Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements (2011)

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39 INTRODUCTION TO SUPPLEMENTS Every year the dietary and nutritional supplement industries introduce another proliferation of chemical compounds in enticing new formats (i.e., energy-boost drinks, bottled flavored water augmented with vitamin mixes, nutritional supplement candy chews, caffeine-infused chewing gum, high-energy food bars, lose-weight crash-diet measures, and so on). Marketers engage popular professional athletes and other celebrities in splashy advertising designed to encourage consumers to use such products to achieve a better, more healthful or exciting lifestyle. However, manufacturers offer little published medical and human performance research data to support or back up advertising claims about many such supplements. This chapter covers a variety of chemical substances and/or psychoactive compounds that commercial drivers might ingest on occasion, but which do not fit neatly into the two categories of hypnotics and stimulants described in chapters three and four. This encompassing chapter includes coverage of traditional nutritional, herbal, and health food supplements; relaxants; insomnia treatments; dietary compounds used to control a person’s weight; and energy boosters such as drinks, candies, and gums. Many of these products are aug- mented with active chemical ingredients, some of which are psychoactive. Certainly these have effects on performance; the principal concern here being their effects on vehicle operator performance. These consumer products are available across the counter in grocery, convenience, and drug stores; in health food shops; and at shopping center kiosks. Importantly, many of them are readily available in convenience shops not far from the fuel pumps at highway rest stops. This chapter attempts to outline what is known about these chemical substances, and to identify the supplements that appear to warrant additional research to determine their efficacy and their safety issues relating to truck and bus/motorcoach drivers. DEFINITIONS OF SUPPLEMENTS A dietary supplement is normally thought of as a product taken by mouth that contains an “ingredient” intended to beneficially supplement what one normally eats. The Dietary Supplement Health and Education Act (DSHEA) of 1994 places dietary supplements in a special category under the general umbrella of “foods,” not drugs, and requires that every such ingredient or combination of ingredients be labeled as dietary supplements. Manufacturers of supplements are responsible for ensuring the safety of the ingredient(s), but by statute the FDA is not authorized to require data supporting safety from the manu- facturer, as it does for food additives or drugs (see the FDA website on Center for Food Safety and Nutrition at: http:// www.cfsan.fda.gov and Kurtzweil 1999; GAO-09-250 2009). Dietary supplements are widely available through a rapidly expanding market of products commonly advertised as bene- ficial for better health, performance enhancement, and dis- ease prevention (IOM report: Greenwood and Oria 2008). The “dietary ingredients” in these products may include vitamins, minerals, herbs, other botanicals, amino acids, and substances such as enzymes, organ tissues, and gland tissue or secretions. Dietary supplements can be extracts or concentrates, and may be found in many forms including tablets, capsules, gel caps, liquids, and powders, and in food bars, flavored candy-like chews, and chewing gum. Information on their label must not represent the product as a medication, as a conventional food, or as a sole item of a meal or diet. An ergogenic aid is defined as anything that helps enhance energy utilization and usually promotes physical performance in the body. Nutritional sup- plements such as sports drinks (e.g., Gatorade™) or those meant for inclusion in meals might be classified as ergogenic aids. An ergolytic agent is anything that possesses the ability to decrease work output such as exhibiting a negative effect on muscle activity (U.S. Army CHPPM 2004). Dietary supplements available to commercial drivers range from those that might impart beneficial effects, to better health and performance with negligible side effects, to others that have uncertain benefits and that potentially might be harmful to health and performance. The challenge is to determine which supplements fall into each of these two categories. In the United States there are no commercial transportation-wide policies regarding dietary supplements. Some safety concerns over supplements, especially the lack of appropriate guidance for their use, were described when IOM assessed supplements for the military (Greenwood and Oria 2008). The paucity of medical guidance for use of sup- plements prompts similar concerns that commercial drivers who take supplements might inadvertently compromise their own performance or health. Without usable information and guidance, drivers also might forgo taking dietary supplements that potentially could improve their performance or health. Nutritionists portray how what we eat or consume can help us achieve adequate or even optimal performance levels CHAPTER FIVE SUPPLEMENTS: NUTRITIONAL, HERBAL, ENERGY BOOSTERS, DIETARY, AND HEALTH FOODS

(McArdle et al. 1991). Dr. C. Everett Koop, former Surgeon General of the U.S. Public Health Service, was fond of saying “we are what we eat” as he cautioned Americans that most of the ten frequent disease killers in our society are related to what we eat. Nutrition experts recommend a balanced diet high in complex carbohydrates and low in fat to help individuals attain peak performance. Although it is true that some supple- ments may provide health benefits, others are unnecessary, because in a proper diet the food we eat should be able to supply all the nutrients, vitamins, and minerals our bodies require. Additionally, many supplements, if taken incorrectly, or if they happen to contain metals, toxicants, or much larger doses of whatever identifiable compound the consumer thought he or she was taking, can cause risks to one’s health. Ubiquitous advertisements promote many pills, powders, gels, drinks, and more to help a person gain weight or muscle mass, to lose weight, or to simply feel better; or they promise to make one faster or stronger, and so on. An evaluation of the numerous dietary supplements available is especially difficult because many such products contain multiple ingredients, they can have a changing compo- sition over time, or because individuals use them intermittently at doses that tend to be difficult to measure, and mostly the amounts ingested are not recorded (IOM report: Greenwood and Oria 2008). The descriptions that follow do not lend themselves to orderly “clumping” of supplement products into categories. The attempt here is to describe chemical substances that are widely included in commercial products; in particular, highlighting those that contain psychoactive ingredients that in some way might affect the performance or health of commercial drivers who take them. In an attempt to be somewhat comprehensive, this syn- thesis also provides modest coverage of other ingestible items that do not strictly qualify as nutritional supplements per se (e.g., drinking appropriate amounts of water to sustain proper hydration); however, they are included in this report because such practices involve additional chemical sub- stances (e.g., fluoride and/or sodium and minerals contained in drinking water) that may impact driver health or perfor- mance. Again, the emphasis in the main body of this chapter is predominately to describe substances with psychoactive effects. In cases where the synthesis team did not identify sufficiently strong evidence in the scientific literature, we rel- egated what we have to say about those substances (supple- ments or not) to Appendix C to this report. Such is the case, for example, with several of the herbal substances used as relaxants; stress and tension alleviants, for sleep-inducing supplements involving amino acids; and with the use of daily multi-vitamins. In the cases where the scientific evidence iden- tified for psychoactive effects was slim, those descriptions appear in the Appendix C of this report (see Table 4). Caveat, a general caution: Most nutritional, health, and dietary supplements sold commercially (e.g., in health food shops or grocery stores) are not approved by the FDA. Many of these chemical components are 40 covered under the Federal Dietary Supplement Act. However, because the quality of dietary supplements is not regulated by the FDA, their production is not regulated by the Good Manufacturing Practices Act. The contents and quality of dietary and nutritional supplements on the store shelves varies dramatically. There is no guarantee that the labeling of the contents in packaging accurately depicts what the package, bottle, or other container actually holds. Objective validation of claims of safety or efficacy is not readily available. The supplement business is a “buyers beware” market- place (Kurtzweil 1999; Straus 2002; GAO 2009). Consumers therefore must exercise caution with all health food supplements. Products imported to the United States from overseas suppliers, especially some products in the pharmaceutical and food industries, have perpetually raised issues of manufacturing quality assurance. Depending on the source or supplier, the manufacturing standards for these compounds is not always in accordance with the quality assurance that might be found for products typically monitored for compliance in the U.S. market. There have been instances in which herbal and health supplements or component ingredients acquired from overseas, espe- cially those purchased over the Internet, were contam- inated with toxic metals or with other drugs. Federal government agency (e.g., FDA, NIDA, and DEA) alerts and warnings about hazardous products sometimes lag months behind outbreaks of problems with such imported purchases. To minimize the risks of contam- ination health food, dietary, and herbal supplements should be purchased only from reliable sources. Deter- mining what constitutes a reliable source can at times be problematic. PSYCHOACTIVE HERBAL SUPPLEMENTS Guarana (Paullinia cupana) Guarana comes from the seeds of a South American plant— a shrub—the vast majority of which is grown in a small area in northern Brazil. Guarana gum or paste is derived from the seeds, rich in xanthenes approximately equivalent to caffeine. Guarana paste is inserted into herbal supplements to food and beverages. Viewed as a tonic in South America, and especially so in Brazil, for decades guarana has been inserted into numer- ous soft drinks much the way caffeine is added to soft drinks in the United States. Now, guarana is increasingly found in drink products in the United States. In Japan, guarana extract formerly was incorporated into chewing gum, and advertised to prevent drowsiness (Sato et al. 1984). Because the major active guarana constituent “guaranine” is nearly identical to caffeine, guarana is claimed to be an effective energy booster and is likely to have similar physio- logical and behavioral effects to those of caffeine. Guarana also contains similar related alkaloids such as theobromine and theophylline—both of which are also found in coffee and tea (Bertrand and Carneiro 1932; Bempong and Houghton 1992; Bempong et al. 1993; Leung and Foster 1996; Walker et al. 2000; TTCP 2001). Each of these compounds has well-

41 known effects as nervous system stimulants. As such they also have some effect on increasing metabolic rate, suppressing appetite, and enhancing both physical and mental performance, and they have a mild diuretic effect. Guarana has been said to decrease fatigue, reduce hunger, help with arthritis, and has been used to treat diarrhea. Guarana has a history of use in treating hangovers from alcohol abuse and headaches related to menstruation (Duke 1985). The mode of action with guarana is primarily attributable to methylxanthine alkaloid caffeine. Guarana’s effects on the CNS therefore are similar to those of caffeine. The duration of effects is similar to that of free caffeine at about 3 to 5 h. Guarana contains about twice the caffeine found in coffee beans (about 3% to 4% caffeine in guarana seeds as com- pared with 1% to 2% for coffee beans). Concentrated guarana extract powders contain caffeine at levels of as much as 40% to 50%. Thus, 5 g of guarana at 3.5% to 5.6% caffeine, taken less than 1 h before activity, will make approximately 175 to 280 mg of caffeine available in the body at the time of commencement of the activity (TTCP 2001). Popular South American guarana supplements deliver about 50 to 200 mg of caffeine per day (similar to the amount found in 1 to 2 cups of strong coffee). Guarana extract powder, providing 500 to 1,000 mg of guaranine, is claimed to provide mild stimulant properties and enhanced physical and mental performance. Higher levels of intake have not been demonstrated to provide additional increases in performance, but may result in adverse side effects such as tension, irritability, and nausea. Guarana mostly acts as a cognitive enhancer through increased catecholamine production. The likely psychoactive effectiveness of caffeine probably also applies to guarana. Claimed benefits are that guarana improves mood and cognitive performance, and assists in fighting fatigue. In one of the earliest published studies on guarana’s effects on performance, Galduroz and Carlini (1994, 1996) conducted a long-term study on normal, elderly, adult subjects, but found no significant psychoactive effects on thinking or mental functions. However, in lab studies with healthy young adults, Kennedy et al. (2004) demonstrated the psychoactive effects and the cognition-enhancing properties of guarana. These researchers gave 75 mg of a dried ethanolic extract of guarana (approximately 12% caffeine), 200 mg of Panax ginseng, and a combination of the two (75 mg/200 mg) to 28 healthy young participants (ages 18 to 24) in a multi-day study. Cognitive performance and subjective mood were assessed pre-dose Category Where Found Use/Effect Comments Herbals Guarana Ginkgo Biloba Health food stores, truck stops, inserted into soft drinks and energy drinks Mild stimulants; have some effect on cognitive and reaction time performance Some studies indicate mild effects akin to those of caffeine. No adverse effects demonstrated Ginseng, Passion Flower, Kava Kava, Valerian, St. Johnís Wort Health food stores, boutique over-the- counter shops Relaxants to alleviate tension, stress, induce sleep Psychoactive effects not substantiated, relegated write- up to report’s appendix Physical Performance Enhancers Carbohydrates White rice, bread, pasta, and sugars Can improve/maintain physical performance As restorative can improve memory Amino Acids: Tryptophan, Tyrosine Health food stores, found in meats Tyrosine helpful for stress resistance; some sleep improvements Scant evidence of cognitive performance enhancements Multi-vitamins, Minerals and Antioxidants Purchased in numerous stores Replace/supplement bodily needs not met through good nutrition Not likely to improve performance; but may speed energy recovery Anabolic Steroids Naturally in body, available through athletic outlets DHEA for muscle building and popular with longevists Can enhance well-being, but also impair cognition; must continue treatment to prevent loss of effects Hydration Water Ubiquitous supply; now available in bottles everywhere Essential nutrient; proven benefits to the body Bottled water may contain sodium and minerals, not fluoride Vitamin and Mineral Drinks/Waters Sold in grocery stores Feel good drinking them vs. sodas Not much noticeable effect, taste is okay Functional Energy Drinks (FEDs) In many stores and highway rest stops Belief they restore or boost energy; used as alcohol drink mix FEDs contain large amounts of caffeine, taurine, sugar, etc. Energy Bars, Chews, etc. Stores, truck stops Energy boost, picker- uppers, suppress hunger Not enough data to verify energy boost effects Dietary and Weight Loss Products Health food stores, diet clubs, over the Internet To lose weight; mostly in fad dieting Often contain multiple substances not verified for efficacy or safety TABLE 4 LIST OF SUPPLEMENTS AFFECTING HEALTH AND PERFORMANCE

and at 1, 2.5, 4, and 6 h post-dose using serial subtraction tasks and mood scales from the cognitive drug research (CDR) computerized assessment battery. Throughout the day, all three treatments resulted in improved task performance compared with placebo. For guarana, improvements were seen across attention tasks (but with reduced accuracy) and on a sen- tence verification task. Both ginseng and the ginseng/guarana combination increased the speed of attention task performance, and enhanced speed of memory task performance, but exhib- ited little evidence of modulated accuracy. Guarana, and the combination of guarana with ginseng, and to a lesser extent ginseng itself, led to significant improvements in serial sub- traction task performance. In another study, Kennedy et al. (2008) assessed the acute effects of either a mix of vitamin/mineral/guarana supplement or placebo drink in 129 healthy young adults (ages 18 to 24). Thirty minutes post-dose, participants completed six con- secutive runs on a 10-min battery of cognitive demand tests (i.e., 60 min of testing). The vitamin/mineral/guarana com- bination resulted in improved task performance in compari- son with placebo in terms of increased speed and accuracy of performing a rapid visual information processing task. While on the supplement mix, subjects reported attenuation of mental fatigue on a mental fatigue scale. Few other experimental studies of guarana were located. The findings of Kennedy et al. apparently have not yet been replicated. Therefore, one cannot yet strongly support state- ments regarding the cognitive performance benefits of guarana. As with caffeine, guarana also is likely to be effective in enhancing physical performance when a person is working at a high percentage of aerobic capacity. Guarana may have moderate positive effects on anaerobic performance and muscular endurance. Guarana tends to suppress appetite and therefore is potentially useful for weight loss and obesity control. Neither guarana, nor simply caffeine by itself, appear to be especially effective as stand-alone weight loss aids; how- ever, in combination with other thermogenic and nervous system stimulants, guaranine or caffeine may extend the activity and potency of certain supplement ingredients. As with any caffeine-containing substance, too much guarana can lead to nervousness, tension, and headaches. No long- term adverse consequences have been reported with guarana (TTCP 2001). In the United States, the commercial bottled drink industry and marketers of energy boost compounds recently began inserting considerable amounts of guarana into their products, along with other psychoactive compounds (including caffeine, taurine, and ginseng). Guarana is found in some soft drinks, colas, lemonade, energy drinks, supplement powders, and food bars. Many of these new products containing guarana are found on the “energy boost product shelves” at truck stops along major highways in the United States. 42 Assessment of guarana. The work of Kennedy et al. (2004, 2008) indicates the potential of guarana use for bring- ing about positive effects on cognitive performance. Because guarana has already invaded the supplement marketplace in the United States, further research on guarana appears warranted. Studies are needed to examine the effects of typical doses of guarana individually as well as synergistically when com- bined with other psychoactive ingredients currently in food supplements available on the store shelves. Further, educational materials about the make-up of guarana and its potential effects on health and performance are needed for the user public, and for commercial drivers and for their employers. Ginkgo Biloba For thousands of years extracts and infusions made from the leaves of the small bushy Ginkgo Biloba tree have been used in traditional Chinese medicine for treatment of a variety of problems including asthma and digestive disorders. Ginkgo biloba represents one of the most studied and commonly used herbal remedies in the world. In many western countries, especially in Europe, the use of an extract made from the green ginkgo leaf serves as a popular OTC herbal supplement advertised for its antioxidant properties, and as a prescribed remedy for use on a number of vascular problems, treat- ment of memory loss, dementia, and macular degeneration (O’Hara et al. 1998). Ginkgo biloba’s popularity grew in the United States during the late 1990s and it continues through today. In 2002, the National Health Interview Survey found that ginkgo was the third most popular natural product in the United States and determined that ginkgo was being used in some form by about 4% of American adults. Two main groups of active constituents responsible for ginkgo biloba’s medicinal effects are terpene lactones and ginkgo flavone glycosides, present in varying concentrations in the leaf of the ginkgo tree. Ginkgo effects may arise from a single active ingredient or by the combined actions of the many active ingredients. Approximately 40 different flavonoids have been isolated. Commercial extracts of ginkgo are generally standardized with regard to the content of the primary active components, with the flavone glycosides and terpenoids compromising 24% and 6% of the total extract, respectively. At the physiological level, ginkgo extract is both a platelet- activating factor antagonist and a free radical scavenger. The exact mode of action of ginkgo biloba in the body is not precisely known. The bioactive properties of ginkgo biloba extracts are varied. Ginkgo appears to modulate a number of neurotransmitter systems and it exerts effects on cellular metabolism. These and other mechanisms underlie a number of reported health effects of ginkgo, including improvements in blood circulation and neuroprotective roles after various neuronal insults (Kennedy et al. 2000), for treatment of certain forms of tinnitus (ringing in the ears), for short-term memory loss, for senile dementia, and as a blood thinner to prevent stroke. As therapy, the usual dosage has been 120 to 240 mg

43 of ginkgo biloba daily, or 40 to 120 mg as a prophylactic brain tonic (Kleijnen and Knipschild 1992). There is a lack of standardization of ginkgo biloba extracts in the supplement marketplace, making dose comparisons across studies difficult. Little information has been published regarding the pharmacokinetics, pharmacodynamics, and/or the duration of ginkgo effects (Gilbert 1997). Preliminary data for some active ingredients give a time-to-peak plasma at 1 to 3 h and a half-life of 3 to 6 h. A usual dose of ginkgo extract ranges from 120 to 600 mg. Chronic treatments usually administer 120 mg of ginkgo daily for up to 6 weeks, and this has demonstrated no adverse effect on performance of healthy young subjects. Ginkgo is said to improve aspects of cognitive perfor- mance. Claims for ginkgo extract include those suggesting it enhances mental function in healthy individuals and that it has been shown to be effective in the elderly for “cerebral insufficiency” (an imprecise term describing memory loss, confusion, depression, dizziness, and tinnitus). More than 400 animal and clinical trials looking at a variety of medicinal properties and clinical uses for ginkgo biloba suggested that its purported cognitive-enhancing effects are most likely attributable to its flavonoid and ginkgolide compounds (the latter found nowhere else in nature), which may arise from uptake inhibition and enhanced release of neurotransmitters (Kleijnen and Knipschild 1992). Kennedy et al. (2000) examined ginkgo extract (at doses of 120 mg, 240 mg, and 360 mg) for cognitive performance effects, at 1, 2.5, 4, and 6 h after administration using measures from the CDR computerized assessment battery. Ginkgo produced a number of significant changes on performance measures, the most striking of which was a dose-dependent improvement of the “speed of attention” factor following both the 240- and 360-mg doses, which was evident at 2.5 h, and was still present at 6 h after administration. Additionally, there were time- and dose-specific changes in performance (positive and negative) on the other three cognitive factors (accuracy of attention, speed of memory, and quality of memory) of the CDR. Across three such experiments, the effects of the 120-mg dose of ginkgo (normal dose level) on cognitive speed were equivocal, even appearing to have a negative effect on speed of attention task performance; only modest effects were demonstrated in memory task performance (Kennedy et al. 2000, 2007; Scholey and Kennedy 2002). There were improvements in self-rated mood following ginkgo, and to a lesser extent a combination product (ginkgo, guarana, and vitamin mix) as well (Kennedy et al. 2002). Some studies reported that ginkgo improved memory in healthy subjects, but an absence of effects on other cognitive tasks (Warot et al. 1991; Wesnes et al. 1997; Rigney et al. 1999). Rigney et al. (1999) reported positive ginkgo extract effects (acutely administered) were more pronounced for memory, particularly working memory, and the effects demonstrated were dose-dependent, but not in a linear dose-related manner. They concluded that the cognitive-enhancing effects of ginkgo are more likely to be apparent in individuals aged 50 to 59 years. Elsewhere, beneficial effects of ginkgo on cognitive performance have been reported after 4 to 6 weeks of treatment in elderly individuals and for those suffering from dementia. Using a similar test paradigm to the one previously men- tioned, Kennedy et al. (2001) examined the combined effect of administering both ginkgo biloba and Panax ginseng on cognitive performance, memory, and mood. They gave a com- bination dose of 320, 640, and 960 mg, along with a matching placebo, to 20 healthy young adult volunteers, and tested at 1, 2.5, 4, and 6 h after the day’s treatment. The most striking result was a dose-dependent improvement in performance on a “quality of memory” factor for the higher dose. This effect appeared targeted at secondary memory rather than the work- ing memory component. There was also a dose-dependent decrement in performance of the “speed of attention” factor for both the 320- and 640-mg doses. Canter and Ernst (2007) reviewed 15 studies with random- ized, placebo-controlled, double-blind clinical trials looking for the effects of standardized ginkgo biloba extracts on cognitive function. They did not find enough convincing evidence for a robust positive effect of ginkgo biloba on any aspect of cognitive function in healthy young individuals after either acute or longer-term administration. Thus, of the few studies with healthy young subjects, the only effects of ginkgo have been modest improvements in memory. No reports described cognitive performance of healthy individuals being impaired by ginkgo extract. Assessment of ginkgo biloba. Canter and Ernst (2007) presented what may appear to be a convincing indictment. In reality, there were not a sufficient number of reportable studies of ginkgo biloba and cognitive or psychomotor performance to make definitive statements in this synthesis about the effi- caciousness or utility of ginkgo biloba to meet the primary interests of the commercial driving community. Additional targeted research might help elucidate these issues. Herbal and Nutritional Supplement Remedies to Relieve Stress and Tension, and Promote Relaxation and Sleep Proponents of nutritional supplements advocate various herbs to relieve stress. These herbal compounds include Passion Flower, Lavender Oil, Kava, Valerian, Ginseng, and Saint John’s Wort. Additional nutrient supplements that help with anxiety or stress are proteins such as 5-HTP, and amino acids such as Tryptophan, Tyrosine, and Theanine. Most of these supplement products are commercially available in boutique health food stores, nutrition shops, and in some grocery stores. Although the synthesis team identified some descriptive and scientific reports of studies of their effects on health and

performance, for many of these substances the evidence of their importance as psychoactive substances that might impact commercial driver performance was not significant. These are described in Appendix C. ENERGY SUPPLEMENT DRINKS, FOOD BARS, CANDY CHEWS, AND OTHERS Caffeine was described extensively as a stimulant in chap- ter four. It was pointed out that caffeine shows up in numer- ous products best described as supplement drinks, and in sup- plement food bars and gels, advertised to boost one’s energy level. This section describes caffeine (in its various forms), along with other psychoactive substances included as ingre- dients in many of the “energy supplements” readily available in most highway rest stop convenience stores, grocery stores, and so on. Functional Energy Drinks Since the late 1990s, energy drinks (sometimes called caf- feinated FEDs) have become popular, especially so with young adults, producing a growing health concern for adolescents (Babu et al. 2008). The major ingredient in the numerous energy drinks is caffeine, mixed along with other caffeine-like chemicals (e.g., guarana), as well as several other psycho- active ingredients. The range of caffeine in popular FEDs may be from 80 mg to as high as 500 mg of caffeine per serving— which means the caffeine in a single energy drink (of some brands) can exceed that of two six-packs of Cocoa Cola (Reissig et al. 2009). Individuals who consume FEDs give many reasons for why they partake of energy drinks, including because they (1) give a burst of energy, (2) help the consumer to stay awake, (3) increase alertness, (4) improve short-term memory, (5) help students perform better on tests, and (6) mixing alcohol with an energy drink can reduce the severity of a hangover, protect the liver, and keep a person from getting drowsy. College students commonly mix energy drinks with alcohol, leading to numerous complications (Malinauskas et al. 2007; O’Brien et al. 2008). Whereas electrolyte replace- ment sports drinks (e.g., Gatorade®) attempt to replenish the body after strenuous activity or exercise, FEDs do not replenish the body. Mixing a FED and alcohol can significantly dehydrate a person because both substances have diuretic effects (Reisenhuber et al. 2006). In a lab study, Ferreria et al. (2006) demonstrated that the subjective perceptions of headache, weakness, dry mouth, and impairment of motor coordination were less intense when alcohol was combined with an energy drink. However, objective measures of motor coordination, visual reaction time, and breath alcohol con- centration for energy drink plus alcohol were the same as for alcohol alone. Ferreria et al.’s results basically showed that a person subjectively feels less intoxicated than they 44 actually may be. This point was accentuated by the FDA when in the fall of 2010 it pressured the company Physion Projects into withdrawing its alcoholic energy drink “Four Loko™” beer from the marketplace after numerous adverse life-threatening events implicating consumption of quantities of the combination alcohol–caffeine drink occurred on col- lege campuses in the United States. To remain within the spirit of the 1994 Dietary Supplement Health and Education Act, manufacturers of energy drinks claim the ingredients in FEDs are derived from healthy sub- stances, such as vitamins, herbs, and other natural ingredients. Because the FDA does not regulate such supplements, the manufacturer bears the full responsibility for ensuring the product is both effective and safe for human consumption and use. The ingredients must be listed in the “other ingredients” 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. Grosz and Szatmari (2008) indicate there is a paucity of published detail on either the contents or descriptions of the human effects of FEDs. Red Bull™ is the most widely known energy drink, as it is sold in more than 140 countries. Most of the popularly marketed FEDs such as Red Bull™ are made up predominately of sugar water and contain fruit juice flavor- ing and high levels of caffeine and taurine and other herbal stimulants as the principal “active ingredients,” along with small amounts of glucuronolactone, niacin (niacinamide), sodium citrate, and inositol. Other FED ingredients may include guarana, ginseng, and orange rind extract. The man- ufacturers of these drinks claim their stimulating effects are the result of interaction among the various ingredients and they claim the drinks improve physical endurance, reaction speed, and concentration. Among the many commercially available FEDs, one competing brand called “Yellow Jacket Energy Drink” for example is advertised to provide “Twice the Buzz, helping to deliver energy one needs to get through the day.” In addition to caffeine as a major ingredient, some of the more common ingredients also found in many FEDs include: • Taurine—known as 2-aminoethane-sulfonic acid. In 1827, taurine was originally isolated from bull or ox bile (taurus means bull in Latin), but now is available syn- thetically for insertion into energy products. It is pro- duced in the liver and in the brain where it serves as an inhibitory neurotransmitter exerting neuroprotective effects against excitotoxic agents and oxidative stress such as those released during an ischemic episode (Chepkova et al. 2002; Kim 2003). Taurine is the most abundant free amino acid in many body tissues. Taurine is different from other amino acids in that it is not incor- porated into proteins. It plays an important role in osmo- larity regulation and in metabolism and it is found in

45 high concentrations in skeletal muscles where it plays an important role in modulating contractile function. In some cases taurine acts as a mild sedative and as an age-defying antioxidant. It also has potential to steady irregular heartbeats. Only a small number of studies have been published to validate many of the beneficial claims attributed to taurine, especially its claimed beneficial effects in energy drinks. • Glucuronolactone—a natural compound found in the body, about which little is documented. Users of energy drinks generally believe glucuronolactone fights fatigue and increases well-being; however, little has been pub- lished about its inclusion in FEDs (600 mg in a 250 ml can of Red Bull™), thus its effects are not clear (Clau- son et al. 2003). • Niacin—also known as vitamin B-3, among other func- tions, it helps increase so-called good cholesterol (HDL) by preventing the formation of triglycerides, making it a useful cholesterol control drug. There usually is not enough niacin in FEDs to provide this benefit. The niacin contained in the energy drinks (20 mg in a 250 ml can of Red Bull) is not pure enough to give the mild head rush dubbed the “niacin flush” (Clauson et al. 2003). Not much has been reported about potential interactive effects of niacin, if any, with other com- pounds found in FEDs. • Inositol—a carbohydrate found in animal muscle it is sometimes called “meat sugar.” Inositol is a water-soluble fatty lipid, a part of the vitamin B complex (B8) required for formation of healthy cells. It promotes healthy brain development and function, and works closely with choline to move fats out of the heart and liver. Inositol is used for treatment of diabetic nerve pain, panic dis- order, high cholesterol, insomnia, cancer, depression, schizophrenia, Alzheimer’s disease, ADHD, autism, pro- moting hair growth, and the skin disorder psoriasis. There usually is so little inositol in energy drinks (50 mg in a can of Red Bull), that its potential benefits on the body are deemed to be negligible. As a paradox for the drink manufacturers, consumption of large amounts of caffeine may cause a shortage of inositol in the body; thus, heavy coffee drinkers may benefit slightly from taking supplemental inositol. The manufacturers of energy drinks such as Red Bull™ tout the likely combination of energizing effects by placing caffeine along with other ingredients such as taurine (1,000 mg) and glucuronolactone (600 mg) into the beverage (Mayer 2002). Several researchers (Woojae 2003; Van den Eynde et al. 2008) attempted to “debunk” the likely impact of taurine in favor of indicating that it is predominately the caffeine that brings about the energetic effects (desirable or undesirable). Woojae (2003) reported this is likely to be true regarding the increase in cardiac stroke volume witnessed by Baum and Weiss (2001); it pertains as well to the shorter reaction times and improved effects on emotional well-being reported by Seidel et al. (2000), the increased alertness reported by Alford et al. (2001), and improved information processing times reported by Warburton et al. (2001)—all of which were more likely affected by the amounts of caffeine administered than they were by the taurine (Woojae 2003). Woojae argues that the endogenous taurine found in high concentrations in skeletal muscles self- regulates itself and the taurine levels are maintained at a stable level in the brain as well. One can of Red Bull™ is reported to contain between 65 and 80 mg of caffeine, about the same amount of caffeine as can be found in many normal brewed cups of coffee. Thus, Woojae suggests that it is not likely that supplemental taurine would have much effect; it is more likely that the higher caffeine levels in the drinks are responsible for the effects observed when drinking Red Bull or other similar energy drinks, particularly so when quantities of the drink are consumed (Woojae 2003). In examining several popular FEDs, Clauson et al. (2003) determined that most of them contain products such as guarana, ginseng, and taurine in such small amounts that they are far below the amounts expected to deliver either therapeutic benefits or adverse events. By comparison, the drinks usually contain as much as 80 to 300 mg of caffeine and 35 g of processed sugar per 8-ounce serving, amounts known to cause a variety of adverse health effects. Commonly reported adverse effects seen with the amounts of caffeine present in the energy drinks are insomnia, nervousness, headache, and tachycardia. Both caffeine and taurine have direct effects on cardiac function and hemodynamic status. Steinke et al. (2007) assessed whether or not commonly consumed energy drinks alter the blood pressure, heart rate, and electrocardiogram (EKG) parameters in healthy participants. Participants con- sumed 500 mL (two cans) of an energy drink containing caffeine (80 mg) and taurine (1,000 mg). Blood pressure, heart rate, and EKG measures were repeated 30 min, 1, 2, and 4 h after consumption, over a 5-day test. Although no signifi- cant EKG changes were observed, subjects’ heart rate increased 5 to 7 beats per minute (bpm), and systolic blood pressure increased 10 mm Hg after consuming an energy drink. They suggested these physiological levels are likely clinically sig- nificant for consumers who happen to have cardiac disease or for those individuals who regularly consume quantities of such energy drinks. The study by Steinke et al. (2007) was performed on healthy subjects, and it cited amounts of taurine to be 1,000 mg (presumably akin to Red Bull at the time). Some energy drinks available in the year 2010 have increased the amounts of some of the potentially offending ingredients. Effects of such combinations of substances as these apparently have not been assessed on subjects with hypertension while they happen to be using various anti-hypertensive medications. Many commer- cial drivers suffer from hypertension and are being medicated for it, which should raise some concern. In August 2010, these synthesis authors purchased the popular product Monster

Hitman Energy Shooter™ from the OTC energy boost shelf at a local drug store and noted that the listed ingredients for the 3-ounce dietary supplement included 6 g of sugar; 45 mg of sodium; more than 200% of the recommended daily allowance for vitamins B-2, B-3, B-6, and B-12; 2,000 mg of taurine; 400 mg of ginseng; and a 5,000-mg energy blend of glucose, L-carnatine, caffeine, inositol, guarana, glucurono- lactone, and maltodextrin. The label warns individuals not to consume more than one shot of Monster Hitman every 4 h. Kennedy and Scholey (2004) demonstrated that some of the same cognitive performance effects are obtained through combinations of only caffeine and glucose, without adding the other substances into the energy drinks. Van den Eynde et al. (2008) tended to agree, stating that most of the effects of energy drinks on cognitive performance are related primarily to the presence of caffeine. They suggest further investigation is needed into the effects of the lesser known ingredients of energy drinks (e.g., taurine and glucuronolactone) to gain a better understanding of the possible interactions of the multiple substances. Warburton et al. (2001) identified experimental design inadequacies in the literature (e.g., pre-test cutbacks on caffeine by participants that might have produced caffeine withdrawal during testing). Subsequently, they designed an experiment to examine whether or not test participants with minimal pre-test deprivation from caffeine would produce similar results to participants who ordinarily were asked to abstain from caffeine before their participation in experiments. They concluded that moderate doses of caffeine and taurine can improve information processing in individuals who could not have been in caffeine withdrawal at the time of their par- ticipation in the testing. Their caffeinated/taurine group of participants improved attention and verbal reasoning, but there was no significant effect on memory (Warburton et al. 2001). Reyner and Horne (2002) investigated the effectiveness of a well-known FED for reducing sleepiness in drivers. After restricting their sleep to 5 h the night before, 12 healthy young adults drove a car simulator between 1400 and 1700 h. Following a pretreatment 30-min drive, participants were given 250 ml of a FED (containing sucrose, glucose, 80 mg caffeine, taurine, glucuronolactone, and vitamins: equivalent to Red Bull) versus a control drink with the same volume and taste but without the caffeine, taurine, and glucuronolactone. Two hours of continuous driving ensued. Compared with the controls, energy drink participants significantly reduced sleep- related (fatigue) driving incidents (e.g., lane drifts) and reported less subjective sleepiness for the first 90 min of the drive. There was a trend for the EEG to reflect less sleepiness during this period. It was concluded that FEDs can be beneficial in reducing sleepiness and sleep-related driving incidents dur- ing monotonous afternoon driving following modest sleep restriction the night before (Horne and Reyner 2001; Reyner and Horne 2002). Additional studies of this type should be 46 pursued with commercial drivers in instrumented driving simulators as well. Jay et al. (2006) did a crossover design experiment with 15 young adults, simulating a first night-shift protocol with two conditions: participants taking an energy drink (FED) and a baseline control (non-FED) condition. Both test conditions involved a period of extended wakefulness from 0700 on one 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 condition, an energy drink was administered twice during the night. Sleepiness was assessed during the period of extended wakefulness and for a further 6 h after awaking. Comparison of sleep periods (measured with EEG) showed that sleep onset latency remained unchanged, as did stage 2 and slow wave sleep. However, sleep efficiency was significantly reduced, and total sleep time was 29.1 min shorter in the FED condition. The study demonstrated the residual effects of the FED’s active ingredients impacting on some aspects of daytime sleep following a simulated night shift. Subsequent performance however was unaffected. Jay et al. stated that the results deem FEDs effective for use in alertness control during a single night shift and warrant investigation into FED use over suc- cessive night shifts (Jay et al. 2006). Such calls for additional research should also be made for the commercial driving community, where the obvious applications and implications of FEDs should be pursued. A major reason popular energy drinks raise public health concerns is because they contain high levels of caffeine, and typically not all the ingredients and the quantities of each are accurately labeled on popular products. In their review of a large variety of energy drinks, Reissig et al. (2009) stated that in the year 2006, annual worldwide energy drink consumption increased 17% from the previous year to 906 million gallons, with Thailand leading the world in energy drink consumption per person. The United States led the world in total volume sales. These Johns Hopkins researchers published tabular information about the caffeine contents in energy drinks by brand name, indicating that the caffeine content ranged from 50 mg to 505 mg per 12-ounce serving. One drink, a 1-ounce “ammo” drink, had the greatest concentration at 171 mg of caffeine per ounce of drink; whereas Red Bull™ was listed as having 9.6 mg of caffeine per ounce, or 67 mg caffeine per 8-ounce can. A commercially available product, SoBe’s “No Fear” drink, contains 141 mg of caffeine per 16 ounces. Coca-Cola Classic had the least caffeine at 2.9 mg/oz. With a concern that consumers may be unaware of the consequences of caffeine intoxication, Reissig et al. (2009) wrote that from 2002 to 2004 a U.S. poison control center received 42 cases of caffeine abuse from caffeine-enhanced beverages. Caffeine intoxication includes symptoms such as nervousness, anxiety, restlessness, insomnia, gastrointestinal upset, tremors, tachycardia, and psychomotor agitation. Clauson et al. (2003) found four case reports of caffeine-

47 associated deaths as well as four separate cases of seizures associated with the consumption of energy drinks. Reissig et al.’s review (2009) calls on the FDA to insist on requiring the manufacturers to disclose the amount of caffeine in energy drinks on the label of the containers. Australian medical researchers tested 30 young adults 1 h before and 1 h after consuming one 20 ml can of sugar-free Red Bull (DeSciscio et al. 2008). In August 2008, these researchers publicly stated that just one can of the popular stimulant energy drink, Red Bull (whose marketing advertises “Red Bull gives you wings”), can increase the risk of heart attack or stroke, even in young persons (Reuters news articles, Canberra, Australia, Nov. 2008). The senior researcher, Scott Willoughby, reported that 1 h after volunteers drank Red Bull their blood systems were no longer normal, but were abnor- mal in a way that would be expected in a patient with cardio- vascular disease. In an interview, Willoughby suggested the drink caused the blood to become “sticky,” which he declared to be a pre-cursor to cardiovascular problems. Willoughby (2008) advises that Red Bull could cause important compli- cations if combined with stress or high blood pressure, impair- ing proper blood vessel functioning and probably increasing the risk of blood clotting and stroke. There have not been sufficient conclusive studies on the combined effects of caffeine and taurine in Red Bull™, Monster Hitman Energy Shooters™, or other FEDs, and the true contents and the full extent of health risks mostly are not listed on containers of such products. For these reasons, the popular drink Red Bull is banned in Norway, Uruguay, and Denmark. Nevertheless, it is still widely sold, and it was estimated that 3.5 billion cans of Red Bull have been sold in 143 countries around the world. Assessment of functional energy drinks. Most of the FEDs available in the public marketplace advertise ingredients that include sugar, caffeine, taurine, and some vitamins or small amounts of other chemical substances, a few of them adding to the combination of psychoactive substances. The relatively small number of reputable studies in the literature mainly indicated that most of the psychoactive effects from the FEDs can be attributed to the concentration of caffeine contained. Effects owing to secondary substances, apparently added largely to satisfy marketing ploys, are likely to be slight. How- ever, health and performance concerns remain about verifying the potential synergistic or interactive effects of the several ingredients found in FEDs, which individuals may consume in considerable quantity while they happen simultaneously to be taking medications and other chemical substances. Several experiments described previously demonstrated the potential applicability of FEDs for reducing sleepiness and sleep-related driving incidents after sleep restriction (e.g., Reyner and Horne 2002). The effectiveness of FEDs was also shown during simulated first-night shift work, as high- lighted by Jay et al. (2006); however, FEDs also adversely impacted recovery sleep on the following day. Additional research with FEDs is called for, preferably to be conducted in driving simulators to elucidate the implications of judicious use of FEDs by commercial drivers. Subsequently, guidance about the measured effects of FEDs on health and performance would be appreciated in the commercial trans- portation industries. Five- and Six-Hour Power Energy Booster Drinks The earlier write-up on FEDs portrays a number of health concerns, particularly in consuming multiple servings or simultaneously mixing the popular FEDs in combination with alcohol. In part, in response to those reports, the energy drink industry now markets newer alternative energy drinks. Intense advertising on U.S. television and a wide availability in convenience stores, including truck fuel stops, has made two of these new drinks the best known to date: (1) the new “2-ounce shot”: 5-Hour Energy™ drink (distributed by Living Essentials), and (2) another 2-ounce shot drink called 6-Hour Power™. Both products identify themselves as “vitamin supplement drinks.” The label on the 5-Hour Energy™ bottle, and the company’s website, suggest that its unique blend of vitamins provides a boost of energy, and its combination of amino acids provides cognitive enhancements, such as an increased ability to focus and a better mood. The company’s advertising says 5-Hour Energy™ is different from other energy drinks because it excludes guarana, contains only as much caffeine as is found in one cup of coffee, and it has “zero sugar, zero net carbo- hydrates, and only four calories.” The lack of sugar and reduced amount of caffeine are said to eliminate the “crash effect,” a reduction in energy below baseline that most users of other energy drinks (FEDs) experience owing to their high levels of sugar and high caffeine content. Living Essentials claims these drinks will make a person feel “awake, alert, and productive for hours—without the jitters and crash associated with other energy drinks”—and therefore 5-h energy is perfect for “combating a groggy morning, that afternoon lull, or to moti- vate you to work out.” The label on the bottle of the 5-Hour Energy™ drink indi- cates that it contains 30 mg of niacin, 40 mg of vitamin B-6, 400 mcg of folic acid, 500 mcg of vitamin 12 (as cyanocobal- amin), and 0 mg of sodium. The energy blend of 1,870 mg of liquid contains taurine, glucuronolactone, malic acid, n-acetyl, l-tyrosine, l-phenylalanine, caffeine, and citicoline. Although the amount of caffeine contained is not specified, the instruc- tions on the bottle warn consumers to limit themselves to “two shots of 5-Hour Energy a day, spaced hours apart.” Thus, if the contents really only have the equivalent caffeine found in a cup of coffee, there would appear to be less of a risk of someone who properly uses 5-Hour Energy™ encountering difficulties attributable to consuming too much caffeine than

FIGURE 2 A sample of psychoactive supplements found at interstate highway convenience stores. there would be in consuming the more widely known FEDs, each of which present significantly more caffeine. No confir- matory scientific data were located on this topic. The company website for the 6-Hour Power vitamin sup- plement drink conveys minimal helpful information about their product. The ingredients listed on the bottle include vita- mins B-6, B-12, and C; niacin; folic acid; sodium; an energy blend of taurine; malic acid; caffeine; tyrosine; and a blend of three enzymes. Assessment of hour power booster drinks. Although these vitamin-laced drinks may not harm a person if taken according to the directions, there is also no published evidence that they have the efficacy and functional validity for safe on-the-road usage. For this synthesis, no research reports were located documenting the efficacy, safety, or cognitive effects and other performance and health implications of using either the 5-Hour Energy or the 6-Hour Power “shots.” Additional research is recommended on this potential alternative to the FEDs if for no other reason than they are apparently now being consumed by so many commercial drivers. Both products can be readily purchased in most drug- stores and grocery stores, and at any truck stop along the nation’s highways. It is not known how many of the super 48 vitamin-laced drinks described here are being consumed by commercial drivers; however, anecdotal evidence from checkout clerks at three major truck stops along Interstate Route 95 noted that truck drivers appear to buy a lot of them, and “swear by them” (G. Krueger, personal communications, Aug. 2009). ENERGY BOOST POWDERS, PILLS, FOOD BARS, ETC. In a way similar to the energy drink market, there also are available a large number of “nutritional-energy boost” food bars, pills, tablets, powders, and so on, each being promoted as energy booster products containing herbs, vitamins, and minerals. Most of these present splashy colors and advertis- ing displays, and offer to increase or enhance performance (whether it be physical or cognitive performance), allevi- ate stress, provide more energy, provide power to achieve, and so on. The MaineWay synthesis team acquired a sampling of a dozen or more such energy boost items directly from truck rest stop stores along highways such as Interstate 95 from Florida to New York, and along Interstate 81 from Virginia through Pennsylvania (Figure 2). [Note that this photo- graph is for information purposes and is not intended as an endorsement of any kind.] These products touted, as energy

49 boosters, were in forms as varied as pills, powders, food bars, packets of capsules, gels, energy gums, mints, can- dies, chews, and more. Examining this sampling for their listed ingredients indicated that most claim to have combi- nations and mixes of such ingredients as ginseng; guarana; vitamins A, B, C, and E; niacin; folic acid; amino acids; beta carotene; bee pollen; various mineral mixes; bioflavonoids; and so on. These products are advertised as stress control and power booster formulas, and boast energy-max and energy-hit pickups. Most such products were prominently displayed on grocery shelves where truck drivers would be sure to see them as they frequent the establishments to refuel, visit the rest rooms, and/or to replenish convenience food supplies. Assessment of vitamin energy boost products. No scientific reports examining or evaluating the three items mentioned previously (i.e., vitamin-laced drinks, electrolyte replacement drinks, or energy boost supplements in pill or bar forms) were located for documentation in this synthesis. Some laboratory research on these many products may be warranted. Controlled laboratory studies could be carried out to examine and report on the efficacy and safety of use of such readily available products by commercial drivers.