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

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83 HERBALS FOR RELAXATION AND STRESS ALLEVIATION Herbal product caution. As with other nutritional sup- plements not subject to FDA rules, commercial herbal products may also be adulterated with unlabeled ingre- dients (Miller et al. 2000; Straus 2002; IOM reports 2005, 2008). Consumer care must be taken to ensure that any potential adverse interactions between some herbs and prescription medications are identified and considered during medical treatment. This is espe- cially important before undergoing medical surgeries wherein the interaction of herbal effects and varying forms of anesthesia may cause serious bodily compli- cations (Izzo and Ernst 2001). Patients planning to undergo surgery are strongly advised to convey what herbs and other supplements they may be taking to the surgeon and anesthesiologist well before surgery and to be sure to discuss the implications. Passion Flower Passion flower is an herbal medicine product used medicinally for stress-alleviating purposes. It consists of an extract of raw material taken from an herbal plant (passiflora incarnate or passifloraceae) with street names of maypop or apricot vine. Passiflora, a perennial vine that may reach 10 m in length, was discovered by Spanish explorers in Peru in the sixteenth century. The ten-petal flower was seen as being symbolic of the passion of Christ (which gives it its catchy name), as it was considered as a sign of divine approval of the Spanish conquest. Various species of the passiflora plant are native to North America and are found in the Midwest and Southeastern United States, and as far south as South America. The medicinal parts of the passiflora plant include the whole or cut dried herb and the fresh aerial parts. For centuries, passion flower has been used as a calming and relaxing herb and as a folk remedy to treat anxiety. Passion flower herb contains free flavonoids (e.g., apigenin, luteolin, quercetin, and campherol), sterols, chlorogenic acid, volatile oil, and traces of alkaloids (harman, harmine harmaline, and harmalol) (Gruenwald et al.’s PDR for Herbal Medicines 1998; Kamaldeep et al. 2004). Passiflora has complex action on the central nervous system (CNS). The pharmacologic activity of passion flower likely derives from the flavonoids and alkaloids. A few studies document sedative action of passion flower in humans. Among the claims for passion flower are that it relieves tension; reduces restlessness, anxiety, and nervousness; and that it induces sleep (Kamaldeep et al. 2001). Proponents recommend it for use by people who wish to feel relaxed in the evening after a stressful day. In 1978, the FDA prohibited use of passion flower in over-the-counter products because it had not been proven to be safe and effective (Robbers and Tyler 2000). However, passion flower is still available as an herbal remedy and is available as a bulk herb in teas, capsules, and as fluid or tincture or in the form of hydroalcoholic extracts. It has been found to exhibit different effects between the alcohol extract and the aqueous extract. The alcohol extracts proved to be anxiolytic and the aqueous extract more a sedative in exper- iments with mice (Soulimani et al. 1997). Passion flower is sold as a commercial product for both oral and topical admin- istration. It can be used as a tea, usually 2 to 4 grams of the dried herb taken two times per day. In well-advertised U.S. commercial sales of the herbal passion flower, its extract is frequently mixed with other relaxant herbs such as valerian and skullcap. It is incorporated as a principal component of a natural herbal product called Good Night Rx™, which, as with most herbal supplements, also contains numerous other ingredients, including kava. Assessment of Passion Flower. No reports were located describing studies of passion flower’s effects on actual induced sleep quantity or quality, or on resultant effects on human performance. Recommendations are to monitor any new devel- opments that may evolve in the supplements market. Kava Kava Kava Kava (piper methysticum) is a somewhat bitter drink containing psychoactive kava pyrones, deriving from the massive gnarly rootstock of the kava-kava shrub. Kava Kava is an integral part of life in the Polynesian South Pacific Islands, as it normally serves as a pleasant drink at the end of a workday. In Fiji, Samoa, and Tonga, the Kava root is dried before it is processed into a powder for use in the Kava drink (Kilham 1996; Lemont et al. 1997). Kava has been pre- scribed as an effective folk remedy for anxiety, insomnia, and back pain. Its history of use largely as a celebratory drink dates back 3,000 years. In the West, Kava is used much the same way alcohol is used at weddings, public festivals, and on holidays, and in ceremonies honoring the dead. Unlike alcohol, kava does not produce or stimulate aggression, and it does not produce hangover. In the 1990s, U.S. nutritional supplement companies intro- duced products that touted kava’s anti-anxiety properties (e.g., Pacific Sensuals produced an elixir called “Erotikava”). Kava products are available in liquid or powdered extract form. Taken in sufficient quantities, kava is said to produce a mild natural “high.” As a natural herbal drink, Kava-Kava is said to have subtle psychoactive properties, and it is claimed to help relax muscles, calm nerves, and to create a general feeling of well-being, peace, relaxation and contentment, and APPENDIX C Nutritional Supplements for Inducing Relaxation,Tension Release, Sleep, and More

to enhance mental alertness and concentration. The ritual of “kava time” involving kava preparation and drinking affords a social time and an opportunity for individual medi- tation. Claims are that drinking kava produces delightful, pleasurable, relaxing, happy, and peaceful experiences with complete mental alertness (Lebot et al. 1992). South Pacific Islanders have found other medicinal uses for kava, includ- ing to help ease anxiety and depression, and to produce rest- ful sleep. Kava is used by athletes as well as businessmen to help “take the edge off ” and to focus concentration. Kilham (1996) reported that kava is a first rate sedative, producing a state of calm, and promoting sleep if taken in sufficient quan- tity. The German Commission E (approximately equivalent of the U.S. FDA) approves kava for treating conditions of nervous anxiety, stress, and restlessness. Because kava tends to reduce appetite, after drinking it near dinner time people usually consume smaller amounts of food. When taken in moderate doses, kava does not produce identifiable side effects. The compounds called kava-lactones and pyrones are primarily what gives kava its kick, and may result in numbing of the mouth, providing mild pain relief, and muscular relaxation. The most significant anti-anxiety studies show that an effective daily dose of kava is 70 to 210 mg of kava-lactones, or 60 to 100 mg of kava-pyrones daily. Kava has not been shown to be physically addictive, but overuse can lead to health problems such as shortness of breath, dry scaly skin, and slight alterations in red and white blood cells and platelets. Taking kava with alcohol, barbiturates, or psychoactive drugs will produce a multiplier effect. Driving automobiles or operating heavy machinery should be avoided when combining kava with other such psychoactive substances. In addition to its psychoactive attributes, an interesting side effect of kava is that there have been reports the extract of the kava root depletes the body of vitamin A and, under chronic use, that kava adversely affects night vision—a key requirement for commercial drivers who spend a considerable amount of time driving at night (Russo 2007). Assessment of Kava. An insufficient amount of quality information about kava was located to make definitive state- ments about it here. Kava is a chemical substance readily avail- able in the supplement marketplace (particularly in Hawaii) and its place within the commercial drivers’ collection of likely substances being consumed should be investigated. Valerian Valerian preparations include extracts derived from the roots of the plants genus Valeriana. Most of the more than 400 extracts available in the United States and Europe are derived from the species Valeriana officinalis. These extracts contain a number of chemicals with CNS activity, includ- ing sesquiterpenes, valepotriates, valerianic acid, and other alkaloids. Commercial valerian preparations include a com- bination of these chemicals in unstated proportions (Houghton 84 1999). Buysse et al. (2005) stated that given the multiple chem- icals that constitute therapeutic extracts it is not surprising the pharmacokinetics and mechanism of action of valerian preparations have not been well described. Valerian is used to induce sleep. Doses used in clinical studies typically range from 400 to 900 mg per day. The effects of valerian extracts on sleep in humans have been investigated in healthy young adults, and with middle-aged and older adults with insomnia. Subjective effects of valerian prepara- tions included decreased sleep latency, improved sleep quality, and decreased awakenings (Leathwood et al. 1982; Lindahl and Landwall 1989). Effects on polysomnograph measures of sleep include increased stage 3 and 4 and reduced stage 1 nonrapid eye movement (NREM) sleep (Schulz et al. 1994; Donath et al. 2000). Buysse et al. (2005) reported that although improved sleep latency and sleep efficiency have been observed in some polysomnograph studies, sleep continuity effects of valerian are inconsistent (Balderer and Borbely 1985; Schulz et al. 1994; Donath et al. 2000; Taibi et al. 2007). Side effects associated with valerian have been reported to be few and mild, and include headache, weakness, and some drowsiness, whereas some reports suggest that mixing valerian with alcohol can seriously impair the ability to communicate. Morning sleepiness is an infrequent side effect (Houghton 1999; Buysse et al. 2005). Assessment of Valerian. No research reports on valerian and performance measurement were located for this synthesis literature review. Monitoring is advised. Ginseng Ginseng (American ginseng is panax quinquefolium) is a popular nutritional herb, used as an adaptogen and a restorative agent, and thought to relieve symptoms of stress, illness, and fatigue. It has been used to treat nervous disorders, anemia, wakefulness, chronic fatigue, and a host of other maladies. Ginseng is composed of a variety of different substances, including flavonoids, vitamins, enzymes, and minerals. It comes from the root of the Panaz ginseng plant, a member of the Araliacae plant family, which grows mainly in China, Korea, and Siberia; but is also available in the United States and Canada. As the ginseng root resembles a tiny man, its name comes from the Chinese words meaning “man-root.” There are 11 species of ginseng plants (Panax genus); all are slow-growing plants with fleshy roots, available year-round, and all their byproducts are used the same way. A myriad of different ginseng supplements are available, including in tablets, capsules, powders, teas, energy drinks, nutrition bars, extracts, and as dried roots. The potency of each may vary. It is difficult to compare doses, because the specific ginsenosides to which beneficial effects have been attributed are unknown; moreover, the ginsenoside concentrations vary from product to product (Cui et al. 1994). Ginseng is often

85 taken orally as a powder (400 to 1200 mg/day) or as an extract (200 to 600 mg/day), and may be taken over a period of from 60 to 120 days. No toxic effects are found with doses up to 4 g/kg for 100 days. Ginseng has been used medicinally in the Far East, pre- dominately in China, for more than 3,000 years as both an aphrodisiac and an adaptogen, helping people adapt better physically and mentally to the surrounding environment. Ginsenosides are the active ingredient that may produce a corticosteroid-like action, and may indirectly augment adrenal steroid genesis. Ginseng stimulates the CNS. It may alter carbohydrate levels and fat metabolism, and it likely enhances the immune system and promotes an analgesic effect. Ginseng is currently one of the most widely taken herbal products throughout the world. As a general tonic it has been identified with a plethora of physiological effects that combat general- ized weakness, fight fatigue, and offer restorative effects for convalescence. However, little empirical evidence is cited to support such effects, and the numerous studies reported are unlikely to stand up to standard scientific methodological scrutiny (Volger et al. 1999). It is claimed that ginseng enhances the natural resistance and recuperative power of the body and produces both stimulant and sedative activity (Lieberman 2001). Claimed benefits of ginseng taken orally include improved mental alertness, memory, cognitive functioning, and intellectual performance. Mood state also can be positively affected. These effects appear to occur only after chronic use. However, there is a lack of adequately controlled research showing behavioral effects following chronic administration of ginseng in humans (Kennedy and Scholey 2003). Recent research demonstrated that single doses of ginseng most notably engender cognitive benefits in terms of improved memory, but can also be asso- ciated with “costs” in terms of attention task deficits following less mnemonically beneficial doses. As was described under the section on guarana, Kennedy et al. (2004) studied the effects of administering 200 mg of panax ginseng, and a combination of ginseng with 75 mg of guarana. Their experiment with healthy young volunteers determined that both ginseng and the combination of ginseng along with guarana increased the speed of attention task perfor- mance and enhanced the speed of memory task performance, with little evidence of modulating accuracy as guarana by itself did. To an extent less than was true with the guarana, ginseng also led to significant improvements in serial sub- traction task performance (Scholey and Kennedy 2002; Kennedy et al. 2004). Reporting results of three such studies, Scholey and Kennedy (2002) indicated there was a highly sig- nificant and sustained increase in the number of serial seven responses following a 320 mg combination of ginkgo-ginseng at all post-treatment times. This was accompanied by improved accuracy following a 640 mg and 960 mg dose of the combi- nation as well (Scholey and Kennedy 2002). For research examining the combination of ginseng with glucose, and the impact of these two on blood glucose levels and cognitive performance, see Reay et al. (2006). Recently, ginseng became known as a sports-enhancing supplement for use in enhancing physical performance, with claims that it gives people renewed energy, vim, and vigor (Ziemba et al. 1999). Ginseng has become one of the most popular herbal supplements around for athletically minded people who want to train better and longer. It is estimated more than six million people in the United States take ginseng regu- larly as a dietary sports supplement. However, thus far, research does not support its claimed benefits. Engels et al. (2003) gave ginseng dietary supplements to 38 young, habitually active adults for 8 weeks, and then asked them to perform a series of all-out effort exercise tests on a stationary cycle. In examining salivary changes in immune response and inci- dence of upper respiratory infection they concluded that the use of ginseng does not serve well as an ergogenic aid to combat physical fatigue during repetitive strenuous physical exertion. Thus, there is not sufficient evidence to attribute positive effects of ginseng on athletic performance; nor apparently does ginseng enhance psychological well-being (Engels et al. 1996; Cardinal and Engels 2001). Ginseng has a relatively good safety record. Despite this, it can cause nervousness and excitability in some people for the first few days of taking it, and it may increase blood pressure. Assessment of Ginseng. Not many experiments were located to relate ginseng to cognitive performance. As suggested by Kennedy and Scholey (2003), further rigorous research on ginseng is needed to delineate its acute effects and to explore the relationship between acute effects and those seen during and following chronic administration regimens. St. John’s Wort Hypericum Perforatum (St. John’s Wort) is purported to have antidepressant-like actions in patients, and to elevate mood and energy in normal individuals. There is no solid evi- dence of enhanced mental or physical performance, but there is modest indication of mild antidepressant-like activity in human studies. As with most medicinal herbs St. John’s Wort may con- tain a number of biologically active compounds, including hyperforin. Field et al. (2000) reported that St. John’s Wort has catecholaminergic and serotoninergic activity in vitro. No long-term adverse effects have been noted when people chronically take it as an herbal antidepressant. However, certain St. John’s Wort preparations have induced gastro- intestinal disturbances. Assessment of St. John’s Wort. No research studies on St. John’s Wort’s effects on performance were found. Moni- toring is advised.

CARBOHYDRATE SUPPLEMENTATION There is evidence that consumption of additional carbohydrates (CHO) before, during, and after physical activity not only improves physical endurance capacity and endurance per- formance (Williams 1998), but also improves memory when blood glucose levels are restored to normal post-prandial levels in healthy elderly people (Manning et al. 1990). Whether or not a memory-enhancing effect occurs in young, active people is unresolved by research (TTCP 2001). The mode of action for employing carbohydrate supple- ments is presumably through maintenance of blood glucose concentrations; glucose being the only fuel available for brain function, unless a person is fasting. To avoid gastrointestinal upsets resulting from high fiber intakes it is recommended that refined complex carbohydrates (e.g., white rice, white bread, and white pasta) and sugars provide some of the CHO. U.S. military nutritionists and medical researchers experimented with field rations in which soldiers take small quantities of CHO infrequently in the form of moderate (5% to 10%) solutions in water or as energy bars (consumed infrequently with water). These studies demonstrate that supplemental CHO can be efficacious if the activity involves a low level of physical work output (IOM-CMNR 2005). CHO feeding at a low level (e.g., 10 to 25 g/hour) is conjectured to lead to benefits in cognitive performance for many hours when physical work output is low. Such treatment protocols could pertain to commercial drivers as well, and ought to be researched for their potential application. In terms of employing nutritional strategies to enhance sleep, there is some evidence that taking supplemental carbo- hydrates can be of assistance in managing one’s sleep schedule. Caldwell et al. (2009) suggested that although eating a meal immediately before the sleep period is not recommended, it is important to maintain good nutrition at all times. If individuals eat immediately before sleep, they should favor grains, breads, pastas, vegetables, and fruits. They should also avoid large meals, high-fat meals, high-acid meals, and sweets. High carbohydrate (CHO) supplementation before bedtime has been associated with reduced amounts of wakefulness and stage 1 sleep, decreased stage 4 sleep, and increased rapid eye movement (REM) sleep (Porter and Horne 1981). The somnolent effects of high CHO meals may depend in part on gender, age, and time of day of consumption (Spring et al. 1982). Afaghi et al. (2007) observed that a 90% CHO meal with a high glycemic index (GI) shortened sleep latency by 50% compared with a low glycemic index meal, and by about 40% when fed 4 h before sleep onset compared with 1 h before. Conversely, drowsiness may be offset immediately after high- and low-GI CHO intake; however, low-GI CHO intake may delay the onset of drowsiness (Landstrom et al. 2000). A comparison of low-fat, high-CHO meals to high- fat, low-CHO meals indicated that higher cholecystokinin (CCK) concentrations after high-fat, low-CHO meals were 86 associated with greater feelings of sleepiness and fatigue (Wells et al. 1997). Assessment of CHO Supplementation. Although it is still popularly believed that taking supplemental carbohydrates can help induce sleep (e.g., the Ehert diet for combating jet lag), the research evidence is too weak to suggest that the effects are worthy of pursuit. No recommendations beyond monitoring developments are made here. AMINO ACIDS There are numerous forms of amino acids; approximately 20 amino acids (organic compounds) occur naturally in animal proteins. Other amino acids are fabricated to be placed into commercially available dietary or nutritional supplements. Many amino acid supplements are used for purposes not particularly pertinent to the sleep induction or improved cog- nitive performance themes of this synthesis. Because most commercially available amino acid supplements seemingly have little effect on cognitive performance, they do not warrant much discussion in this report. Tryptophan The essential amino acid tryptophan, 5-Hydroxytrypto- phan (5 HTP), common in dietary protein, is available as l-Tryptophan, a dietary supplement sold in health food stores. Tryptophan has mild sedative-like effects and appears to induce drowsiness. Many people accept tryptophan as an aid to facilitate sleep. Tryptophan inhibits gluconeogenesis, and probably induces drowsiness as a result of its ability to increase brain levels of serotonin (5-hydroxytryptamine: 5HTP, a calming neuro- transmitter that in moderate levels appears to be involved in the regulation of alertness) and melatonin from the pineal gland (Wurtman et al. 1980). Serotonin has a relatively short half-life because it is rapidly metabolized by monoamine oxidase, and therefore l-tryptophan is likely to have limited efficacy. As for sleep induction, clinical studies have not clearly established tryptophan’s effects on sleep itself. Moja et al. (1984) demonstrated that pre-sleep ingestion of an amino acid mixture containing all essential amino acids caused a decrease in stage 4 sleep latency (fall into deep sleep faster) and an increase in stage 4 sleep duration during the first 3 h of sleep. The half-life of tryptophan is about 2 h; effects last about 4 h. The recommended dose is approximately 1 gram about 30 min before the desired sleep period. Depletion of tryptophan has also been observed to decrease stage 2 sleep, to increase wake time after sleep onset and rapid eye move- ment density, and to shorten the first and second REM period intervals (Voderholzer et al. 1998). Midmorning tryptophan depletion delays REM sleep latency during the following night’s sleep (Arnulf et al. 2002). Tryptophan does not appear

87 to impair performance even immediately after administration (Lieberman 1989). Other advocates touting tryptophan suggest it may increase the threshold of pain, or even reduce pain, and therefore may delay some forms of fatigue; but this has not been defini- tively demonstrated. Tryptophan has been widely employed as an antidepressant with few side effects. The metabolite of tryptophan 5-hydroxytryptophan (5-HTP) has been suggested to have effects similar to those of tryptophan (Wilson and Maughan 1992; TTCP 2001). One widely held belief is that consumption of significant amounts of turkey meat (e.g., at Thanksgiving dinner) results in drowsiness attributable to high levels of tryptophan contained in the meat, levels that are actually comparable to that contained in many other meats. The explanation for Thanksgiving postprandial drowsiness is that it likely has more to do with the large meal consumed, including the turkey, carbohydrates, and alcohol, rather than attributing the drowsi- ness to the turkey meat itself. Assessment of Tryptophan. There is no reported proven efficacy for tryptophan’s purported benefits regarding cognitive performance enhancement (TTCP 2001). It appears it would not be worthwhile to propose more research on tryptophan for its potential use as a sleep inducer. There is only scant evidence supporting ergogenic or cognitive benefits from most amino acids. There are some reports that amino acids such as bioglycin, a biologically active form of glycine, offer slight improvements in memory and attention (File et al. 1999). Branched Chain Amino Acids (BCAA) supplementation (e.g., tyrosine) can serve as energy for working muscles, and is said to reduce or delay the onset of central fatigue (Hassmen et al. 1994; Blomstrand et al. 1997; Struder et al. 1998; TTCP 2001). However, sufficient quan- tities of BCAA can actually be achieved through a balanced diet, and therefore taking supplements is not so important and actually may be a wasted effort. Doses of 6 g/day may offer lean body mass maintenance during times of stress. Doses of 5 to 20 g in pill form and 1 to 7 g of BCAA in liquid form have been found to be safe. Tyrosine Tyrosine, a protogenic amino acid, is one of the 20 amino acids used by the body’s cells to synthesize proteins. The word “tyrosine” from the Greek tyros, meaning cheese, was first discovered in 1846 by von Liebig in the protein casein from cheese. Tyrosine is claimed to improve cognitive mental performance, improve mood and memory, and diminish symp- toms in human subjects exposed to such stressors as cold, high altitude, or during periods of acute psychological and/or intense environmental stress. Thus, tyrosine is said to provide an increased ability to resist stress. Tyrosine is a precursor of central and peripheral cate- cholaminergic neurotransmitters—dopamine and norepi- nephrine. Several studies administered 100 mg/kg of tyrosine taken in two 50 mg/kg doses over several hours. Based on pharmacokinetics, the duration of effect is estimated to be 4 to 6 h; however, there is insufficient behavioral data avail- able. The ratio of tyrosine to other large neutral amino acids; that is, leucine, isoleucine, and valine is important. Tyrosine’s effect is blocked if given with these other amino acids. No serious side effects have been reported during long-term tyrosine therapy for depression; but occasional gastrointestinal distress has been reported. Tyrosine may offer some value in treating stress response to severe exercise, whereas physical performance effects are relatively insignificant. Evidence of tyrosine’s effectiveness in stress resistance is equivocal. Positive articles in the literature include studies with military populations demonstrating tyrosine’s utility during conditions of stress, cold, fatigue (Banderet and Lieberman 1989; Lieberman 1994; Deijen et al. 1999) and during pro- longed work with sleep deprivation (Owasoyo et al. 1992; Neri et al. 1995; Magill et al. 2003). Cognitive performance and mood states may be improved during adverse exposures to cold and altitude, which may lead to an improvement in physical performance. In normal circumstances, tyrosine does not appear to have any significant effect on mood, or cognitive and physical performance (Thomas et al. 1999). Assessment of Tyrosine. Although tyrosine may improve resistance to stress, and there is moderate rationale for reducing fatigue, the evidence for an effect on cognitive function is weak and conflicting. It is unlikely to be effective with acute treatment. Factors that need to be considered regarding taking supplemental amino acids are the dose level, optimal compo- sition of the supplement, and optimal timing of ingestion in relation to exercise (Wolfe 2000). Tyrosine has no direct ergogenic benefit on physical per- formance, but may indirectly enhance performance through cognitive or perceptual mechanisms. The extent of any benefits of taking supplemental amino acids such as tyrosine to reduce fatigue remains unresolved. Tyrosine is a potential candidate for further laboratory research, especially to confirm or not confirm its possible beneficial effects on cognitive perfor- mance (TTCP 2001). MULTIVITAMIN SUPPLEMENTS Good nutritional advice has always been to monitor one’s dietary intake to ensure taking in sufficient quantities of vitamins and minerals, which should first be obtained in the normal daily diet as preventive medicine to preserve good health. The U.S. Army Center for Health Promotion and Preventive Medicine (U.S. Army CHPPM 2004) reminds us that a poor diet with a supplement is still a poor diet. The U.S. Department of Agriculture (USDA) publishes listings of

recommended Required Daily Allowances (RDA) of vitamins to maintain good health. Such RDA lists prompted generations of people to take supplemental multivitamins, especially in the one-a-day vitamin pill form, as common measures for prevention of health problems. Generally, this refers to per- sons taking daily a variety of vitamins in combination, in pill or capsule form (e.g., combinations of vitamin B complex, vitamin C, and E, and so on). Some people take large amounts of vitamins and minerals in hopes of obtaining an ergogenic effect. However, although the effects of nutrients obtained by eating food have been proven to assist in the regulation of normal cellular metabolism, ergogenic effects of vitamin and mineral supplements have not. The Army recently employed the National Academy of Sciences’ Institute of Medicine Committee on Military Nutri- tional Research (IOM-CMNR) to address issues of the use of dietary supplements by U.S. military personnel. One of the concerns raised was soldiers’ excessive use of vita- mins. Greenwood and Oria (2008) reported that eight sur- veys of military personnel depicted a high use of dietary supplements (as high as 60% of respondents in one survey reported using at least one supplement), especially vitamins and minerals, but also other supplements as well. Vitamins and minerals were used by about 45% of service members on active duty. Other popular dietary supplements in use were bodybuilding supplements (21%) and weight-loss products (18%). A call for similar survey data concerning the use of supplemental vitamins among commercial drivers may be warranted. Among the numerous claimed benefits of taking multi- vitamins are: reduced depression, enhanced positive mental attitude (B-complex vitamin mixtures), enhanced physical endurance (B-complex vitamin mixtures), improved recovery from high-intensity activity (Williams 1989; Clarkson 1995), and maintenance of immunocompetence (mostly through antioxidants). There is some evidence for the potential of vitamins to contribute to reduction of depression and there- fore promoting a more positive mental attitude (e.g., from cobalamin) (Applegate and Grivetti 1997). Most likely any effect of taking many of the supplemental vitamins is mediated through correction of subclinical deficiencies in the body, helping to enact corrections in vitamin deficiencies, wherein a person is/was already experiencing a shortfall of the body’s required vitamins or enhancing energy release from meta- bolic fuels. Balk et al. (2007) provided an extensive review of supple- ments of vitamins B-6, B-12, and folic acid, and concluded that the few available randomized controlled trials of the three supplements, alone or in combinations, do not provide adequate evidence for a beneficial effect of supplementation on cognitive function testing in people with either normal or impaired cognition. Although they may not be so clearly beneficial, chronic supplementation with low levels of vita- mins (of the order of the RDA) is almost certainly without 88 untoward effects. However, in general, the effectiveness of taking multivitamins is unresolved. Even the duration of supplemental vitamin effects is not so clear. In the cases of the B group vitamins and vitamin C, because excess water-soluble vitamins are excreted if not needed, any ergogenic effect may be only transient, persisting for hours rather than days following cessation of supplementation. Much of the sup- plemental vitamin compounds consumed are believed to just be sloughed off by the body’s normal digestive processes. Taking a multivitamin does not make up for a diet lacking in nutrients. Taking multivitamins, like other dietary sup- plements, is meant to be a part of an overall healthy lifestyle (Neuhouser et al. 2009). Assessment of Multivitamins. Ensuring that the body takes in adequate levels of vitamins and minerals is important in maintaining good health. The recommended way to do that certainly begins with following a good nutritional diet plan, something many commercial drivers have difficulty meeting (Roberts and York 2000; Krueger and Brewster 2002). Taking supplemental vitamins and minerals has not been sufficiently demonstrated to enhance either cognitive or physical perfor- mance as much as the technique may simply meet the body’s needs not being met through good food nutrition intake. More research may be called for on the possible ergogenic effects of megadoses of B-complex vitamin mixtures, and on the potential of antioxidants to speed recovery from stressful expenditures of physical energy. ANTIOXIDANTS TO FIGHT FATIGUE Antioxidant supplements are meant to produce a reduction in free radical production, especially during exercise (Bucci 1993). Most antioxidants reduce lipid peroxidation. Vitamin C, for example, is thought to act in combination with glutathione to protect cellular membranes from oxygen radicals attach- ing at the surface of the membrane. Ingesting antioxidant vitamins C and E increases plasma concentration, but does not necessarily increase the total plasma antioxidant capac- ity. Although somewhat controversial, it has been argued that increasing antioxidant defense attenuates loss of muscle func- tion associated with stiffness and soreness of untrained mus- cles that have been vigorously exercised. In terms of antioxidants reducing oxidative stress and providing any cognitive benefits, some studies of middle-aged and elderly volunteers reported positive effects of antioxidant supplementation on performance during cognitive tests; how- ever, these have not been replicated. The effects are not very likely to be found for normal younger individuals, especially with acute treatment. Although beta-carotene is a powerful antioxidant, its effects on physical performance have not been adequately studied or reported. The antioxidant quercetin, a naturally occurring flavonoid found in a variety of plant products, including

89 blueberry, red onion and red apple skins, and kale, is reported to have antioxidant and free radical-scavenging properties that may enhance physical and cognitive performance, as well as some health and immunity benefits. Recent nutritional supplement advertising over the Internet, by a commercial vendor, employs one of the world’s best known athletes (cyclist Lance Armstrong) to promote benefits of quercetin as allegedly being able to assist in fighting fatigue (without really addressing what is meant by fatigue). The vendor adver- tises quercetin in a nutritional liquid beverage and in a candy chew format. The advertising infers that U.S. Department of Defense (DoD) testing substantiated claims that products with quercetin in them help individuals fight fatigue. Indeed, DoD-sponsored physical and physiological experiments were conducted in university and military research labs to examine quercetin effects. However, the advantages of quercetin to date (Nieman et al. 2007, 2009) have largely been in protecting endurance athletes (Olympic-type cyclists, marathon runners, etc.) from the onset of upper respiratory infection (URI) after completing their endurance events. U.S. Army biomedical researchers have been examining quercetin for possible applications of inserting it as an additive to food and field rations for soldiers and marines. However, a September 2008 blue ribbon nutrition research panel indi- cated that research has not fully established significant bene- fits of quercetin regarding cognitive performance or fatigue. Although quercetin is in an “interesting phase of nutritional development,” and shows some potential, the evidence sup- porting its positive effects has not been solid enough to merit incorporation of quercetin as a ration component (Army Nutritional Science review, AIBS 2008). Assessment of Antioxidants to Fight Fatigue. One of the principal reasons for reporting about quercetin here is that medical scientists, both within the DoD and as outside nutri- tional science reviewers, express concerns about the willing- ness of commercial vendors to overstate beneficial claims to nutritional supplements in their advertising, particularly over the Internet. It seems particularly egregious to attribute scientific support from DoD testing when those claims are overstated. Internet caution: Much of what is advertised on the Internet has not been properly vetted for its veracity. ANABOLIC STEROIDS Androgenic anabolic steroids are analogs of testosterone used to promote gains in muscular strength and physical and muscular endurance. They are called anabolic because they increase protein synthesis through interaction with specific receptors in various tissues (Friedl 2002a, b). Androgens, dehydroepiandrosterone (DHEA) and androstenedione, the so-called sex steroids, are produced in the ovaries and adrenals for females, and in the testes and adrenals for males. There are no distinctly “male” or “female” hormones, but rather general differences in concentrations between genders. The ovaries are the primary source of estradiol and luteal phase progesterone. The adrenals are the chief source of DHEA and its sulfate ester DHEA-S. The ovaries and adrenals are the main source of androstenedione and testosterone. Male testes pro- duce testosterone (McArdle et al. 1991). As a multi-functional steroid, DHEA has been implicated in a broad range of bio- logical effects in humans and other mammals. Together with DHEA-S, it is the most abundant steroid in humans. In the United States, DHEA, sold increasingly as a food supplement, has been popular with longevists and especially among body builders who take supplemental DHEA for muscle building, or by other athletes who take it as a performance enhancer. The mode of action is an increase in protein syn- thesis, inhibition of catabolic effects of glucocorticoids, and some effects on the CNS. It is difficult to determine an opti- mal dose for DHEA as there is wide variation in individual response. Most people who take DHEA report using a dose of 50 to 100 mg per day, usually cycled two weeks on DHEA and then one week off. Strength athletes often use DHEA in conjunction with anabolic/androgenic steroids, or immedi- ately following a steroid cycle, to combat the steroid-induced reduction in endogenous testosterone production. Some studies show this to be effective for increasing lean body muscle size (mass), total testosterone, and improving muscle strength (Bowers 1999). To achieve the intended effects, chronic use over several weeks is required, combined with appropriate nutrition and physical training. In the presence of an adequate diet, anabolic/androgenic steroids can contribute to increases in body weight, often in lean mass (American College of Sports Medicine 1984). It is claimed that DHEA promotes or enhances mood and well-being (Drake et al. 2000; Alhaj et al. 2006). However, cognitive and mental effects with steroids may be detrimental, as for example high levels of methyltestosterone (40 mg/day) have shown cognitive impairment (Su et al. 1993). Additionally, there is evidence that mood and behavioral disturbances can occur (Williamson and Young 1992). Arlt et al. (2000) indicated anecdotal reports of enhanced sexual drive, partic- ularly among female users, and that DHEA also increased androstenedione levels. Wolf et al. (1997) and Wolf and Kirschbaum (2002) reported increased androstenedione levels with DHEA supplementation and no cognitive performance enhancement in older men and women. A new Steroid Control Act in the United States effectively placed androstenedione under Schedule III of controlled substances beginning in January 2005. However, DHEA was not included in this act. In the United States, both DHEA and DHEA-S are readily available as over-the-counter nutritional supplements and have been advertised with claims that they may be beneficial for a wide variety of ailments (Calfee and Fadale 2006). Assessment of Steroids. It appears that DHEA offers no demonstrated cognitive performance advantages. More

research is needed on DHEA to determine if its use is safe and whether or not it actually improves athletic or physical performance. HYDRATION WITH WATER Water is an absolutely essential nutrient with proven benefits to the body. Body fluid balance is maintained by signals from the hypothalamus, pituitary, and kidneys signaling thirst in response to dehydration or the production of urine in response to over-hydration. When workers or exercisers expend physical energy in hot environments, particularly hot-humid environ- ments, there is always a concern that they do not become dehydrated. In addition to the normal loss of bodily fluids, sweat rates are noticeably higher in hot-humid environments, leading to a quicker loss of body water. In a few hours of intense exercise in the heat, water loss or dehydration can reach proportions that impede body heat dissipation and severely compromise cardiovascular function and work capacity. For an acclimatized person, water loss by sweating may reach a peak of about 3 liters per hour during very strenuous work, especially in the heat, and may average nearly 12 liters (about 26 lb) on a daily basis. As dehydration gradually progresses and plasma volume drops, sweating is reduced and thermoregulation becomes progressively more difficult (McArdle et al. 1991). Maintaining a normal body water level (euhydration) delays psychological strain resulting from such environmental stressors as heat. A body water deficit of 3% to 4% of body weight will reduce sweat rates, elevate heart rate, and increase core body temperature as it is related to a reduction in both sweating and blood flow to the skin. For each 1% decrease in body weight attributable to dehydration, the heart rate increases four beats/min, core temperature increases by 0.15°C, and mean sweat rate decreases by 29 g/h. When water loss reaches 4% to 5% of body mass a definite impairment is noted in physi- cal work capacity (McArdle 1991). These effects also com- bine to reduce the capacity of the brain to carry out cognitive functions. Gopinathan et al. (1988) found that dehydrated subjects demonstrated significant and progressive reductions in the performance of arithmetic ability, short-term memory, and visuomotor tracking at 2% or more body fluid deficit compared with the euhydrated state. That is, if an individual is 2% dehydrated, cognitive and physical performance may both be degraded, and significant impairments in performance occur as water loss continues past 4%. The primary aim of fluid replacement is to maintain plasma volume so that circulation and sweating can progress at opti- mal levels (McArdle et al. 1991). The most effective defense against heat stress is adequate hydration. Physiologists, who champion proper water balance in the body, claim that the subtle cognitive benefits of proper hydration include good states of vigilance, alertness, memory, and problem solving. The benefits to performance continue while a state of euhydration is maintained. 90 Maintaining proper hydration (euhydration) is very impor- tant for commercial drivers, particularly truck drivers who engage in significant physical tasks including loading and unloading of freight, coupling trailers, and securing loads. Dehydration becomes a common circumstance while doing physical labor during late summer months in some geographic locations (e.g., the southeastern United States) where the ambient environment is not only hot, but accompanied by high humidity (∼ >80%). Three to four hours of physical labor (e.g., loading or unloading one’s truck) in such an environment can dehydrate a driver, and make him or her more fatigued and less alert when the driver resumes driving (Krueger and Van Hemel 2001). Adhering to a proper hydration schedule in such circumstances is important, and having a regular drinking plan to replenish lost body fluids is advised. The U.S. Army Research Institute of Environmental Medicine’s (USARIEM) physiological research programs clearly demonstrate the best replacement for lost bodily fluids (hypohydration) is to regu- larly drink plain water. Along with national trends, many commercial drivers now consume large quantities of bottled water, which seems inher- ently preferable to drinking numerous sugar-laden soft drinks containing caffeine and other substances. Some bottled waters contain small quantities of sodium, and if the water source is from springs, they may contain traces of minerals. Com- mercially bottled water does not provide the small quantities of fluoride that municipal tap water provides us. This may be a concern to those prone to teeth cavities. In some locales, caffeine-laced bottled water is readily available at truck rest stops and fast food stores. If hyperhydration (too much body water) occurs, it is likely more attributable to the consumption of too many drinks (e.g., water, coffee, and soft drinks) while driving. An obvious effect here is a need to urinate more frequently. Monitoring urine coloration is important for ensuring proper hydration levels and kidney functioning. The U.S. military’s preventive medicine guidance advocates that soldiers in field operations periodically take notice of the coloration of their expended urine as a check for proper hydration and kidney function- ing. Urine which is repeatedly “too yellowed” is usually an indication of dehydration or improper kidney functioning (USA CHPPM and USARIEM regularly published preventive medicine guidance for military personnel). The surveyed literature did not reveal whether the effects of commercial drivers not stopping frequently enough to perform this function has been assessed or reported. Good health and wellness practices dictate that commercial drivers maintain a proper level of euhydration by monitoring the amount of fluids (preferably water) they consume and elimi- nate (Krueger and Brewster 2002). Assessment of Hydration. An abundance of significant physiological research has demonstrated the importance of maintaining good hydration levels (euhydration) in the body at all times (McArdle et al. 1991; Krueger 1993; USA CHPPM

91 and USARIEM, annually). Commercial drivers must be attuned to their hydration state, and they should follow a drinking plan to replace bodily losses of liquid through sweat, especially when doing strenuous work in hot, humid environments. Adequate levels of hydration can be maintained by drinking copious amounts of simple, clean drinking water. FLAVORED VITAMIN WATERS Beverage dealers now are marketing nutrient-laced, flavored drinks such as “vitamin water” products. The approach is to provide a vitamin-filled, lower-calorie specialized bever- age advertised as being more healthful than the traditional ubiquitous colored and flavored soft drink sodas. Critics charge some of these more expensive premium “healthy” beverages have a lot of calories (albeit fewer than contained in soda soft drinks), but there is a lack of compelling evidence to back up suggestions that the products are actually good for consumers. There is little in the way of published research to suggest products such as Coca Cola’s Glaceau Vitamin Water™ are a good way for the body to absorb vitamins. From another point of view, it is arguable whether or not the nutritional possibilities of Vitamin Water™ constitute a large part of its popular appeal. Many consumers who purchase these newer products indicated that they are not overly concerned with assimilation of the vitamins, but simply drink Vitamin Water™ because they like its taste or that the drinks sound or appear to be more nutritious and less artificial than other sodas. Presumably, some people who drink these beverages may be drinking them in lieu of taking supplemental vitamins. ELECTROLYTE REPLACEMENT DRINKS These drinks, such as Gatorade®, are designed to replace the necessary electrolyte elements lost through perspiration. Such drinks are most effective when taken near the middle or at the end of lengthy exercise or endurance events such as running a marathon, because they can help maintain the balance of electrolytes in the body and restore homeostasis. For short exercise workouts, water will do just as well to replace lost body fluids, and water is much less expensive (physiologists at U.S. Army Research Institute of Environ- mental Medicine, Natick, Massachusetts: G. P. Krueger, per- sonal communication, Nov. 2010). WEIGHT LOSS DIETARY SUBSTANCES Nutritionists, dieticians, and weight-loss experts advocate following healthy approaches to losing weight. In a preface to addressing supplemental dietary pills here, it warrants men- tioning again. “There is no magic bullet for losing weight. The most effective way to lose weight and keep it off is through lifestyle changes. Eat healthy, low-calorie foods, watch portion sizes, and engage in regular physical activity. It is no magic pill, but it works” [www.MayoClinic.com (2010)]. Literally hundreds of weight-loss products (diet pills, powders, and liquids) are available in the commercial market place; obtainable in grocery stores, drugstores, health food stores; or advertised for sale in magazines and on the Internet. Advertising and sales outlets tout a confusing array of ingredients as being helpful for losing weight. Many people have experimented with different weight-loss supplements in search of something that appears to work for them. That time- consuming search engages people in much trial and error, is usually expensive and frustrating, and can even be dangerous to one’s health. Many providers of various products (diet pills, fat burn- ers, etc.) attempt to inform consumers with useful informa- tion about: (a) efficacy—do the products work?, (b) safety, (c) information supplied by the FDA about the products, (d) the reputation of the company advertising the product, (e) guaran- tees and return policies, and (f) price and value. Most weight- loss products are touted to have significant physical effects on the body, but usually not much is written about whether or not the particular product(s) have an impact on cognition or on cognitive performance—one of the principal foci of this synthesis. It is a challenge for consumers to determine which pub- lic information sources are credible or offer veracity in the descriptions or reports provided about diet pills (or other supplements) meant to assist in losing weight. It is difficult to determine whether or not a particular dietary product will be useful and whether or not it is good for the individual. Credible information sources can be found on the FDA website: http://www.fda.gov/cder/consumerinfo/weight_loss_ products.htm or the Internet sites of reputable medical centers, such as the one on “Tools for Healthier Lives” on the website of the MayoClinic (see: www.MayoClinic.com, and click on weight loss). There are many other seemingly credible infor- mation sources, such as Dr. C. Everett Koop’s Web MD site (www.webmd.com). Assessment of Dietary Weight-Loss Products. There are literally hundreds of different dietary weight-loss products in the public marketplace. Because no credible scientific studies on the general class of dietary supplements are cited in this synthesis, it would be inappropriate to offer significant com- mentary on their efficacy for either weight-loss purposes or for sustaining or enhancing performance (physical or cognitive). Additional caution and fat burners. For the consumer it is difficult to know what the contents are of the actual product one acquires, or even if the list of ingredients for a purchased item matches what actually is contained in the bottle. Many weight-loss pills contain a cocktail of ingredients, some with more than 20 herbs, botanicals, vitamins, minerals, or other add-ons, such as caffeine or laxatives. Just how these ingredients interact indi- vidually and collectively with people’s bodies is largely unknown; and using them can be a risky venture, espe- cially if a person is taking other medications as well [www.MayoClinic.com (2010)].

In this synthesis, the point has been made several times that dietary supplements, and therefore weight-loss aids too, are not subject to the same rigorous standards as are prescription drugs or medications sold over-the- counter with FDA approval. Weight-loss products are marketed while demonstrating only limited proof of effectiveness or safety. Without the authorization of the FDA, vendors can and do make health claims about products based on their own review and interpretation of their own research or by citing the research of out- side organizations. If a product is proven to be danger- ous, the FDA can announce it is “pulling a product off the market.” However, such rare FDA action does not always bring about complete withdrawal of the product from the market place, and FDA actions appear to have minimal impact on what products continue to be adver- tised from overseas sources available over the Internet. There is a class of diet pills that offer promise of quick weight loss that warrant special attention here. It can be said that “fat burners” (fast promise weight- loss diet pills) do at least two things. They act on the hypothalamus, the region of the brain that helps regu- late appetite. They also cause release of certain brain chemicals that trigger the body’s stress mechanisms (fight or flight response)—in effect, encouraging the body to burn extra calories to be able to respond to a physical or emotional threat. To stay ready for the attack that never comes, the body keeps burning calories even when the body is at rest. Previously, fat burners generally contained ephedrine, caffeine, and aspirin as their active ingredients. Beginning in 2004, after the FDA banned the use of ephedrine in diet pills in the United States, some manufacturers began using herbal ephedra or Ma huang. Others used citrus aurantium (CA) from mandarin oranges and green tea extract (GTE) (see: www.weightlossforall.com). A sampling of popularly sold fat burners available as over-the-counter-weight-loss-pills, or on the Internet lists caffeine as a main ingredient as it is found in green tea extract. They also contain CA, ginkgo biloba, and Siberian ginseng. Other fast track weight-loss products also list as contents: Guarana, hoodia, HCA theanine (an amino acid in green tea), bitter orange (an “ephedra substitute”), and many other herbs. On its popular website, www.MayoClinic.com (2010), the Mayo Clinic lists 9 to 10 different ingredients commonly found in popular weight-loss pills, along with helpful commen- tary to inform the public about the efficaciousness and potential hazards of each substance. People with intentions of using such crash weight-loss products would do well to consult the Mayo Clinic’s cautions. On its website in January 2009, the FDA provided updated information to augment the “warning announcements” it made in December 2008 informing the public that the FDA had recently identified nearly 30 weight-loss, “natural fat buster” products, each of which may contain unlisted and possibly dangerous ingredients such as sibutramine, a powerful Schedule IV controlled substance anti-obesity prescription drug, as well as a laxative drug (phenolphthalein) suspected as a carcinogen. The FDA identified other substances found in such dietary pills; but indicated none of the offending chemicals were listed as contents on the products. Additionally, according to the FDA, some of the products originating in Asia, but which are being marketed in the United States as dietary supplements are of concern because they contain potentially harm- ful contaminants. [Source: www.fda.gov weight-loss products]. For the latest FDA Consumer information announcements about drugs and supplements in the marketplace, consult the FDA website at: http://www. fda.gov/cder/consumerinfo/DPAdefault.htm. 92