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27 CHAPTER FOUR STIMULANTS AND ALERTNESS-ENHANCING COMPOUNDS INTRODUCTION TO STIMULANTS AND Wake-promoting medications fall into three chemical ALERTNESS-ENHANCING COMPOUNDS classes: (1) direct-acting sympathomimetics, such as the alpha-adrenergic agonist phenylephrine; (2) indirect-acting Many commercial drivers put in long hours of driving on a sympathomimetics, such as amphetamines, methylpheni- daily basis (11 h permitted out of a 14-h work day). Their date (e.g., Ritalin), mazindol, and pemoline; and (3) the "non- situation presents a particularly acute safety concern in that stimulants" that are not sympathomimetics, which have they might develop driver fatigue during long drives common different mechanisms of action, such as modafinil and caffeine in over-the-road operations. Drivers in short-haul operations (Mitler and O'Malley 2005). The pharmacology of sympatho- may alternate lengthy duty periods, waiting to pick up or mimetics is reviewed by Nishino and Mignot (2005). deliver loads locally, or make multiple revenue run deliveries stretching their duty day. In this synthesis the safety concern Prescription Stimulants and Amphetamines turns attention to the possibility of some commercial drivers using wake-promoting compounds (stimulants) in their Introduction attempts to maintain alertness and to sustain or enhance driving performance. Discussion focuses on stimulating and The most potent stimulant of natural origin, cocaine, has wake-promoting compounds often mentioned in the com- medicinal uses; however, for the most part, its current use mercial driving community and devotes special attention to is illicit. Research literature on cocaine and on marijuana the effects on driving safety. (cannabis, another substance illegal in many jurisdictions) and their effects on driving performance are briefly described Caveat. A word of caution, although some of the together in Appendix A to this synthesis report. Legitimate pre- advantages and disadvantages of medical management scription stimulants include amphetamines, methylphenidate, of prescription stimulant use are described, it is not the intent to suggest that stimulants of any type can be and others. Although there is a vast literature documenting a replacement for commercial drivers adhering to a research on most stimulants, the concern here is to describe personal good sleep management program. Obtaining those stimulants that hold some potential for practical use as a sufficient quantity of quality sleep on a daily basis is alertness-enhancing compounds in transportation operations. the most conducive way to maintain alertness and to For interested readers, a considerable number of such literature manage driver fatigue. Sleep also is an important key to maintaining overall good health (Krueger 1989; citations involving research on stimulants and performance are Krueger et al. 2007a, b). listed in the web-only Appendix E (Bibliography). Amphetamine, Dextroamphetamine, STIMULANTS AND ALERTNESS-ENHANCING and Methamphetamine COMPOUNDS Amphetamines and related compounds may be prescribed to A variety of "wake-promoting" chemical compounds, referred treat some medical conditions. Medical uses for amphetamines to as stimulants, include not only those in the Schedule II drug include the treatment of narcolepsy, attention deficit/ADHD, category, such as amphetamine-like compounds, but also and treatment-resistant depression. include the two most common and less threatening stimulants: caffeine and nicotine. Some stimulant drugs have a role in the Amphetamines (with common street names such as clinical treatment of conditions such as excessive sleepiness uppers or speed) once were available over the counter. The attributable to sleep disorders (e.g., narcolepsy), ADHD, and three most common stimulant drugs amphetamine, dextro- depression (Mitler and O'Malley 2005; Kay et al. 2009). amphetamine, and methamphetamine are similar in their Because their pharmacologic profiles are diverse, clinicians effects. In years past, many segments of the population, guide the selection of stimulating agents based on a variety especially workers with extensive or irregular work hours, of factors, including time of onset, length of activity, degree of took amphetamines orally, often in excessive amounts. As with tolerance in chronic use, side effects expected, abuse liability, all stimulants, amphetamines can produce dependence and and, importantly, a knowledge of whether and how the use of therefore as their use became commonplace they became iden- such medication might affect a person's job performance. tified as having a high abuse potential. A prescribed dose of

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28 amphetamines for medical treatments has often been between tantly for our purposes here modafinil, adrafinil, and possibly 2.5 and 15 mg per day. Repeated drug users on a "speed binge" armodafinil would appear to have some application for com- have been known to inject hundreds of times those amounts mercial drivers in maintaining alertness, even while driving. every 2 to 3 h (Davis 1996). OTC availability of such amphet- amines was stopped in the United States in 1971 by the In the United States, modafinil is classified as a stimulant, Controlled Substances Act when they became Schedule II and as a nonnarcotic Schedule IV controlled substance. The drugs, and they are now legally obtainable only by prescription use of modafinil therefore requires a prescription. Modafinil is (Hart and Wallace 1975). However, illegal clandestine labo- available under the trade names ProVigil, Vigil, Alertec, ratories produce large amounts of amphetamines, particularly Modiodal, and Modasomil. As with other stimulants, methamphetamines, for illegal distribution. The abuse potential modafinil increases the release of monoamines, but also elevates of amphetamines has also led to a reduction in prescription hypothalamic histamine levels, leading some researchers to issuance by physicians. consider modafinil a "wakefulness promoting agent" rather than a classic amphetamine-like stimulant. Lagarde and Military forces of several countries have expended con- Batejat (1995) described modafinil as a "eugregoric," meaning siderable research effort in medical research labs examining "good arousal" (Lagarde et al. 1995). This unique class of the potential for the use of amphetamines in operational eugregoric compounds contains only modafinil, its chemical applications. For the sake of completeness in this synthesis a precursor adrafinil (Milgram et al. 1999), and armodafinil, all limited amount of the performance research done with several three of which were developed as "wake promoting agents" of the more prominent stimulants and amphetamines is briefly to improve wakefulness. They are sometimes referred to as described in Appendixes A and B. Appendix B also lists somnolytics (Mitler and O'Malley 2005). details of the U.S. military's drug management protocol adhered to in the use of stimulants in operations and training. As the primary metabolite of adrafinil, modafinil's activity is similar; however, adrafinil requires a higher dose to achieve Amphetamine assessment. The use of many stimulants equipotent effects. The basis of modafinil's uniqueness lies in such as amphetamines (with the exception of caffeine, nico- its ability to stimulate only when stimulation is required; as a tine, and perhaps modafinil/armodafinil) in any operational result, the "highs and lows" associated with other stimulants environment is inherently risky. [See for example the treatise such as amphetamines are absent with eugregorics. The lows on methamphetamine and driving behavior risks by Logan are sometimes referred to as "recovery sleep" and modafinil, (1996, 2002).] Whereas use of amphetamines is not likely to unlike amphetamines, is said not to produce the need for this become acceptable operational practice for ameliorating the prolonged recovery, or "rebound hypersomnia." A totally effects of sleep loss or drowsy driving in drivers of commercial unique feature of modafinil and adrafinil therefore is that a vehicles, urine drug testing and post-crash forensic analyses person wishing to remain awake can use either of them to do indicate that some commercial drivers do partake of amphet- so with a far greater level of alertness, but at the same time the amines and other stimulants not usually recommended with compounds will not prevent the person from sleeping if he or intentions of driving. she wants to (Buguet et al. 1995; Grady et al. 2010). Modafinil Modafinil is thought to have less potential for abuse than other stimulants owing to the absence of any significant Modafinil (ProVigil), chemical name 2-diphenylmethyl- euphoric or pleasurable effects; therefore, it is thought to be sulfinyl-acetamide, is a chemically unique, stimulant-like nonaddictive. The central stimulating effect of modafinil shows compound that was developed in France in the 1970s80s dose and time-related features (McClellan and Spencer 1998; (Nishino and Mignot 2005). Modafinil is a primary metabo- Nishino and Mignot 2005). Prescription single-dose levels of lite of adrafinil (Olmifon), a mild CNS-stimulant drug used modafinil are normally between 100 and 400 mg taken orally. in Europe to relieve excessive sleepiness and as a vigilance- Based on their studies, Buguet et al. (2003) recommended promoting compound. Adrafinil is a prodrug, primarily metab- 200 mg of modafinil for use in sustained operations. As with olized in vivo to modafinil, resulting in nearly identical phar- some other studies, they demonstrated that the 400-mg dose macological effects; however, it has not been approved for has not been shown to be more effective than a 200-mg dose. use in the United States. In 2004, modafinil (as Provigil) was Modafinil achieves maximum levels in the blood between approved by the FDA for treatment of narcolepsy, for SWSD, 2 to 4 h after administration, and its half-life ranges from and for persistent and excessive daytime sleepiness associ- approximately 10 to 15 h (Robertson and Hillreigel 2003). ated with effectively treated obstructive sleep apnea. In some Modafinil exhibits maximum vigilance-enhancing properties, countries, modafinil is approved for idiopathic hypersomnia peaking 4 h after a dose of 200 mg. A participant can re-dose (all forms of excessive daytime sleepiness where causes with 100 to 200 mg every 4 to 6 h. Occasional side effects cannot be established). In June 2007, the FDA also approved such as headache can occur with 300 mg/day doses; and at of a related compound: armodafinil (Nuvigil) as a stimulant- higher doses (>800 mg) increased blood pressure and increased like drug for the treatment of narcolepsy and SWSD, and as supine pulse, increased urination, palpitation, tachycardia, an adjunctive treatment for obstructive sleep apnea. Impor- excitation, and aggressive tendencies may occur. There also

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29 have been some reports of modafinil-inducing skin rashes; a (Lagarde and Batejat 1995; Lagarde et al. 1995; Batejat and small number of them severe enough to require hospitalization. Lagarde 1999), who found that 200-mg doses of modafinil every 8 h reduced episodes of microsleep and maintained more Since the mid-1980s, numerous clinical trials and studies normal (i.e., rested) mental states and performance levels confirmed the ability of modafinil and adrafinil to increase (measured through questionnaires, visual scales, and sleep awakeness and alertness without the serious side effects of latency tests) than placebo for 44 h of continuous wakefulness dependency. Studies during sleep deprivation found modafinil (but not for a full 60 h of sleep deprivation). The modafinil to be as effective as amphetamines and large doses of caffeine participants sustained a satisfactory level of vigilance with for maintaining vigilance, alertness, and cognitive performance an absence of sleep episodes, unlike the placebo group that with only minor side effects (Lagarde and Batejat 1995; gradually declined and slipped into microsleep episodes as Lagarde et al. 1995; Pigeau et al. 1995; Akerstedt and Ficca one might expect when remaining awake for longer than 24 h. 1997; Baranski and Pigeau 1997; Baranski et al. 1998, 2004; Batejat and Lagarde 1999; Wesensten et al. 2002, 2004; Since that time, military forces in France, the United Caldwell et al. 2004; Caldwell and Caldwell 2005). Walsh Kingdom, and the United States have shown a particular et al. (2004) demonstrated that the physiologic sleepiness interest in modafinil as an alternative for amphetamine-- and neurobehavioral deficits that occur during a typical night the drug traditionally employed in combat situations where shift can be attenuated by modafinil. For them, 200 mg of troops face sleep deprivation during lengthy missions. Their modafinil also had beneficial effects on some measures of respective medical research labs have done experiments on executive function (e.g., optimal telegram test involving verbal potential operational applications for modafinil. These studies creative thinking, card sorting, and number sequencing). showed that modafinil reduces degradation of cognitive perfor- mance, enhances vigilance, and promotes alertness and arousal Mitler and O'Malley (2005) described the research of the during extended or sustained operations. It was claimed that U.S. Modafinil in Shift Work Sleep Disorder Study Group, modafinil "could keep an army on its feet and fighting for three with its concern for shift workers who, like many commercial days and nights with no major side-effects" (TTCP 2001). drivers, suffer at least transiently from effects of both sleep deprivation and circadian misalignment. A Harvard Medical Caldwell and colleagues (2000) found that 200 mg of School project enacted a double-blind, placebo-controlled, modafinil every 4 h maintained simulator flight performance 3-month study of more than 200 night-shift workers (Czeisler of military helicopter pilots at or near well-rested levels et al. 2005). At baseline, the shift workers were pathologically despite 40 h of continuous wakefulness; however, there were sleepy, as their Multiple Sleep Latency Test (MSLT) fall some complaints of nausea and vertigo (attributed to the high asleep times were approximately 2 minutes, they demonstrated dose of modafinil used). In a subsequent flight simulator study significant cognitive impairment (slower reaction times mea- with U.S. Air Force F-117 fighter jet pilots, three 100-mg sured by a psychomotor vigilance task), and they exhibited doses of modafinil, administered every 5 h, sustained flight numerous mistakes, near-misses, or accidents at work or while driving home after work. When workers took 200 mg of performance within 27% of baseline levels during the later modafinil at the beginning of their night shift, all of these mea- part of a 37-h period of continuous wakefulness. Similar sures improved substantially. Furthermore, this treatment did beneficial effects were seen on measures of alertness and not interfere with their ability to sleep during time off duty cognitive performance (Caldwell et al. 2004, 2009). Further- (Czeisler et al. 2005). more, the lower dose of modafinil (100 mg) produced these positive effects without causing the side effects noted in the On the basis of this and other evidence, the FDA, in 2004, earlier study (Caldwell et al. 2000, 2009). approved modafinil for treatment of excessive sleepiness resulting from SWSD. Together with a program of non- Caldwell and Caldwell (2005) and Caldwell et al. (2009) pharmacologic measures to protect sleep time and sleep ability suggested that because these and similar studies found such in this shiftwork population, this represents a potentially life- positive results with modafinil, the eugregoric compound is saving treatment for these adults (Mitler and O'Malley 2005). gaining popularity in military communities as a way to enhance Subsequently, in June 2005, armodafinil (Nuvigil) was also the alertness of sleepy personnel. Modafinil is considered approved by the FDA for treatment of SWSD. This research safer and less addictive than the amphetamines; it produces less with modafinil and the subsequent FDA approval of its use for cardiovascular stimulation, has lower potential to exacerbate SWSD present distinct implications for practical applications hypertension and cardiac arrhythmias than amphetamine; and, as a fatigue countermeasure for commercial drivers whose despite its half-life of approximately 12 to 15 h, the drug's shift-work schedules often are "nonstandard." Additional impact on sleep architecture is minimal. Alternatively, other research is needed to determine appropriate protocols for the experimental data suggest that modafinil is less effective than use of modafinil and/or armodafinil as potential alertness and amphetamine (Mitler and Aldrich 2000). fatigue management countermeasures for commercial drivers. At the Walter Reed Army Institute of Research, Wesensten The first important study employing modafinil as a stimulant et al. (2002) tested modafinil in 50 healthy adults to determine in humans was done by French military medical researchers whether it should replace caffeine for restoring performance

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30 and alertness during 48 h of total sleep deprivation. They (as an adjunct for treatment of the underlying obstruction), reported that performance and alertness were significantly and SWSD. Bittencourt et al. (2008) reported on a placebo- improved by modafinil at 200 and 400 mg relative to placebo, controlled study employing modafinil with confirmed obstruc- and effects were comparable to those obtained with 600 mg tive sleep apnea patients who also were on effective contin- of caffeine. There was a trend toward better performance at uous positive airway pressure (CPAP) treatment. The study higher modafinil doses, suggesting a dose-dependent effect, but found that modafinil, used adjunctively with CPAP, reduced the differences between modafinil doses were not significant. daytime subjective sleepiness in obstructive sleep apnea Performance-enhancing effects were especially salient during patients who regularly use CPAP. Although participants still the time frame of 6 a.m. through 10 a.m. They concluded experienced some sleepiness, modafinil helped improve objec- that, as with caffeine, modafinil maintained performance and tive measures of behavioral alertness and reduce functional alertness during the early morning hours, when the combined impairments. effects of sleep loss and the circadian performance and alert- ness trough is usually manifest. Few instances of adverse Assessment of modafinil. As laboratory research cited subjective side effects (nausea, heart pounding, etc.) were in this review indicates, modafinil offers many of the same reported (Wesensten et al. 2002). stimulant benefits as caffeine and amphetamines, but with slightly different physiological side effects, some which are less Thus, equivalent performance- and alertness-enhancing offensive, such as not being as threatening to blood pressure effects were obtained with two drugs (caffeine and modafinil) as caffeine tends to be. Several of the studies demonstrated possessing different mechanisms of action. Wesensten et al. the utility of modafinil during circadian lulls of mid-afternoon (2002) also concluded that modafinil did not offer significant and after midnight. Importantly, unlike any other stimulant advantages over caffeine (which is more readily available (including caffeine), a person taking modafinil can still decide and less expensive) for improving performance and alertness to go to sleep; that is, to "overrule the stimulating effects" during sleep loss. and be able to take a nap without interference from the "drug" (Ballas et al. 2002). That feature can offer a real boost for A later study at Walter Reed indicated that a single 400-mg commercial driving applications, and that aspect of modafinil dose of modafinil was as effective as 600 mg of caffeine or could be explored in subsequent research programs looking 20 mg of d-amphetamine for sustaining the simple psycho- for just such an application. motor and cognitive performance of sleep-deprived volunteers for 12 h post-dose (Wesensten et al. 2004a, b). In terms of Studies as those described earlier have prompted a call for efficacy alone, these Walter Reed laboratory data suggest more research to determine the level of effectiveness of using that modafinil effects are similar to those of high-dose caffeine modafinil in potential operational protocols with commercial and moderate amounts of dextroamphetamine. In a U.S. vehicle drivers. Of the "newer chemical stimulants" being Air Force 88-h sleep loss study of simulated military ground identified, modafinil (and chemically related compounds) operations, 400-mg doses of modafinil per day were mildly may offer the most significant potential as an efficacious helpful at maintaining the alertness and performance of sub- and safe chemical countermeasure to fatigue and could be jects compared with placebo; but the researchers concluded of assistance to commercial drivers (even for chronic use) that this dose was not high enough to compensate for most of in the quest for alertness management in highway driving. the effects of complete sleep loss (Whitmore et al. 2006). In particular, additional research should help to develop a suitable "usage protocol," including identification of recom- A 3-year-long study involving chronic treatment with mended dose levels, the time of day of administration, the time modafinil was conducted in Europe, where modafinil has been of administration within a work shift or during adjustments available with a prescription for more than two decades. That to shift changes, any limitations for the duration of treatment study determined that modafinil reduced drowsiness in 83% of with modafinil (e.g., weeks or months), and determination of hypersomniac patients and 71% of narcoleptics, and the pro- whether or not there are interactions with other chemical longed use of modafinil for up to 3 years did not exhibit any compounds that drivers frequently ingest, especially caffeine systematic indication of related health risks (Baranski et al. and antihistamines. 2001). Studies of modafinil that were carried on for longer than a month's duration indicated that modafinil may be effective in Caffeine appetite suppression and therefore may offer some assistance in weight loss protocols. This topic also requires substantive Caffeine (1,3,7-trimethylxanthine) and the related methylxan- research to delineate the factors associated with this variable. thines theobromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine) are alkaloid compounds widely found Because of the importance of sleep disorders in the in plants throughout the world. According to the Institute of commercial driving community, it is worth mentioning that Medicine (IOM) Committee on Military Nutrition Research modafinil and armodafinil have been used to promote wake- (IOM-CMNR 2001), more than 60 different plant species fulness in patients with excessive sleepiness associated with contain caffeine. The primary sources of these compounds narcolepsy, obstructive sleep apnea/hypopnea syndrome are coffee (Caffea arabica), kola nuts (Cola acuminate), tea

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31 (Thea sinensis), and chocolate (Coca bean). In addition to shop 16-ounce coffees may contain as much as 550 mg of appearing in omnipresent coffees, teas, chocolates, and other caffeine. Decaffeinated coffees generally have less than 10 to widely known sources caffeine is also available in alternative, 20 mg of caffeine per 8-ounce cup. convenient pharmaceutical packages of tablets or pills, from 50- to 300-mg doses (e.g., Vivarin and NoDoz), in the form Ice teas sold commercially have a range of from about of caffeinated chewing gum (e.g., StayAlertTM or Jolt Energy 6 mg to 60 mg of caffeine in a typical 8-ounce serving. The GumTM), is contained in some candies and breath mints FDA limits soft drinks to 71 mg of caffeine per 12 ounces. (e.g., HyperMintsTM or EuromintsTM), and is even available as Depending on the particular brand, many commercial soft caffeine-charged, bottled, noncarbonated natural spring clear drinks (bottle or can) in the United States contain anywhere water (e.g., Edge2-0TM) and other caffeine-charged water prod- from 45 to 125 mg of caffeine per 12-ounce drink. Most but ucts (e.g., Java Water, Aqua Java, Water JoeTM, PotenzaTM, and not all diet soft drinks are devoid of caffeine. For a compre- FYXX Hybrid WaterTM). Some truck stops sell chocolate- hensive chart of the caffeine content of popular ingestibles, covered roasted coffee beans to munch on to provide drivers including soft drinks, caffeinated waters, chocolates, and with a "special picker-upper" while driving. Also readily medications, see Mitler and O'Malley (2005) and a popular available in many grocery stores and in most highway rest Internet website listing amounts of caffeine in many beverages: stop convenience stores are numerous beverages advertised http://www.energyfiend.com/the-caffeine-database. as "energy drinks," commonly referred to as functional energy drinks (FEDs), wherein the major ingredient is caffeine, Caffeine ingested in beverages (e.g., in coffee) enters which is usually mixed with other caffeine-like chemicals the body through the digestive process, and is absorbed by (e.g., guarana) as well as other psychoactive ingredients. FEDs the stomach within 30 to 60 min after oral administration. are described separately in chapter five under supplements. Caffeine is rapidly and completely absorbed in humans, with 99% being absorbed within 45 min of ingestion. The peak Caffeine is the most widely consumed psychoactive or absorption time for caffeine received in pill or liquid form CNS stimulant in the world (Smith and Tola 1998). In occurs before 60 to 90 min. Plasma concentrations may be addition to its natural occurrence in some foods and coffee, influenced by the route and form of administration or other caffeine is used commercially as a food additive, and as a components of the diet, and the peak may range between drug or a component of many pharmaceutical preparations. 20 and 120 min after oral ingestion. Once absorbed, caffeine When administered in the amounts commonly found in foods, is distributed rapidly throughout body water. Caffeine is suf- beverages, and drugs, caffeine has measurable effects on ficiently lipophilic to pass through all biological membranes certain types of human performance. Caffeine use has been and it readily crosses the bloodbrain barrier. The mean half- associated with increased alertness and enhanced physical life of caffeine in plasma of healthy individuals is normally performance, and as a countermeasure to the effects of sleep about 3 to 5 h, although its half-life may range between 1.5 deprivation. Extensive research has been done on each of and 9.5 h. This wide variation in reported half-life may be the these effects of caffeine. Interested readers are encouraged to result of individual variation in excretion rates or whether consult IOM's excellent summary of research findings on the the individual smokes (which decreases half-life) or uses oral efficacy of caffeine use (IOM-CMNR 2001), and the book contraceptives (increases half-life). The pharmacological Caffeine by Spiller (1998). effects of caffeine (similar to those of other methylxanthines) include mild stimulation and wakefulness, the ability to Caffeine is most often ingested by drinking some of the sustain intellectual activity, and decreased reaction times most popular and ubiquitous beverages such as coffee, tea, (IOM-CMNR 2001). coca, colas, sodas, or other soft drinks that contain sizeable amounts of the stimulant. There is a wide range in the amount U.S. Army medical researchers demonstrated that caffeine of caffeine in these beverages. The amount of caffeine in a in chewing gum form (StayAlertTM), which promotes caf- cup of coffee is dependent on: (1) the source, quality, and feine absorption through saliva in the mouth, exhibits notice- quantity of coffee beans used to make the coffee; (2) the able alerting effects in approximately 7 min. Peak absorption of distributor's chemical processing techniques; (3) whether caffeine from chewing gum occurs in 30 min (Kamimori et al. the coffee is in whole-bean form or as coffee grounds; and 2002; McLellan et al. 2003, 2005a, b). This application pro- (4) the particular brewing techniques selected for its prepa- vides a much faster "picker-upper" when a person is partic- ration. In the United States, brewed cups of regular coffee ularly drowsy, but for practical reasons cannot cease work for normally contain approximately 75 to 250 mg of caffeine per a nap. Caffeinated chewing gum would appear to offer good 8-ounce cup. Popular specialized coffees served in restaurants; application potential for commercial drivers. for example, espresso, lattes, and iced coffees vary in portion size (e.g., 8, 12, or 16 ounces per cup) and therefore vary in The observable, subjective effects of caffeine last about the amount of caffeine they contain, but rarely exceed 250 to 4 h and may include a sense or feeling of experiencing 300 mg per cup. However, some espressos contain more caf- a slightly higher heart rate and elevated body temperature, feine, ranging from 10 to 90 mg of caffeine per 1-ounce serv- a noticeable perky mood, increased alertness, and signs ing, and therefore have a greater "kick" per cup. Boutique of improved cognition (i.e., reaction time and memory) and

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32 physical performance. Caffeine consumed both at rest and not subjects were tested following a period in which they had during exercise increases a variety of physiological processes abstained from using caffeine just before the test, the tasks (heart rate, respiratory rate, blood pressure), most likely used to assess cognitive behavior, the age and gender of the through the secretion of epinephrine, and includes cardio- participants, the subjects' longer term history of caffeine use, vascular, respiratory, renal, and smooth muscle effects. and whether the test subjects were rested or sleep-deprived. Caffeine has been touted as an ergogenic aid for enhancing There has been some debate about whether caffeine enhances physical performance, both aerobic and anaerobic functions, cognitive performance or simply restores degraded perfor- and muscular endurance as it increases arousal in the CNS, mance following caffeine withdrawal in rested individuals which may lead to reduced perception of the intensity of [James 1994, 1995, 1998; for further details consult the full physical effort put forth (Cole et al. 1996; Baranski et al. IOM report (IOM-CMNR 2001)]. 2001, TTCP 2001; IOM-CMNR 2001). Caffeine use is asso- ciated with a reproducible increase in endurance time in phys- As is the case with most stimulants, the body adapts or ical activities of moderate intensity and long duration. It has adjusts somewhat to the intake of caffeine, and therefore some been shown to improve pulmonary function and aerobic per- tolerance occurs with prolonged use of caffeine. Daily heavy formance, and it may also improve anaerobic performance coffee drinkers build up a degree of tolerance to the point while improving orthostatic tolerance as well. In describ- that when they want to obtain an acute "jolt" from taking in ing caffeine's effects on voluntary muscle activation, the caffeine, perhaps to temporarily restore alertness, that person Hoffman reflex, motor-evoked potentials, self-sustained firing, needs to take in a higher dose of caffeine to feel the desired pain, and sensation, Kalmar and Cafarelli (2004) suggested effects. This is why commercial drivers attending the FMCSA- that caffeine may be useful in the study of central fatigue. ATRI lectures on "mastering alertness and managing driver Caffeine's effectiveness in enhancing either physical or cog- fatigue" are told as a part of a strategy for fatigue management nitive performance dissipates within 24 h. to use caffeine sparingly most of the time, and to conserve their timing for caffeine intake until they absolutely need a boost The effects of caffeine on cognitive performance are (e.g., in the middle of the circadian lull of the mid-afternoon). diverse. Behavioral measures indicate a general improvement At that time it is recommended that drivers take in 1 to 2 cups in the efficiency of information processing after caffeine, of caffeinated coffee or beverages (O'Neill et al. 1996; Krueger whereas EEG data support the general belief that caffeine and Brewster 2002, 2005). acts as a stimulant. Studies using event-related potential mea- sures have indicated that caffeine has an effect on attention, Chronic high caffeine users, when they abruptly stop, independent of specific stimulus characteristics. Behavioral may experience symptoms of withdrawal, including fatigue, effects on response-related processes are mainly related to depression, headache, nausea, and muscle spasms; the most more peripheral motor processes. likely withdrawal symptom is a "caffeine withdrawal head- ache" (Baranski et al. 2001; TTCP 2001). The best way to Caffeine has been demonstrated to improve or enhance reduce withdrawal symptoms is to, over time, gradually lower vigilance and alertness in both rested and sleep-deprived indi- the caffeine dosage (i.e., drink less caffeinated coffee). Drink- viduals. Caffeine is shown to improve and maintain psycho- ing just another cup of caffeinated coffee usually helps dissi- motor performance and a variety of cognitive functions during pate a caffeine withdrawal headache. prolonged wakefulness (Hogervorst et al. 1999; Hindmarch 2000). Foskett et al. (2008) demonstrated that prior caffeine Some research with caffeine suggests that it can enhance ingestion improved soccer players' passing accuracy and ball performance on some types of cognitive tasks and elevate control. Military medical research labs demonstrated caffeine some aspects of mood in rested individuals independent of its to be effective during situations involving combat-like stress ability to reverse symptoms of withdrawal and regardless of (IOM-CMNR 2001; TTCP 2001). Its' effectiveness is related the background consumption of caffeine. Warburton (1995) to the dose of caffeine ingested (Baranski et al. 2001). Owing demonstrated that caffeine administered in doses of 0.75 mg to its low abuse potential and wide availability, caffeine offers and 150 mg to adult male, nonsmoking, regular caffeine users, significant utility for use in workplace fatigue countermeasures. without abstinence from caffeine before treatment, improved For example, caffeine was used successfully to sustain aircrew attention, problem solving, and delayed recall, and it signifi- alertness during flights over Iraq in support of Operation cantly improved mood ratings. Rogers et al. (1995), using Southern Watch in August 1992 (Belland and Bissell 1994). caffeine doses of 0 (placebo), 70, and 250 mg/day in caffeine users (>200 mg/day) and nonusers (<15 mg/day), demonstrated The IOM report on caffeine states that although both com- that although caffeine withdrawal had a negative effect on mon experience and the results of scientific investigations mood, it did not affect psychomotor performance. Jarvis (1993) support the belief that caffeine enhances performance on reported the results of a large survey on coffee and tea a variety of cognitive tasks, a review of the experimental consumption showing a highly significant dose-response literature reveals inconsistencies in the amount of caffeine relationship between habitual caffeine intake and psychomotor required to produce positive effects on cognitive behavior. performance, simple reaction time, choice reaction time, inci- The discrepant findings are explained by differences among dental verbal memory, and visuospatial reasoning. This report experiments in the number of variables, including whether or demonstrated that tolerance to the performance-enhancing

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33 effects of caffeine, if it occurs at all, is incomplete, with the Researchers at the Walter Reed Army Institute of Research result that higher daily caffeine consumers tend to perform compared and evaluated several stimulant compounds better than do low consumers. (including caffeine, modafinil, and dextroamphetamine) for their effects on complex cognitive processes subsumed under By employing a variety of standardized tests, caffeine's the construct of executive functions (Wesensten et al. 2005b; effects on cognitive function and mood can be detected in rested Killgore et al. 2009). Executive functions include a broad individuals, both users and nonusers of caffeine. Studies spectrum of complex higher-order cognitive abilities necessary demonstrate that 200 mg (or more) of caffeine is efficacious to plan and coordinate actions, to monitor and adjust behavior, in maintaining or returning cognitive performance to a rested and to focus attention and suppress distractions. In a double- level (Lieberman et al. 1987; Lieberman 2001). Only certain blind placebo-controlled study, Killgore et al. (2009) directly behavioral functions appear to be susceptible to the influence compared the effects of three stimulants (caffeine, modafinil, of moderate doses (32256 mg) of caffeine. In particular, in and dextroamphetamine) by examining specific aspects of well-rested individuals, low and moderate doses of caffeine executive function and working memory measured by the preferentially affect functions related to vigilance (i.e., the Tower of London (i.e., planning and visuospatial working ability to maintain alertness and appropriate responsiveness memory), Tower of Hanoi (planning, strategy, sequencing, to the external environment for sustained periods of time), but inhibition of pre-potent responses), and the Wisconsin Card have limited effects on memory and problem-solving abilities. Sorting Test (abstract concept formation, mental set shifting) Higher doses of caffeine (above 300 mg) can interfere with in individuals deprived of sleep for two consecutive nights. the performance of tasks requiring fine motor control (Durlach After being awake for 45 to 50 h, participants were tested on 1998; Rogers and Dernoncourt 1998) and may even produce computerized versions of the three tests. At the doses tested other adverse effects, especially promoting high blood pressure (caffeine 600 mg, modafinil 400 mg, or dextroamphetamine (Kamimori 2000; Baranski et al. 2001). 20 mg) the modafinil and dextroamphetamine groups com- pleted the Tower of London task in significantly fewer moves With regard to commercial drivers' use of caffeine, a than the placebo group, and the modafinil group demonstrated principal interest is its ability to assist in restoring alertness, greater deliberation before making moves. In contrast, subjects especially when a person is at least partially sleep-deprived. receiving caffeine completed the Tower of Hanoi task in Judicious use of caffeine can restore alertness, performance fewer moves than all three of the other groups, although speed on mental tasks, and positive mood states. Smith and Rubin of completion was not influenced by the stimulants. Finally, (1999) found that caffeine had a similar profile to amphet- the modafinil group outperformed all other groups on indices amines in that caffeine reversed sleep-deprivation-induced of perseverative responding and perseverative errors from the longer response times, and reduced the number of errors on a Wisconsin Card Sorting Test. Killgore et al. (2009) concluded visual vigilance task, as well as the sleep deprivation-induced that each stimulant may produce differential advantages decrements in a running memory test. Bonnet and Arand depending on the cognitive demands of the task. (1994) found that caffeine increased alertness and perfor- mance on a visual vigilance task, mental arithmetic tests, and logical reasoning in sleep-deprived subjects. Caffeine has Caffeine and Driving Performance also been demonstrated to be effective in simulated combat- like conditions. The military found caffeine to be an effective Although many studies examined either the effects of fatigue cognitive aid in rested, sleep-deprived, and stressed war- on driving or of caffeine on cognitive or psychomotor per- fighters (TTCP 2001). Research suggests that doses of caffeine formance, little attention has been paid to the interaction of between 150 and 600 mg are effective in alleviating sleep- caffeine and fatigue on driving-related skills (Gibson et al. deprivation-induced decrements in cognitive performance 2006). Studies reporting the effects of caffeine on actual (Penetar et al. 1994; Kelly et al. 1996). Caffeine is also driving performance usually involved automobile simulators effective in delaying sleep onset in sleep-deprived subjects (e.g., Heatherly et al. 2004). Several studies focused on com- (Penetar et al. 1993, 1994; Smith 1999; Bonnet 1999). parisons of caffeine to nap taking or other sleep-related variables. For example, Biggs and colleagues (2007) studied In an attempt to determine if low-dose repeated adminis- driver's perceptions of simulated driving performance after tration of caffeine would be effective in work periods requiring sleep restriction and caffeine. Whereas caffeine improved extended wakefulness, Wyatt et al. (2004) determined that measures of lane drift, the relationship between perceived and 0.3 mg of caffeine per kilogram of body weight, administered actual performance after fatigue countermeasures remained each hour for 29 h of wake episodes, is effective in countering inconclusive. In a French study, two dozen drivers took an the detrimental performance effects of sustained operations. on-the-road driving test between 2:00 a.m. and 3:30 a.m. after In the war zones of Iraq and Afghanistan, U.S. military forces being given either a placebo (decaffeinated coffee), regular have routinely been issuing caffeinated chewing gum (100 mg coffee, or were allowed to take a 30-min nap. Highway lane of caffeine per stick of gum) for just such countermeasure appli- crossings were counted as the measure of interest because cations to partial sleep loss (Kamimori et al. 2002; McLellan lane crossings are involved in many sleep-related crashes. et al. 20032004, 2005). Such a strategy could be evaluated During the 90-min drives, the decaf drinkers recorded a total for its application to commercial driving scenarios. of 159 lane crossings while drowsy (during the early morning

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34 drives), compared with just 2 lane crossings during daytime beverages, predominately updating research on coffee, tea, pretest data collection drives. Those who took naps did better and cocoa. Their collection of 40 papers is based on a March than the drivers who drank decaf, crossing lines only 84 times. 1999 symposium on the topic to specifically address anti- However, the coffee drinkers (with caffeine) did the best in oxidative phenolic compounds found in the beverages, and to the early morning drives, crossing lines a total of 27 times examine health benefits, such as the anticancer, anti-aging, (Philip et al. 2006; Sagaspe et al. 2007). and heart disease prevention properties of these beverages. Select papers in this volume also describe health benefits of In quest of suitable countermeasures to drowsy driving, "green tea" (Chen and Fong 2000; Hara 2000) and present an other researchers sought to combine techniques of napping analysis of coffee phenols and phenolic acids (Cohen 2000). and ingesting caffeine. Such is the case with car simulator research done by Horne and Reyner (1996), whose studies Assessment of caffeine. In summary, caffeine is a relatively confirm that consuming caffeinated coffee just before taking safe and effective means of maintaining or restoring cogni- a short nap (20 min) and then resuming driving may be an tive performance even under conditions of operational stress effective strategy to sustain acceptable driving performance-- (e.g., Baranski et al. 2001; IOM-CMNR 2001; Caldwell et al. a strategy that has been advocated for commercial drivers as 2009). Caffeine restores cognitive function during prolonged well, particularly in the afternoon circadian lull (G. Krueger's wakefulness and it can enhance certain types of cognitive per- fatigue and alertness courses for FMCSA and ATRI, held formance, most notably vigilance and reaction times in rested more than 100 times from 1996 to 2006). individuals regardless of whether or not they are regular caf- feine users. The doses of caffeine most likely to be effective Subsequent research by DeValck and Cluydts (2001) and without causing undesirable mood effects are within the range DeValck et al. (2003) determined that both a 300-mg dose of of 100 to 600 mg. slow-release caffeine and a 30-min nap were successful in counteracting a driver's sleepiness in a partial sleep deprivation The amounts of caffeine cited for regular soft drinks, or study. The remedial effect of slow-release caffeine lasted longer for single cups of coffee, may appear somewhat low com- than that of the nap and was also effective in afternoon sessions. pared with the doses administered in some of the laboratory They declared slow-release caffeine to be a valuable counter- experiments cited in this synthesis. However, it is often the measure, and suggested that it is preferable to even a short nap. number of caffeinated drinks consumed by a person in short duration that determines the amount of caffeine consumed Laboratory studies of similar issues, but without including a and the resultant effect on the CNS, including impact on driving component, appear to verify the utility of the combined alertness, cognitive enhancement, degree of blood pressure countermeasure techniques. Schweitzer et al. (2006) evaluated changes, nervousness experienced, and other known effects. the effects of combining naps with administration of caffeine Heavy caffeine consumers, including many commercial drivers on performance and alertness in both laboratory and field (G. P. Krueger, personal communications, 19962006), often settings. In the lab study (a parallel groups design), 68 healthy drink 10 or more cups of caffeinated coffee or 10 or more participants were assigned to 1 of 4 experimental conditions: caffeinated soft drinks (even FEDs) per day. (1) participants in one group were given an evening nap oppor- tunity before the first 2 of 4 consecutive, simulated night shifts The paucity of actual highway driving studies examining plus placebo taken all 4 nights; or (2) caffeine (4 mg/kg) taken effects of caffeine suggests that more research on this obvious nightly; (3) others got the combination of the nap and caffeine fatigue countermeasure needs to be conducted to delineate condition; and (4) the fourth group received a placebo. The lab- numerous unanswered usage protocol variables for commer- oratory study found that napping, caffeine, and their combi- cial driver alertness management and fatigue countermeasure nation all improved alertness and performance as measured programs. Questions should be addressed that identify for by Maintenance of Wakefulness Tests and by the Psychomotor commercial drivers when to use caffeine, in what doses, what Vigilance Task (PVT); however, the combination of napping format (e.g., beverages, tablets, chewing gum, and timed release and caffeine was best in improving alertness. In their field capsules), how often, and what effects should be anticipated; study, 53 shiftworkers who worked nights or rotating shifts for example, clarifying how long before preparing to sleep were permitted an evening nap on the first 2 of 4 consecutive should one refrain from its use, etc. In particular, additional night shifts plus taking caffeine nightly, versus shiftworkers research should be done on the potential for use of slow-time- who took a placebo nightly without being allowed to take naps. released caffeine capsules and on caffeinated chewing gum Napping plus caffeine improved performance as measured by applications. The studies by Horne and Reyner (1996), those of the Psychomotor Vigilance Task (faster reaction times) and DeValck and Cluydts (2001), and De Valck et al. (2003), and decreased subjective sleepiness in individuals working the the work of Schweitzer et al. (2006) suggest that additional night shift. Schweitzer et al. (2006) concluded that napping research on caffeine, particularly slow-release caffeine, in con- plus caffeine helps improve performance and alertness of junction with judicious nap taking, may lead to valuable fatigue night-shift workers. countermeasure applications for long-haul commercial drivers. Parliament et al. (2000) provided a comprehensive review of Cautions of caffeine use. As with any stimulant there recent developments in the flavor and chemistry of caffeinated are risks in consuming too much caffeine too regularly

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35 (IOM-CMNR 2001). Certainly, it is inadvisable to regu- vation (i.e., nicotine withdrawal) or whether he or she is a larly drink too much caffeinated coffee and continually nonsmoker and therefore a newcomer to tobacco/nicotine use subject the body to a slightly elevated blood pressure. (Heishman et al. 1994; Ernst et al. 2001). In nicotine-dependent Drinking coffee in moderation is always recommended. Some studies, with caffeine doses ranging from 100 to individuals, tobacco deprivation (withdrawal) can impair 600 mg per day, found that caffeine use occasionally attentional and cognitive abilities within 12 h of smoking may result in mild gastrointestinal problems, insomnia, cessation (Gross et al. 1993; Lyvers et al. 1994; Bell et al. anxiety, restlessness, diuresis leading to dehydration, 1999). Reinitiating nicotine administration or cigarette smok- and increased physiological tremor. With higher doses ing can reverse such performance deficits to pre-deprivation of caffeine, intakes of 1 g of caffeine (15 mg/kg), mild levels (Parrott and Roberts 1991; Bell and Jacobs 1999). side effects have been observed progressing from rest- lessness, nervousness, and irritability to more serious Today, the topic of nicotine deprivation and performance is effects such as delirium, nausea, emesis, and neuro- very much prevalent in transportation industries because, for muscular tremors. At extreme high doses (e.g., 10 g) example, some airlines enforce no-smoking policies for their caffeine can cause vomiting, convulsions, and even pilots, potentially bringing about flight performance decre- death. The fatal acute oral dose of caffeine in humans ments in pilots who are smokers (see flight simulator research is estimated to be between 10 and 14 g (150 and 200 mg/kg) (IOM-CMNR 2001). on this subject by Mumenthaler et al. 1998, 2003, 2010). Whether improved performance associated with relief from Nicotine withdrawal should be considered cognitive enhancement, or simply labeled restoral to baseline performance levels, Nicotine is classified as a stimulant. It is also classified as a has been questioned (Hughes 1991; Heishman et al. 1994). relaxant, primarily because it increases levels of dopamine in Heishman (1998) pointed out that few studies examined the the brain (a hormone/neurotransmitter that causes sensations cognitive effects of a history of smoking, and research reports of pleasure). Nicotine increases heart rate, blood pressure, do not often report pre-deprivation performance levels of test and respiratory function. It produces pleasure by attaching to participants. The absence of such data makes it difficult to the nicotinic acetylcholine receptor on certain nerve cells, determine whether nicotine functions to reverse deprivation- which in response release the chemical signal glutamate, induced performance decrements or if it produces true behav- telling connected neurons to release dopamine. The more the ioral enhancement. Although nicotine appears to have been nerve cells are excited, the more dopamine is released and shown to, at least in part, reverse deprivation-induced deficits the more pleasant the feeling (McGehee et al. 2002). in performance, conversely true enhancement of performance has yet to be clearly demonstrated either in nonsmokers or Nicotine is readily available in the form of several tobacco nondeprived smokers (Heishman 1998). True enhancement sources, including ubiquitous cigarettes, cigars, and chewing would be most effectively demonstrated if nicotine or smok- tobacco. It is also available in the form of nicotine skin patches ing were shown to facilitate or improve performance in non- (subcutaneous), nicotine chewing gum (polacrilex), and other smokers or in nonabstinent smokers (Heishman et al. 1994; products predominately advertised for assistance in smoking Heishman 1998; Ernst et al. 2001). cessation plans. Relatively few placebo-controlled studies have exam- ined the acute effects of nicotine taken in through smoking Research interest in the effects of nicotine and tobacco (Sherwood 1993; Heishman et al. 1994; Heishman 1998; smoking on human performance has waxed and waned since Ernst et al. 2001). The findings of numerous nicotine studies the early 1900s (Heishman 1998). In the 1990s, owing to have been inconsistent (Perkins et al. 1990, 1994; Foulds et al. renewed attention from the scientific and public health policy 1996; Ernst et al. 2001). The results in many studies have communities, a significant amount of research was conducted been discrepant, including improved performance in motor in programs such as those sponsored by NIDA. Extensive responses (LeHouezec et al. 1994; Bates et al. 1995), sustained literature reviews by Sherwood (1993) and by Heishman et al. attention, and recognition memory, but no effect or impair- (1994) generally concurred that nicotine enhances a limited ment in selective attention (Foulds et al. 1996), conditioned range of behavior and has complex effects on human perfor- learning, and recall memory (Ernst et al. 2001). No studies mance, but that any performance improvements are small in report true enhancement of sensory abilities, or improvements magnitude. The appearance of these review articles prompted in cognitive abilities such as problem solving and reasoning numerous additional studies that examined the effects of (Heishman 1998). Foulds et al. (1996) reported that subcuta- nicotine and smoking on performance, especially cognitive neous nicotine (skin patches) improved response time on a functioning (Heishman 1998). logical reasoning test in nicotine-deprived smokers, but had no effect in nonsmokers. Most study reports do not critique Much like the considerations involving caffeine studies, whether laboratory measures generalize to performance in interpretation of the performance effects of nicotine depends the real world. in part on whether it was tested under conditions of nicotine- deprivation or nondeprivation. That is, effects are dependent Ernst et al. (2001) examined the influence of past smoking on whether a research subject is in a state of tobacco depri- history on cognitive performance by comparing 4 mg of acute

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36 nicotine administration (polacrilex gum) and placebo in 12-h Therefore, contrary to widespread and common belief, the abstinent smokers to that of ex-smokers and nonsmokers. study by Newhouse et al. demonstrated that nicotine may not An improvement effect of acute nicotine administration be an effective stimulant for maintaining alertness during (independent of smoking history) was seen only with respect sustained performance operations. to reaction time on a 2-letter search task. Working memory performance was related to smoking history (smokers per- The ambient smoke associated with burning cigarettes in formed most poorly and never smokers were best). A logical the cab or operator compartment of one's vehicle is likely to reasoning task showed no effects of either acute or chronic add to driver drowsiness. This is in part because exposure to nicotine exposure. Ernst et al. concluded that nicotine may tobacco smoke adds to carboxyhemoglobin in the blood, influence the focusing of attention in smokers as well as non- and it cuts down on oxygen flow within the bloodstream smokers, and that trait-like differences in some cognitive (Benignus 1991). In addition, cigarette and cigar smoke tend to domains, such as working memory, may be either long-term be irritants to the eyes and nasal passages. Some commercial effects or etiological factors related to smoking. drivers insist that during lengthy drives they stop to take a walk- around smoke break to help restore alertness. In so doing, the The literature includes several studies of nicotine and rest break away from driving, especially the act of walking simulator driving performance. Other studies reported nico- around produces some recuperative alertness value in the tine effects on laboratory tests meant to be representative form of overall bodily stimulation. Given Heishman's (1998) of driving-like tasks. The studies depict a wide variation in assessments of nicotine's "restoral of alertness" to smoker designs, and produce conflicting and somewhat inconclusive withdrawal, and the results of research such as that of New- results. As one example, Sherwood (1995) examined the house et al. (1992), it is reasonable to conclude the recuperation psychomotor effects of acute administration of single smoked in alertness during the drivers' smoke breaks is not likely cigarettes with varying amounts of nicotine (<0.1, 0.6, 1.0, or attributable to the nicotine consumed per se, as much as it is 2.1 mg) on a 1-h computer-based driving simulation (four times probably the result of the "restoral effect" for nicotine deprived in 4 days) comprising continuous tracking and brake reaction smokers, and to the physical stimulation effected by the exer- time tasks. Brake reaction times were decreased as they cise gained by walking around in the fresh air outside the truck. improved over all active treatment levels of nicotine; however, tracking accuracy was enhanced after only two cigarettes of Research sponsorship. Turner and Spilich (2006) middle strength were smoked. Sherwood concluded that ciga- reviewed a sample of 91 published papers investigat- rette smoking may improve driving performance, and that there ing the effects of tobacco or nicotine use on cognitive performance. This review is cited here because Turner may be an optimal nicotine dose for the enhancement of cogni- and Spilich's principal aim was to determine if the pat- tive and psychomotor functions. However, making conclusive tern of conclusions drawn by researchers acknowledg- statements about the effects of smoking based on such short- ing tobacco industry financial support differed from duration studies (employing only 1 h drives) can be misleading. the pattern of conclusions drawn by researchers who apparently did not have tobacco industry support. Scientists acknowledging tobacco industry support In a flight simulator study, Mumenthaler et al. (1998, 2003) typically reported that nicotine or smoking improved showed that nicotine improved scores on individual flight tasks cognitive performance, whereas researchers not report- such as approach to landing, a task that requires sustained ing financial support from the tobacco industry were attention; they concluded that nicotine may improve late-day more nearly split on their conclusions. The authors con- flight performance in nonsmoking aviators. Mumenthaler et al. cluded that the existence of a possible bias in the pub- lished literature according to a funding source must be (2010) also demonstrated that nicotine withdrawal effects for given serious consideration (Turner and Spilich 2006). smoker-pilots, who are not allowed to smoke in the flight deck, The same cautions should pertain to pharmaceutical exhibit adverse affects on their simulator flight performance. industry-sponsored studies of any chemical substance or new drug. Perhaps the most pertinent psychological performance study examining nicotine applications for alertness enhance- Assessment of nicotine. The health risks of tobacco use ment during continuous operations (but also d-amphetamine) and smoking have been well-publicized for more than a quarter is that of Newhouse et al. (1989, 1992). In that Walter Reed of a century and by now should be well-known by everyone. study, nicotine was infused intravenously at doses of 0.25, Risks of cancer, heart and lung disease, hypertension, and 0.37, and 0.5 mg after 48 h of wakefulness. They found that cardiovascular and circulatory problems prevail as health nicotine had no significant impact on MSLT measures or on risks from smoking and tobacco use. For all of these health- psychomotor performance. Additionally, nicotine did not risk-related reasons, this synthesis does not support recom- effectively improve cognitive performance (as measured mendations for use of nicotine-containing tobacco (cigarettes, on several tests in the Walter Reed cognitive Performance cigars, or chewing tobacco) for maintaining alertness during Assessment Battery); nor did nicotine improve alertness. commercial driving. Nor does it support nicotine administra- This prompted Newhouse et al. (1992) to conclude that nico- tion by means of skin patches or gum form with commercial tine was "not an effective stimulant for maintaining cogni- drivers, although more research on these aspects of the nico- tive alertness during sustained performance operations." tine topic may be warranted.

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37 Nicotine Treatment for Smoking Cessation safety concerns about the use of varenicline among persons operating aircraft, trains, buses, and other vehicles or in other Nicotine polacrilex gum, when used properly, has been settings where a lapse in alertness or motor control could demonstrated to be an effective medication for treatment of lead to massive, serious injury. The Institute reported that nicotine dependence (U.S. Surgeon General's Report 1988). more than 1,000 complications linked to varenicline were Nicotine polacrilex can provide therapeutic effects such as reported in the first quarter of 2008, including 15 traffic the reduction of tobacco withdrawal symptoms, reduction accidents, 52 incidents of loss of consciousness and black- of the tendency to smoke cigarettes, reduction of the effect of outs, and 50 deaths. relapse factors such as weight gain, and possibly reduction of urges to smoke (Henningfield et al. 1990). However, all of On May 16, 2008, the FDA became convinced that these actions of nicotine are related to the dose level actually varenicline (ChantixTM) had serious side effects and exhibited being obtained, and inadequate nicotine doses may produce symptoms including anxiety, nervousness, tension, depressed no beneficial effect (Henningfield and Woodson 1989). Often, mood, unusual behaviors, and thinking about or attempting it appears that patients use nicotine polacrilex with insuffi- suicide. The FAA removed ChantixTM from the list of medica- cient instruction either to obtain adequate dose levels or to tions considered safe for pilots and air traffic controllers. achieve specific benefits (Cummings et al. 1988; Jarvik and On May 23, 2008, the FMCSA issued an advisory warning Henningfield 1988). For many patients who were unable to stating that varenicline (ChantixTM) may adversely affect quit smoking with the use of nicotine polacrilex, the problem commercial drivers' ability to operate vehicles safely, and may have been a failure to obtain the medication in suffi- that medical examiners should not certify a driver taking cient doses and not medication failure per se (Henningfield ChantixTM. et al. 1990). Another medication used for smoking cessation, bupro- Insomnia and daytime fatigue and sleepiness are recog- pion (Wellbutrin or Zyban) is also associated with adverse nized as one of the criteria for nicotine withdrawal syndrome effects, including insomnia, tremors, agitation, rash, and (Underner et al. 2006). Nicotine replacement therapy could confusion. Kolber et al. (2003) and Ross and Williams (2005) be potentially hazardous to individuals whose occupations reported that with concomitant use of tramadol (Ultram) require alertness, such as drivers of commercial vehicles, the threshold for seizure is lower, and interactions of the because of the effect of the nicotine replacement disrupting two medications promotes additional side effects. sleep and causing unusual and distressing dreams (Colrain et al. 2004). Erectile Dysfunction (anti-impotence) Medications When nicotine is placed in the mouth, the amount actu- ally absorbed through the buccal mucosa is determined by Erectile dysfunction (ED) medications do not fit neatly the pH of the salvia, because nicotine is a weak organic into the category of stimulant drugs; however, for the sake base that is best absorbed in the nonionic form. Nicotine of including them in this synthesis, their description is absorption can be substantially impaired by consumption presented here. Several medications used for treatment of of acidic drinks such as coffee and carbonated beverages ED are some of the most popular and widely used drugs in (fruit juices and soft drinks) either while using the polacrilex the United States and Europe (e.g., sildenafil and vardenafil) (chewing gum) or immediately before using polacrilex. For (Kloner and Zusman 1999). Contrary to popular belief, silden- details, see a review, and published research on this topic afil is not an aphrodiasiac, does not work in the absence of by Henningfield et al. (1990). sexual arousal, and does not make a potent man more virile (DeMey 1998). After oral administration, sildenafil is rapidly Smoking Cessation Drug Warning absorbed, reaching peak plasma concentrations in 30 to 120 min. For pharmacokinetic details on sildenafil see Johnson At a time when many commercial drivers are attempting to stop and Lewis (2006). smoking or to cease using chewing tobacco, it is important to note that use of a popular smoking-cessation prescription drug, Vardenafil (Levitra) was introduced in the United States varenicline (ChantixTM), warranted dangerous side effects in 2003, but currently is not one of the most widely pre- warnings, as issued by three U.S. federal agencies, the FDA, scribed treatments for ED, as other newer ED medications FAA, and FMCSA (May 2008). The drug acts at sites in the are more popular. After oral administration of vardenafil, brain affected by nicotine and may help those who wish to peak plasma concentrations are obtained within 30 to 60 min. stop smoking by providing some "nicotine-like" effects to Vardenafil and its active metabolite have a terminal half- ease the withdrawal symptoms and by blocking the effects life of approximately 4 to 5 h (Johnson et al. 2006). of nicotine from cigarettes if users resume smoking. An Institute for Safe Medication Practices review of hundreds of Johnson et al. (2006) pointed out that although they are "adverse event" reports (2007) forwarded to the FDA by relatively safe, the several ED medications available have Chantix maker Pfizer Pharmaceutical identified immediate certain side effects that present a possibility of creating safety

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38 hazards in aviation operations. One such potential side effect effective in these conditions because when there is a long is a condition known as "blue tinge"--the inability to dis- shortage of oxygen, such as during flight at high altitude, criminate between blue and green colors, which could hinder it leads to pulmonary hypertension ("high blood pressure in execution of certain tasks such as a pilot relying on instru- the lungs") and the drugs could help fight that condition by ments during adverse meteorological conditions and/or dur- improving the flow of oxygen through the body. This may be ing night flights (Borrillo 1998). Additionally, vardenafil has counteracted by supplemental oxygen available or required been shown to potentiate the hypotensive effects of nitrates for pilots flying above certain altitudes. Israeli Air Force commonly employed in treatment of certain heart conditions research began after some exploratory work in other low oxy- (Bischoff 2004). Work at FAA's CAMI is directed at chemical gen environments, such as those concerning mountain climbers postmortem analysis of biological samples taken from pilots on extremely high mountain climbs (Times of London, Feb. 7, who died in airplane crashes. Those numbers demonstrate 2008). The active ingredient in Cialis (tadalafil) helped increases in postmortem ED medications found in pilots. climbers ward off fatigue and dizziness at greater altitudes What effect or role the ED medications have played in recent (Richalet et al. 2005). aircraft crashes has not yet been determined (Johnson et al. 2006; Johnson and Lewis 2006). Monitoring those investi- ED medication assessment. Although neither potential gations is warranted to determine if there are safety-related benefits nor significant problem areas were identified with parallels in the commercial driving industry. the use of ED medications during driving operations, it is incumbent on the commercial driving community to continue No reports evaluating the cognitive performance effects to monitor research results and other medical developments, of taking ED or anti-impotence medications were located. particularly any revealing adverse events attributable to use However, unconfirmed news accounts report that several of these popular medications. military forces have been doing exploratory research on sildenafil (Viagra) to assess its efficacy in assisting high- Table 3 summarizes in tabular form some of the basic infor- altitude fighter pilots to fight off fatigue and "foggy heads." mation concerning stimulants and wake-promoting chemical The hypothesis is that the ED family of drugs might be substances and their possible uses. TABLE 3 LIST OF STIMULANTS AND WAKE PROMOTING SUBSTANCES Category Availability Use/Effect Comments Permitted for CMV drivers Caffeine Ubiquitous, in coffee, Alertness maintenance, Need for operations usage tea, soft drinks, slight boost to energy protocol and guidance; highlight energy drinks, risks; e.g., high BP tablets, and so on Nicotine Tobacco use, Soothing with smoking Not effective for restoring or smoking, skin habit maintaining alertness patches performance; causes cancer Functional Energy Drinks Energy drinks, Popular drinks with hopes No substantive research data on (FEDs) [see see chapter chews, candies, for slight stimulant effects effects; risk of taking too many five: nutritional supplements FEDS, interactions with other supplements] chemicals possible Modafinil Only with Rx for SWSD, ADHD, Promising for alertness, but not prescription; mostly Narcolepsy yet commonly accepted for CMV as prescription for Stimulant without untoward driver use ProVigil for SWSD effects Need more research and usage or ADHD protocol guidance Generally Not Permissible for CMV Drivers Amphetamines: Legally available by Stimulation helps sustain Risk of loss of CDL or job if prescription for performance, but with other caught using without prescription medical treatment undesirable effects only, 391.41.b-12 d-amphetamine Controlled Used for short-duration military operational applications; use not likely applications limited permissible in CMV operations to military Methamphetamine Prescription and on Treatment for ADHD Not practical, risk of abuse Methylphenidate the street Cocaine Illicit; bought on the Recreational, addictive Risk of loss of CDL, job streets Ephederine FDA cautions; still Mostly a weight loss fat Can be dangerous available burner BP = blood pressure; SWSD = shiftwork sleep disorder; ADHD = Attention Deficit Hyperactivity Disorder.