 50 (4.5%) ,0.001 76 (6.8%) 68 (6.1%) 66 (5.9%) 55 (5.0%) 26 (2.3%) 21 (1.9%) 4.9 (3.8) 112 (10.1%) 37 (3.3%) 51 (4.6%) 42 (3.8%) 31 (2.8%) 26 (2.3%) 26 (2.3%) 2.6 (3.5) 61 (5.5%) ,0.001 0.027 0.003 0.002 1.000 0.473 ,0.001 ,0.001 46 (4.1%) 45 (4.1%) 1.000 Notes: The percentage “yes” on a particular item is shown. *Additional question, added by the authors. Abbreviations: AMED, alcohol mixed with energy drinks; BYAACQ, Brief Young Adult Alcohol Consequences Questionnaire; SD, standard deviation. The data clearly show that alcohol consumption exceeds levels of consumption that are generally accepted as safe, and the majority of students engaged in binge drinking, especially on days when they did not consume AMED (see Table 2). Therefore, there is still a lot of work to do in preventing excessive alcohol consumption amongst Dutch students. From our data, it is apparent that focusing specifically on AMED consumption is not warranted. The significance of the study results lies in the fact that this is the first large-scale survey using appropriate methodology (ie, a within-subject design) 958 submit your manuscript | www.dovepress.com Dovepress to determine whether mixing alcohol with energy drinks has an effect on overall alcohol consumption when compared with consuming alcohol only. This information cannot be obtained reliably from between-group comparisons. It can be argued that recall bias may interfere with obtaining reliable survey data. However, when applying a within-subject design, there is no reason to assume that participants will recall consumption characteristics differently between AMED or alcohol-only occasions. To avoid the possibility of recall bias entirely, a prospective study design may be a solution, International Journal of General Medicine 2012:5 Dovepress but it would be expensive and time-consuming to achieve a sample size as large as that in the current survey. Interestingly, when applying a between-groups design, as used by other researchers to compare alcohol-only and AMED groups for demographics and alcohol-only consumption patterns, the groups differed from each other on variables concerning alcohol-only consumption and its consequences, drug use and smoking, following a standard pattern of AMED > alcohol only. This observed pattern could be caused by underlying personality characteristics that might differ between the groups, for instance levels of risk-taking behavior. The same authors that claim increased alcohol consumption caused by energy drinks based on such a between-groups design also report that AMED consumers have higher scores on (impulsive) sensation-seeking and childhood conduct problems.11,12 Moreover, having a sportsrelated identity is associated with frequency of energy drink consumption, mediated by masculine norms and level of risk-taking behavior.11,12,26 Increased levels of risk-taking behavior may be reflected by a generally disinhibited behavioral pattern for an individual. The findings of the current study and others11,12,26 confirm that individuals who consume more alcohol also use more drugs.27 Taken together the focus of research should not be on AMED consumption but on persons who are involved in heavy alcohol consumption per se. Future research is needed to explore the possibility that this specific group of alcohol consumers have different personality characteristics, ie, higher risk-taking, underlying their pattern of increased substance use. The reduction in alcohol consumption reported for the AMED group when mixing alcohol with energy drinks as compared with drinking alcohol only was not expected. It was hypothesized that there would be no difference and we have no clear explanation for this observed decrease in alcohol consumption. When looking at the ingredients of energy drinks, it could be speculated that taurine (a nonessential amino acid and an ingredient of most energy drinks) may have an effect on alcohol consumption, given that a modest reduction of voluntary ethanol consumption induced by taurine has been found in rats.28 Other ingredients in energy drinks are unlikely to play a role. However, the low intraclass correlations with a maximum of 0.6 suggest interindividual differences, indicating that factors other than coconsumption of energy drinks may explain the observed decrease in alcohol consumption. A possible reason for decreased overall alcohol consumption may be that spirits and energy drinks are generally more expensive than beer and wine. Wagenaar et al showed that the price of alcohol beverages is inversely related to the quantity International Journal of General Medicine 2012:5 Consuming alcohol mixed with energy drinks of alcohol consumed.29 However, it is unknown if and how much students had to pay for their alcoholic and energy drinks on the occasions they reported in our survey, or whether they were consumed at home or in a bar. Our data show that the maximum number of drinks consumed when drinking alcohol only (10.7) was much higher than last month’s maximum number of alcoholic drinks on AMED occasions (4.5). In fact, the maximum number of alcoholic drinks on AMED occasions equals that of the 4–5 rule, whereas this is doubled for the maximum monthly consumption of alcohol only (when not mixing). Therefore, it is understandable that negative consequences are experienced more commonly when people do not mix alcohol with energy drinks. It is likely that alcohol-related consequences occur most often on heavy drinking days and less often on days during which few alcoholic drinks are consumed. Although we have information on the number of drinking days, it would not be correct to use this information as a covariate in statistical analysis. The main reason for this is that it is unknown how many of the total drinking days were heavy drinking days (ie, close to the maximum monthly number of drinks) and how many were “normal” drinking days (ie, without experiencing negative consequences). Although there are data on the number of days spent intoxicated and the number of days on which more than 4–5 alcoholic drinks were consumed, including these values in the statistical analysis would result in speculative interpretation of the data, because it can only be guessed if and how many negative consequences subjects experienced on each of these days. The most firm conclusion supported by our data is that people consume less alcohol when they mix alcohol with energy drinks, both on average drinking days and on their maximum heavy drinking occasions. It is understandable that fewer negative consequences are experienced when alcohol consumption is reduced by mixing it with energy drinks. Our analysis shows that the student sample obtained does not differ significantly from the total Utrecht student population.25 Also, there is no reason to assume that students from Utrecht University are very different from those attending other universities in The Netherlands. Nevertheless, a limitation of this survey is that it was conducted only in The Netherlands, which may limit the generalizability of its results to other countries. Therefore, this study will be replicated in other parts of the world, including Australia and the US. These surveys will also adopt a within-subject design and include a sufficient number of participants in the AMED group to ensure adequate statistical power in order to submit your manuscript | www.dovepress.com Dovepress 959 Dovepress de Haan et al have confidence in the results. Furthermore, any underlying personality characteristics likely to cause differences in alcohol-only consumption per se need to be examined in greater detail. In conclusion, the results of this survey show that mixing alcohol with energy drinks decreases overall alcohol consumption, and decreases the likelihood of experiencing negative alcohol-related consequences. Disclosure This survey was supported by a grant from Red Bull GmbH. Red Bull GmbH was not involved in the design and conduct of the study, collection, management, analysis, interpretation of the data, or preparation of the manuscript. JV has received research support from Takeda Pharmaceuticals and Red Bull GmbH, and has been a scientific advisor for Takeda, SanofiAventis, Transcept, Sepracor, Red Bull GmbH, Deenox, Trimbos Institute, and CBD. BO is a scientific advisor for Emotional Brain BV and has received research support from Emotional Brain, PsychoGenics Inc, Sepracor, Servier, Abbott, and the Dutch Brain Research Organization. The other authors have no potential conflicts of interest to disclose. References 1. Hasin DS, Stinson FS, Ogburn E, Grant BF. Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry. 2007;64:830–842. 2. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual causes of death in the United States, 2000. JAMA. 2004;291:1238–1245. 3. Young-Wolff KC, Enoch MA, Prescott CA. The influence of geneenvironment interactions on alcohol consumption and alcohol use disorders: a comprehensive review. Clin Psychol Rev. 2011;31:800–816. 4. World Health Organization. Global Status Report on Alcohol and Health. Geneva, Switzerland: World Health Organization; 2011. 5. McCambridge J, McAlaney J, Rowe R. Adult consequences of late adolescent alcohol consumption: a systematic review of cohort studies. PLoS Med. 2011;8:e1000413. 6. Hingson RW, Zha W, Weitzman ER. Magnitude of and trends in alcoholrelated mortality and morbidity among US college students ages18–24, 1998–2005. J Stud Alcohol Drugs. 2009;Suppl 16:12–20. 7. Spear LP. Adolescent neurobehavioral characteristics, alcohol sensitivities, and intake: setting the stage for alcohol use disorders? Child Dev Perspect. 2011;5:231–238. 8. Verster JC, Aufricht C, Alford C. Energy drinks mixed with alcohol: misconceptions, myths, and facts. Int J Gen Med. 2012;5:187–198. 9. Reissig CJ, Strain EC, Griffiths RR. Caffeinated energy drinks – a growing problem. Drug Alcohol Depend. 2009;99:1–10. 10. O’Brien MC, McCoy TP, Rhodes SD, Wagoner A, Wolfson M. Caffeinated cocktails: energy drink consumption, high-risk drinking, and alcohol-related consequences among college students. Acad Emerg Med. 2008;15:453–460. 11. Arria AM, Caldeira KM, Kasperski SJ, et al. Increased alcohol consumption, nonmedical prescription drug use, and illicit drug use are associated with energy drink consumption among college students. J Addict Med. 2010;4:74–80. 12. Arria AM, Caldeira KM, Kasperski SJ, Vincent KB, Griffiths RR, O’Grady KE. Energy drink consumption and increased risk for alcohol dependence. Alcohol Clin Exp Res. 2011;35:365–375. 13. Miller KE. Energy drinks, race, and problem behaviors among college students. J Adolesc Health. 2008;43:490–497. 14. Thombs DL, O’Mara RJ, Tsukamoto M, et al. Event-level analyses of energy drink consumption and alcohol intoxication in bar patrons. Addict Behav. 2010;35:325–330. 15. Berger LK, Fendrich M, Chen HY, Arria AM, Cisler RA. Sociodemographic correlates of energy drink consumption with and without alcohol: results of a community survey. Addict Behav. 2010;36:516–519. 16. Verster JC, Alford C. Unjustified concerns about energy drinks. Curr Drug Abuse Rev. 2011;4:1–3. 17. Skeen MP, Glenn LL. Imaginary link between alcoholism and energy drinks. Alcohol Clin Exp Res. 2011;35:1375–1376. 18. Penning R, de Haan L, Verster JC. Caffeinated drinks, alcohol consumption, and hangover severity. Open Neuropsychopharmacol J. 2011;4:36–39. 19. Rossheim ME, Thombs DL. Artificial sweeteners, caffeine, and alcohol intoxication in bar patrons. Alcohol Clin Exp Res. 2011;35:1891–1896. 20. Woolsey C, Waigandt A, Beck NC. Athletes and energy drinks: reported risk-taking and consequences from the combined use of alcohol and energy drinks. J Appl Sport Psychol. 2010;22:65–71. 21. Price SR, Hilchey CA, Darredeau C, Fulton HG, Barrett SP. Energy drink co-administration is associated with increased reported alcohol ingestion. Drug Alcohol Rev. 2010;29:331–333. 22. Roy M, Dum M, Sobell LC, et al. Comparison of the quick drinking screen and the alcohol timeline followback with outpatient alcohol abusers. Subst Use Misuse. 2008;43:2116–2123. 23. Sobell LC, Agrawal S, Sobell MB, et al. Comparison of a quick drinking screen with the timeline followback for individuals with alcohol problems. J Stud Alcohol Drugs. 2003;64:858–861. 24. Verster JC, Herwijnen J, Olivier B, Kahler CW. Validation of the Dutch version of the Brief Young Adult Alcohol Consequences Questionnaire (B-YAACQ). Addict Behav. 2009;34:411–414. 25. de Haan L, de Haan H, Olivier B, Verster J. Alcohol mixed with energy drinks: methodology and design of the Utrecht Student Survey. Int J Gen Med. 2012;5:889–898. 26. Miller KE. Wired: energy drinks, jock identity, masculine norms, and risk taking. J Am Coll Health. 2008;56:481–490. 27. de Haan L, Kuipers E, Kuerten Y, van Laar M, Olivier B, Verster JC. The RT-18: a new screening tool to assess young adult risk-taking behavior. Int J Gen Med. 2011;4:575–584. 28. Olive M. Interactions between taurine and ethanol in the central nervous system. Amino Acids. 2002;23:345–357. 29. Wagenaar AC, Salois MJ, Komro KA. Effects of beverage alcohol price and tax levels on drinking: a meta-analysis of 1003 estimates from 112 studies. Addiction. 2009;104:179–190. Dovepress International Journal of General Medicine Publish your work in this journal The International Journal of General Medicine is an international, peer-reviewed open-access journal that focuses on general and internal medicine, pathogenesis, epidemiology, diagnosis, monitoring and treatment protocols. The journal is characterized by the rapid reporting of reviews, original research and clinical studies across all disease areas. A key focus is the elucidation of disease processes and management protocols resulting in improved outcomes for the patient.The manuscript management system is completely online and includes a very quick and fair peer-review system. Visit http://www.dovepress.com/ testimonials.php to read real quotes from published authors. Submit your manuscript here: http://www.dovepress.com/international-journal-of-general-medicine-journal 960 submit your manuscript | www.dovepress.com Dovepress International Journal of General Medicine 2012:5 COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT COT Statement on the interaction of caffeine and alcohol and their combined effects on health and behaviour Introduction 1. The Committee was asked by the Food Standards Agency to comment on concerns that caffeine in energy drinks may interact with alcohol1 in causing adverse behavioural or toxic effects. Background 2. Since 2004, energy drinks have been the fastest growing sector of the drinks market in the UK, with an average growth of 12% per year (BSDA, 2011). The popularity of consuming energy drinks mixed with alcoholic beverages has also increased, especially amongst young males. Moreover, individuals who consume high quantities of both energy drinks and alcohol, are perceived to engage in a greater degree of risk-taking. This has raised concerns about the health effects of caffeine and alcohol in combination. In particular, a phenomenon described as “wide awake drunk” has been postulated, in which the stimulatory effect of caffeine prevents consumers of alcohol from realising how intoxicated they are, thereby increasing the potential for toxic injury and adverse behavioural effects (Reissig et al, 2009). In a report by the Scottish Prisons Service, “Buckfast Tonic Wine”, which contains substantial quantities of caffeine as well as 15% alcohol by volume, was linked with violence in young offenders in Scotland. Among a sample of 172 young offenders, 43% admitted consumption of Buckfast Tonic Wine before their most recent offence (Scottish Prisons Service, 2009). Most energy drinks contain levels of caffeine approximately equivalent to those found in coffee (approximately 80mg caffeine per 250ml can, although drinks with smaller volumes and higher caffeine concentrations have appeared on the market in recent years) along with other substances such as sugar, taurine and glucuronolactone. 3. The Scientific Committee on Food (SCF), which advised the European Commission before the creation of the European Food Safety Authority (EFSA), looked at the safety of energy drinks in 1999 and 2003 (SCF, 1999; SCF, 2003). As part of their second assessment, the SCF examined the evidence for a toxic interaction between caffeine and alcohol. They concluded that most studies 1 In this document, the term alcohol will refer to ethanol present in alcoholic beverages. suggested that caffeine would not exacerbate the adverse effects of alcohol, and that at lower blood alcohol levels, caffeine may improve performance of simpler tasks (SCF, 2003). 4. The SCF also looked at evidence for interactions between alcohol and other constituents of energy drinks such as taurine and glucuronolactone. They observed that both taurine and alcohol inhibit the release of the antidiuretic hormone vasopressin, and therefore might act in concert to increase loss of water and sodium from the body, leading to a short-term risk of dehydration. In a 13-week study in rats, taurine was shown to cause behavioural effects in all dose groups tested (300, 600 and 1000 mg/kg bw/day), including persistent increased activity, occasional chewing of limbs, and in the 1000mg/kg bw group only, a possible decrement (not statistically significant) in motor performance on a rotarod2. The lowest dose was equivalent to 6 times the mean acute intake from energy drinks (50mg/kg bw). The SCF concluded that some alcohol–taurine interactions were possible, including “behavioural interactions”, but these were neither marked nor consistent in human and animal studies. The SCF was of the opinion that focused neurological studies should be carried out on taurine, and concluded that glucuronolactone would not be expected to interact with alcohol or other constituents of energy drinks. 5. The COT was asked to consider the literature published since the SCF opinion of 2003, and to advise on the potential for interactions between caffeine and alcohol. Current European legislation on caffeine 6. Under European Directive 2002/67/EC on the labelling of foodstuffs containing quinine and foodstuffs containing caffeine, beverages containing more than 150 mg/l caffeine (other than those based on coffee or tea) must carry the statement ‘High caffeine content’ in the same field of vision as the name of the product, followed by a reference in brackets to the caffeine content expressed in mg per 100ml. Under the new Food Information Regulation (EU 1169/2011), which comes into effect on the 13 December 2014, beverages containing more than 150 mg/l caffeine (other than those based on coffee or tea) must carry the statement ‘High caffeine content. Not recommended for children or pregnant or breast feeding women’ in the same field of vision as the name of the beverage, followed by a reference in brackets to the caffeine content expressed in mg per 100ml. Consumption of caffeine 7. Caffeine (1,3,7-trimethyl xanthine) is probably the most widely used psychoactive substance worldwide (Benowitz, 1990). Its molecular structure is shown in Figure 1: 2 Animals are trained to stay on a rotating bar which gradually accelerates. Animals that fall off receive a foot‐ shock. The speed of the rotating bar at which the animals fall off is taken as the performance score. Rotarod trials occur before and after treatment to compare performance. N N O N N O Figure 1: Caffeine 8. In 2004, the Dietary Caffeine and Health Study estimated a mean caffeine intake of 241mg/day in 6,000 individuals from the Bristol area who completed a questionnaire quantifying consumption of coffee, tea, chocolate products, cola drinks and energy drinks (Heatherley et al, 2006b; Heatherley et al, 2006a). This level of intake is similar to those indicated by a UK survey of consumption of coffee, tea and colas, carried out in 1988 – 3.98 mg/kg body weight per day (i.e. 279 mg/day for a 70 kg person) for the general population and 3.43 mg/kg body weight per day (i.e. 240 mg/day for a 70 kg person) for pregnant women (Barone and Roberts, 1996). In terms of instant coffee, this would be equivalent to 2-2.5 average sized mugs (260ml), assuming an average content of 100 mg caffeine per mug. The survey did not address other sources of caffeine such as chocolate, cold and flu remedies, headache treatments and energy drinks. In a more recent study, mean caffeine intakes were found to be 238 mg/day in women before they became pregnant, and reduced to 159 mg/day during pregnancy (CARE Study Group, 2008). 9. Recently, estimates of caffeine intake in the UK were derived from the rolling National Diet and Nutrition Survey (NDNS)3. These were based on the first two years of the survey and applied to respondents who reported consuming foods containing caffeine in 4-day food diaries (in which quantities were gauged approximately and not by weighing). The intake assessment was restricted to foods within 35 NDNS food groups that potentially contained caffeine (these included coffee, tea, cocoa, energy and soft drinks and dietary supplements). The caffeine content of dietary constituents was estimated from various sources, including information received from food manufacturers and earlier MAFF surveys (MAFF, 1998). The mean (± standard deviation) total caffeine intakes of men and women aged 19-64 were estimated to be 130 (±88) and 122 (±87) mg/d respectively. The corresponding figures for older men and women in the 65+ age range were 143 (±94) and 131 (±88) mg/d. Boys and girls in the age range of 11-18 years had lower intakes (46 (±43) and 44 (±45) mg/d) (Fitt et al, 2012). A breakdown of caffeine intake from caffeinated beverages in all NDNS respondents who reported consumption of such products indicated that coffee contributed more caffeine (49.5 3 The NDNS provides detailed, quantitative information on food consumption, nutrient intakes, nutritional status and related characteristics. The NDNS is, in its current form, a four year rolling survey. The sample size for the survey is 500 adults and 500 children per year, covering people of all ages from 1½ years upwards living in private households. People living in institutions are not covered, and pregnant and lactating women are also excluded. The survey includes boosted samples in Scotland, Wales and Northern Ireland to enable cross-country comparisons. So far, only results from the first two years of the survey have been published (Department of Health, 2011). (±32.3) mg/d) than tea (36.2 (±11.3) mg/d) and energy and soft drinks (34.5 (±21.4) mg/d). The inclusion of a larger range of products containing caffeine (e.g. chocolate products and energy drinks) in the recent analysis of NDNS data, as well as differences in the dietary assessment methods and in the assumed caffeine content of dietary constituents, may account for the differences in estimation of caffeine intake between different studies. High level intakes were not reported in these studies. Biochemistry and psychopharmacology of caffeine 10. Caffeine is completely absorbed in the small intestine and the peak blood concentration occurs around 1-2 hours after ingestion. Caffeine is distributed throughout total body water and enters the brain quickly after absorption, but rate of metabolic clearance is variable, the half-life ranging from 2.3 to 9.9 hours in adults following single doses of caffeine (Arnaud, 2011), with a mean half-life of 4.3 hrs being reported in healthy non-smoking adult males (Seng, 2009). Extensive interindividual variation occurs in caffeine metabolism due to factors such as alcohol and smoking habits, pregnancy, genetic polymorphisms and level of caffeine consumption. At low doses (<5mg/kg bw or 3-4 cups of coffee), pharmacokinetics can be represented accurately using a one-compartment model with first order absorption (Csajka et al, 2005). Metabolism of caffeine proceeds through three main pathways illustrated in Figure 2 (percentages refer to the mean proportion of caffeine converted to each metabolite). Some of the metabolites of caffeine themselves have pharmacological activity (Casarett et al, 1996). O N O N N N caffeine CYP 1A2 CYP 2E1 CYP 2E1 O O O HN N N NH N N O O N N O N H N N N 1,7-dimethylxanthine (paraxanthine) 84% theobromine 12% theophylline 4% O HN O O NH N HN N O NAT2 O N N 1-methylxanthine N O 5-acetylamino-6-formylamino-3-methyluracil Figure 2: Metabolism of caffeine 11. Caffeine’s primary biologically relevant mechanism of action is as a nonspecific adenosine antagonist. Adenosine receptors are found throughout the body, and adenosine acts presynaptically to inhibit neuronal release of several neural transmitters, reduces spontaneous firing of neurons, produces sedation and has anticonvulsant activity (Benowitz, 1990). The pharmacologically active dose of caffeine can vary considerably between individuals as tolerance is rapidly developed to its effects. However, levels of 2-3 mg/kg bw have been shown to stimulate central nervous system activity in humans (FDA, 1978). 12. Adenosine is involved in a number of fundamental processes such as ATPrelated energy production and RNA synthesis, but it is also released in response to metabolic stress and acts to protect the brain by suppressing neural activity (Latini and Pedata, 2001). Adenosine A2A receptors are largely concentrated in the basal ganglia region and may be involved in the dopamine system (which is involved in reward and arousal). Adenosine may also be involved in the sleep-wake cycle (Basheer et al, 2004; Latini and Pedata, 2001). 13. Caffeine may also have secondary effects that are not related to adenosine, since it acts also as a competitive non-selective phosphodiesterase inhibitor, allowing the build up of cyclic AMP in cells and therefore modulation of many biological processes (Essayan, 2001). 14. In the central nervous system, caffeine acts primarily as a stimulant, increasing arousal and vigilance, reducing fatigue and decreasing motor reaction times in some tasks. At higher doses, caffeine can induce insomnia, anxiety, tremors, and seizures (Benowitz, 1990). The ADORAA2A 1083TT genotype of the adenosine A2A receptor has been associated with lower caffeine intakes, suggesting a genetic link to the degree of caffeine consumption (Cornelis et al, 2007). 15. Studies carried out in adults showed improvements in aerobic endurance, anaerobic performance, choice reaction time, concentration and immediate-recall memory following consumption of an energy drink (80 mg caffeine, equivalent to 1.1 mg/kg bw for a 70 kg adult; (Alford et al, 2001), and 0.58, 1.70 or 1.75mg/kg bw (Howard and Marczinski, 2010)) in comparison with controls consuming a dummy energy drink or water. Following a mental depletion task (designed to require significant concentration on a number of tasks at one time), caffeine was found to increase aggression compared to placebo, but no effects were observed in groups which did not undertake the mental depletion task. In contrast, during a second experiment when a no pill control group was included along with the caffeine and placebo groups, no difference was observed in aggression between the caffeine and no-pill control groups, following the mental depletion task (Denson et al, 2011). Consumption of alcohol 16. Alcohol is widely consumed in the UK with at least one alcoholic drink being reported as consumed in the week before interview by 68% of men and 54% of women in the 2009 General Lifestyle Survey carried out by the Office for National Statistics. In the same report, mean weekly consumption of alcohol in the 12 months before interview was 16.3 units for men and 8.0 units for women, equivalent to 2.33 g/kg bw for a 70kg man and 1.33 g/kg bw for a 60kg woman (Office of National Statistics, 2009). However, these data were for the total population, including those who did not drink alcoholic beverages, and the mean consumption of those who did drink alcohol would have been higher. During the week before interview, 37% of male participants exceeded the recommended limit for men of 4 units (32 g alcohol4) in a single day, and 29% of female participants exceeded the corresponding limit for women of 3 units (24 g alcohol). Biochemistry and psychopharmacology of alcohol 17. Alcohol is rapidly absorbed from the stomach and intestine, and distributed widely through simple diffusion from blood into tissues. It is metabolised to acetaldehyde, primarily through the action of alcohol dehydrogenase (ADH) using the co-enzyme nicotinamide adenine dinucleotide (NAD), but also by CYP 2E1. Acetaldehyde is converted to acetic acid, through the action of the NAD-dependent enzyme acetaldehyde dehydrogenase (AcDH) (Casarett et al, 1996) (see Figure 3). 4 www.drinkaware.co.uk. One unit of alcohol equals 8g pure alcohol. HO HO ethanol ADH (NAD) O acetaldehyde AcDH (NAD) O acetic acid Figure 3: Metabolism of ethanol 18. Alcohol is a central nervous system depressant, but its mode of action has not been fully elucidated. It is thought to act in the central nervous system (CNS) by binding to the GABA-A receptor, which mediates rapid inhibitory neurotransmission throughout the CNS. The outward signs of alcohol intoxication, such as impaired sensory and motor function, slowed cognition and stupefaction, are a result of this receptor-binding activity (Kumar et al, 2009). 19. A major effect of alcohol is to impair inhibitory responses. It is thought that behaviour is governed by two distinct systems: one that activates a response and one that inhibits a response. As an example, in tests for behavioural inhibition, participants are required to respond appropriately to “go” signals on a computer, but when a “stop” signal is observed then they should inhibit their response. The impaired ability to inhibit responses when under the influence of alcohol has received much attention because of the social implications of excessive consumption (Marczinski and Fillmore, 2003). Doses of 0.62 g/kg bw absolute alcohol (43.4 g for a 70 kg adult) have been shown to reduce response inhibition using “stop/go” software as described above under laboratory conditions (Fillmore and Vogel-Sprott, 1999). The neuronal pathways directly responsible for the effects on responseinhibition are not clear. 20. Studies looking at the effects of lower doses of alcohol on attention tasks indicate that attention concentrated on a single source of information is not impaired by alcohol, but in divided attention tasks, especially those where two tasks follow each other closely, reaction time is increased (Moskowitz and Burns, 1971). Co-consumption of alcohol, caffeine and other psychoactive substances 21. Accurate estimates of the extent to which alcohol and caffeine are consumed together are not available. One of the reasons for this is that drinks containing alcohol and caffeine are often sold separately and mixed by the consumer rather than being formulated in a single product – for example rum with cola or energy drinks with vodka. 22. Four studies looking at the energy drink and alcohol consumption of university students in the US and Canada showed an association between consumption of energy drinks and alcohol. Some of these studies investigated alcohol-related adverse incidents, and showed that high consumers of both energy drinks and alcohol were at greater risk of such incidents than consumers of alcohol alone (Arria et al, 2011; O'Brien et al, 2008; Price et al, 2010; Velazquez et al, 2011). One Canadian study found a significant association of combined energy drink and alcohol consumption with risk-taking behaviours, including consumption of illicit drugs (Brache and Stockwell, 2011). In another study, general caffeine consumption in 1213 year olds in high school was significantly associated with the use a year later, not only of caffeine, but also of nicotine and alcohol (Collins et al, 2011). 23. In a field study of 1255 bar patrons, individuals who consumed alcohol mixed with energy drinks were at three-fold increased risk of leaving a bar highly intoxicated and four-fold increased risk of intending to drive, when compared to other patrons who consumed alcohol but not mixed with energy drinks. The mean quantity of alcohol consumed by individuals who drank only alcohol was 95.3g, as compared with 108.3g for those who also consumed energy drinks but not mixed with the alcohol, and 152.2g for those who consumed alcohol mixed with energy drinks. Group sizes for those consuming energy drinks and alcohol were small (46 consumed both but not mixed and 45 consumed both mixed) (Thombs et al, 2010). 24. In contrast, in a survey of 1503 Dutch students, those who consumed alcohol with an energy drink consumed less alcohol than those who drank alcohol alone, although the difference did not reach statistical significance (p=0.056). Those who consumed alcohol with a cola beverage consumed significantly more alcohol than those who consumed alcohol alone (p=0.001) or those who combined energy drinks with alcohol (p=0.001). The group sizes for those consuming cola and energy drinks with alcohol were small; 45 and 24 respectively (Penning et al, 2011). 25. There has been some suggestion that high intake of caffeine might be a marker for the use of other drugs, both legal and illegal, and also for other addictive behaviours such as excessive gambling and excessive use of the internet (Arria et al, 2010; Istvan and Matarazzo, 1984; Kaminer, 2010; Pallanti et al, 2006). 26. Studies based on a cohort of male and female mono- and dizygotic twin pairs, looked at caffeine, smoking, alcohol and drug consumption habits. These investigations suggested that the association between high consumption of caffeine and alcohol depended on familial factors, which were primarily genetic. Modelling indicated two genetic factors – one linked to illicit drug use and the other to use of legal drugs including caffeine and alcohol (Hettema et al, 1999; Kendler et al, 2006; Kendler et al, 2007; Kendler et al, 2008). However, this finding has yet to be independently confirmed. 27. In a cohort of male di- (n=183) and monozygotic (n=173) twins, heavy consumption of alcohol and heavy smoking were significantly associated [phenotypic Pearson correlation r=0.22 (p<0.001)], as were heavy smoking and heavy coffee consumption [phenotypic Pearson correlation r=0.28 (p<0.001)]. In contrast, heavy consumption of coffee and alcohol were more weakly related [phenotypic Pearson correlation r=0.14 (p<0.001)] (Swan et al, 1997). Further comparisons between diand monozygotic twins suggested that co-consumption of coffee and alcohol had a genetic basis, and co-consumption of alcohol, coffee and nicotine is determined in part by genetic predisposition (Swan et al, 1996). 28. In a population of 1925 patients who had voluntarily sought treatment for substance abuse disorders, a statistically significant relationship was found between the frequencies of using caffeine, nicotine and alcohol, but there was no significant association of exposure to caffeine and nicotine with exposure to other substances of abuse such as heroin, cannabis and glue (Kozlowski et al, 1993). 29. In a sample of 105 Israeli alcoholics undergoing treatment, caffeine and alcohol consumption were significantly correlated (p<0.05). When the sample was subdivided into those with (n=62) and those without (n=43) a family history of alcoholism (defined as at least one primary family member meeting the DSM-IV criteria for alcohol dependence) no differences were observed between the two groups in alcohol or caffeine consumption (Amit et al, 2004) 30. The balance of evidence suggests that higher intake of caffeine is associated not only with higher alcohol intakes but also with use of other psychoactive substances. There is limited evidence that the relationship may be determined, at least in part, by genetic predisposition. It appears that, at least in some population groups, there is a correlation between high consumption of alcohol and of energy drinks specifically. However, it is unclear whether this is because consumption of energy drinks causes people to drink more alcohol, or because people who are inclined to more risky behaviour tend generally to consume larger quantities of psychoactive substances, including caffeine and alcohol. Health effects of co-consumption of alcohol and caffeine 31. It has been suggested that when consumed together, energy drinks and alcohol might interact in several ways (Weldy, 2010): • • • • • • Carbonation tends to increase the absorption of alcohol (although some noncarbonated energy drinks are available, the majority of sales are of carbonated products) Diluted alcohol is emptied from the stomach into the faster absorbing small intestine more quickly than alcohol at higher concentrations. Caffeine blunts the sedative effects of alcohol Caffeine prevents sleep, allowing greater opportunity for consumption of alcohol before loss of consciousness At low blood alcohol levels, caffeine appears to decrease some of the physical and mental impairment resulting from alcohol, although at higher blood alcohol levels no such effects are observed. Energy drink ingredients give the consumer a false sense of physical and mental competence and decrease their awareness of impairment by alcohol. Does caffeine counteract the neuro-cognitive effects of alcohol consumption? 32. There is some evidence that caffeine can ameliorate some of the neurocognitive effects of alcohol, but the findings have not been consistent in all studies, and the underlying mechanisms are unclear. In a review of the data published up to 1988, the authors concluded that because of variation in the doses of caffeine and alcohol administered, the behavioural effects assessed, and other aspects of study design, it was not possible to determine whether there was a counteracting effect of caffeine (Fudin and Nicastro, 1988). 33. A number of studies published since the SCF opinion of 2003 have investigated the effects of combined alcohol and caffeine consumption on various aspects of neurological function. Doses ranged from 1.1 to 5.6 mg/kg bw for caffeine and 0.18 to 1.07 g/kg bw for alcohol. Many of these studies used driving simulators and doses of approximately 2-3 cups of coffee or 1-2 cans of energy drink with 1-2 standard measures of vodka. Results have been inconsistent, with some studies finding that caffeine did not antagonise the physiological effects of alcohol and others suggesting that some important aspects of alcohol intoxication were ameliorated, especially effects on motor reaction time, mean tracking performance and memory reaction time (Alford et al, 2012; Attwood et al, 2011; Azcona et al, 1995; Burns and Moskowitz, 1990; Ferreira et al, 2004; Ferreira et al, 2006; Fillmore et al, 2002; Fillmore and Vogel-Sprott, 1999; Hasenfratz et al, 1993; Howland et al, 2011; Kerr et al, 1991; Marczinski et al, 2011; Marczinski et al, 2012a; Marczinski et al, 2012b; Marczinski and Fillmore, 2003; Marczinski and Fillmore, 2006). Conflicting results have also been obtained in studies designed to test perceived degree of alcohol intoxication with and without caffeine. The most direct subjective ratings of intoxication5 were no different when alcohol was consumed with and without caffeine. Where conflicts have been found, these were in less direct subjective6 measures (Alford et al, 2012; Ferreira et al, 2006; Marczinski and Fillmore, 2006). A recent review concluded that the available literature did not support the argument that energy drinks mask the effects of alcohol intoxication and increase alcohol consumption (Verster et al, 2012). A more detailed description of the primary studies can be found in Annex 1. 34. In conclusion, the heterogeneity of methods and neurological end-points in reported studies prevents firm conclusions on whether caffeine counteracts the acute neuro-cognitive effects of alcohol. It should be noted that because of ethical constraints, the levels of alcohol consumed in these studies were relatively low. Case reports of deaths and acute illness following consumption of caffeine alone or in combination with alcohol 35. Through a literature search, the National Programme on Substance Abuse Deaths has identified seven cases from the UK in which a coroner named caffeine alone (five cases) or in combination with alcohol (two cases) as a factor contributing to death. In another case report, the parents had linked the death of their son to caffeine consumption (Corkery, 2012). One study in the peer-reviewed literature describes acute renal failure following consumption of three litres of energy drink mixed with one litre of vodka (Schoffl et al, 2011). 36. Analysis of phone calls to the New South Wales Poisons Information Service over a seven year period revealed that of 297 calls concerning caffeinated energy drinks, 73% related to recreational exposures (others concerned accidental consumption by children or deliberate self-poisoning). The median age of the cases was 17 years. Co-ingestion of other substances was reported in 46% of calls relating to recreational exposure, most frequently alcohol (23% of recreational users) and other caffeine-containing products such as cola and caffeine tablets (20%). Features of serious toxicity such as hallucinations, seizures and cardiac ischaemia were described in 21 calls. Among the callers, 128 people sought or were advised to 5 Examples of direct subjective measures on intoxication include participants being asked how many drinks they had consumed, for an estimate of blood alcohol or being asked to rate their level of intoxication on a scale ranging from least ever to most ever. 6 Examples of less direct subjective measures of intoxication include participants being asked how competent they felt to drive a car or how fatigued they felt. seek, urgent medical attention, of whom 70 had co-consumed other substances (Gunja and Brown, 2012). 37. Although some of the cases described in this section suggest acute toxic effects of caffeine and/or alcohol, they do not allow firm conclusions about the contribution of either substance or of whether caffeine increases the acute toxicity of alcohol. Serious cardiac outcomes 38. In its opinions of 1999 and 2003, the SCF noted anecdotal reports of serious cardiac outcomes in young people following consumption of energy drinks with alcohol, but observed that the reports were incomplete and that consumption of energy drinks and alcohol often occurred in combination with other drugs, thus limiting the conclusions that could be drawn. The Committee identified one paper on cardiac effects of co-consumption of alcohol and caffeine that had been published since the SCF opinion (Wiklund et al, 2009). However, because of the small size of the study that it described, it did not allow useful conclusions. The role of expectations 39. The Committee noted evidence that individuals’ expectations of behavioural effects following consumption of alcohol and/or caffeine may lead them to behave differently when exposed (Fillmore et al, 2002; Fillmore and Vogel-Sprott, 1995; Harrell and Juliano, 2009). However, it was not clear how far psychological mechanisms of this sort contributed to behavioural outcomes following consumption of caffeine and alcohol in combination. Conclusions 40. The increasing consumption of drinks containing caffeine mixed with alcohol has raised concerns about the physical and mental health effects of these psychoactive substances in combination. A phenomenon known as “wide awake drunk” has been suggested, in which the stimulatory effects of caffeine may prevent consumers of alcohol from realising how intoxicated they are, leading to increased risk of toxic injury and adverse behavioural effects such as increased risk-taking, violence and criminal activity. 41. The balance of evidence suggests that higher intake of caffeine is associated not only with higher alcohol intakes, but also with use of other psychoactive substances. There is limited evidence that the relationship may be determined at least in part, by genetic predisposition. It appears that, at least in some population groups, there is a correlation between high consumption of alcohol and of energy drinks specifically. However, it is unclear whether this is because consumption of energy drinks causes people to drink more alcohol, or because people who are inclined to more risky behaviour tend generally to consume larger quantities of psychoactive substances, including caffeine and alcohol. 42. A number of studies have suggested that caffeine can ameliorate some effects of alcohol, especially on motor reaction time, mean tracking performance and memory reaction time, but other investigations have failed to support this. The evidence that perceptions of alcohol intoxication are modified by caffeine is conflicting. Overall, the heterogeneity of methods and neurological end-points in reported studies prevents firm conclusions on whether caffeine counteracts the acute neuro-cognitive effects of alcohol 43. Published case reports of deaths and acute illness following consumption of caffeine and alcohol in combination do not allow conclusions as to whether caffeine increases the acute toxicity of alcohol. 44. Individuals’ expectations of behavioural effects following consumption of alcohol and/or caffeine may lead them to behave differently when exposed. However, it is unclear how far psychological mechanisms of this sort contribute to behavioural outcomes following consumption of caffeine and alcohol in combination. 45. Overall, the Committee concludes that the current balance of evidence does not support a harmful toxicological or behavioural interaction between caffeine and alcohol. 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Int.J Gen.Med 5 187-198 Weldy, D L (2010) Risks of alcoholic energy drinks for youth. J Am Board Fam.Med 23 (4) 555-558 Wiklund, U, Karlsson, M, Ostrom, M, and Messner, T (2009) Influence of energy drinks and alcohol on post-exercise heart rate recovery and heart rate variability. Clin Physiol Funct.Imaging 29 (1) 74-80 Annex 1: Studies on the effects of alcohol and caffeine on neurological function. Reference Alford et al, 2012 Caffeine dose 0, 2.2 mg/kg bw (energy drink) Alcohol dose 0, 0.79 g/kg bw Attwood et al, 2012 0,2 mg/kg bw (dissolved caffeine powder 0, 0.6 g/kg bw Azcona et al, 1995 0, 5.6 mg/kg bw (encapsulated caffeine powder) 0, 2.93, 5.87 mg/kg bw (encapsulated caffeine powder) 1.14 mg/kg bw (energy drink) 1.14 mg/kg bw (energy drink) 0, 0.8 g/kg bw Burns & Moscowitz, 1990 Ferreira et al, 2004 Ferreira et al, 2006 Observed effects Recognition reaction time slowed by alcohol alone (p=0.02) but similar to baseline following alcohol and caffeine consumption. Word memory was impaired by alcohol regardless of whether or not caffeine was co-consumed (p=0.001). Stroop test error rate was not increased by alcohol alone and was actually improved in the alcohol and energy drink group (p=0.028). Stroop completion times were decreased by energy drink (p=0.004) and were decreased further still by alcohol mixed with energy drink (p=0.024) Subjective measures of intoxication did not differ between test and control groups. Caffeine appeared to antagonise the effects of alcohol on omission errors in the stop-signal task (p=0.016) but had no effect on simple reaction time (p=0.34) or performance of go – no-go tasks (P=0.95) and worsened the accuracy on the Stroop test (p=0.019). Simple Reaction Time increased by alcohol and ameliorated by caffeine (p <0.05). 0, 0.5, 0.99 g/kg bw Alcohol had effects on alertness, tracking, visual search, reaction time and information processing. Caffeine ameliorated all but information processing (none of the results were statistically significant). 0.3 g/kg bw Following a physical test on a cycle ergometer, no differences were observed in physical parameters between the alcohol group and the alcohol and energy drink group. Alcohol and energy drink consumed together did not reduce deficits in objective motor co-ordination (p=0.11) and visual reaction time (p=0.12) caused by alcohol alone. 0, 0.18, 0.3 g/kg bw Fillmore, Roach and Rice, 2002 0, 4 mg/kg bw (dissolved caffeine powder) 0.65 g/kg bw Fillmore & VogelSprott, 1999 0, 4.4 mg/kg bw (dissolved caffeine powder) 0, 3.3 mg/kg bw (dissolved caffeine powder) 0, 0.62 g/kg bw 0, 5.47 (men), 5.63 (women) mg/kg bw (Dissolved caffeine powder) 0, 5 mg/kg bw (encapsulated caffeine powder) 0, 2, 4 mg/kg bw (dissolved caffeine powder) 0, 2, 4 mg/kg bw (dissolved 0, 1.07 (men), 0.92 (women) g/kg bw Hasenfratz et al, 1993 Howland et al, 2011 Kerr, 1991 Marczinski and Filmore, 2003 Marczinski and Filmore, 2006 0, 0.7 g/kg bw 0, 0.18 g/kg bw 0, 0.65 g/kg bw 0, 0.65 g/kg bw Groups led to expect that caffeine would counteract the effects of alcohol showed greater impairment of performance in a pursuit rotor task than groups led to expect no such counteracting effect (p=0.037). No significant differences were found in subjective measures of intoxication between the groups consuming caffeinated and noncaffeinated drinks. No effects observed on reaction time. Mean number of inhibitions was significantly reduced following alcohol consumption compared to baseline whereas following alcohol and caffeine consumption number of inhibitions was higher than baseline (p<0.002). In a rapid information processing (RIP) task, mean reaction time and processing rate were improved by caffeine (p<0.01; p<0.05); the reaction time was increased by alcohol (p<0.05); the combination of alcohol and caffeine did not differ from baseline suggesting that caffeine was able to offset the alcohol induced performance decrements. Alcohol significantly impaired driving and sustained attention/reaction time. Caffeine did not appear to antagonise the effects of alcohol. No significant differences were found in subjective measures of intoxication between the groups consuming caffeinated and noncaffeinated drinks. Caffeine appeared to antagonise the effect of alcohol on short term memory and choice reaction time (not statistically significant) and mean tracking performance (p<0.05). No effects were observed on critical flicker fusion (measures arousal). Alcohol impaired inhibitory and activational aspects of behavioural control. Caffeine antagonised response activation (p=0.03) but not inhibition (p>0.81). Alcohol impaired the speed of reaction time and accuracy of response in go/no-go and auditory discrimination tasks. Caffeine antagonised Marczinski et al, 2011. Marczinski et al, 2012a Marczinski et al, 2012b caffeine powder) 0, 1.2 mg/kg bw (energy drink) 0, 0.6 mg/kg bw (energy drink) 0, 1.2 mg/kg bw (energy drink) 0, 0.65 g/kg bw 0, 0.36 g/kg bw 0, 0.65 (men), 0.57 (women) g/kg bw the effects of alcohol on speed of reaction time (p<0.02), but not accuracy (p>0.15). Alcohol impaired the inhibitory failures and response times compared to placebo in a cued go/no-go task. Caffeine ameliorated some impairment of response times (p<0.05) but not inhibition (p>0.27). Subjective measurements of intoxication were not significantly different between those consuming alcohol alone and in combination with caffeine. Subjects consuming energy drink and alcohol were more likely to feel motivation to consume more alcohol at 10, 20, 40 and 60 mins after dosing (p<0.01) compared to baseline, whereas the alcohol alone group felt motivation only 10 and 20 minutes after dosing (p=0.01). Subjective measurements of intoxication were not significantly different between those consuming alcohol alone and in combination with caffeine, but there were non-significantly reduced perceptions of mental fatigue and stimulation in the caffeine and alcohol group compared with the alcohol alone group. Alcohol slowed dual task information processing and impaired simple and complex motor coordination. No antagonistic effects were observed from caffeine. Annex Two: Search Criteria and databases used As the Scientific Committee on Food (SCF) looked at alcohol and caffeine interactions in 2003, only references published after this time were included in the literature review. Some references that were not included by the SCF but published prior to 2003 came to light through searching the reference lists of later papers. When considered relevant, these were also reviewed. Because of the availability of human studies, animal studies were not considered unless they were considered particularly relevant. Searches using Pubmed Caffeine, alcohol, behaviour (limits 01/01/2003-present) Caffeine, alcohol, interactions (limits 01/01/2003-present) Energy drinks, alcohol, behaviour (limits 01/01/2003-present) Energy drinks, alcohol, interactions (limits 01/01/2003-present) Caffeine, alcohol, behaviour (limits 01/01/2003-present; human studies only) Caffeine, alcohol, interactions (limits 01/01/2003-present; human studies only) Energy drinks, alcohol, behaviour (limits 01/01/2003-present; human studies only) Energy drinks, alcohol, interactions (limits 01/01/2003-present; human studies only) Searches using Google Scholar All in title: Caffeine, alcohol, (NOT rat, mice) (since 2003, articles excluding patents) All in title: “Energy drinks”, alcohol, (NOT rat, mice) (since 2003, articles excluding patents) February 2012 COMMITTEE ON TOXICITY OF CHEMICALS IN FOOD, CONSUMER PRODUCTS AND THE ENVIRONMENT COT STATEMENT ON THE INTERACTION OF CAFFEINE AND ALCOHOL AND THEIR COMBINED EFFECTS ON HEALTH AND BEHAVIOUR: LAY SUMMARY 1. The Committee on Toxicity (COT) was asked by the Food Standards Agency to comment on concerns that caffeine in energy drinks may interact with alcoholic beverages in causing adverse behavioural or toxic effects. 2. Since 2004, energy drinks have been the fastest growing sector of the drinks market in the UK. The popularity of consuming energy drinks mixed with alcoholic beverages has also increased. Moreover, individuals who consume high quantities of both energy drinks and alcohol, are perceived to engage in a greater degree of risk-taking. This has raised concerns about the health effects of caffeine and alcohol in combination. In particular, a phenomenon described as “wide awake drunk” has been suggested, in which the stimulatory effect of caffeine prevents consumers of alcohol from realising how intoxicated they are, thereby increasing the potential for toxic damage to the body and adverse behavioural effects. Most energy drinks contain levels of caffeine approximately equivalent to those found in a cup of coffee (approximately 80mg caffeine per 250ml can). 3. Currently beverages containing more than 150 mg/l caffeine (other than those based on coffee or tea) must carry the statement ‘High caffeine content’. Under new Regulations, which come into effect on the 13 December 2014, these beverages must carry the statement ‘High caffeine content. Not recommended for children or pregnant or breast feeding women’ in the same field of vision as the name of the beverage, followed by a reference in brackets to the caffeine content expressed in mg per 100ml. There are currently no legal restrictions on the amount of caffeine that may be present in a food or drink product. 4. Caffeine acts primarily as a stimulant, increasing arousal and vigilance, reducing fatigue, and decreasing reaction times in some tasks. At higher doses, it can induce insomnia, anxiety, tremors, and seizures. Susceptibility to the effects of caffeine varies between individuals as people develop tolerance with repeated exposure. 5. Alcohol is widely consumed in the UK with at least one alcoholic drink being reported as consumed in the week before interview by 68% of men and 54% of women in the 2009 General Lifestyle Survey carried out by the Office for National Statistics. It depresses brain function, and outward signs of intoxication including impaired sensory perception and control of movements, slowed cognition, and stupor. How exactly it causes these effects has not been fully elucidated. 6. Accurate estimates of the extent to which alcohol and caffeine are consumed together are not available. One of the reasons for this is that drinks containing alcohol and caffeine are often sold separately and mixed by the consumer rather than being formulated in a single product – for example rum with cola or energy drinks with vodka. 7. Various studies were identified which provided relevant information. These included studies of the association between consumption of energy drinks and alcohol, and whether this is influenced by genetic constitution; of risk-taking behaviour, adverse alcohol-related incidents and use of illicit drugs in people who consume alcohol with energy drinks; and of brain function following experimental dosing with caffeine and alcohol in combination. In addition a number of published reports described cases of illness or death following consumption of caffeine with alcohol. 8. The balance of evidence suggests that higher intake of caffeine is associated not only with higher alcohol intakes but also with use of other psychoactive substances. There is limited evidence that the relationship may be determined, at least in part, by an individual’s genetic make-up. It appears that, at least in some population groups, there is a correlation between high consumption of alcohol and of energy drinks specifically. However, it is unclear whether this is because consumption of energy drinks causes people to drink more alcohol, or because people who are inclined to more risky behaviour tend generally to consume larger quantities of psychoactive substances, including caffeine and alcohol. 9. A number of studies have suggested that caffeine can reduce the outward effects of alcohol, especially on reaction times, but other investigations have failed to support this. The evidence that perceptions of alcohol intoxication are modified by caffeine is conflicting. Overall, the range of methods used in reported studies prevents firm conclusions on whether caffeine counteracts the short-term effects of alcohol on brain function. 10. Published case reports of illness or death following consumption of caffeine and alcohol in combination do not allow firm conclusions about the contribution of either substance, or of whether caffeine increases the toxicity of alcohol. 11. Overall, the COT concludes that the current balance of evidence does not support a harmful toxicological or behavioural interaction between caffeine and alcohol. However, because of limitations in the available data, there is substantial uncertainty, and if important new evidence emerges in the future, then this conclusion should be reviewed. 12. The full COT statement can be found at: http://cot.food.gov.uk/pdfs/cotstatementcaffalco201204.pdf Lay summary to COT statement 2012/04 December 2012 Beverage Category Value Share BarScan Energy Category Report Value Share, MAT to August 2012 Source: BarScan Weighted 12 Month Venues October 2012 Beverage Category Shares 7% 3% Tap Beer is by far the largest category generating 44 percent of total beverage sales revenue over the bar. 8% The next largest category is spirits with 14 percent. Vodka spirits makes up around 20 percent of the spirits category’s sales. 7% 44% The next largest categories are packaged beer (10%), wine (8%), premixed spirits (7%), non-alcoholic drinks (7%) and cider (3%). Post mix drinks are the largest segment within the nonalcoholic category and generate 68 percent of revenue. The remaining non-alcohol drinks segments are single serve drinks including energy with 28 percent of sales and ‘poured’ drinks (i.e. juices, cordials etc.) with four percent of non-alcoholic drinks revenue over the bar. The Energy Category The energy category drives only a small proportion of sales over the bar with 0.44 percent of total beverage revenue. Non-alcoholic energy accounts for 90 percent of the segment’s sales (or 0.4% of total beverages) with alcoholic drinks making up the remaining 10 percent of sales (or 0.04% of total beverages). 14% 10% Tap Beer Packaged Beer Spirits Premixed Spirits Wine Cider Non Alcoholic Category & Segments Share of Total Beverages Value Share, MAT to August 2012 Source: BarScan Weighted 12 Month Venues With respect to each of their categories, non-alcoholic energy drinks make up five percent of the non-alcoholic category and 20 percent of single serve segment. 0.45% Total Energy 0.42% Alcoholic energy drinks generate only a small proportion of premixed spirits at 0.6 percent of the categories revenue. 0.40% Energy Drinks for Occasions BarScan measures the performance of bar departments within each venue. This allows greater insights of what patron’s drink based on the occasion. For example, noalcoholic energy drinks share of total beverage sales in entertainment bars (i.e. night clubs, live music etc.) at three percent is considerably higher than public bars, bistro’s and gaming bars where the segment generate less than 0.3 percent of beverage sales. Confidential & Proprietary • Copyright © 2012 BarScan BarScan Energy Drinks Report Page 1 of 2 Non Alcoholic Energy 0.38% 0.04% Alcoholic Energy 0.04% MAT August 2012 Quarter August 2012 Energy Brands’ Share Top 5 Energy Brands Share of Total Energy Value Share, Source: BarScan Weighted 12 Month Venues Over three out of four energy drinks sold over the bar is a Red Bull. The brands share of energy drinks for the year to August is 76 percent and even higher for the quarter at 78 percent. Mother Energy, with eight percent share is the second largest energy drink followed by Monster Energy with six percent share for the year to August 2012. Alcoholic energy drink brands shares are all relatively small. Red Bull’s dominance is partly driven by distribution. Eighty percent of venues selling energy drinks sold Red Bull. In comparison, Mother Energy is sold in a little over 20 percent of venues - based on the quarter to August 2012. Most venues only sell one brand of non-alcoholic energy drink at a point in time. Energy Brands’ Pricing The average price paid for a can of Red Bull is $4.68 based on the quarter to August 2012. This is virtually in line with the other key brands. A large proportion of energy drinks will also be sold with a nip of vodka or a shot of Jagermeister. On average, this would equate the purchase price of a vodka and Red Bull to $10.60 and a Jagermeister and Red Bull to $11.50 in the Hotels channel. This assumes that the whole can is served to the patron as opposed to part poured. Energy Drinks’ Hotel Ranging Three quarters of venues have sold a non-alcoholic energy drink in the quarter to August 2012. In comparison, only one in five venues have sold an alcoholic energy drink. However, the proportion of bars selling energy drinks is considerably smaller at 54 percent for non-alcoholic and ten percent for alcoholic energy drinks. 76% Red Bull 78% 8% Mother Energy 8% 6% Monster Energy 5% 6% Pulse 5% 3% Elevate 3% MAT August 2012 Quarter August 2012 Top 5 Energy Brands Average Price per Serve Price Incidence per Serve, Quarter August 2012 Source: BarScan Weighted 3 Month Venues $4.58 Red Bull (250ml) $4.39 Mother Energy (250ml) Monster Energy (250ml) $4.64 In other words, energy drink’s penetration within venues is smaller than the category’s distribution across venues. For more details on BarScan go to http://www.barscan.com.au Check out BarTalk for new facts and figures, media releases and anything else that caught our eye for a good talking point!. Confidential & Proprietary • Copyright © 2012 BarScan BarScan Energy Drinks Report Page 2 of 2 $8.61 Pulse (300ml) $6.98 Elevate (300ml)