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

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SYNTHESIS PROBLEM STATEMENT APPLIED TO THE LITERATURE REVIEW This chapter outlines four issues that set the stage for litera- ture review of chemical substances. This chapter also briefly describes the effects of alcohol (ethanol) on performance (about which much is known) to provide a baseline against which to judge research findings about effects of other chemicals and drugs. Subsequent chapters report on published findings describing the principal categories of psychoactive chemicals of direct pertinence to commercial driver perfor- mance and health. Chapter three reviews sleep-promoting substances, including hypnotics, and treatment medications prescribed for insomnia and other sleep disorders, as well as antihistamines often used to promote sleep. Chapter four covers stimulants and alertness compounds; those meant to keep one awake while working. Chapter five reviews dietary, nutritional, herbal, and energy boost compounds, or simply “supplements” that contain psychoactive components. Appendix A presents information on other psychoactive chem- ical substances within the U.S. National Institute of Drug Abuse’s (NIDA’s) list of addictive illicit drugs (drugs of abuse such as marijuana and cocaine), for which there is literature on performance effects, including research on the effects of such chemicals on driving performance. Although illicit drugs and other chemical substances do not warrant a viable role for operational use by commercial drivers, their occasional use by some commercial drivers is confirmed in employer random drug screening tests of drivers and by government-sponsored crash and accident investigation reports and statistics from numerous countries, including the United States. DRUG DEFINITIONS AND CATEGORIZATION The first issue is one of determining how to categorize or label the numerous classes of psychoactive chemical substances in this report. Chemicals, medications, or drugs could be identified in the way that medical practitioners consider them, as potential treatments for diseases, illnesses, and medical maladies or as prescription drugs or alternatively as non- prescription treatment drugs. Some drugs also could be clas- sified as “controlled substances,” which refers to their potential for abuse and physical as well as psychological dependence [see for example the extensive list of drugs, Schedules I through V, provided by the U.S. Drug Enforcement Admin- istration (DEA) (CFR Title 21 Chapter II) and the lists of the Food and Drug Administration (FDA)]. Examples of 6 Schedule II controlled substances include opioids, often pre- scribed to treat pain, and stimulants, sometimes prescribed for narcolepsy or Attention Deficit Hyperactivity Disorder (ADHD). Depressants may be prescribed to alleviate anxiety or for treatment of certain sleep disorders such as insomnia, and their controlled substance classification varies based on the factors identified earlier. Although there are concerns about how such drugs may affect driving performance, in some instances individuals afflicted by certain medical conditions may actually drive better when using the prescribed drugs, presumably because the drug treatment works to assist patients with their particular maladies (Barkley et al. 2005). With some generalization, the effects of drugs can be discussed in terms of drug types or drug categories. For example, NIDA classifies illicit drugs into seven major drug categories on the basis of their psychoactive effects on the central nervous system (CNS). These classes and sample drugs within each class (derived from NIDA documents, 2006) are listed in Table 1. Narrative sections in this synthesis focus on several but not all of these drug categories. The American Medical Association has published fairly extensive information on the driving-related effects of legally prescribed drugs (AMA 2003), as did the U.S. National Highway Traffic Safety Administration (NHTSA 2005) and the International Council on Alcohol, Drugs and Traffic Safety (ICADTS 2006). In reviewing such informative lists, NHTSA’s David Shinar stated that “short of saying that all drugs are bad (and even that statement is not true) it is difficult to have a general discussion about drug effects on perfor- mance” (Shinar 2007b). This he says is because different drugs have different pharmacological properties that cause differ- ent physiological and physical signs and symptoms, and consequently have different effects on attitudes and behavior in general, and on driving-related attitudes and behaviors in particular. Shinar says it is nearly impossible and (fortunately) unnecessary to discuss separately each of the drugs in the categories identified in the governmental sanctioned lists mentioned above (Shinar 2005, 2007b). The FMCSA has provided guidance for medical examiners of commercial drivers and rules governing the use of certain medications by commercial drivers. These are widely distrib- uted and available on FMCSA websites, and will be dis- cussed with each medication or substance; however, for most medications the FMCSA has given guidance based on the CHAPTER TWO RESEARCH ISSUES REGARDING PSYCHOACTIVE CHEMICALS

7disease entity rather than on the medications themselves. The exceptions are insulin, 391.41(b)(3), which is forbidden for use by drivers of commercial vehicles (except by wavier under 49 CFR 391.64) and controlled substances, which are forbidden with the notable exception under 391.41(b)(12). Insulin will not be discussed in detail here. Because this synthesis is primarily designed to serve the roadway safety community, the chemical substances described here could be categorized into clusters of the “most likely substances to be ingested by commercial drivers” and into additional categories that address “how these chemicals are likely to impact vehicle driver performance, safety, and health”; that is, as (1) hypnotics and sleep-promoting compounds; (2) stimulants and alertness-producing compounds; and (3) hormonal, herbal, dietary, and energy-boosting supple- ments. This latter scheme of chemical categorization is largely followed in this synthesis report. However, combinations of these categorizations are evident in the narrative descriptions presented, as some chemical substances belong to more than one of the several categories that fit their description. CHEMICAL SUBSTANCE EFFECTS AND DRIVING PERFORMANCE The second issue of importance for this synthesis is to present research findings about chemicals such that the results cited relate to commercial driver performance and health. Relating many of the published drug performance effects from laboratory studies to the performance of com- mercial drivers in on-the-road scenarios can be tenuous. Driving any ground vehicle involves many task elements, including physically handling the machinery (a car, bus, truck, or motorcycle) by steering, shifting gears, braking, staying within the lanes on the road (lane tracking), manipulating a vehicle through physical obstacles (e.g., highway, country, and city driving, in traffic, backing-up, and parking). The act of driving also involves many psychological and cognitive aspects of reasoning, judgment, decision making, reaction time, remaining continuously alert, paying attention to details, using keen visual perception during vigilance (visual, auditory, and kinesthetic vigilance), monitoring information, navi- gating between locations, responding to hazards on the road, and so on. In the case of commercial drivers, other cognitive aspects of the job entail communication interactions with employers, dispatchers, shippers, and receivers. Bus and motorcoach drivers interact with passengers, charter and tour coordinators, tour-guide personnel, and others. In addition to the obvious physiological and cognitive tasks mentioned previously, many truck drivers carry out numerous physical activities and other ancillary duties involving pre-trip safety inspections, loading and unloading of cargo, securing loads (tarping, chaining, etc.), applying heavy chains to wheels, fueling, and other aspects of the job; whereas bus and motorcoach drivers, especially those involved in driving tour groups, often handle significant amounts of baggage (Krueger and Van Hemel 2001). Therefore, simply stating that a chemical substance or a drug affects performance readily invokes a question of what is implied by “performance” and how much of a drug effect is unacceptable for accomplishing individual tasks, completing a job, violating some safety principle, and risking adverse driving incidents. In June 2005, TRB’s Committee on Alcohol, Other Drugs and Transportation held a symposium to discuss the role of Drugs in Traffic. Many of the experts addressed involvement of drugs (licit and illicit) in traffic injuries and deaths. In his presentation on Drug Effects and their Significance for Traffic Safety, Shinar (2005) suggested that several implicit assump- tions are usually made in the study of drugs and their effects on performance: • Psychoactive drugs should have an effect not only on mood but also on cognitive and psychomotor functioning. Furthermore, Drug Category Examples of Drugs in Category 1. Cannabinoids marijuana, hashish 2. CNS Depressants barbiturates, benzodiazepines, flunitrazepam, GHB, methaqualone 3. Dissociative Anesthetics ketamine, PCP, and analogs 4. Hallucinogens LSD, mescaline, psilocybin 5. Opioids and Morphine Derivatives codeine, fentanyl and analogs, heroin, morphine, opium, oxycodone HCL, hydrocodone bitartrate, acetaminophen 6. CNS Stimulants amphetamines, methamphetamines, cocaine, MDMA, methylphenidate, nicotine (add in caffeine and ephedrine here even though they are not illegal) 7. Other Compounds anabolic steroids, dextromethorphan, inhalants Source: NIDA (2006). PCP = Phencyclidine; HCL = hydrogen chloride; MDMA = 3,4-Methylenedioxymethamphetamine (ecstasy). TABLE 1 NIDA’S DRUG CLASSIFICATION

these effects should be reflected in performance on measures related to these functions (such as stability, reaction time, and speech) and should reflect some significant deviation from the norm. • These cognitive changes are expected to be of such magnitude that they are both observable to a trained person and quantifiable with some standardized tests. • Since driving is a fairly complex psychomotor and cognitive task, drug impairments should affect driving performance, usually in a negative manner. • Individuals who take drugs often drive while under their influ- ence, either because they do not appreciate their impairments or because their judgment is impaired. • The resulting Driving Under the Influence of Drugs (DUI) problem can be dealt with in much the same way as DWI (Driving While Intoxicated—with ethanol) (Shinar 2005, p. 68). The focus of this synthesis report is not on the role of drugs in crashes, but rather on what is known about the effects of chemicals on driving performance per se. This synthesis reviews, in brief, numerous scientific and research-oriented studies in the literature. For scientists and researchers defining theoretical and empirical questions to be answered through good basic laboratory and applied field experiments is key to determining the impact of chemical substances on sleep and alertness (loss or gain) and on work-related performance (enhancement or degradation). The most important factors are the “measures of performance” that provide the best under- standing of the effects of various drugs or other chemical substances as they are related to driver performance on the roadway. It is not sufficient to report that an experimental study found that a single ingestion of a particular dose of a drug affects certain lab-based task performances that appear to be of little practical consequence, or in particular to report degradation in performance types that do not appear to have direct application to driving a truck or bus or motorcoach. For example, stating that a particular drug “alters a person’s critical flicker fusion: CFF,” or it “adversely affects psycho- motor tracking, or reaction time, or judgment, or decision- making,” without offering practical examples of how to apply the finding to vehicle driving circumstances necessitates a “stretch of inference” for understanding the implications regarding roadway safety. One such set of scientific issues was delineated by Babkoff and Krueger (1992) who identified a set of at least eight plausible research protocol criteria (mostly based on measures of reaction time and measures of performance accuracy) that could be examined in laboratory experiments for deciding whether or not to use a stimulant to ameliorate performance degradation effects attributable to excessive sleep loss. This they identified in a paradigm with a particular aim of sustain- ing soldier performance during near continuous, around-the- clock military operations, where typically not much sleep is obtained by operational personnel. However, even reaction time measures are not always straightforward indications of equipment operator performance. Human factors research specialists involved in roadway crash investigations point to the many nuances and fine points of at least four identifi- 8 able stages associated with drivers’ perception-response time immediately before becoming involved in a crash sequence, including detection, identification, decision, and response, demonstrating that in-depth assessments of driver reaction time (e.g., in accident reconstruction) are not a trivial matter (Olson 2007). Not only is driving a fairly complex psychomotor and cognitive task, but it is a planned behavior. Different persons may drive from the same starting point to the same end point while employing different strategies; from the level of trip planning, to navigation, to reacting to specific situations. The additional involvement of chemical substances in driving scenarios make cause-and-effect analyses even more difficult, and can obfuscate even the simplest explanations of drug- induced response times reported in the experimental literature. For example, individuals under the effects of alcohol often experience overconfidence in their driving, and they speed. In contrast, individuals under the effects of marijuana often feel impaired and tend to drive slower. However, both drugs impair judgment and the ability to respond correctly to emer- gency situations (Shinar 2005, 2007b). There is also the issue of individual differences in the vari- ability of metabolism and behavioral responses or reaction effects to medications, drugs, and other chemicals. Metabolism and effects of drugs on individuals vary, in some cases quite significantly. That is, some people appear to manage satisfacto- rily with medications or chemical substances that in a similar situation would severely impair another person’s behavioral responses (McBay 1997; Shinar 2007b). These considerations raise important questions of how best to relate laboratory-based psychological and physiolog- ical performance measures to predicting driver behavior in “real world” situations on the highway. Obtaining and inter- preting research quality measures of driving performance is not simple. From these descriptions it can be understood that determining that drugs in a laboratory experiment affect cognitive performance on generic psychological tasks is not always readily transferable to real-world roadway experiences. For example, some experiments have demonstrated that whereas low doses of a drug given to an experimental partic- ipant produce slight performance effects, these slight effects can actually become more pronounced when the nature of the task asked of research subjects is intensified, such as when the cognitive workload is increased or when subjects are asked to do multi-tasking (Pickworth et al. 1997; Shinar 2007). The “application leap” from lab-based findings to the “real world” is often not an easy one. Researchers usually agree however that if a drug adversely affects a fine-tuned measure of human performance (e.g., reaction time, signal detection, or precision tracking) in a controlled laboratory study it is reasonable to expect that such a drug-affected performance is not likely to improve while the individual is driving; performance on the road might even be worse.

9DRUG AND ALCOHOL INFLUENCES IN CRASH STATISTICS The third issue concerns assessing whether drug-involved automobile and truck and bus crash statistics can determine whether drugs or alcohol actually were factors in causing the crashes, or whether drugs merely were concomitantly just present at the time of the crashes. Numerous studies, reviews, and statistical treatises of highway accident reports document the large numbers of drivers, injured or dead in crashes, who had evidence of drugs or alcohol in their bodies. These determinations are often made through the analysis of blood or tissue samples taken soon after the crashes (e.g., NTSB 1990, 1995; DeGier 2005; TRB Committee on Alcohol and Other Drugs 2005). DeGier (2005), while focusing on medi- cinal drugs, cited numerous studies reporting traffic and drug statistics for 13 European countries, and indicated that the quest for knowledge on the prevalence of drugs other than alcohol in road traffic is hampered by methodological problems encountered with epidemiological studies of drugs and driving, including problems with sample collection and data collection procedures. DeGier estimated the presence of illicit drug use in the general driver population, at least in Europe, to be in the range of 1% to 5%, whereas the prevalence of medicinal drugs affecting driving performance is higher (5% to 10%). In an overview of studies on drug-impaired driving in the United States, Jones et al. (2003) reported that benzodiazepines were found to be present in 4% of noncrash-involved drivers. In a FMCSA research and analysis brief, Gruberg (2007) esti- mated that in 2005 1.7% of drivers with commercial driver’s licenses (CDLs) used controlled substances, and 0.2% used alcohol [>0.04 BAC (breath alcohol concentrations)] while performing their duties. In 1994, the U.S.DOT first issued regulations requiring testing of safety-sensitive employees in transportation indus- tries “for use, in violation of law or Federal Regulation, of alcohol and drugs listed in the Controlled Substances Act” (Federal Register 1994). The DOT stated that drivers shall not use controlled substances, except when the use is pursuant to the instructions of a “physician who is familiar with the driver’s medical history and assigned duties, and has advised the driver that the prescribed substance or drug will not adversely affect a driver’s ability to safely operate a commer- cial motor vehicle” [391.41 (b)(12)]. The stated intent of the federal workplace drug testing program is/was to identify individuals who use “illegal substances” (Federal Register 1994; see also Section 503, Public Law 100-71). For safety- sensitive employees, including commercial drivers, random drug screening tests collect urine specimens that are tested for phencyclidine and cocaine (illegal drugs), and amphetamines, marijuana and opiates, which may be prescribed by a medical practitioner or taken without a prescription (Gruberg 2007). Regardless of jurisdiction, use of “medical marijuana” is pro- hibited by drivers of CMVs (FMCSA Frequently Asked Ques- tions for Drug and Alcohol Compliance, FAQ: www.fmcsa. dot.gov/rules-regulations/topics/medical/faq.aspx.) However, some other “legal drugs,” which also are con- trolled substances and must be obtained by medical prescrip- tion, are known to have adverse effects on actual or simulated driving as well. Some of these include the hypnotics such as diazepam, flurazepam, and loprazolam, or various anti- depressants and antihistamines. Many drugs, especially some prescribed medications, can influence vision, vigilance, and even impulsiveness. Problems such as driver fatigue, lack of attention, vigilance deficits, and suicidal and aggressive tendencies (singularly or in combination) can contribute to causing crashes. OTC medications available without prescrip- tions, but which are also known to be psychoactive, include drugs such as the antihistamines containing diphenhydramine (e.g., Benadryl®). Most likely because they are usually pre- scribed by a medical practitioner, not subject to high abuse potential, and not commonly used for “recreational purposes,” tests for these drugs, and many others, are rarely performed on impaired ground vehicle drivers (whether commercial drivers or not). If two or more drugs are found in a vehicle driver, it is essential that the combined effect on performance be considered and evaluated (McBay 1997). In civil and commercial aviation transportation, procedures have been put in place by the NTSB and the FAA’s Civil Aeromedical Institute (CAMI) to do toxicological analyses of postmortem samples from pilot fatalities in aviation crashes to determine whether performance impairment from a medical condition(s) and/or drug and ethanol use was a contributing factor in a particular crash (Chaturvedi et al. 2005; Canfield et al. 2006; Botch and Johnson 2008). However, in both trans- portation communities (aviation and ground motor vehicle crash investigations) it is usually by inference that drug-crash causal conclusions are drawn and there is some uncertainty about the veracity of those conclusions. The problem is exemplified by McBay (1997), who addressed issues of whether enough is known about the effects of drugs on driving performance to permit expert witnesses to testify in court cases about the likely impairment effects of drugs on a driver. Although McBay reported that adequate methods are available for the identification and determination of the amount of drugs through examination of blood, urine, hair, sweat, saliva, and other specimens taken from drivers shortly after crashes, the major problem is in relating the drug concentrations in the specimens to actual driving impairment. Specimens other than blood may be useful in determining drug use, but none is helpful in determining whether there was an active drug in the body that was affecting driving performance at the time of a crash. Interpretation of the effects produced at various concentrations of drugs in blood specimens depends on many factors not generally available to an expert witness for use as a basis for formulating acceptable scientific opinions. Some of the factors are: the impossibility of reliably back-calculating a concentration(s) to a prior time, individual differences in metabolism, single or chronic dosing, tolerance, withdrawal, inter- and intra- laboratory methods and variances, multiple drug use, method

of use, and the ranges of drug concentrations produced in different individuals ingesting the same size dose. Thus, although concentrations of drugs and metabolites in body fluids can be determined, unfortunately the concentrations of most drugs and their correlation with impairment or improve- ment of driving are not readily known (McBay 1997). In 1983, a panel of medical experts reached a consensus concerning drug concentrations and driving impairment (which was reaffirmed in 1989). The panel reported that: “In order to establish that use of a drug results in impairment of driving skills and to justify a testing program to respond to this hazard, certain facts must be available: 1. The drug can be demonstrated in laboratory studies to produce a dose-related impairment of skills asso- ciated either with driving or with related psychomotor functions. 2. Concentrations of the drug and/or its metabolites in body fluids can be accurately and quantitatively measured and related to the degree of impairment produced. 3. Such impairment is confirmed by actual highway experience. 4. Simple behavioral tests such as can be done at the road- side by police officers with modest training can indicate the presence of such impairment to the satisfaction of the courts. 5. A range of concentrations of the drug can be incorpo- rated in laws relating to impaired driving as ipso facto evidence” (Blanke et al. 1985; McBay 1989, 1997). McBay, Shinar, and others appear to be in agreement that these criteria have been met for just one drug, ethanol (alcohol). The adverse effects of alcohol on driving performance have been well-established. Experts can testify to its effects based both on blood and BACs. However, most of what is known about alcohol and driving performance is not available for other drugs. It is not certain that these listed criteria can be met for most other drugs that now are of concern to highway safety (McBay 1997; Shinar 2007b). DRUG INFLUENCES ON PERFORMANCE COMPARED WITH ALCOHOL EFFECTS The three issues outlined previously serve as a segue to the fourth issue, which is that in the scientific literature, human performance researchers often report lab study drug effects by comparing them with the better-identified effects of ethanol (alcohol) on performance. Research on alcohol performance effects provides a “baseline” for relating and understanding how much impact other chemical substances have in affecting driver performance. This is so largely because: • Predictable processing of alcohol (ethanol) in the body is well-understood; • The effects of alcohol on so many forms of performance have been thoroughly studied and described; and 10 • Many individuals have experienced alcohol-impaired performance (even while driving), and thus they can more readily relate to comparisons employed to explain the effects of other chemical substances researched in experiments (Shinar 2007a). Alcohol effects are so pervasive and consistent that the World Health Organization recommended that alcohol-related impairment serve as a benchmark for other impairments (Willette and Walsh 1983). In his book, Traffic Safety and Human Behavior, Shinar wrote: “Despite the numerous studies on the effects of drugs on driving-related skills, on driving, and on crashes; and in contrast to the role of alcohol in driving and highway safety, we are amazingly ignorant of the role of drugs other than alcohol in driving and safety” (Shinar 2007a, p. 434). Shinar goes on to say there are two general reasons for this. Compared with other drugs, alcohol is a very simple drug. It spreads quickly and evenly throughout different body tissues so that blood alcohol levels correspond very well to concentrations of alcohol in the brain. There is a direct dose-response relation- ship so that the amount of impairment is directly related to the amount of alcohol that enters the blood and, consequently, the relationship between alcohol intake, blood concentration, and impairment is quite reliable and straightforward (Moskowitz 2002, 2007; Shinar 2007a). Alcohol affects just about every capacity we have including multiple perceptual, attentional, cognitive, decision, memory, and motor functions—all critical for safe driving (Ogden and Moskowitz 2004). The impairing effects can be demonstrated at very low alcohol levels and as the amount of alcohol in the blood rises, the number of func- tions that are impaired and degree of impairment increases (Moskowitz and Robinson 1988; Moskowitz and Fiorentino 2000; Ogden and Moskowitz 2004). The psychomotor performance research literature reports a large number of alcohol and performance studies and a con- siderable number of those were done in driving simulators. Moskowitz and Robinson (1988) analyzed 177 studies that examined effects of low levels of alcohol (BAC levels of 0.10% or less) on driving-related functions and behaviors. They summarized their results in terms of the likelihood of impairment as a function of the BAC for nine different driving-related categories: reaction time, tracking, vigilance, divided attention, information processing, visual function, perception, psychomotor skills, and driving skill. Their sig- nificant findings were: (1) that alcohol in almost any amount impairs driving or driving-related skills, for all functions studied, and as the BAC level increases, impairment increases; (2) all aspects of driving behaviors studied are impaired as the BAC equals 0.10% or higher; and (3) there are differences among the cognitive functions in their sensitivity to alcohol. The most sensitive function—producing impairment at the lowest levels of BAC—was divided attention. Approximately 50% of the studies demonstrated impairment in divided atten- tion at BAC less than 0.05%. The next most sensitive function

11 was tracking, with similar percentages showing impairment at BAC equal to 0.05%—significant because tracking and divided attention are inherent in almost all driving tasks. The least sensitive function was vigilance, with very few studies showing impairment below BAC equal to 0.08%. Moskowitz and Robinson concluded that although some individuals may be more affected by small concentrations than others, “there is no lower threshold level below which impairment does not exist for alcohol.” A driving simulator study by Roehers et al. (1994) demonstrated that sleepiness and low-dose ethanol combine to impair simulated automobile driving, an impair- ment that extends beyond the point at which breath ethanol concentrations reach zero. Similarly, Holloway (1994) examined 155 empirical studies (1985–1993) to reach three conclusions. First, sensitivity to the subjective intoxicating effects of alcohol was greater than that for all other performance classes and appeared to display a “threshold” with respect to BAC rather than the linear relation evident in performance data. Second, sensitivity to performance impairment in “controlled” performance and simulator tasks was greater than that for psychophysical functions of “automatic performance.” Finally, a variety of task-, subject-, and environmental-characteristics or conditions were found to mediate the magnitude and sensitivity to alcohol effects, particularly at low doses. Holloway (1994) concluded that because alcohol sensitivity can vary from time to time, person to person, and situation to situation, the setting of a “safe” BAC will always be arbitrary, being based on low, but non-zero incidence of effects below that level. Unlike establishing the relationship of alcohol to perfor- mance, the case for determining similar links of the presence of other drugs to that of cognitive performance (enhancements or decrements) is not so straightforward. Different sampling techniques and different residuals of the same drug have very different implications for the presence of drug impairment. For example, marijuana [with the active ingredient Tetrahydro- cannabinol (THC)] is absorbed in fatty tissues and is then released back into the blood and urine as a metabolite that has no psychoactive effects (THC-COOH). Thus, detection of THC in the blood is indicative of recent ingestion; but detection of marijuana metabolites in the urine or the blood only indicates that marijuana has been used, and that the use could be as long as a few weeks ago. The second reason is that alcohol is a singular drug with specific repeatedly demonstrated effects, whereas other “drugs” as a generic category include different drugs that have different effects. These drugs are not evenly absorbed in all body tissues or even in the same brain centers; they do not necessarily have the same or similar physiological and behavioral effects and often do not exhibit a direct dose-response relationship. Finally, drugs other than alcohol are often taken in com- bination (also in combination with alcohol) and depending on the specific drugs, the specific doses, and the user’s past experience with drugs, they have joint effects that may be addi- tive, synergistic, or antagonistic, and generally very difficult to predict (Shinar 2007a). INFLUENCE OF CHEMICALS ON DRIVER PERFORMANCE The three chapters that follow provide a brief capsule view of the voluminous material that could be cited to describe many psychoactive chemical substances that occasionally may be ingested by commercial drivers. More is known about the effects on performance of some of these chemicals than about others. In particular, less is known regarding newer drugs now available in the pharmaceutical marketplace, and this is especially true with regard to the nutritional supplements. From published research reports, short descriptions summarize a few pertinent points about each drug or medication and focus on aspects most pertinent to the occupation of commercial truck and bus and motorcoach drivers. Some augmented material for each chapter is relegated to supplemental coverage in the appendixes. Selections of particular experimental studies and their results were made by the synthesis authors with the expectation that those cited provide reasonable explanations of what the general trends in the literature portend. In particular, the selections demonstrate the significance of several data gaps in our knowledge base about the effects of psychoactive sub- stances on driving performance.