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

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

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

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

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75 Unlike alcohol, THC does not distribute evenly in all anything about a driver's impairment on the basis of his/her tissues, and its rate of absorption and elimination is different plasma concentration of THC and THC-COOH determined for experienced and inexperienced users. The method of in a single sample." measurement of THC in the body greatly affects the impli- cations for impairment and the estimated time of ingestion. In the marijuana research program sponsored by NHTSA, Although the subjective level of a psychological or a physio- but conducted in the Netherlands, the conclusions in the logical "high" experienced by participants in well-controlled NHTSA final report read in part: marijuana studies is highly correlated with the THC level in the blood stream (Robbe 1994), it is difficult to assess and This program of research has shown that marijuana, when determine a relationship between a person's THC blood or taken alone, produces a moderate degree of driving impair- plasma concentration and performance impairing effects. 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- Physiologically, THC raises a person's heart rate and has tional in comparison with changes produced by many med- CNS effects. Cannabinoid receptors are concentrated in several icinal drugs and alcohol. Drivers under the influence of distinct regions of the brain (the cerebellum, hippocampus, marijuana retain insight in their performance and will com- basal ganglia, and cortex) and therefore the effects of THC are pensate, where they can, for example by slowing down or increasing effort. As a consequence, THC's adverse effects on quite varied. Although THC does not have a large effect on driving performance appear relatively small. [Source: NHTSA sensory functions, it impairs cortex-mediated higher-order final report, Nov. 1993 (DOT HS 808 078)]. perceptual functions, resulting in distorted time and dis- tance perception (Laberge and Ward 2004; NHTSA 2005; Carter (1980) studied effects of chronic marijuana use in NIDA 2006). Costa Rica. Subjects were 86 chronic marijuana users and 156 nonusers. The users self-reported smoking an average The most commonly noted psychological effects of mari- of 10 marijuana cigarettes a day for a minimum of 10 years juana and the THC contained therein include enhanced mood, and an average of 17 years. The cigarettes contained 1.3% to in which individuals normally feel better; but effects might 3.7% THC. Some of the marijuana user subjects earned their also include irritability and disturbance of memory and judg- living by driving trucks, buses, or taxies, and some preferred ment (Croft et al. 2001). It impairs cognitive functions that to drive while under the influence of the drug. The study dis- result in slowed thinking and reaction time, impaired mem- cerned no real consequences of prolonged use of the drug as ory and learning, difficulties in sustaining or shifting atten- it reported: "no hard data were obtained regarding the effect tion, and in problem solving. Marijuana also impairs motor of marijuana use on driving ability" (Carter 1980). McBay functions leading to loss of coordination and to impaired reported that Carter's findings were in keeping with controlled balance (NHTSA 2005), and marijuana users may experience studies carried out in Jamaica and Greece. Although Beirness sensations of confusion, anxiety, euphoria, and sleepiness et al. (2005) reported the incidence of cannabis in motor (Shinar and Schechtman 2005; Shinar 2007b). These perfor- vehicle crashes, until actual driving studies are performed that mance degradations manifest themselves in driving (Smiley report blood concentrations in heavy chronic marijuana users, 1999). However, in experimental situations, subjects can often one can only speculate what the long-term effects might be "pull themselves together" to concentrate on simple tasks for (McBay 1997). brief periods of time, thus making it difficult to generalize from lab findings of performance effects to real life scenarios A NIDA study examined the performance effects of several (NHTSA 2003, 2005; NIDA 2005). drug classes using repeated measures design. Eight volunteers were administered two doses of ethanol (0.3 and 1.0 g/kg), A series of lab-based studies in the Netherlands (Robbe and marijuana (1.3% and 3.9% THC), amphetamine (10 and 30 mg), O'Hanlon 1993; Robbe 1994) examined effects of marijuana hydromorphone (1 and 3 mg), pentobarbital (150 and 450 mg), on actual driving performance. After subjects smoked stan- or placebo on separate days (Pickworth et al. 1997). The larger dardized marijuana cigarettes, they drove in traffic for 64 km dose of each drug increased subjective reports of drug strength; (40 miles) at speeds of up to 100 km/h (62 mph). A com- however, only ethanol and pentobarbital impaired performance monly employed lab-based standardized test [standard devia- on circular lights, digit symbol substitution, and serial math tion of lateral position (SDLP)] measured driving impairment tasks. Both ethanol and pentobarbital impaired performance in the form of vehicular weaving. Plasma specimens were on card-sorting tasks, wherein impairment was evident at lower analyzed for THC and its carboxy metabolite (THC-COOH). It doses as the cognitive load increased. Results illustrated was concluded that: "THC's effects on SDLP were equivalent differences among drugs producing performance impairment to those associated with BACs [blood alcohol concentrations] at doses that cause subjective effects. Increasing cognitive in the range of 0.30.7 mg/mL. Other driving performance requirements (increased workload) detected performance measures were not significantly affected by THC. THC's impairment at lower doses. Marijuana had a significant effect effects after smoking doses up to 300 mg/kg of hashish never on a serial addsubtract task in that response time was signif- exceeded those of alcohol at BACs of 0.8 mg/mL." Robbe icantly slower (46%) by the 3.9% THC marijuana cigarette and O'Hanlon (1993) said "it appears not possible to conclude smokers at 30 min. Marijuana did not have a significant effect

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

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77 and periphery. It is also a dopaminergic agonist (Angrist et al. sure, rapid heart rate, dizziness, seizures, strokes, heart attacks, 1997). Ephedrine fuels metabolism, causing irregularities even death. Overdoses can cause paranoid psychosis, delu- in thermoregulation; that is, the body produces more heat. sions, cerebral hemorrhage, and cardiac arrest. Ephedrine alkaloids increase cardiac output and muscle con- traction, raise blood sugar, and serve as a bronchodilator to For a decade or more (circa 1990s2005), following the open bronchial pathways for easier breathing (Astrup et al. lead of the weight-room athletes, many Americans took 1991). In the past, ephedrine was used as a CNS stimulant in ephedrine as an ingredient in numerous over-the-counter diet narcolepsy and depressive states (Nutto 1983). More recently, pills in attempts to control their body weight. Then new fears ephedrine has been replaced by alternative treatments for about adverse side effects attributable to ephedrine came to these disorders. public light. There have been newsworthy reports of promi- nent athletes taking ephedrine and experiencing heat stroke, The usual dose is 24 mg orally. The duration of ephedrine followed by cardiac arrest, leading to multiple organ failure effects is from 6 to 8 h (plasma half-life 3 to 6 h), with drug and even death on the playing field. These incidents pointed clearance from the body within 24 h (Angrist et al. 1997). out the real risks associated with ephedrine, especially when It is claimed that ephedrine makes a person more alert, gives exercising in the heat. Those reports of serious adverse events an energy lift, suppresses appetite, and is commonly used in with ephedrine prompted the FDA to prohibit its sale in dietary supplements; however, it is still available in various attempts to lose weight. Many athletes have taken ephedrine forms in select locations in the United States (Schweitzer 2005). for various purposes in their work-out routines, especially for weight control. It is claimed that ephedrine enhances Anecdotal reports periodically surface indicating that aerobic and anaerobic capacity, muscular strength, and mus- some commercial drivers take ephedrine in some form, cular endurance. Ephedrine has been demonstrated to have at least occasionally. Some commercial drivers who have thermogenic properties, and it promotes fat metabolism problems with weight control (numerous truck drivers are (Vallerand et al. 1989) particularly when taken in combination known to be obese) take ephedrine as a component of com- with caffeine. mercially available dietary compounds in their attempts to control their weight. For some drivers who fancy themselves Ephedrine has been shown to reduce the perception of as being athletic, there still may be a misguided belief that physical fatigue (Moolenaar et al. 1999). However, there ephedrine will help them keep physically fit and also alert. is a paucity of data to support declaring ephedrine to be However, because ephedrine produces too many untoward an ergogenic aid or for actually having long-term weight side effects and adverse reactions it is recommended that loss value. commercial drivers steer clear of ephedrine. Getting the word out to drivers to avoid ephedrine has not been completely Preliminary research on cognitive functions finds that systematic. ephedrine enhances vigilance; but there is insufficient pub- lished information to confirm that. Although no reports examining ephedrine and driving were located, Moolenaar Caffeine Combined with Ephedrine and colleagues (1999) examined the effects of 60 mg of The technique of combining caffeine and ephedrine has ephedrine on a 3-way divided attention task (which they been used in several forms of diet pills in the United States. called a driving-related task) for an uninterrupted 4-h period, The advertising claims benefits include improved vigilance, during which numerous physiological measures were mon- enhancements in mood, reduced fatigue, quicker reaction itored for 15 participants. The performance of a placebo times, and improved accuracy at mental arithmetic (Baranski group deteriorated over time, whereas the performance of the et al. 2001; TTCP 2001). As for the mode of action, both sub- ephedrine group improved. They concluded the development stances (ephedrine and caffeine) stimulate the CNS. Ephedrine of fatigue was partially offset by a single therapeutic dose of is also an agonist for peripheral and adrenergic receptors. ephedrine. No real conclusions can be made about ephedrine Caffeine is an antagonist of CNS and peripheral adenosine and driving-like performance on such scant data reports; receptors, also thought to modulate release of Ca++ from more research on that aspect of ephedrine would be required. sarcoplasmic reticulum. Together they may potentiate each other, and physical performance is enhanced (Astrup et al. There are known hazards with ephedrine use (Bell et al. 1991; Young et al. 1998; Pasternak et al. 1999). The duration of 1999). Pittler et al. (2005) reviewed the literature for adverse the combined effect of caffeine and ephedrine is about 5 to 8 h, events of herbal food supplements taken for body weight with peak plasma concentrations occurring 1.5 to 2 h after reduction. For herbal ephedra and ephedrine-containing food ingestion. Clearance of one drug is normally not affected by supplements, they found reports of increased risk of psychi- clearance of the other (Bordeleau et al. 1999). atric, autonomic or gastrointestinal adverse events, and heart palpitations. Therapeutic doses of ephedrine can cause minor Studies by Bell and colleagues examined the effects of hand tremors, increased blood pressure, tachycardia, fear, combinations of caffeine and ephedrine on running perfor- anxiety, restlessness, and insomnia. Long-term use is not mance and found that the combination raised metabolic heat recommended. Severe side effects include high blood pres- production and posed risks of hyperthermia during exercise-

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