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

Chapter:Appendix A - Additional Research on Chemicals Affecting Performance and Health

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Suggested Citation:"Appendix A - Additional Research on Chemicals Affecting Performance and Health." National Academies of Sciences, Engineering, and Medicine. 2011. Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements. Washington, DC: The National Academies Press. doi: 10.17226/14534.
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Suggested Citation:"Appendix A - Additional Research on Chemicals Affecting Performance and Health." National Academies of Sciences, Engineering, and Medicine. 2011. Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements. Washington, DC: The National Academies Press. doi: 10.17226/14534.
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Suggested Citation:"Appendix A - Additional Research on Chemicals Affecting Performance and Health." National Academies of Sciences, Engineering, and Medicine. 2011. Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements. Washington, DC: The National Academies Press. doi: 10.17226/14534.
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Suggested Citation:"Appendix A - Additional Research on Chemicals Affecting Performance and Health." National Academies of Sciences, Engineering, and Medicine. 2011. Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements. Washington, DC: The National Academies Press. doi: 10.17226/14534.
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Suggested Citation:"Appendix A - Additional Research on Chemicals Affecting Performance and Health." National Academies of Sciences, Engineering, and Medicine. 2011. Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements. Washington, DC: The National Academies Press. doi: 10.17226/14534.
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Suggested Citation:"Appendix A - Additional Research on Chemicals Affecting Performance and Health." National Academies of Sciences, Engineering, and Medicine. 2011. Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements. Washington, DC: The National Academies Press. doi: 10.17226/14534.
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Suggested Citation:"Appendix A - Additional Research on Chemicals Affecting Performance and Health." National Academies of Sciences, Engineering, and Medicine. 2011. Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements. Washington, DC: The National Academies Press. doi: 10.17226/14534.
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Suggested Citation:"Appendix A - Additional Research on Chemicals Affecting Performance and Health." National Academies of Sciences, Engineering, and Medicine. 2011. Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements. Washington, DC: The National Academies Press. doi: 10.17226/14534.

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71 This appendix contains descriptive information on a select number of chemical substances, predominately illicit drugs that commercial drivers should not be using in their operations, but for which there is substantial literature describing the effects of such drugs on either human performance or health. In a community wishing to employ and retain only reliable and safe drivers, mandatory compliance, and random urine screening tests of commercial drivers, occasionally detects metabolites of illicit drugs, evidence that some drivers do indeed use marijuana or cocaine as well as other illegal drugs readily available on the street. In using illicit drugs, drivers put their jobs in jeopardy. For the sake of completeness, this appendix contains descriptions of additional chemical substances and describes some known effects on performance, especially cognitive performance. CENTRAL NERVOUS SYSTEM DEPRESSANTS Central nervous system (CNS) depressants are often referred to as sedatives and tranquilizers because they are drugs that slow normal brain functions. When taken as prescribed by a physician, depressants may be beneficial for the relief of anxiety, irritability, tension, and as treatment for insomnia. In listing drugs that can be involved with personal abuse, the National Institute of Drug Abuse (NIDA) suggests depres- sants produce reduced anxiety; a feeling of well-being; low- ered inhibitions; slowed pulse and breathing; lowered blood pressure; poor concentration and fatigue; confusion; impaired coordination, memory, and judgment; addiction; respiratory depression and arrest; and, in extreme cases, death. The most common CNS depressants include methaqualone and gamma- hydroxybutyrate (GHB). NIDA reports that depressant drugs of abuse are known by the street names of barbs, reds, and yellows (for barbiturates), as candy and downers (for benzo- diazepines), and as ludes and quads (for methaqualone). Several of the better-known depressants were once com- monly prescribed as treatments for anxiety and sleep disorders. In excessive amounts they produce a state of intoxication very similar to that produced by a large intake of alcohol. It is the drowsiness and calmness that depressants cause that brings about the potential for both physical and psychological dependence, and often leads to their abuse. Impairing effects of depressants typically peak at 2 to 3 h after ingestion, and can last for up to 6 h. After that (or the following morning) there are typically few or no impairments (Ghoneim et al. 1975). However, as long as the sedating effects persist, they may impair driving-related functions and therefore constitute a potential danger in the context of driving (Shinar 2007b). Physiological and physical symptoms of impairment include problems with ocular convergence, increased pulse rate, a decrease in body temperature, horizontal gaze nystagmus, and poor coordination as reflected in the walk- and-turn test. In this respect, the effects of CNS depressants are similar to those of alcohol—the most commonly abused depressant (Schnechtman and Shinar 2005; Shinar 2007a). In a review of 35 studies of different CNS depressants (barbiturates, nonbarbiturates, tranquilizers, and antidepres- sants) Clayton (1976) grouped the effects into sensory and perceptual, cognitive, and motor functions. Clayton reported that most of the depressant drugs did not produce significant impairments on most of the laboratory tasks measured. How- ever, of the sensory and perceptual functions, critical flicker fusion and dynamic visual acuity were impaired by several of the drugs, whereas static acuity, depth perception, and visual search were relatively immune to the drugs tested. Of the cognitive skills, there was slight evidence of impairments on short-term memory tasks, although mental arithmetic was relatively unaffected. Of the commonly tested motor tasks, the one most significantly impaired was tracking. Shinar (2007b) reported that for every finding of a significant drug effect cited in Clayton’s review there were at least four others where the impairing effects were not statistically significant. Clayton (1976) explained why it is so difficult to reach firm conclusions about practical effects of prescribed psychotropic drugs on driving performance by citing differences in methodology, tasks used in testing, drug doses, and in choice of test partic- ipants. Since Clayton’s 1976 review, experimental studies of drug effects and other literature reviews have not sub- stantially clarified the picture (Shinar 2007b). This synthe- sis briefly reviews some descriptive literature on specific CNS depressants. The first three CNS depressants described, methaqualone, GHB, and flunitrazepam, are of little direct interest in the context of this synthesis, which is directed at commercial driving concerns, but are briefly described here for the sake of completeness in addressing the drugs listed in the NIDA chart of illicit drugs that could be used as hypnotics (chapter three). Methaqualone Methaqualone, a synthetic sedative, is normally administered orally, and is rapidly absorbed from the digestive tract. Intox- ication effects include euphoria/depression, poor reflexes, slurred speech, and, with large doses, possibly coma. Contin- ued use in large doses can lead to tolerance and dependence. In the 1970s and 1980s, methaqualone was sold under various APPENDIX A Additional Research on Chemicals Affecting Performance and Health

72 brand names such as Quaalude, Sopor, Parest, Mequin, Optimil, and Somnafac. NIDA lists additional street names for metha- qualone as ludes, mandrex, quad, and quay. When it was more popular, methaqualone was widely abused on the street, and it caused many cases of serious poisoning. No literature is cited here for methaqualone as it is an inappropriate drug for the commercial driving community. Gamma-hydroxybutyrate Historically, gamma-hydroxybutyric acid, gamma-hydroxy- butyrate (GHB) has been used in a medical setting as a general anesthetic to treat conditions such as insomnia, clinical depres- sion, narcolepsy, and, more rarely, alcoholism, and to improve athletic performance (Benzer 2007). NIDA lists GHB effects as causing drowsiness, meaning it could be listed as a hypnotic. GHB is approved by the FDA (as Xyrem™) for medical use in treating cataplexy and excessive daytime sleepiness in patients with narcolepsy, a condition incompatible with the profession of commercial driving. GHB administered as a liquid may act directly as a neuro- transmitter, but is unusual because it crosses the blood–brain barrier after oral administration. GHB is also a metabolite of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA); thus, it is found naturally in the brain, but at con- centrations much lower than doses that are abused (NIDA). The exact mechanism of action of GHB is unclear; however, some evidence suggests it may modulate dopamine activity, specifically by increasing the availability of cerebral dopamine. GHB’s effects on the CNS include sedation and, in higher doses, even coma. Some research reports on a paradoxical mix of sedative and stimulatory properties of GHB, as well as a so-called “rebound effect,” experienced by individuals using GHB as a sleeping agent, wherein they awake suddenly after several hours of GHB-induced deep sleep (Mamelak 1989). GHB also has been investigated as an anesthetic agent, and when used this way has few effects on cardiovascular or respiratory systems (Buysse et al. 2005). NIDA lists street names for GHB as G, Georgia home boy, grievous bodily harm, and liquid ecstasy. GHB has significant abuse potential. It is classified as one of several “club drugs” used to facilitate date rape, particularly when combined with alcohol (see the NIDA website on club drugs: www.nida.nih. gov/infofacts/clubdrugs.html). GHB is an illegal drug in many countries. Adverse health consequences associated with GHB include nausea/vomiting, headache, loss of consciousness, loss of reflexes, seizures, coma, and possibly death. No literature is cited here on GHB, as it is not of practical pertinence to the commercial driving community. Flunitrazepam Flunitrazepam is a CNS depressant frequently associated with sexual assault (date rape). NIDA lists the various street names: Rohypnol: forget-me pill, Mexican Valium, R2, Roche, roofies, roofinol, rope, rophies. One effect is memory loss for the time a person is under the drug’s effects. Side effects include visual and gastrointestinal disturbances, and urinary retention. No studies regarding health or performance with flunitrazepam are cited here, as it is not an appropriate drug for the commer- cial driving community. BARBITURATES The barbiturates Amytal, Nembutal, Seconal, and Phenobar- bital were once among the drugs most frequently prescribed by physicians to induce sedation and sleep. Barbiturates are identified as ultrashort, short, intermediate, and long-acting depending on the time it takes for the effects to occur after the drug has been taken. Small doses calm nervous conditions, and larger doses cause sleep 20 to 60 min after being taken orally. Intoxication effects of barbiturates include sedation, drowsi- ness and depression, unusual excitement, fever, irritability, poor judgment, slurred speech, dizziness, and life-threatening withdrawal (NIDA 2006). As with other depressants, if the dosage of a barbiturate is increased, the effects may progress through successive stages of sedation to sleep, coma, and to death (Davis 1996). Because of the significant risk of barbi- turate addiction, approximately 15 years ago physicians began prescribing other drugs to induce sedation and sleep. NIDA lists street names for such barbiturates as barbs, reds, red birds, phennies, tooies, yellows, and yellow jackets. Two studies (Pickworth et al. 1997 and Mintzer et al. 1997) evaluated effects of Phenobarbital on performance, without interactions of alcohol. Results suggested that barbiturates affected psychomotor functions in ways similar to that of alcohol and benzodiazepines. Owing to their dramatic effects barbiturates are no longer considered to be helpful medications to induce sleep in practical workplace applications. Barbiturates may be viewed to a small extent in drivers who are prescribed or take medications for headache syndromes containing butalbital (Fiorinal® or Fioricette®). Methylphenidate and Pemoline Methylphenidate (MPH: Ritalin®, Cocerta, Metadate, or Methylin) is a psychostimulant drug belonging to the piperidine class of compounds. It increases the levels of dopamine and norepinephrine in the brain through reuptake inhibition of the monoamine transporters. MPH possesses structural similarities to amphetamine, and although MPH is less potent, its pharma- cological effects are even more closely related to those of cocaine, but without all the addictive tendencies. MPH is approved for treatment of attention-deficit hyperactivity dis- order (ADHD), postural orthostatic tachycardia syndrome, and narcolepsy; and for off-label use in treatment-resistant cases of lethargy, depression, neural insult, obesity, and obsessive- compulsive disorder. In 1961, the FDA approved the MPH medication as Ritalin® for use by children with behavior

73 problems, especially ADHD. Methylphenidate is fairly short acting, with the effects lasting approximately 4 h, with a half- life of 3 h (Nishino and Mignot 2005). Historically, methylphenidate has been used extensively to treat excessive daytime sleepiness associated with narcolepsy and ADHD (Connors and Taylor 1980; Mitler et al. 1986). Most of the research on effects of methylphenidate on perfor- mance has been directed toward assisting people who have been diagnosed with ADHD, especially children (see for exam- ple Coons et al. 1981; Peloquin and Klorman 1986; Fitzpatrick et al. 1998; DeGrandpre 1999; Fone and Nutt 2005); but also for the treatment of narcolepsy (e.g., Mitler et al. 1986). Other studies demonstrated some positive effects of MPH on information processing in that MPH increased response speed on cognitive performance tasks, but with some accom- panying side-effects (Naylor et al. 1985). When these exper- imenters manipulated response complexity, the drug effect increased as response complexity increased, but was not affected by stimulus complexity. Their data were interpreted to mean that MPH affects response selection rather than stimulus processing. Several other studies reported improvement in accuracy and response speed with administration of methyl- phenidate in tasks designed to test short-term memory scan (Talland 1970; Coons et al. 1981; Peloquin and Klorman 1986; Brumaghim et al. 1987). During the late 1980s and early 1990s, U.S. military medical research labs experimented with using either or both stimulants, methylphenidate and pemoline, as potential alternatives to amphetamines in helping to sustain soldier performance during sleep deprived operations (e.g., Babkoff et al. 1992). Babkoff et al. administered 10 mg of MPH every 6 h for eight doses in a study involving 48 h without sleep. About one-fourth of the significant differences between MPH and placebo involved instances when MPH subjects performed worse than placebo subjects. These researchers subsequently abandoned further examination of methylphenidate. One other study, by Bishop et al. (1997), reported that sleepiness, as measured by Multiple Sleep Latency Testing (MSLT), was reduced by 10 mg of methylphenidate given twice per day after one night of sleep deprivation, and performance on reaction time and vigilance tasks was improved. For a meta-analysis comparison of methyl- phenidate and modafinil, both used as cognitive enhancers, see Repantis et al. (2010). Pemoline (formerly marketed as Cylert), another CNS stimulant, is structurally different from the amphetamines and methylphenidate, but possesses pharmacological activity similar to other stimulants. Unlike amphetamine, pemoline does not modulate noradrenaline and is reported to be free of adverse effects on mood and the cardiovascular system. In the United States, pemoline was a Schedule IV controlled drug under the Controlled Substances Act. Formerly, pemoline was used to treat ADHD and narcolepsy (Mitler et al. 1986). However, after it was found to have too many complications, such as hepatic failure (liver damage), the FDA withdrew approval in 2005. Pemoline was effectively withdrawn from the pharmaceutical marketplace in both Canada (1999) and the United States (2005). However, 4-methylaminorex, a more potent analogue of pemoline, has recently appeared as a black market drug with abuse potential similar to methamphetamine (Rodriguez and Alfred 2009). Although in the research programs (e.g., at the U.S. Naval Health Research Center) positive effects with both MPH and pemoline were somewhat equivocal, pemoline demonstrated a better chance of countering the effects of sleep loss. Even though initially pemoline demonstrated the potential to reverse sleep deprivation effects (e.g., Gelfand et al. 1968; Babkoff et al. 1992; Nicholson and Turner 1998) it never really gained much favor relative to other available stimulants (e.g., modafinil). Studies of both MPH and pemoline quickly were displaced with laboratory examinations of other stimu- lants to meet the military’s needs. No reports examining either MPH or pemoline and driving performance per se were located. As was mentioned earlier, pemoline is now virtually gone. Although drug tests for MPH are not normally performed with drivers, MPH has been iden- tified in post-mortem studies of highway traffic crashes, but generally not so in aviation crashes. ANTIDEPRESSANTS Robbe and O’Hanlon (1995) administered a dose of 77 mg/day of the tricyclic anti-depressant amitriptyline and found it produced severe drowsiness and strikingly impaired perfor- mance on nearly every test on the first day, but its effects were practically gone after 1 week of treatment. Amitriptyline is fre- quently used off-label as a hypnotic for sleep induction and/or maintenance at lower doses. Another antidepressant, paroxe- tine, a Selective Serotonin Reuptake Inhibitor, administered in the usual dose of 20 mg, had no effect on performance. Paroxetine at 40 mg did not affect road tracking but slightly impaired performance in some psychomotor tests in a persis- tent manner (Robbe and O’Hanlon 1995). Ramaekers et al. (1994) reported that when mianserin (10 mg 3xd) and doxepin (25 mg 3xd) were administered for 8 days, mianserin and dox- epin both impaired driving on day 1; however, after 8 days of doxepin treatment impairments dissipated, but not during mianserin treatment. O’Hanlon and Freeman (1995) stated depression itself and the chronic use of the antidepressant amitriptyline are associated with a greater than normal risk of traffic accidents. Otherwise, impairments associated with depression generally resolve in those patients showing a favor- able response to antidepressant therapy, regardless of the drug. These findings must be individualized however owing to the varying responses to therapy. In April 2010, the FAA announced a new policy on anti- depressants. On a case-by-case basis, pilots who take one of four antidepressant medications—fluoxetine (Prozac), sertra-

74 line (Zoloft), citalopram (Celexa), or excitalopram (Lexapro) will be allowed to fly if they have been satisfactorily treated on the medication for at least 12 months. COCAINE In addition to the stimulants described in chapter four, there is an extensive literature about the performance effects of a few others; notably cocaine. Cocaine acts on the CNS by stimulating the cerebral cortex, and it mediates psycho- stimulant effects by blocking catecholamine reuptake (mainly dopamine). Cocaine’s structure is different from amphetamine- like compounds (Nishino and Mignot 2005). It is most often used as a part of a vasoconstricting topical anesthetic. Cocaine, often abused outside of a medical setting, generally gives rise to a sense of well-being, which is dose-dependent (Rush et al. 1999). Increased alertness and motor performance are often reported by cocaine users (Epstein et al. 1999). The duration of effect is usually between 30 and 90 min. The usual dose would be an oral, nasal, or injection dose ranging from 50 to 300 mg. Injection or inhaling no more than 1 to 1.5 mg/kg (maximum dose 50 mg) just prior to activity produces the effects within minutes. A cocaine-like amphetamine (96 mg) did not improve performance in research subjects before sleep loss; however, cocaine significantly improved reaction time performance and alertness as measured by the Profile of Mood States rating scale after 24 and 48 h of sleep loss (Fischman and Schuster 1980). In a series of studies, researchers at the Southern California Research Institute (SCRI) examined cocaine effects on driving performance. Twenty-four healthy males, ages 21 to 40 years, who were self-admitted cocaine users, participated. An initial experiment with cocaine (96 mg intranasaly) and alcohol (0.58 g/kg) found no impairment of driving-related laboratory tasks attributable to the cocaine (Moskowitz and Burns 1989). In a second experiment, with 96 mg of cocaine, subjects performed better with cocaine than with placebo, with the greatest differences observed during a test battery beginning 3 h after dosing. Because the second test time coincided with the anticipated afternoon physiological lull, the findings raised questions about the drug effects and circadian rhythm (Burns 1993). Burns reported further studies of time-of-day differences associated with cocaine’s effects. In a nighttime experiment, divided-attention and vigilance data agreed with the previously reported afternoon data. When subjects were tested near midnight, scores were better with cocaine than with placebo, and the effects of cocaine on performance per- sisted past the period of acute stimulation. Divided-attention reaction times were faster with 96 mg of cocaine, whereas 126 mg of cocaine prevented slowing of vigilance response times. Burns concluded that cocaine effects may be task- dependent, as well as dose-dependent (Burns 1993). Chronic use of cocaine leads to drug addiction and related problems. The use of large amounts of cocaine can cause tachycardia, hypertension and ventricular fibrillation, hallu- cinations, nausea, vomiting, anorexia, convulsions, coma, and death. A single dose of 1.2 g of cocaine could be fatal; however, death is also known to have occurred with a dose as small as 20 mg. Hyperthermia, resulting from peripheral vaso- constriction, is a potentially serious problem with continued cocaine use and therefore cocaine can be potentially lethal for those doing exercise (or work) in very warm environments or hot climates. Interestingly, cocaine and adrenaline enhance the other’s sympathomimetic effect. Nonmedically supervised cocaine use is illegal in the United States. The risks of using cocaine, especially a high likelihood of drug addiction, far outweigh any perceived ergogenic benefits. Use by commercial drivers or other heavy equipment operators can result in job loss. For these reasons, no additional research on cocaine is reported here. CANNABINOIDS [THC FROM MARIJUANA AND HASHISH] Cannabinoids are compounds extracted from the cannabis sativa plant (marijuana) or the cannabis indica plant (hashish— Arabic word meaning grass), or they can be produced synthet- ically. They also can be produced in the body after ingestion and metabolism of cannabis, or even occur naturally within the body or brain (Solowij 1998; Shinar 2007b). Marijuana or THC dependency can develop with chronic use. In the United States, in states where it is permitted, chronic treatment with medical marijuana is legitimately prescribed as a sedative because it is used for treatment of some medical conditions to reduce sensation of chronic pain and discomfort. Legitimate medical uses for THC include treatment of pain, anorexia, and chronic illness such as AIDS or cancer. Under Federal Regulations Part 40, medical marijuana is not authorized for commercial driver’s license (CDL) holders. Marijuana is normally considered to be a recreational drug in the form of dried tops and leaves of the cannabis sativa plant. NIDA lists street names for marijuana as blunt, dope, ganja, grass, herb, weed, joints, Mary Jane, pot, reefer, sinsemilla, and skunk; and for hashish, names such as boom, chronic, gangster, hash, hash oil, and hemp. The primary psy- choactive cannabinoid found in both marijuana and hashish is delta-9-tetrahydrocannabinol (THC). Because of the time it takes to reach the blood stream, the effects of THC are quicker and greater when it is smoked (e.g., in marijuana cigarettes), with time-to-peak levels in the brain being about 7 to 8 min. If it is inhaled into the lungs, marijuana effects are noticeable almost immediately. When marijuana is taken orally (eaten), the psychoactive peak effects appear within 10 to 30 min, and may remain for about one hour, but dissipate after more than 1 to 2 h. The half-life of THC is about one week; however, THC gets absorbed into body fat, and traces of THC metabolites (such as THC–COOH) that by themselves have no psychoactive properties can be detected in urine for as long as a month following ingestion (Chesher 1995).

75 Unlike alcohol, THC does not distribute evenly in all tissues, and its rate of absorption and elimination is different for experienced and inexperienced users. The method of measurement of THC in the body greatly affects the impli- cations for impairment and the estimated time of ingestion. Although the subjective level of a psychological or a physio- logical “high” experienced by participants in well-controlled marijuana studies is highly correlated with the THC level in the blood stream (Robbe 1994), it is difficult to assess and determine a relationship between a person’s THC blood or plasma concentration and performance impairing effects. Physiologically, THC raises a person’s heart rate and has CNS effects. Cannabinoid receptors are concentrated in several distinct regions of the brain (the cerebellum, hippocampus, basal ganglia, and cortex) and therefore the effects of THC are quite varied. Although THC does not have a large effect on sensory functions, it impairs cortex-mediated higher-order perceptual functions, resulting in distorted time and dis- tance perception (Laberge and Ward 2004; NHTSA 2005; NIDA 2006). The most commonly noted psychological effects of mari- juana and the THC contained therein include enhanced mood, in which individuals normally feel better; but effects might also include irritability and disturbance of memory and judg- ment (Croft et al. 2001). It impairs cognitive functions that result in slowed thinking and reaction time, impaired mem- ory and learning, difficulties in sustaining or shifting atten- tion, and in problem solving. Marijuana also impairs motor functions leading to loss of coordination and to impaired balance (NHTSA 2005), and marijuana users may experience sensations of confusion, anxiety, euphoria, and sleepiness (Shinar and Schechtman 2005; Shinar 2007b). These perfor- mance degradations manifest themselves in driving (Smiley 1999). However, in experimental situations, subjects can often “pull themselves together” to concentrate on simple tasks for brief periods of time, thus making it difficult to generalize from lab findings of performance effects to real life scenarios (NHTSA 2003, 2005; NIDA 2005). A series of lab-based studies in the Netherlands (Robbe and O’Hanlon 1993; Robbe 1994) examined effects of marijuana on actual driving performance. After subjects smoked stan- dardized marijuana cigarettes, they drove in traffic for 64 km (∼40 miles) at speeds of up to 100 km/h (∼62 mph). A com- monly employed lab-based standardized test [standard devia- tion of lateral position (SDLP)] measured driving impairment in the form of vehicular weaving. Plasma specimens were analyzed for THC and its carboxy metabolite (THC-COOH). It was concluded that: “THC’s effects on SDLP were equivalent to those associated with BACs [blood alcohol concentrations] in the range of 0.3–0.7 mg/mL. Other driving performance measures were not significantly affected by THC. THC’s effects after smoking doses up to 300 mg/kg of hashish never exceeded those of alcohol at BACs of 0.8 mg/mL.” Robbe and O’Hanlon (1993) said “it appears not possible to conclude anything about a driver’s impairment on the basis of his/her plasma concentration of THC and THC-COOH determined in a single sample.” In the marijuana research program sponsored by NHTSA, but conducted in the Netherlands, the conclusions in the NHTSA final report read in part: This program of research has shown that marijuana, when taken alone, produces a moderate degree of driving impair- ment which is related to the consumed THC dose. The impair- ment manifests itself mainly in the ability to maintain a steady lateral position on the road, but its magnitude is not excep- tional in comparison with changes produced by many med- icinal drugs and alcohol. Drivers under the influence of marijuana retain insight in their performance and will com- pensate, where they can, for example by slowing down or increasing effort. As a consequence, THC’s adverse effects on driving performance appear relatively small. [Source: NHTSA final report, Nov. 1993 (DOT HS 808 078)]. Carter (1980) studied effects of chronic marijuana use in Costa Rica. Subjects were 86 chronic marijuana users and 156 nonusers. The users self-reported smoking an average of 10 marijuana cigarettes a day for a minimum of 10 years and an average of 17 years. The cigarettes contained 1.3% to 3.7% THC. Some of the marijuana user subjects earned their living by driving trucks, buses, or taxies, and some preferred to drive while under the influence of the drug. The study dis- cerned no real consequences of prolonged use of the drug as it reported: “no hard data were obtained regarding the effect of marijuana use on driving ability” (Carter 1980). McBay reported that Carter’s findings were in keeping with controlled studies carried out in Jamaica and Greece. Although Beirness et al. (2005) reported the incidence of cannabis in motor vehicle crashes, until actual driving studies are performed that report blood concentrations in heavy chronic marijuana users, one can only speculate what the long-term effects might be (McBay 1997). A NIDA study examined the performance effects of several drug classes using repeated measures design. Eight volunteers were administered two doses of ethanol (0.3 and 1.0 g/kg), marijuana (1.3% and 3.9% THC), amphetamine (10 and 30 mg), hydromorphone (1 and 3 mg), pentobarbital (150 and 450 mg), or placebo on separate days (Pickworth et al. 1997). The larger dose of each drug increased subjective reports of drug strength; however, only ethanol and pentobarbital impaired performance on circular lights, digit symbol substitution, and serial math tasks. Both ethanol and pentobarbital impaired performance on card-sorting tasks, wherein impairment was evident at lower doses as the cognitive load increased. Results illustrated differences among drugs producing performance impairment at doses that cause subjective effects. Increasing cognitive requirements (increased workload) detected performance impairment at lower doses. Marijuana had a significant effect on a serial add–subtract task in that response time was signif- icantly slower (46%) by the 3.9% THC marijuana cigarette smokers at 30 min. Marijuana did not have a significant effect

76 on the other 13 performance measures in the study. Pickworth et al. (1997) stated that their results differed from those of several studies that showed performance impairment after smoking marijuana. In a meta-analysis by Berghaus et al. (1998) of 60 studies that examined cannabis results, as well as 197 studies of alcohol effects, both the similarity of THC and alcohol-related impairments and their differences were illustrated. They are similar in that at some level of drug dose both affect a wide variety of cognitive functions. They are dissimilar in that the level of blood alcohol needed to show impairment is nearly the same in all studies, with the median approximately 0.07% (slightly above the threshold for driving in most European countries and slightly below the threshold for automobile drivers in the United States); by contrast, the range of THC concentrations needed to affect the various cognitive functions is quite large, with some functions—the inter-related functions of tracking, psychomotor behavior, and driving/simulator performance—being impaired at low THC levels, whereas others—such as information processing and visual functions— are impaired at much higher THC levels (Heishman et al. 1990, 1997; Wilson et al. 1994; Ramaekers et al. 2004). Shinar says this is important because the uniformity of impairment with alcohol provides a rationale for setting specific BAC lim- its, whereas the lack of uniformity for THC concentrations makes it difficult to determine safe driving threshold levels for THC. Berghaus et al. (1998) conducted an extensive review of 87 findings on the effects of THC dosing on various driving- related psychomotor tasks. They reported that the dose- response relationship is not very consistent, and surmised that when inhaled the effect of cannabis peaks within the first hour, and diminishes afterwards. However, when eaten (digested), the effects may be delayed 1 to 2 h. Even under careful exper- imental conditions, within the first hour of smoking and with a high dose of more than 18 mg/ml THC, 40% of study results failed to demonstrate THC impaired performance. The tests reflected a mix of psychomotor tasks, some very sensitive to THC, and some not. The most sensitive tasks, the ones that show the greatest and most consistent impairments, are the ones that involve attention, tracking, reaction time, learning, and short-term memory. Recall of information learned after cannabis ingestion is greatly impaired, whereas recall of infor- mation in long-term memory is not impaired (Ramaekers et al. 2004). Even though crash statistics suggest alcohol is involved in a far greater number of highway crashes, cannabis intoxication is still very much a problem (perhaps in some countries more than others) in that significant numbers of highway crashes, many of them fatal, are at least in part attributable to driving under the influence of marijuana. Laumon et al. (2005) exam- ined fatal crash incidents in France for 10,748 drivers with known drug and alcohol concentrations involved in fatal crashes (2001 to 2003); they reported 681 drivers tested posi- tive for cannabis, including 285 with an illegal BAC (>0.5 g/l). The presence of cannabis was associated with increased risk of responsibility (odds ratio 3.32), and a significant dose effect was identified. The prevalence of cannabis (2.9%) estimated for the driving population is similar to that for alcohol (2.7%). At least 2.5% of fatal crashes were estimated as being attrib- utable to cannabis, compared with at least 28.6% for alcohol. Although alcohol may be the bigger problem in France, the study concluded that driving under the influence of cannabis increases the risk of involvement in a crash (Laumon et al. 2005). Ojaniemi et al.’s (2008) assessment of crash statistics in Finland illustrated that cannabinoids may be an even more pronounced problem in more than 27% of that country’s highway crashes, and Jones (2005) and Holmgren et al. (2007) indicated positive findings of THC in 20% to 25% of crashes in Sweden. Baldock (2007) reported similar concerns over the influence of marijuana in injury crashes in Australia, as did Kelly et al. (2004) and Longo et al. (2000a, b). Some of these seemingly high crash numbers no doubt are in part attributable to the more lax approach to use of marijuana and highway safety enforcement rules in several European countries. In summary, cannabis impairments to performance (1) are not very consistent; they dissipate quickly after about an hour so that just a few hours after ingestion they are no longer significant, even though cannabinoid metabolites can be detected in the urine for several weeks after ingestion; (2) are recognized as troublesome in traffic safety regulations enforced in some countries (including the United States), but not others (e.g., Costa Rica); and (3) raise additional concerns over whether or not regular users become addicted to marijuana and other illegal substances. The incidence of numbers of commercial drivers in the United States who participate in marijuana or hashish use is largely unknown. However, it is generally believed that because of enforced random urine screening for this and other illegal drugs, and the impending threat of losing one’s job and livelihood, the rate of users in the transportation industry seems at least manageable from a safety standpoint [this observation is largely based on the personal experiences of the first author, G. Krueger, during a decade of teaching and interacting with more than 4,000 safety and risk man- agers in alertness, fatigue, and health and wellness courses (Krueger and Brewster 2002, 2005)]. EPHEDRINE (MA-HUANG) Ephedra is a plant containing the stimulant ephedrine, an over-the-counter substance found in dietary supplements and weight loss products (e.g., Xenadrine™, Ripped Fuel™, and other commercial names). Along with its alkaloids, ephedrine takes on street names as Desert Herb, Joint Fir, Popotillo, Sea Grape, Yellow Horse, and Teamster’s Tea. Ephedrine is a known stimulant that produces sympathomimetic actions, which act on alpha and beta adrenergic receptors in the CNS

77 and periphery. It is also a dopaminergic agonist (Angrist et al. 1997). Ephedrine fuels metabolism, causing irregularities in thermoregulation; that is, the body produces more heat. Ephedrine alkaloids increase cardiac output and muscle con- traction, raise blood sugar, and serve as a bronchodilator to open bronchial pathways for easier breathing (Astrup et al. 1991). In the past, ephedrine was used as a CNS stimulant in narcolepsy and depressive states (Nutto 1983). More recently, ephedrine has been replaced by alternative treatments for these disorders. The usual dose is 24 mg orally. The duration of ephedrine effects is from 6 to 8 h (plasma half-life 3 to 6 h), with drug clearance from the body within 24 h (Angrist et al. 1997). It is claimed that ephedrine makes a person more alert, gives an energy lift, suppresses appetite, and is commonly used in attempts to lose weight. Many athletes have taken ephedrine for various purposes in their work-out routines, especially for weight control. It is claimed that ephedrine enhances aerobic and anaerobic capacity, muscular strength, and mus- cular endurance. Ephedrine has been demonstrated to have thermogenic properties, and it promotes fat metabolism (Vallerand et al. 1989) particularly when taken in combination with caffeine. Ephedrine has been shown to reduce the perception of physical fatigue (Moolenaar et al. 1999). However, there is a paucity of data to support declaring ephedrine to be an ergogenic aid or for actually having long-term weight loss value. Preliminary research on cognitive functions finds that ephedrine enhances vigilance; but there is insufficient pub- lished information to confirm that. Although no reports examining ephedrine and driving were located, Moolenaar and colleagues (1999) examined the effects of 60 mg of ephedrine on a 3-way divided attention task (which they called a driving-related task) for an uninterrupted 4-h period, during which numerous physiological measures were mon- itored for 15 participants. The performance of a placebo group deteriorated over time, whereas the performance of the ephedrine group improved. They concluded the development of fatigue was partially offset by a single therapeutic dose of ephedrine. No real conclusions can be made about ephedrine and driving-like performance on such scant data reports; more research on that aspect of ephedrine would be required. There are known hazards with ephedrine use (Bell et al. 1999). Pittler et al. (2005) reviewed the literature for adverse events of herbal food supplements taken for body weight reduction. For herbal ephedra and ephedrine-containing food supplements, they found reports of increased risk of psychi- atric, autonomic or gastrointestinal adverse events, and heart palpitations. Therapeutic doses of ephedrine can cause minor hand tremors, increased blood pressure, tachycardia, fear, anxiety, restlessness, and insomnia. Long-term use is not recommended. Severe side effects include high blood pres- sure, rapid heart rate, dizziness, seizures, strokes, heart attacks, even death. Overdoses can cause paranoid psychosis, delu- sions, cerebral hemorrhage, and cardiac arrest. For a decade or more (circa 1990s–2005), following the lead of the weight-room athletes, many Americans took ephedrine as an ingredient in numerous over-the-counter diet pills in attempts to control their body weight. Then new fears about adverse side effects attributable to ephedrine came to public light. There have been newsworthy reports of promi- nent athletes taking ephedrine and experiencing heat stroke, followed by cardiac arrest, leading to multiple organ failure and even death on the playing field. These incidents pointed out the real risks associated with ephedrine, especially when exercising in the heat. Those reports of serious adverse events with ephedrine prompted the FDA to prohibit its sale in dietary supplements; however, it is still available in various forms in select locations in the United States (Schweitzer 2005). Anecdotal reports periodically surface indicating that some commercial drivers take ephedrine in some form, at least occasionally. Some commercial drivers who have problems with weight control (numerous truck drivers are known to be obese) take ephedrine as a component of com- mercially available dietary compounds in their attempts to control their weight. For some drivers who fancy themselves as being athletic, there still may be a misguided belief that ephedrine will help them keep physically fit and also alert. However, because ephedrine produces too many untoward side effects and adverse reactions it is recommended that commercial drivers steer clear of ephedrine. Getting the word out to drivers to avoid ephedrine has not been completely systematic. Caffeine Combined with Ephedrine The technique of combining caffeine and ephedrine has been used in several forms of diet pills in the United States. The advertising claims benefits include improved vigilance, enhancements in mood, reduced fatigue, quicker reaction times, and improved accuracy at mental arithmetic (Baranski et al. 2001; TTCP 2001). As for the mode of action, both sub- stances (ephedrine and caffeine) stimulate the CNS. Ephedrine is also an agonist for peripheral α and β adrenergic receptors. Caffeine is an antagonist of CNS and peripheral adenosine receptors, also thought to modulate release of Ca++ from sarcoplasmic reticulum. Together they may potentiate each other, and physical performance is enhanced (Astrup et al. 1991; Young et al. 1998; Pasternak et al. 1999). The duration of the combined effect of caffeine and ephedrine is about 5 to 8 h, with peak plasma concentrations occurring 1.5 to 2 h after ingestion. Clearance of one drug is normally not affected by clearance of the other (Bordeleau et al. 1999). Studies by Bell and colleagues examined the effects of combinations of caffeine and ephedrine on running perfor- mance and found that the combination raised metabolic heat production and posed risks of hyperthermia during exercise-

78 heat stress (Bell and Jacobs 1999). In a study of 2 h of brisk treadmill walking in a 40°C hot, dry environment, Bell and colleagues (1999) observed that increased metabolic heat production was offset by increased heat dissipation and the internal body temperature change was not greater than dur- ing a control trial. They also found caffeine combined with ephedrine produced improvements in vigilance, performance of mental arithmetic in terms of both speed and accuracy, and reaction time. Mood was also enhanced, and fatigue state was lessened (Bell et al. 2001). Haller and Benowitz (2000) reported the likelihood of adverse cardiovascular and CNS events resulting from use of ephedra-containing supplements, which makes the use of a caffeine-ephedra combination inadvisable. Although hyper- thermia is more likely when prolonged, strenuous exercise and intense environmental stress are concurrent, the effects of caffeine in this situation have not been adequately exam- ined (Institute of Medicine–Committee on Military Nutrition Research 2001). There is insufficient information to make a definitive judgment on the combined effects of caffeine and ephedrine on cognitive performance. More research on this topic to determine those combined effects would be warranted if it were not for the known adverse effects of ephedrine reported earlier, which makes the entire issue moot. In terms of the hazards associated with taking combinations of the two stimulants; nausea and vomiting has been reported in lab and field studies when hard exercise is performed after ingesting combinations of caffeine and ephedrine. Other potential side effects include insomnia, nervousness, anxiety and wakefulness, minor hand tremors, increased blood pres- sure, and appetite suppression; all such symptoms dissipate within 24 h of cessation of use. As is mentioned in the section on ephedrine, during the past decade there have been high visibility (newsworthy) events involving the untimely deaths of prominent profes- sional and collegiate athletes whose deaths were attributed to the use of commercially available ephedrine while exercising in high heat and high humidity. These tragic cases each witnessed dramatic effects on body temperature regulation during humid, heat-stress-producing conditions. Subsequent public warnings to all athletic teams have advised against the use of ephedrine. The conditions of the use of ephedrine by the general public, perhaps in the form of dietary pills that likely also contain caffeine, and any propensity to consume such pills along with additional amounts of caffeine (perhaps simply by drinking coffee) is unknown. Recently, the sale of ephedrine in dietary supplements has been prohibited by the FDA (Schweitzer 2005). Despite the ban, many ephedra products are still sold on the Internet. Their purchase and use should be avoided.

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Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements Get This Book
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TRB’s Commercial Truck and Bus Safety Synthesis Program (CTBSSP) Synthesis 19: Effects of Psychoactive Chemicals on Commercial Driver Health and Performance: Stimulants, Hypnotics, Nutritional, and Other Supplements identifies available information and research gaps relating to the use of chemical substances by commercial drivers and is intended to provide up-to-date information to inform decision makers about the near-, mid-, and long-range planning needs for research and educational outreach programs.

The report is designed to help the commercial transportation safety community and the Federal Motor Carrier Safety Administration in addressing issues involving the proliferation and availability of psychoactive chemical substances.

Appendixes D and G to CTBSSP Synthesis 19 are available only in the pdf version of report.

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