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44 performance, for many of these substances the evidence of actually may be. This point was accentuated by the FDA their importance as psychoactive substances that might impact when in the fall of 2010 it pressured the company Physion commercial driver performance was not significant. These are Projects into withdrawing its alcoholic energy drink "Four described in Appendix C. LokoTM" beer from the marketplace after numerous adverse life-threatening events implicating consumption of quantities of the combination alcoholcaffeine drink occurred on col- ENERGY SUPPLEMENT DRINKS, FOOD BARS, lege campuses in the United States. CANDY CHEWS, AND OTHERS Caffeine was described extensively as a stimulant in chap- To remain within the spirit of the 1994 Dietary Supplement ter four. It was pointed out that caffeine shows up in numer- Health and Education Act, manufacturers of energy drinks ous products best described as supplement drinks, and in sup- claim the ingredients in FEDs are derived from healthy sub- plement food bars and gels, advertised to boost one's energy stances, such as vitamins, herbs, and other natural ingredients. level. This section describes caffeine (in its various forms), Because the FDA does not regulate such supplements, the along with other psychoactive substances included as ingre- manufacturer bears the full responsibility for ensuring the dients in many of the "energy supplements" readily available product is both effective and safe for human consumption and in most highway rest stop convenience stores, grocery stores, use. The ingredients must be listed in the "other ingredients" and so on. section instead of the "supplement facts" section on product labeling; however, the specific amounts do not have to be included, and typically manufacturers do not list them. Functional Energy Drinks Grosz and Szatmari (2008) indicate there is a paucity of Since the late 1990s, energy drinks (sometimes called caf- published detail on either the contents or descriptions of the feinated FEDs) have become popular, especially so with young human effects of FEDs. Red BullTM is the most widely known adults, producing a growing health concern for adolescents energy drink, as it is sold in more than 140 countries. Most of (Babu et al. 2008). The major ingredient in the numerous the popularly marketed FEDs such as Red BullTM are made up energy drinks is caffeine, mixed along with other caffeine-like predominately of sugar water and contain fruit juice flavor- chemicals (e.g., guarana), as well as several other psycho- ing and high levels of caffeine and taurine and other herbal active ingredients. The range of caffeine in popular FEDs may stimulants as the principal "active ingredients," along with be from 80 mg to as high as 500 mg of caffeine per serving-- small amounts of glucuronolactone, niacin (niacinamide), which means the caffeine in a single energy drink (of some sodium citrate, and inositol. Other FED ingredients may brands) can exceed that of two six-packs of Cocoa Cola include guarana, ginseng, and orange rind extract. The man- (Reissig et al. 2009). ufacturers of these drinks claim their stimulating effects are the result of interaction among the various ingredients and Individuals who consume FEDs give many reasons for they claim the drinks improve physical endurance, reaction why they partake of energy drinks, including because they speed, and concentration. Among the many commercially (1) give a burst of energy, (2) help the consumer to stay available FEDs, one competing brand called "Yellow Jacket awake, (3) increase alertness, (4) improve short-term memory, Energy Drink" for example is advertised to provide "Twice (5) help students perform better on tests, and (6) mixing the Buzz, helping to deliver energy one needs to get through alcohol with an energy drink can reduce the severity of a the day." hangover, protect the liver, and keep a person from getting drowsy. College students commonly mix energy drinks with In addition to caffeine as a major ingredient, some of the alcohol, leading to numerous complications (Malinauskas more common ingredients also found in many FEDs include: et al. 2007; O'Brien et al. 2008). Whereas electrolyte replace- ment sports drinks (e.g., Gatorade®) attempt to replenish · Taurine--known as 2-aminoethane-sulfonic acid. In the body after strenuous activity or exercise, FEDs do not 1827, taurine was originally isolated from bull or ox bile replenish the body. Mixing a FED and alcohol can significantly (taurus means bull in Latin), but now is available syn- dehydrate a person because both substances have diuretic thetically for insertion into energy products. It is pro- effects (Reisenhuber et al. 2006). In a lab study, Ferreria duced in the liver and in the brain where it serves as an et al. (2006) demonstrated that the subjective perceptions of inhibitory neurotransmitter exerting neuroprotective headache, weakness, dry mouth, and impairment of motor effects against excitotoxic agents and oxidative stress coordination were less intense when alcohol was combined such as those released during an ischemic episode with an energy drink. However, objective measures of motor (Chepkova et al. 2002; Kim 2003). Taurine is the most coordination, visual reaction time, and breath alcohol con- abundant free amino acid in many body tissues. Taurine centration for energy drink plus alcohol were the same as is different from other amino acids in that it is not incor- for alcohol alone. Ferreria et al.'s results basically showed porated into proteins. It plays an important role in osmo- that a person subjectively feels less intoxicated than they larity regulation and in metabolism and it is found in
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45 high concentrations in skeletal muscles where it plays the increased alertness reported by Alford et al. (2001), and an important role in modulating contractile function. improved information processing times reported by Warburton In some cases taurine acts as a mild sedative and as an et al. (2001)--all of which were more likely affected by the age-defying antioxidant. It also has potential to steady amounts of caffeine administered than they were by the irregular heartbeats. Only a small number of studies have taurine (Woojae 2003). Woojae argues that the endogenous been published to validate many of the beneficial claims taurine found in high concentrations in skeletal muscles self- attributed to taurine, especially its claimed beneficial regulates itself and the taurine levels are maintained at a effects in energy drinks. stable level in the brain as well. One can of Red BullTM is · Glucuronolactone--a natural compound found in the reported to contain between 65 and 80 mg of caffeine, about body, about which little is documented. Users of energy the same amount of caffeine as can be found in many normal drinks generally believe glucuronolactone fights fatigue brewed cups of coffee. Thus, Woojae suggests that it is not and increases well-being; however, little has been pub- likely that supplemental taurine would have much effect; it is lished about its inclusion in FEDs (600 mg in a 250 ml more likely that the higher caffeine levels in the drinks are can of Red BullTM), thus its effects are not clear (Clau- responsible for the effects observed when drinking Red Bull son et al. 2003). or other similar energy drinks, particularly so when quantities · Niacin--also known as vitamin B-3, among other func- of the drink are consumed (Woojae 2003). tions, it helps increase so-called good cholesterol (HDL) by preventing the formation of triglycerides, making In examining several popular FEDs, Clauson et al. (2003) it a useful cholesterol control drug. There usually is determined that most of them contain products such as guarana, not enough niacin in FEDs to provide this benefit. ginseng, and taurine in such small amounts that they are far The niacin contained in the energy drinks (20 mg in a below the amounts expected to deliver either therapeutic 250 ml can of Red Bull) is not pure enough to give the benefits or adverse events. By comparison, the drinks usually mild head rush dubbed the "niacin flush" (Clauson et al. contain as much as 80 to 300 mg of caffeine and 35 g of 2003). Not much has been reported about potential processed sugar per 8-ounce serving, amounts known to cause interactive effects of niacin, if any, with other com- a variety of adverse health effects. Commonly reported adverse pounds found in FEDs. effects seen with the amounts of caffeine present in the energy · Inositol--a carbohydrate found in animal muscle it is drinks are insomnia, nervousness, headache, and tachycardia. sometimes called "meat sugar." Inositol is a water-soluble fatty lipid, a part of the vitamin B complex (B8) required Both caffeine and taurine have direct effects on cardiac for formation of healthy cells. It promotes healthy brain function and hemodynamic status. Steinke et al. (2007) development and function, and works closely with assessed whether or not commonly consumed energy drinks choline to move fats out of the heart and liver. Inositol alter the blood pressure, heart rate, and electrocardiogram is used for treatment of diabetic nerve pain, panic dis- (EKG) parameters in healthy participants. Participants con- order, high cholesterol, insomnia, cancer, depression, sumed 500 mL (two cans) of an energy drink containing schizophrenia, Alzheimer's disease, ADHD, autism, pro- caffeine (80 mg) and taurine (1,000 mg). Blood pressure, moting hair growth, and the skin disorder psoriasis. heart rate, and EKG measures were repeated 30 min, 1, 2, and There usually is so little inositol in energy drinks (50 mg 4 h after consumption, over a 5-day test. Although no signifi- in a can of Red Bull), that its potential benefits on the cant EKG changes were observed, subjects' heart rate increased body are deemed to be negligible. As a paradox for the 5 to 7 beats per minute (bpm), and systolic blood pressure drink manufacturers, consumption of large amounts of increased 10 mm Hg after consuming an energy drink. They caffeine may cause a shortage of inositol in the body; suggested these physiological levels are likely clinically sig- thus, heavy coffee drinkers may benefit slightly from nificant for consumers who happen to have cardiac disease or taking supplemental inositol. for those individuals who regularly consume quantities of such energy drinks. The manufacturers of energy drinks such as Red BullTM tout the likely combination of energizing effects by placing caffeine The study by Steinke et al. (2007) was performed on healthy along with other ingredients such as taurine (1,000 mg) and subjects, and it cited amounts of taurine to be 1,000 mg glucuronolactone (600 mg) into the beverage (Mayer 2002). (presumably akin to Red Bull at the time). Some energy drinks Several researchers (Woojae 2003; Van den Eynde et al. 2008) available in the year 2010 have increased the amounts of attempted to "debunk" the likely impact of taurine in favor of some of the potentially offending ingredients. Effects of such indicating that it is predominately the caffeine that brings combinations of substances as these apparently have not been about the energetic effects (desirable or undesirable). Woojae assessed on subjects with hypertension while they happen to be (2003) reported this is likely to be true regarding the increase using various anti-hypertensive medications. Many commer- in cardiac stroke volume witnessed by Baum and Weiss (2001); cial drivers suffer from hypertension and are being medicated it pertains as well to the shorter reaction times and improved for it, which should raise some concern. In August 2010, these effects on emotional well-being reported by Seidel et al. (2000), synthesis authors purchased the popular product Monster
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46 Hitman Energy ShooterTM from the OTC energy boost shelf pursued with commercial drivers in instrumented driving at a local drug store and noted that the listed ingredients for simulators as well. the 3-ounce dietary supplement included 6 g of sugar; 45 mg of sodium; more than 200% of the recommended daily Jay et al. (2006) did a crossover design experiment with allowance for vitamins B-2, B-3, B-6, and B-12; 2,000 mg 15 young adults, simulating a first night-shift protocol with of taurine; 400 mg of ginseng; and a 5,000-mg energy blend two conditions: participants taking an energy drink (FED) and of glucose, L-carnatine, caffeine, inositol, guarana, glucurono- a baseline control (non-FED) condition. Both test conditions lactone, and maltodextrin. The label warns individuals not to involved a period of extended wakefulness from 0700 on one consume more than one shot of Monster Hitman every 4 h. day to 0730 hours the next (24.5 h awake), followed by an 8-h daytime recovery sleep (0730 to 1530 h). During the FED Kennedy and Scholey (2004) demonstrated that some of condition, an energy drink was administered twice during the the same cognitive performance effects are obtained through night. Sleepiness was assessed during the period of extended combinations of only caffeine and glucose, without adding wakefulness and for a further 6 h after awaking. Comparison the other substances into the energy drinks. Van den Eynde of sleep periods (measured with EEG) showed that sleep onset et al. (2008) tended to agree, stating that most of the effects of latency remained unchanged, as did stage 2 and slow wave energy drinks on cognitive performance are related primarily sleep. However, sleep efficiency was significantly reduced, to the presence of caffeine. They suggest further investigation and total sleep time was 29.1 min shorter in the FED condition. is needed into the effects of the lesser known ingredients of The study demonstrated the residual effects of the FED's energy drinks (e.g., taurine and glucuronolactone) to gain active ingredients impacting on some aspects of daytime sleep a better understanding of the possible interactions of the following a simulated night shift. Subsequent performance multiple substances. however was unaffected. Jay et al. stated that the results deem FEDs effective for use in alertness control during a single Warburton et al. (2001) identified experimental design night shift and warrant investigation into FED use over suc- inadequacies in the literature (e.g., pre-test cutbacks on cessive night shifts (Jay et al. 2006). Such calls for additional caffeine by participants that might have produced caffeine research should also be made for the commercial driving withdrawal during testing). Subsequently, they designed an community, where the obvious applications and implications experiment to examine whether or not test participants with of FEDs should be pursued. minimal pre-test deprivation from caffeine would produce similar results to participants who ordinarily were asked to A major reason popular energy drinks raise public health abstain from caffeine before their participation in experiments. concerns is because they contain high levels of caffeine, and They concluded that moderate doses of caffeine and taurine typically not all the ingredients and the quantities of each are can improve information processing in individuals who could accurately labeled on popular products. In their review of a not have been in caffeine withdrawal at the time of their par- large variety of energy drinks, Reissig et al. (2009) stated that ticipation in the testing. Their caffeinated/taurine group of in the year 2006, annual worldwide energy drink consumption participants improved attention and verbal reasoning, but there increased 17% from the previous year to 906 million gallons, was no significant effect on memory (Warburton et al. 2001). with Thailand leading the world in energy drink consumption per person. The United States led the world in total volume Reyner and Horne (2002) investigated the effectiveness of sales. These Johns Hopkins researchers published tabular a well-known FED for reducing sleepiness in drivers. After information about the caffeine contents in energy drinks by restricting their sleep to 5 h the night before, 12 healthy brand name, indicating that the caffeine content ranged from young adults drove a car simulator between 1400 and 1700 h. 50 mg to 505 mg per 12-ounce serving. One drink, a 1-ounce Following a pretreatment 30-min drive, participants were "ammo" drink, had the greatest concentration at 171 mg of given 250 ml of a FED (containing sucrose, glucose, 80 mg caffeine per ounce of drink; whereas Red BullTM was listed caffeine, taurine, glucuronolactone, and vitamins: equivalent as having 9.6 mg of caffeine per ounce, or 67 mg caffeine per to Red Bull) versus a control drink with the same volume and 8-ounce can. A commercially available product, SoBe's taste but without the caffeine, taurine, and glucuronolactone. "No Fear" drink, contains 141 mg of caffeine per 16 ounces. Two hours of continuous driving ensued. Compared with the Coca-Cola Classic had the least caffeine at 2.9 mg/oz. controls, energy drink participants significantly reduced sleep- related (fatigue) driving incidents (e.g., lane drifts) and reported With a concern that consumers may be unaware of the less subjective sleepiness for the first 90 min of the drive. consequences of caffeine intoxication, Reissig et al. (2009) There was a trend for the EEG to reflect less sleepiness during wrote that from 2002 to 2004 a U.S. poison control center this period. It was concluded that FEDs can be beneficial in received 42 cases of caffeine abuse from caffeine-enhanced reducing sleepiness and sleep-related driving incidents dur- beverages. Caffeine intoxication includes symptoms such as ing monotonous afternoon driving following modest sleep nervousness, anxiety, restlessness, insomnia, gastrointestinal restriction the night before (Horne and Reyner 2001; Reyner upset, tremors, tachycardia, and psychomotor agitation. and Horne 2002). Additional studies of this type should be Clauson et al. (2003) found four case reports of caffeine-
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47 associated deaths as well as four separate cases of seizures lighted by Jay et al. (2006); however, FEDs also adversely associated with the consumption of energy drinks. Reissig impacted recovery sleep on the following day. et al.'s review (2009) calls on the FDA to insist on requiring the manufacturers to disclose the amount of caffeine in energy Additional research with FEDs is called for, preferably to be drinks on the label of the containers. conducted in driving simulators to elucidate the implications of judicious use of FEDs by commercial drivers. Subsequently, Australian medical researchers tested 30 young adults 1 h guidance about the measured effects of FEDs on health and before and 1 h after consuming one 20 ml can of sugar-free performance would be appreciated in the commercial trans- Red Bull (DeSciscio et al. 2008). In August 2008, these portation industries. researchers publicly stated that just one can of the popular stimulant energy drink, Red Bull (whose marketing advertises Five- and Six-Hour Power Energy Booster Drinks "Red Bull gives you wings"), can increase the risk of heart attack or stroke, even in young persons (Reuters news articles, The earlier write-up on FEDs portrays a number of health Canberra, Australia, Nov. 2008). The senior researcher, Scott concerns, particularly in consuming multiple servings or Willoughby, reported that 1 h after volunteers drank Red Bull simultaneously mixing the popular FEDs in combination their blood systems were no longer normal, but were abnor- with alcohol. In part, in response to those reports, the energy mal in a way that would be expected in a patient with cardio- drink industry now markets newer alternative energy drinks. vascular disease. In an interview, Willoughby suggested the Intense advertising on U.S. television and a wide availability drink caused the blood to become "sticky," which he declared in convenience stores, including truck fuel stops, has made to be a pre-cursor to cardiovascular problems. Willoughby two of these new drinks the best known to date: (1) the new (2008) advises that Red Bull could cause important compli- "2-ounce shot": 5-Hour EnergyTM drink (distributed by Living cations if combined with stress or high blood pressure, impair- Essentials), and (2) another 2-ounce shot drink called 6-Hour ing proper blood vessel functioning and probably increasing PowerTM. Both products identify themselves as "vitamin the risk of blood clotting and stroke. supplement drinks." The label on the 5-Hour EnergyTM bottle, and the company's There have not been sufficient conclusive studies on the website, suggest that its unique blend of vitamins provides a combined effects of caffeine and taurine in Red BullTM, boost of energy, and its combination of amino acids provides Monster Hitman Energy ShootersTM, or other FEDs, and the cognitive enhancements, such as an increased ability to focus true contents and the full extent of health risks mostly are not and a better mood. The company's advertising says 5-Hour listed on containers of such products. For these reasons, the EnergyTM is different from other energy drinks because it popular drink Red Bull is banned in Norway, Uruguay, and excludes guarana, contains only as much caffeine as is found Denmark. Nevertheless, it is still widely sold, and it was in one cup of coffee, and it has "zero sugar, zero net carbo- estimated that 3.5 billion cans of Red Bull have been sold in hydrates, and only four calories." The lack of sugar and reduced 143 countries around the world. amount of caffeine are said to eliminate the "crash effect," a reduction in energy below baseline that most users of other Assessment of functional energy drinks. Most of the FEDs energy drinks (FEDs) experience owing to their high levels of available in the public marketplace advertise ingredients that sugar and high caffeine content. Living Essentials claims these include sugar, caffeine, taurine, and some vitamins or small drinks will make a person feel "awake, alert, and productive amounts of other chemical substances, a few of them adding for hours--without the jitters and crash associated with to the combination of psychoactive substances. The relatively other energy drinks"--and therefore 5-h energy is perfect for small number of reputable studies in the literature mainly "combating a groggy morning, that afternoon lull, or to moti- indicated that most of the psychoactive effects from the FEDs vate you to work out." can be attributed to the concentration of caffeine contained. Effects owing to secondary substances, apparently added The label on the bottle of the 5-Hour EnergyTM drink indi- largely to satisfy marketing ploys, are likely to be slight. How- cates that it contains 30 mg of niacin, 40 mg of vitamin B-6, ever, health and performance concerns remain about verifying 400 mcg of folic acid, 500 mcg of vitamin 12 (as cyanocobal- the potential synergistic or interactive effects of the several amin), and 0 mg of sodium. The energy blend of 1,870 mg of ingredients found in FEDs, which individuals may consume liquid contains taurine, glucuronolactone, malic acid, n-acetyl, in considerable quantity while they happen simultaneously to l-tyrosine, l-phenylalanine, caffeine, and citicoline. Although be taking medications and other chemical substances. the amount of caffeine contained is not specified, the instruc- tions on the bottle warn consumers to limit themselves to Several experiments described previously demonstrated "two shots of 5-Hour Energy a day, spaced hours apart." the potential applicability of FEDs for reducing sleepiness Thus, if the contents really only have the equivalent caffeine and sleep-related driving incidents after sleep restriction found in a cup of coffee, there would appear to be less of a risk (e.g., Reyner and Horne 2002). The effectiveness of FEDs was of someone who properly uses 5-Hour EnergyTM encountering also shown during simulated first-night shift work, as high- difficulties attributable to consuming too much caffeine than