Literature documenting experimental research on drugs is reviewed in this chapter. Two general types of research are treated, (1) research conducted in a laboratory testing human performance on tasks believed to be related to driving, and (2) research conducted either in a driving simulator or on a closed course testing performance of actual driving tasks. The discussion is organized by drug class, with individual studies within a class being discussed with respect to their design, their findings, and their conclusions. Some studies compared different classes of drugs, and these studies are placed with the class that seemed to be their major focus. Classes of drugs considered are:
Laboratory studies have used a variety of tests to determine the effect of drugs on performance assumed to be related to driving. Some of the more commonly used tests are:
Simulator studies have been conducted across a range of levels of complexity, from subjects seated in front of a screen operating simulated vehicle controls to subjects seated in a mounted module experiencing realistic dynamic motion feedback from their inputs to the simulated vehicle controls. The Daimler-Benz simulator in Germany is an example of the most advanced driving simulators and has been used in a number of studies of the effect of drugs on driving performance. NHTSA's National Advanced Driving Simulator (NADS), currently initiating operations, is another example of the most sophisticated driving simulators. The NADS consists of a large dome in which entire cars and the cabs of trucks and buses can be mounted. This allows the driver to feel acceleration, braking and steering cues as if he or she were actually in a real car, truck or bus.
Closed-course driving studies have typically been conducted on a road or open area closed to other vehicles. Instrumented vehicles are used, and the vehicle's actual responses to driver inputs to steering, braking, and acceleration controls are measured.
Laboratory Studies
Only four laboratory studies published after 1980 were found for this class of drugs. In the first study, Stevenson, Pathria, Lamping, et al. (1986) administered diazepam (7.5 mg) or fentanyl (a synthetic opioid, 100 micro-grams), or placebo, to 5 male and 4 female students. They measured performance on a tracometer (a driving-related task sanctioned by the National Research Council), before, 30 minutes after drug administration, and 120 minutes after drug administration. The results showed that both drugs impaired performance on four tracometer tasks (correct reaction time, non-overshoot movement time, overshoot movement time, and total response time). Interestingly, although fentanyl has a shorter half-life time than diazepam (2 hours vs. 9 hours), in general, the impairments with fentanyl increased after 2 hours, whereas the impairments with diazepam decreased (indicating lack of relationship between drug plasma level and size of effect).
More recently, Kubitzki (1997) compared the performance of 22 patients 25-45 years old who had been undergoing methadone treatment for 1-5 years, with the performance of matched (for age, sex, and education) control subjects. The methadone dosage levels of the subjects was not indicated, though presumably subjects were tested at their therapeutic doses. The groups were compared on several cognitive and psychomotor tasks, including tracking, reaction time, "cognitive perceptual speed" and driving on a closed course. The results failed to yield any significant differences between the two groups; leading the author to conclude that there is no performance-based reason to preclude such people from driving at the dosages tested.
In their evaluation of the correlation between drug presence and various signs and symptoms, Zancaner, Giorgetti, Dal Pozzo, et al. (1997), examined the blood or urine of 480 Italian drivers stopped by police for DWI. Although the frequencies of the different drugs are not reported in their paper, they did find a few suspects with opiates, and noted that relative to unimpaired people, a "high percentage" of them had poor coordination, especially as observed with the finger-to-nose test.
The most recent analysis of codeine impairment was reported by Compton, Shinar, and Schechtman (2000), who analyzed its effects on signs and symptoms included in the Drug Evaluation and Classification program (DEC). The only statistically significant effect they found was a reduction in pupil size, both in the light and in the dark.
In summary, although the data related to driving-related skills is sparse, narcotics can impair some behaviors, but further studies are needed to determine their effect on motor coordination, reaction time, and movement control.
Closed-course and Driving Simulator Studies
We found no recent closed-course or driving simulator studies of acute effects narcotic drugs. However, in an earlier study, Linnoila and Hakkinen (1974) studied the behavior of Finnish professional military drivers, 19-22 years old, in a driving simulator. Different groups of 10 subjects each were provided with either no drugs, alcohol, diazepam (10 mg), codeine (50 mg), alcohol+codeine, or alcohol+diazepam. The driving task started 30 minutes after drug/alcohol administration. Results showed that the number of "collisions" was greatest with codeine alone (more than with alcohol or with alcohol+codeine). The drivers under the influence of codeine and codeine+alcohol also went off the road more often and neglected more of the instructions than the control groups. Thus, codeine definitely impaired driving, but the drug-alcohol interaction was not simple.
An interesting recent study addressed the chronic use of narcotics as a treatment for pain (Galski, Williams, and Ehle, 2000). Sixteen patients with chronic nonmalignant pain on Chronic Opioid Analgesic Therapy (COAT) underwent a comprehensive off-road driving evaluation using several measures believed to be predictive of on-road driving performance. The evaluation consisted of a pre-driver evaluation, a simulator evaluation, and behavioral observation during simulator performance. Patients in the COAT group were compared to a historical control group of 327 cerebrally compromised patients (CComp) who had undergone the same evaluation and then passed an on-road, behind-the-wheel evaluation (n = 162) or failed the behind-the-wheel evaluation (n = 165). The results revealed that COAT patients generally outperformed the CComp patients as a group. Notably, COAT patients had a relatively poorer performance than CComp patients on specific neuropsychometric tests in the pre-driver evaluation; however, the differences were not statistically significant. Behaviorally, COAT patients were generally superior to CComp patients, but COAT patients had greater difficulty in following instructions, had a tendency toward impulsivity, and were similar in these respects to the Ccomp subjects who failed the behind-the-wheel evaluation. The authors concluded that COAT did not appear to significantly impair the perception, cognition, coordination, and behavior measured in off-road tests.
CENTRAL NERVOUS SYSTEM DEPRESSANTS
Benzodiazepines
The benzodiazepine family of depressants are used therapeutically to produce sedation, induce sleep, relieve anxiety and muscle spasms, and to prevent seizures. The most common side effect of benzodiazepines is sedation, due to their CNS depressant action (Kunsman, Manno, Przekop et al., 1992). Benzodiazepines are distinguished from each other in terms of the duration of their effects. Long half-life benzodiazepines sustain their effects - and their side effects - for more than nine hours. Examples are alprazolam (Xanax), chlordiazepoxide (Librium), clorazepate (Tranxene), diazepam (Valium), halazepam (Paxipam), lorazepam (Ativan), oxazepam (Serax) and prazepam (Centrax). Shorter half-life benzodiazepines typically reach their peak within two to three hours and include estazolam (ProSom), flurazepam (Dalmane), quazepam (Doral), temazepam (Restoril) and triazolam (Halcion).
Laboratory Studies. A large number of pertinent laboratory studies have appeared since 1980. Rothenberg and Selkoe (1981) measured saccadic eye movements in response to a dot that jumped 2-36 degrees nasally from the center of the visual field, in a random fashion. Performance of 6 healthy volunteers was measured 75 minutes after administration of 0, 5 or 10 mg diazepam. Bittencourt, Wade, Smith, and Richens (1981) performed a similar study of eye movements, both studies finding an impairment in visual search performance.
Also in 1981, Landauer (1981) published a review of the literature in which he concluded that no studies clearly indicated whether orally administered diazepam adversely affects the ability of a patient to drive a car. He noted that while it is preferable for anxious, aggressive, or depressed patients not to drive, diazepam tends to relieve these symptoms, and its use by such patients should not lead to an automatic prohibition of car driving
However, Soames (1982) disagreed with Landauer's contention, asserting that the bulk of evidence suggests that diazepam is harmful to driving ability, even in appropriate patient populations, and that the detrimental effects of alcohol on driving ability are also exacerbated by diazepam. He recommended that patients taking diazepam should avoid driving, especially if they have taken any alcohol.
Parrott, Hindmarch, and Stonier (1982) administered either clobazam, nomifensine (an antidepressant), a combination of the two, or placebo, five times over a period of 3 days each. They tested the effect of the drugs on the performance of twelve female volunteers of age 28-46 immediately after the 5th administration or later in the afternoon. No effects were found (relative to placebo) on any of the performance measures for all three drug conditions. The authors noted that the results are quite consistent with those of previous studies, in so far as they suggest that there is an adaptation effect in response to chronic administration of these drugs.
Spinweber and Johnson (1982) used a between-group design to evaluate the effects of 0.5 mg triazolam on performance on various psychomotor tasks. Their subjects were 20 male poor sleepers, an average age of 21 years old, who were awakened 1.5, 3, and 5 hours after nighttime drug administration, over a period of 6 nights. They found performance was worst at the short intervals of 1.5 and 3 hours after drug administration.
Griffiths, Bigelow and Liebson (1983) administered low and high doses of diazepam and pentobarbital to 12 men with a history of sedative drug abuse, over a period of 5 days, followed by 10-14 days of placebo. They found that both diazepam and pentobarbital produced dose-related deteriorations in choice reaction time and daytime sleeping. However, only diazepam produced dose-related decreases in staff rating of patients' mood and social interaction, and increases in staff rating of hostility and unusual behavior. The maximal drug effect for both dosages appeared 2 hours after drug administration.
In his analysis of the effects of different drugs on attention tasks, Moskowitz (1984) briefly mentions an unpublished study in which his subjects performed a central tracking task and a peripheral target detection task after ingesting flurazepam (0, 15, 30, and 55 mg). There were dose-related long-term impairments (up to 12 hours after drug intake) of flurazepam on both the central tracking task and the peripheral target detection, and the magnitude of the effects increased as the attentional level of the central task increased. According to Moskowitz, the drug-impaired subjects' ability to divide their attention, caused them to disregard one of the two tasks - with different subjects disregarding either the central or the peripheral task. Thus, the impairing effect was most noticeable when the performance scores from the two tasks was combined.
Roache and Griffiths (1985) evaluated the effects of 0.5, 1.0, 2.0, and 3.0 mg triazolam (Halcion) and 100, 200, 400, and 600 mg pentobabital (Nembutal - a standard barbiturate hypnotic) on 8 male drug abusers, 20-40 years old. Performance was measured 1, 2, 3, 4, 6, 8, 12, and 24 hours after administration. They found dose-related and time-related effects on most subjective measures, performance measures, and staff ratings of observed effects. The effects peaked at 2-3 hours for both drugs.
Roth and Roehrs (1985) observed that studies of so-called hypnotic drugs have generally focused on the effects the drugs have on sleep, but that it is now clear that they also have effects that can extend beyond the usual sleep period. These residual effects of hypnotics are assessed by studying the effects of these drugs on performance. Their paper discusses the issues critical to evaluating studies of the effects of hypnotics on performance, concluding that dose and half-life are important variables in determining the degree to which these daytime effects occur following nighttime use. However, the authors found several issues still unresolved, viz.:
In a recent paper, Vera and associates (2001) compared the residual effects of benzodiazepines on attention and psychomotor performance with the effects of certain non-benzodiazepine compounds on these parameters. Their concern was the residual effects on diurnal wakefulness in healthy volunteers after nocturnal administration of a single dose of diazepam (10 mg), zolpidem (10 mg), zopiclone (7.5 mg), gamma-amino-beta-hydroxybutyrate (GABOB) (500 mg), or placebo. The drugs were given at 10:00 p.m., a half-hour before bedtime. The morning after dosing, psychomotor performance was measured using a simple reaction time task, with two stimulation patterns (isochronus and stochastic). The results indicated no residual effects on reaction time after diazepam, zopiclone, and zolpidem intake. In comparison to its baseline, only GABOB produced a marked decrease in the isochronus reaction time 9 hours after its administration and produced no significant change in stochastic reaction time. The authors concluded that residual impairment on reaction time following intake of hypnotics should be considered on the basis of the stimulation pattern used (stochastic vs isochronus).
In another paper, Landauer (1986) revisited the issue of driving by patients who receive benzodiazepine tranquilizers, asserting that groups that believe that such patients should be prevented from driving a car disregard the fact that there exists no study to show that these drugs are a causal factor in crashes. His paper reviewed the effect of diazepam, one of the older compounds. The author concluded that some studies have shown that performance on psychomotor skill tests are at times affected by diazepam medication, a few studies report a decrement in performance, some found an improvement, but the results of the vast majority of studies are inconclusive. Landauer found that if detrimental effects do occur, they usually appear during the early stages of medication and when high doses are given. He states that many published studies suffer from methodological errors, and that there is little evidence that the tests used by the different teams measure the same aspect of behavior. He also concluded that there is insufficient epidemiologic data to adequately describe the relationship between all drugs and road safety, and notes that large-scale field studies have not been attempted with any pharmaceutical drug.
Stevenson, Pathria, Lamping, et al. (1986), administered diazepam (7.5 mg), fentanyl (a synthetic opiod, 100 micro-grams), or placebo, to 5 male and 4 female students. They measured performance on a "tracometer" (described only as "an NRC-sanctioned driving related task"), before drug administration, 30 minutes after drug administration, and 120 minutes after drug administration. Results showed that both drugs impaired performance on four tracometer tasks (correct reaction time, non-overshoot movement time, overshoot movement time, and total response time). Interestingly, although fentanyl has a shorter half-life time than diazepam (2 hours vs. 6-9 hours), in general the impairments with fentanyl increased after 2 hours, whereas the impairments with diazepam decreased.
Rodrigo and Lusiardo (1988) partially replicated a study by Ghoneim and associates (1984). They administered placebo, low, medium, and high doses (.2mg/ kg) diazepam to four groups of female college students, and measured their recall for categorized word lists, uncategorized word lists, and digits, up to 190 minutes after drug administration. They found an impairment in performance that was maximal at 1-2 hours after drug intake. There was no impairment in a tonal discrimination task, indicating that whatever deteriorations are observed in memory are not due to reduced alertness. Their conclusion is that the impairment is in the transfer of information from short-term memory to long-term memory, and that recall of information in long-term memory may actually be improved (probably because of reduced retroactive interference).
Koelega (1989) reviewed 26 studies that focused on the effects of different benzodiazepines on vigilance and found that with young (non-patient) volunteers, vigilance is relatively sensitive to benzodiazepine impairment, especially when d (the measure of sensitivity in signal detection theory) or reaction time is used, but also when a simple measure such as percent correct detections is used. The response criterion did not seem to be affected by the benzodiazepines reviewed.
Bourin, Auget, Colombel, and Larousse (1989) studied the effects of single oral doses of bromazepam (3 mg), buspirone (10 mg), and clobazam (10 mg), on 10 men and 10 women volunteers with mean age 22 years old, in a double blind crossover design. They obtained different effects on different drugs relative to placebo. All drugs impaired short-term free recall of 12 pictures (presented at the rate of one every 10 seconds) after 30 seconds. Clobazam dosing did not impair performance on any of the other tasks. Bromazepam and buspirone impaired performance of the digit symbol substitution test. Choice reaction time was slowed by both bromazepam and buspirone. However, the effect on the choice reaction time was found only after 6 hours and not after 2; a puzzling finding for which no explanation was provided. Koelega (1989) also noted that many studies that use multiple measures of performance often find different measures to be the most and least sensitive to drug impairment.
Meyden, Bartel, Sommers, et al. (1989) evaluated the effects of acute administration of two different benzodiazepines - 20 mg of clobazam and 2 mg of clonazepam - on 10 healthy volunteers. Clobazam had essentially no effects on the array of psychomotor tasks, whereas clonazepam significantly impaired performance on visual search and various measures of alertness compared to placebo. Thus, the study showed that two drugs from the same family (benzodiazepines), used for the same medicinal purpose (anticonvulsants) can have very different sensory and cognitive side effects.
Moser, Macciocci, Plum, and Buckmann (1990) administered 2 and 4 mg flutoprazepam to18 healthy 20-45 years old volunteers, in a cross-over design, and tested reaction time for "simple and complex shape recognition" (not defined further). They found that, relative to performance before drug dosing and relative to performance with placebo, performance 2.5 hrs after drug administration (time of peak plasma level) was significantly impaired, but only with the high 4 mg dose level.
Fisch, Baktir, Karlaganis, et al. (1990) studied the effects of 0.25 mg triazolam on pursuit rotor performance of 9 elderly and 9 middle-aged healthy volunteers, before, and 2 hours after drug ingestion. Age-related differences were obtained under the control condition, and they increased after drug ingestion.
Johnson, Spinweber, and Gomez (1990) evaluated the effects of 250 mg caffeine the morning after intake of either 15 or 30 mg flurazepam (with long half-life), 0.25 or 0.50 mg triazolam (with short half-life), or placebo at bedtime the night before the testing. The subjects were 80 healthy male volunteers, with mean age of 20.3 years. Performance measures were taken before and after treatment. The results showed that the drugs caused a feeling of sleepiness, and caffeine counteracted the effects of these feelings. Despite the differences in the subjective scores, no consistent significant differences were found between any of the groups on any of the performance measures. The authors noted that their failure to find improved performance after caffeine ingestion "joins the growing list of inconsistent results" (p. 165). However, the fact that they also failed to find differences between the placebo and the drug dose groups suggests that their measures in general (for an unknown reason) were not very sensitive to the drug effects as well.
Leigh, Link and Fell (1991) administered 2.5 mg lorazepam to 12 male volunteers 19-46 years old in a within-subject single-blind study design. They evaluated the subjects' subjective feelings and psychomotor performance before drug administration and over a period of 1.5 hours to 24 hours after administration. They found time-related impairments on almost all measures of subjective feelings of drowsiness, lethargy, clumsiness, and related feelings, as well as decrements in a number of the performance measures, including choice reaction time, motor control and coordination, and rapid information processing.
Preston, Wolf, Guarino, and Griffiths (1992) compared the effects of three sedatives: 1 and 4 mg lorazepam (benzodiazepine anxiolytic), 2.5 and 9 gram methocarbamol (central muscle relaxant), and 100, 200, or 400 mg diphenhydramine (antihistamine with sedative properties). The drugs were given in dosages 2-8 times the recommended therapeutic doses to 14 male regular drug abusers, ages 20-38. The use of the high doses was based on the assumption that recreational dosages are much higher than therapeutic doses. Testing was performed for 5 hours after ingestion. The researchers found both dose-related and time-related drug effects on performance and sensation of drug effects, with maximal effect at approximately 2-3 hours. Performance on psychomotor tasks deteriorated for all three drugs, especially at the high dose level. At the high dose level, both diphenhydramine and lorazepam impaired performance on choice reaction time to circular lights, balance on one-leg-stand, digit symbol substitution test, and short-term recall for numbers and pictures. Methocarbamol impaired performance only on the balance test, and the digit symbol substitution test. These results demonstrate that, with sufficiently high dose levels, impairments can be observed, but with dose levels typical of therapeutic doses, the impairments can be negligible.
Kunsman, Manno, Manno, et al. (1992) administered 15 mg temazepam and alcohol that yielded average levels of .08, .07, and .04 BAC, at the times of testing (30, 90, and 150 minutes, respectively, after the ethanol-drug intake). They found that, in combination, temazepam+alcohol impaired divided attention, tracking, and reaction time over a 3-hour period. Tapping rate was not significantly reduced by either drug alone or by their combination. No temporal effects or plasma concentration relationships with impairment were obtained. Divided attention was also impaired by temazepam alone and by alcohol alone, but pursuit tracking and choice reaction time were not impaired by each drug alone. The authors also noted that "when each drug was given alone, performance was highly variable. Some subjects were impaired, some subjects improved, and some subjects showed no effect versus placebo" (p. 610). Individual differences in rate of absorption of the drugs may also account for the lack of temporal effect. This is because at any given time concentration levels were still increasing in some subjects, decreasing in some subjects, or leveled off in others.
Based on their own study (above) and those of others, Kunsman, Manno, Przekop, et al. (1992) reviewed the effects of benzodiazepines in general, and temazepam in particular. Their conclusions with respect to the following psychomotor tasks were:
Kunsman, Manno, Przekop, et al. (1992) also focused their attention on the specific benzodiazepine, temazepam, a drug typically taken at night before going to sleep. Multiple studies that evaluated temazepam's effects on the following morning generally failed to show decrements in psychomotor performance with low dosages. However, with high dose levels of 30 mg, impairments in a number of tasks have been found.
Martin, Siddle, Gourley, et al. (1992) investigated the effect of temazepam on P300 (a brain signal that indicates recognition of an event) in a paradigm that may be relevant for traffic behavior. Because crash scenes have not been used previously in P300 research, Experiment 1 (n=8) examined whether the P300 elicited by safe traffic scenes and scenes of imminent traffic crashes were sensitive to the probability of crash occurrence. The type of stimulus to which subjects responded (pictures of imminent crashes or safe traffic scenes) was crossed with the probability (0.1 or 0.5) of the relevant event. The results indicated that P300 amplitude increased with decreasing probability of the relevant stimulus. Experiment 2 (n=12) employed a drug treatment (10 mg temazepam) and a placebo treatment (100 mg Vitamin E). Generally, the ingestion of temazepam decreased P300 amplitude and increased P300 latency at all sites. Reaction time, on the other hand, was not influenced by drug administration. The data demonstrate the clear effect of minor tranquilizers on the psychological processes associated with P300.
Evans, Troisi, and Griffiths (1994) compared the effects of alprazolam (0.5, 1.0, 2.0 mg) and with those of a non-benzodiazepine antidepressant (tandospirone, from the azapirone family, 40, 80, 160 mg) on 14 male habitual drug abusers, in a double-blind cross-over study. Both drugs showed dose-related and time-related effects, but the impairments with alprazolam were much more severe. Alprazolam had significant effects on choice reaction time to circular lights, digit symbol substitution test, balance (one-leg-stand for 30 seconds), and a number entering and recall test (a task where 8-digit numbers on screen had to be entered on computer and then recalled either immediately or after 10 seconds). Performance on all tasks with the 2.0 mg dose was approximately 50% of the pre-drug dose levels (except for circular lights where it was 70%). Interestingly, the stronger the alprazolam dose, the more the subjects said they liked it and the more they said they would be willing to pay for it.
Suzuki, Uchiumi, and Murasaki (1995) compared the effects of 0.8 mg alprazolam with those of DN-2327 - a partial diazepine receptor agonist - in doses of either 2 or 3 mg. Their subjects were 12 healthy males, with an average age of 41 years old. The design was a crossover double blind, with 2 weeks between sessions to wash out previous drug effects. The performance measures included a letter cancellation task, a visual vigilance task (in which a recurring pair of dots 48 mm apart on a computer screen were occasionally displaced to 60 mm apart), and a Sternberg's memory task with a memory set ranging from 1 to 6 digits. Performance was most impaired on the high dose DN-2327 followed by alprazolam and 2 mg DN-2327, which generally did not differ significantly from each other. The results indicated the difference between the drugs is in their effects on the information encoding process rather than on the central, decision-making, processing stage.
Fafrowicz, Unrug, Marek, van Luijtelaar, Noworol, and Coenen, (1995) tested the latency of saccadic eye movements (simple reaction time) in response to a target light that appeared either while the fixation light was on (overlap condition) or 200 milliseconds after it disappeared (gap condition). In a within-subject design, they tested 5 volunteers 30 minutes after taking either placebo, 5 mg buspirone (a non-sedative anxiolytic), or 5 mg diazepam. They found that diazepam - but not buspirone increased simple reaction time, and the effect was the same in the gap and overlap condition. Their conclusion was that diazepam slows down the shifting of attention or the engagement of attention with a new target rather than the first step of the attention - disengaging attention from the existing target. As such it would be detrimental especially in attending to peripheral targets under conditions of overload, such as in driving in congested traffic. Possibly, the prolonged latencies may be due to the sedative vigilance-lowering effect of diazepam.
Kelly, Foltin, Serpick, and Fischman (1997) evaluated the effects of acute administration of different doses of alprazolam on 6 healthy volunteers, in a within- subject design. There was a dose-dependent drop in performance on most measures, but of the four dose levels studied (placebo, 0.25, 0.5, and 1.0 mg), only the 1.0 mg dose had significant effects. The effects were found on the digit symbol substitution test, time estimation (based on a time production test where subjects had to press a button every 45 seconds or more), short-term memory (number recognition test where subjects had to compare a list of digits to one stored in memory), and two measures of learning ability. The authors note that these results are consistent with those of previous studies with alprazolam. Kelly and associates also noted that studies using the same measures obtained different patterns of impairments with amphetamine.
The most extensive and recent summary of the relevant side-effects of benzodiazepines is probably that of Berghaus and Grass (1997), who summarized over 500 experimental results of studies that related performance on driving-related psychomotor and perceptual tasks to benzodiazepine impairment. They found a clear-cut relationship between the serum concentration and the percent of studies that obtained a significant effect. Note, though, that multiple results were recorded for each study, so these are not independent "results." Similar relationships were obtained for other benzodiazepines such as temazepam, flunitrazepam, flurazepam, alprazolam, bromazepam, diazepam, oxazepam, and lorazepam. One exception was clobazam for which significant effects were first obtained at the very high serum level of 400 ng/ml. Berghaus and Grass also found that the percent of studies obtaining an impairment was much higher (by as much as 30%) when the serum concentration was measured during the absorption phase, than when it was measured during the elimination phase. We note that this effect is similar to that obtained for alcohol, but it is much stronger with benzodiazepines.
We note that Berghaus and Grass' summary masks some of the perplexing discrepancies that are often obtained between similar drugs or similar samples. For example, an earlier review of studies that compared different types of depressants - such as barbiturate hypnotics, non-barbiturate hypnotics, and tranquilizers - showed that often the results with the same dependent measure conflicted. Some of the differences among the studies that could have been responsible for these discrepancies include variations in experimental design (for example, within vs. between subjects), drug dose, and drug-test interval.
In a related study, Berghaus and Friedel (1997) analyzed the percent of studies showing impairment as a function of time since administration of benzodiazepine. While studies with clobazam (at 10 or 20 mg) and temazepam (10 mg) generally yielded no significant impairments at all, most studies with other benzodiazepines showed impairments for up to 5-6 hours (midazolam, diazepam, oxazepam, triazolam, and lormetazepam), and studies with some high-dose long-life benzodiazepines [nitrazepam (10 mg) flunitrazepam (2 mg), and flurazepam (30 mg)] showed significant impairments lasting as long as 18-24 hours.
As part of an evaluation of the Drug Evaluation and Classification program (DEC), Compton, Shinar, and Schechtman (2000) compared the effects of different drugs on performance of the standard DEC tests. Using alprazolam as a representative depressant drug, they found that it produced effects similar to those of alcohol: nystagmus, poor performance on all balance tests (one leg stand, finger-to-nose test, and walk-and-turn test), slowed reaction to light, and poor ocular convergence to nearby objects.
In summary, despite significant differences among the individual benzodiazepines, they generally impair performance on most performance tasks, in particular those that tap visual encoding of information (such as attention, vigilance, visual search, peak saccadic velocity, and critical flicker fusion), and short-term memory (such as digit symbol substitution test, memory scan, recognition memory, and serial subtraction). However, some non-sedative anxiolytics (such as buspirone, clobazam and temazepam) do not seem to impair performance on any of the driving-related functions that have been studied.
Closed-course and Driving Simulator Studies. In an earlier study, Linnoila and Hakkinen (1974) investigated the behavior of Finnish professional military drivers in a driving simulator. Different groups of 10 subjects each were provided with either no drugs, alcohol, diazepam (a long-life benzodiazepine) (10 mg), codeine (50 mg), alcohol+codeine, or alcohol+diazepam. The driving task started 30 minutes after drug/alcohol administration, and performance was measured in terms of simulated collisions and frequency of going of the road. But an interesting side effect was noted in terms of following instructions, which was worst for the drivers impaired by alcohol alone. A smaller effect of neglecting instructions was noted for those dosed with diazepam. Interestingly, the effect of the combination diazepam+alcohol was also smaller than the effect of alcohol alone. The drivers who received diazepam had significantly more collisions but did not go off the road any more often than those without any drug. As expected, drivers with diazepam+alcohol had more collisions and more instances of going off the road than either the diazepam-only group or the alcohol-only group. In fact, none of the diazepam only drivers went off the road. Thus, it appears that while diazepam may not impair cognitive functions involved in following instructions, it does affect vehicular control, and the effect is at least additive with alcohol. Interestingly, in another simulation study, impairments were noted after 12 hours with long-acting flurazepam, but not with the short-acting drugs for which no effects were noted at all (Willumeit, Ott, and Neubert, 1984). Together, the two studies imply that if benzodiazepines impair driving, it is more likely that it is only the long-life benzodiazepines that do so.
Hobi, Kielholz, and Duback (1981) examined the effect of bromazepam on fitness to drive. On 3 days (1, 8, 15) the acute (on day 1) and subacute (days 8 and 15) effects of bromazepam on variables of driving ability were studied in 55 young male medical students, randomly divided into 3 groups (placebo, 1.5 mg, 3.0 mg). The drug was well tolerated (no notable side effects). Dose-effects showed trends in group 3 (3.0 mg) with a stronger subjective impression of performance impairment which was, however, not confirmed by objective performance assessment, although time of reaction to optical stimuli was significantly longer after the 3 mg dose. In the discussion, it is pointed out that the results of this type of study in healthy subjects can only be regarded as indicative.
Moskowitz and Smiley (1982) studied the effects on driving skills of buspirone and diazepam, singly and in combination with alcohol. Three groups of 16 subjects each (8 men and 8 women) received either 20 mg of buspirone, 15 mg of diazepam, or placebo daily for 9 days. On day 9 they also received alcohol (men, 0.85 g/kg; women, 0.72 g/kg (2)). On days 1, 8, and 9, subjects were tested on a driving simulator and given four sessions of divided attention tasks examining tracking and visual search performance. Extensive evidence of performance impairment associated with diazepam contrasted with improved performance under chronic buspirone treatment. Alcohol effects were additive.
Betts and Birtle (1982) noted that most drugs that affect the central nervous system impair driving, at least temporarily, and that hypnotic drugs of the benzodiazepine group have some "hangover" effect next morning and have been shown to impair performance in (experimental) psychomotor tasks, though the degree of impairment depends on the dose of the hypnotic, its plasma half life, and individual variability. However, they found no evidence that other researchers had looked at the effect of these drugs on actual driving and devised an experiment to do so. They chose a drug with a relatively short half life, temazepam, and one with a longer one, flurazepam. After testing subjects' ability to negotiate a path through cones on a closed driving course, the authors concluded that a single nighttime dose of both hypnotics degraded driving behavior enough to create increased crash risk.
Willumeit, Neubert, Ott, and Hemmerling (1983) investigated lormetazepam, then a new benzodiazepine derivative, in a driving simulator trial and compared it with placebo and flurazepam. Twelve healthy subjects participated in this double blind, crossover study. The aim of the investigation was to estimate any negative effects on traffic performance after subchronic (7 days) ingestion. The results indicated that lormetazepam, even in relatively high doses, does not significantly affect reaction times compared with placebo. Flurazepam, on the other hand, significantly prolonged the general reaction time to signals presented by the driving simulator. Driving performance was significantly worse after flurazepam than after lormetazepam. The cardiovascular functions were influenced neither by the subchronic ingestion of lormetazepam nor by flurazepam,
The same authors (1984) recruited 16 healthy volunteers of a mean age of 26.4 years to participate in a driving simulator test in an eightfold crossover study under double-blind conditions. The additional influence of alcohol was tested acutely after a single administration of 2 mg lormetazepam, a new, highly effective derivative from the benzodiazepine class, 10 mg mepindolol sulphate, a new beta blocker without sedating properties, and 10 mg diazepam. All drugs were compared with placebo and the test was performed 1, 2 and 3 hours after oral intake. The aim was to investigate particularly the risks relevant in road traffic caused by simultaneous intake of these substances with alcohol. For this purpose, besides the driving simulator, an accurate reaction test and self-rating scales were used, the latter in order to assess subjective stress and anxiety levels. Lormetazepam, due to its strong sedating property, showed a reduction in driving performance and an increase in reaction time and pulse rate as compared with placebo, and these effects were highly potentiated by alcohol. Mepindolol sulphate expectedly reduced pulse rate when compared with placebo, otherwise there were no significant differences. Diazepam, like lormetazepam, caused a reduction in driving performance and reaction capacity and an increase in pulse rate compared with placebo, but the intensity and duration of the effect were less than with lormetazepam and did not reach statistical significance. No significant potentiating effects were observed after the application of alcohol.
Ellinwood and Heatherly (1985) noted that the adverse effects of minor tranquilizers, and more specifically, benzodiazepines, on psychomotor and cognitive performance have been documented repeatedly over the years, and epidemiological studies have provided sufficient evidence of their role in traffic crashes. These studies indicate that drug plasma level (DPL) is insufficiently correlated with impairment and that other factors need to be considered in determining the impairment vulnerability. They reviewed several sources of individual variability, particularly as they relate to differential impairment effects. They found that these sources include such factors as acute peak effects, acute tolerance, chronic tolerance, benzodiazepine receptor affinity and individual sensitivity, and concluded that these factors need to be examined before quantification of DPL is introduced as a criterion for driving under the influence. They also concluded that behavioral testing itself may become the critical means of assessing drug- and/or drug with alcohol-induced driving impairment if acceptable standardized procedures can be developed. They noted the rapid onset of impairment associated with acute effects of more lipid-soluble drugs.
The validity of simulated driving, relative to real driving was directly tested by Laurell and Tornros (1986). They tested 18 healthy volunteers, 20-34 years old, in the morning after 1 and 3 nights of taking 0.25 mg triazolam (short-life benzodiazepine, with a half life of 2.3 hours) or in the morning after 1 and 3 nights of taking 5 mg nitrazepam (long-life benzodiazepine, with a half-life of 29 hours), or placebo. The performance tests consisted of both simulated monotonous driving and real driving on the morning after drug administration. In the simulated driving, the subjects had to drive a monotonous road and respond to emergency situations, and performance was measured in terms of reaction time. In the real driving test they drove within a lane of cones and had to switch lanes in response to a sudden obstacle, and the dependent measure was the number of cones knocked over. Significant drug effects were obtained only in the simulated driving and only for the long-life nitrazepam. These results suggest that their simulated driving task was either more demanding than their real driving task or that the drivers were less concerned about their actions in the simulator than about the actual cost of errors in real driving. Since the tasks were quite different, both factors may have contributed to the performance difference.
O'Hanlon and Volkerts (1986) described the most recent of several related studies of the residual effects of hypnotic drugs on actual driving performance that have been conducted using a standard approach. In it, 12 female insomniacs and hypnotic users acted as subjects. They were treated in two separate series with placebo for 2 nights, then hypnotic medication for 8 nights followed by placebo again for 3 nights. In one series, the medication was nitrazepam (10mg) and in the other, temazepam (20 mg). Eleven subjects completed both series in a double-blind, crossover (with respect to drugs) design. Their driving performance was repeatedly tested on a 100 km primary highway circuit, in normal traffic, during both the morning and afternoon (10-11 hours and 16-17 hours after drug and placebo ingestion, respectively). Nitrazepam but not temazepam significantly impaired driving performance, the difference lasting throughout the active medication period. These results along with those obtained in the earlier studies are compared to show degrees of driving impairment which follow the use of various hypnotic drugs.
Linnavuo, Ylilaeaekkoelae, Mattila, et al. (1987) developed and tested a computerized device for simultaneous measurement of coordinative and reactive skills related to driving. The experiment involved two consecutive trials of psychoactive agents in healthy volunteers. The test system was comprised of a vehicle, a driving computer, and the programming and measurement computer. The computerized driving program projected to a color TV screen a winding road, and the driver had to keep the car on the road by turning the steering wheel. The driving proceeded at a fixed, fairly rapid rate for 5 minutes, and the number of tracking errors (deviations from the road) as well as the tracking percentage (relative length of the track driven off the road) were computed separately for both halves of the track. During the latter half of the track, 60 visual or/and sound stimuli were given in random order, and the driver had to respond to them by pressing a button or by pushing a foot pedal. The number of reaction errors and cumulative reaction time were recorded. The program also provided a histogram that related the number of deviations from the road to their duration, enabling a visual judgement of the severity of errors. Matched versions (mirror image, reverse direction) of tracks of varying severity were offered to reduce learning effect during the trial. When testing the device in two placebo-controlled double-blind and crossover trials, a considerable practice effect on tracking and reaction strategies took place, but after proper training, the baselines remained reasonably stable. In spite of the practice effect, an impairment of coordinative skills by lorazepam 2.5 mg or by diazepam 15 mg was demonstrated whereas ethyl alcohol 0.8 g/kg impaired reactive skills more than eye to hand coordination. Additive drug-drug and drug-alcohol combined effects were also found.
In a later study similar to their 1986 study cited above, Tornros and Laurell (1990) evaluated the effects of 2 mg flunitrazepam, 30 mg flurazepam, 0.5 mg triazolam, and placebo on the fourth morning following four nightly drug ingestions. The subjects were 24 healthy, moderate-drinking, Swedish volunteers, and the design was a double blind, randomized crossover. The subjects' task was to drive as fast as possible through a demanding 20 km course in a moving- base driving simulator. Following the test, they were given alcohol, and when the BAC level reached .05, they were tested again. The dependent measures were average speed and number of "crashes." Alcohol had an additive effect on speed, increasing average speed for all drugs. Before intake of alcohol, speed was lowest and crashes were highest with flurazepam. The other two drugs yielded similar speeds to those of placebo, but lower crash rates.
Brookhuis, Volkerts, and O'Hanlon (1990) assessed the residual effects of lormetazepam 1 mg and 2 mg in soft gelatine capsules on driving performance and compared the effects to those of flurazepam 30 mg, which is also a powerful hypnotic, but possesses a far less favorable pharmacokinetic profile with a long-acting sedative metabolite. Driving performance was tested 10 to 11 hours and 16 to 17 hours post administration, after 2 days on placebo (baseline), and 2, 4 and 7 days of drug treatment (active), and after 1 and 3 days following the resumption of placebo (washout). The driving test consisted of operating an instrumented motor-vehicle over a 72 km highway circuit in light traffic. Flurazepam 30 mg significantly impaired the ability to control the lateral position of the vehicle compared to placebo baseline measurements. The degree of impairment was substantial in the female subjects and was greater in the morning than in the afternoon. Lormetazepam 1 mg showed no residual effect on driving performance. Lormetazepam 2 mg impaired driving performance to some extent on the following morning, 10 to 11 hours post administration, but no residual effect was found in the afternoon. All drugs improved sleep quality and prolonged sleep duration to more or less the same extent.
O'Hanlon, Vermeeren, Uiterwijk, et al. (1995) studied the effects of benzodiazepine (diazepam, lorazepam) and benzodiazepine-like anxiolytics (alpidem, suriclone) and a 5-HT-3 antagonist (ondansetron) on actual driving performance in three double-blind, placebo-controlled studies. Subjects were healthy volunteers in two studies and anxious patients in the third. Treatments lasted for 8 days. Standardized testing occurred within the first full day and on the last day of treatment. No important differences existed between volunteers' and patients' baseline and/or placebo performances, and both groups responded similarly to comparable drugs/doses. Benzodiazepine and benzodiazepine-like anxiolytics produced marked and pervasive driving impairment, which lasted throughout treatment; but ondansetron produced no impairment.
O'Hanlon (1984) also evaluated drug effects on actual driving performance in a series of three earlier studies. His subjects drove a 100 km at 95 km/hr on a 50 km route while their lateral position in the lane was monitored. The primary difference among the three studies was the drug under investigation. In all studies, subjects served as their own controls (with placebo). The first study was conducted on 24 female former users of hypnotic drugs, and the study's drugs were flurazepam and secobarbitone. The second study was conducted on 16 female former drug users and the drugs evaluated were loprazolam and flunitrazepam. The third study included 20 healthy males, and the drugs evaluated were amitriptyline, doxapine, mianserin, and opiates. The three experiments demonstrated that the standard deviation of the lateral position in the lane was a sensitive measure of impairment from doxapine (25 mg three times daily), mianserin (10 mg 3 times daily), and amitriptyline (25 mg 3 times daily). Also, relative to placebo, there was also an excellent power function fit between loprazolam concentration and standard deviation of the lateral position. However oxaprotiline had no effect on lateral control.
In another earlier study, O'Hanlon, Haak, Blaauw, and Riemersma (1982) had 9 police driving instructors drive twice in succession on a 50 km highway loop in Holland, in the late evening hours under 4 different conditions - 10 mg diazepam, 5 mg diazepam, placebo, and nothing - and once at 1:00 AM. Thus, the drug effects could be compared to three control conditions: late evening placebo, late evening with nothing, and early morning with nothing. They found that the drug impaired lateral control but not speed control, and the effect was significant only with the higher, 10 mg, dose condition. In that condition there were marked impairments in lateral control with 10 mg diazepam, relative to all other conditions, which did not differ significantly from each other. In addition, the drop in performance between the control conditions and the 10 mg drive had "a corresponding drop in the subjective arousal." This led the authors to suggest that the drop in arousal is the mediating factor that causes the drop in performance after taking diazepam. However, this conclusion contradicts that of Rodrigo and Lusiardo (1988) in a later study (see below).
Barbiturates
Tedeschi, Bittencourt, Smith, and Richens (1983b) gave five healthy volunteers a single oral dose of the barbiturate drug amylobarbitone sodium (200 mg) and placebo in a double blind randomized experiment and measured peak velocity of horizontal saccadic eye movements, saccadic duration and smooth pursuit velocity at intervals up to 6 hours after drug administration. The treatment produced a statistically significant decrease of both saccadic and smooth pursuit eye velocity with the maximum effect observed 2 hours after drug administration. The effect on peak saccadic velocity was still statistically significant 6 hours after treatment. The maximum impairment in eye movement performance ranged between 25% and 29%. The results indicated that both saccadic and smooth pursuit systems were unable to generate the required eye velocity under the influence of a therapeutic dose of amylobarbitone sodium.
Only two other studies were found that evaluated the effects of barbiturates on performance without the interactions of alcohol. Both used different amounts of pentobarbitol, and the results of both suggest that barbiturates affect psychomotor functions in ways similar to that of alcohol.
In the first study Mintzer, Guarino, Kirk, et al. (1997) compared the effects of placebo, acute doses of the barbiturate pentobarbitol (150, 300, 600, and 750 mg/kg), and doses of ethanol (0.5, 1.0, and 2.0 g/kg) on psychomotor and cognitive performance. The subjects were 8 male volunteers, with a history of drug abuse, who were given all drug and alcohol levels (but not in combination). The researchers noted that both alcohol and pentobarbital produced similar dose-related effects on all psychomotor and cognitive measures, leading them to conclude that there is a "barbiturate-like rather than benzodiazepine-like profile of effects for ethanol".
Pickworth, Rohrer, and Fant (1997) evaluated the effects of two dose levels of marijuana, amphetamine, hydromorphine, pentobarbitol, and placebo on eight volunteers who received each drug dose on a separate day in a within-subjects design. They found that only alcohol and pentobarbitol impaired performance on reaction time to circular lights, digit symbol substitution test, serial math tasks, and card sorting. They also found that as the cognitive load of the card sorting task increased, ethanol and pentobarbitol impairments were detected at the lower doses.
CENTRAL NERVOUS SYSTEM STIMULANTS
Two types of stimulants are encountered in drivers: legal and illicit. The most common legal stimulant is caffeine (either in drinks or in pills), and the most common illicit stimulants are probably cocaine and amphetamine. Stimulants such as amphetamine causes changes in brain levels of dopamine, norepinephrine, and serotonin. These changes and interactions with other neurotransmitters may cause a wide array of impairments associated with euphoria, fatigue, confusion, and paranoia (Gjerde, Christophersen, and Morland, 1992).
Moskowitz and Burns (1981) observed that experiments examining whether central nervous system stimulants can antagonize the behavioral effects of alcohol have produced a considerable literature, with studies of caffeine-alcohol effects in humans indicating support for an antagonism of alcohol effects by caffeine for reaction time measures by ambiguity in results from other objective performance measures. They also concluded that evidence from animal studies which have examined wider dose ranges for both alcohol and caffeine indicates antagonism on many measures of motor behavior with low to moderate caffeine and alcohol doses. On the other hand, they found that these earlier studies involving high caffeine doses appear to increase rather than offset the impairment due to alcohol.
Tedeschi, Bittencourt, Smith, and Richens (1983a) conducted two studies in which they administered either placebo or 15 mg d-amphetamine. In one study, with five subjects 22-32 years old, the drug was taken orally and in the other, with 6 subjects 20-35 years old, it was given intravenously. The authors measured effects on ocular behavior (peak saccadic velocity, saccadic duration, and saccadic reaction time). No differences were obtained between the placebo and amphetamine conditions with oral administration. However, with intravenous administration, there was no drop in peak velocity, and no increase in saccadic duration, but there was a drop in saccadic reaction time relative to drops obtained with placebo - especially at 30-50 minutes after drug administration. These results show the counteractive effects of amphetamine on fatigue-related eye movement effects - but only when administered intravenously.
Ward, Kelly, Foltin, and Fischman (1997) evaluated the effects of d-amphetamine on 6 healthy males living for 11 days in a residential laboratory. On each day they received either 0, 5, or 10 mg/kg d-amphetamine, a 6.5 hour work period and before a 6.5 hour recreation period. Amphetamine speeded up response on some tasks without any impairments in accuracy, and with no subjective effects. However, the researchers also found that amphetamine impaired digit symbol substitution test, and number recall in short-term memory. However, Pickworth, Rohrer, and Fant (1997) also failed to find any effects of amphetamine on reaction time to circular lights, digit symbol substitution test, serial math tasks, and card sorting.
Zancaner, Giorgetti, Dal Pozzo, Molinari, Snenghi, and Ferrara (1997) examined the blood or urine of 480 Italian drivers stopped by police for driving while impaired by alcohol or drugs, and correlated their findings with the results of clinical evaluations of impairment. Their results - not detailed in very exact terms - revealed that the following signs are indicative of drug impairments from stimulants:
Compton, Shinar, and Shechtman (2000) also found that amphetamine was associated with increase in pulse rate and blood pressure but not in motor coordination, pupil reaction to light, or ocular convergence.
Mascord, Dean, Gibson, et al. (1997) compared the differential effects of five different stimulants "commonly used by truck drivers" on vital signs and a three-way divided attention task. The divided attention task consisted of a central tracking task, a peripheral visual discrimination task, and responding to a random visual "emergency" signal consisting of a red light display. The stimulants were all administered in a placebo-controlled design under laboratory conditions. They included caffeine (200 mg), ephedrine hydrochloride (60 mg), pseudoephedrine hydrochloride (60 mg), phentermine (30 mg) and diethylpropion (75 mg). For each drug, the performance and physiological measures were calculated by calculating a "drug-placebo" score. The results showed no significant effects on the divided attention task and no differences in systolic blood pressure or oral temperature. However, heart rate was lower after the intake of caffeine.
Ornstein, Iddon, Baldacchino, Sahakian, et al. (2000) studied groups of subjects whose primary drug of abuse was amphetamine or heroin, comparing them with age- and IQ-matched control subjects. The study consisted of a neuropsychological test battery which included both conventional tests and also computerized tests of recognition memory, spatial working memory, planning, sequence generation, visual discrimination learning, and attentional set-shifting. Many of these tests have previously been shown to be sensitive to cortical damage (including selective lesions of the temporal or frontal lobes) and to cognitive deficits in dementia, basal ganglia disease, and neuropsychiatric disorder. Qualitative differences, as well as some commonalities, were found in the profile of cognitive impairment between the two groups. The chronic amphetamine abusers were significantly impaired in performance on the extra-dimensional shift task (a core component of the Wisconsin Card Sort Test), whereas in contrast, the heroin abusers were impaired in learning the normally easier intra-dimensional shift component. Both groups were impaired in some of tests of spatial working memory. However, the amphetamine group, unlike the heroin group, were not deficient in an index of strategic performance on this test. The heroin group failed to show significant improvement between two blocks of a sequence generation task after training and additionally exhibited more perseverative behavior on this task. The two groups were profoundly, but equivalently, impaired on a test of pattern recognition memory sensitive to temporal lobe dysfunction. The authors concluded that these results indicate that chronic drug use may lead to distinct patterns of cognitive impairment that may be associated with dysfunction of different components of cortico-striatal circuitry.
In summary, it appears that while amphetamine is associated with some physiological reactions such as an increase in heart rate, mydriasis, and conjunctival congestion, it is usually not associated with easily observable behavioral impairments.
Laboratory Studies
Moskowitz (1984) conducted multiple studies on the separate and joint effects of alcohol and different drugs on divided attention. He found two differences in attention that distinguished between alcohol and smoked marijuana (with 50, 100, and 200 g/kg): (1) marijuana impaired peripheral detection of lights under both the focused and divided attention conditions, while alcohol did not, and (2) alcohol increased fixation durations in simulated driving while marijuana did not.
Perez-Reyes, Hicks, Bumberry, et al. (1988) gave six healthy moderate male users combinations of alcohol (placebo, 0.42 g/kg, and 0.85 g/kg) and marijuana cigarettes (with 0 or 2.4% THC). They measured accuracy and latency of performance in their "Simulator Evaluation of Drug Impairment" and found that marijuana increased alcohol-related impairments in a synergistic manner. They also found that marijuana accelerated heart rate.
Heishman, Stitzer, and Bigelow (1988) in a within-subject design, gave each of 6 male volunteers with mean age 26 years old one alcohol + marijuana dose on each of six counterbalanced sessions. Alcohol doses were .00, .07 or .13 BAC, and the marijuana cigarettes had 0, 1.3, or 2.7% THC. Marijuana produced only minimal decrement in the digit symbol substitution test, while alcohol impaired performance on all three cognitive measures used: simple reaction time to circular lights, digit symbol substitution test, and pursuit tracking on a choice reaction time. Heart rate increased in a dose-related manner in response to marijuana, but not in response to alcohol.
In a second study with marijuana only, Heishman, Stitzer, and Yingling (1989) gave 12 male users of marijuana cigarettes doses of 0, 1.3, or 2.7% THC, in a within-subject design, in 3 experimental sessions separated by 48 hours. As before, they found that subjects' feelings of a "high" and heart rate increased in a dose-related manner. More important, performance on short-term memory tasks as measured on forward and reverse attention span was impaired, and for the high dose condition, only performance was also impaired on the digit symbol substitution test. However, unlike the Moskowitz 1984 study, they did not find any impairments in a divided attention task.
Heishman, Huestis, Henningfield, and Cone (1990) evaluated marijuana effects on three regular users, using 0, 2.6%, and 5.1% THC, in a within-subject design. They obtained a subjective "high" for all subjects and a slight impairment in serial reaction time task (where subjects had to respond to a series of lights that appeared randomly, within a circle of 16 bulbs, and the score was the number of lights responded to in one minute). For two out of the three subjects, they also obtained impairments in digit recall and serial addition/subtraction. No significant impairments were found a day after smoking the marijuana. Performance in a visual search task (two-letter cancellation task) and logical reasoning were not affected by marijuana in a consistent manner.
Chait and Perry (1994) studied the effects of marijuana (0 or 3.6% THC) alone or in combination with alcohol (.00 or .09 BAC), in a within-subject design, on 10 male and 4 female volunteers with a mean age of 25 years. They used both subjective measures of mood and objective measures of performance to observe both immediate effects and day-after effects. The visual analogue measures of feeling high and feeling drunk were very similar in magnitude for the marijuana alone and alcohol alone conditions, suggesting that they were able to match the level of perceived intoxication of the two drugs. Significant performance impairments due to marijuana were obtained only for time production (of 30, 60, and 120 seconds intervals). Alcohol resulted in overproduction (with subjects producing longer intervals), while marijuana caused underproduction. Performance on digit symbol substitution test, one-leg-stand, backward digit span, and free recall were impaired by alcohol only, and logical reasoning and divided attention were not impaired by either marijuana or alcohol. When impairment was demonstrated, it was only immediately following drug ingestion, with very little residual effects on the following day.
Heishman, Arasteh, and Stitzer (1997) evaluated the effects of placebo, three levels of alcohol (.025, .05, and .10 BAC), and three levels of marijuana (4, 8, or 16 puffs of marijuana cigarettes with 3.55% THC, yielding an average of 63, 150, and 188 ng/ml plasma THC) on five male, 18-26 years old volunteers. The order of the seven doses was random across subjects, and sessions were separated by one week. Subjective ratings on 12 perceived effects were made on visual analogue scales. Performance tests included simple reaction time, digit symbol substitution test for 90 seconds, number recognition test based on Sternberg test with variable memory set of seven digits, time estimation for durations of 5, 20, and 80 seconds, and immediate free recall for a list of 20 concrete nouns presented sequentially at the rate of 1 per 2 seconds. The results showed that heart rate increased in a dose-related manner for marijuana dosing but not for alcohol. Subjective ratings of impairment were very similar for the high doses of alcohol and marijuana, indicating that subjectively they were equivalent in their perceived strength. Both alcohol and marijuana impaired performance on digit symbol substitution test and immediate free recall. However, time perception and reaction time were not affected by either.
Berghaus, Kruger, Vollrath (1998) reviewed 66 studies that together provided 761 findings on different measures of perceptual-cognitive-motor performance. As expected, they found that the higher the concentration of THC, the greater the number of measures that were likely to indicate impairment: from 40% of the measures at 5 ng/ml plasma to a high of 70% of the measures at 55 ng/ml plasma. However, results with higher concentrations of THC were based on very few studies and are therefore less reliable.
Finally, in their analysis of the effects of different drugs on behavioral signs and symptoms recorded by drug recognition experts (DREs), Compton, Shinar, and Schechtman (2000) noted that marijuana caused a slowed pupil reaction to light, an increase in pupil size (both in the light and in the dark), an increase in pulse rate, and poor ocular convergence (of the two eyes toward a close object). Unlike alcohol, marijuana did not produce nystagmus or affect any of the common balance tests (one-leg-stand, finger-to-nose, and walk-and-turn).
Closed-Course and Driving Simulator Studies
Several studies have compared driving performance of cannabis-dosed drivers with that of drivers under the influence of either placebo or alcohol. These studies can be divided into two categories: driving in a simulator and driving an instrumented vehicle on the road.
Smiley et al. (1981) used an interactive simulator and found that in her high- dose condition (200 mcg/kg body weight THC), variability of lateral position in the lane, headway, and velocity increased significantly. Perceptual impairments were also manifested in an increase in reaction time to a subsidiary task, increase in missed turnoffs, and increase in crashes into obstacles on the road. However, a similar study reported by Stein, Allen, Cook, and Karl (1983) found far fewer effects of marijuana dosing. One possible explanation provided by Smiley to account for the difference between her findings and those of Stein's, is that Stein only measured performance over a 15-minute period whereas Smiley measured performance over a 45-minute period. It is then possible that the marijuana effects either increased over time, or that the ability of the drivers to continue to cope with these effects decreased over time. Unfortunately, a temporal analysis of performance over time to test this hypothesis was not conducted in either study.
The extensive studies by Robbe and O'Hanlon (1993), revealed that under the influence of marijuana, drivers are aware of their impairment, and when the experimental task allows it, they tend to actually decrease speed, avoid passing other cars, and reduce other risk taking behaviors. Given adequate warning, these drivers can also respond correctly and rapidly to dangerous situations. In contrast, the same studies showed that alcohol-impaired drivers are generally not aware of being impaired, and consequently they do not adjust their driving accordingly, and manifest more risk-taking behaviors.
In her recent review of the significant negative effects of marijuana, Smiley (1998) noted that performance in divided attention tasks is impaired. This is manifested in poorer performance on subsidiary tasks. The implication of this is that in situations where the drivers cannot adjust their speed to accommodate their slowed information processing, marijuana-impaired drivers may be less able to handle unexpected events.
Two recent studies were conducted on the effects of marijuana and alcohol, alone and in combination, on driving performance. The two studies that used similar levels of alcohol and marijuana doses, but different measures of performance, reached somewhat different conclusions. The first of these studies, by Lamers and Ramaekers (1999) compared the effects of alcohol and THC alone and in combination, on subjectively-rated driving performance scores, relative to a placebo condition in a within-subject design. The 16 subjects (8 males and 8 females) had a mean age of 23, were all occasional users of alcohol and marijuana, and were treated on each session with either placebo and/or low levels of alcohol (.04 BAC) and/or low levels of THC (100 grams/kg THC). Although the levels were low, subjects generally correctly identified if they were truly dosed or not. Their task was to drive through city streets while responding to traffic controls, crossing intersections and making turns at intersections. Using driving instructors' performance scores, Lamers and Ramaekers found essentially no differences between the dosed and non-dosed conditions. However, they also found that drivers under the THC-only condition evaluated their performance as significantly worse than under the placebo, the alcohol and the alcohol+THC condition. Thus, the study confirmed the hypothesis that, unlike alcohol, marijuana actually enhances rather than mitigates the perception of impairment. The only negative behavioral effect of THC was a slight reduction in the frequency of intersections searched for cross traffic (based on the drivers' eye movement records). Although statistically significant, the drop was negligible: from a mean frequency of 85% of the intersections in the placebo condition, to a mean frequency of 82% in the combined alcohol+THC condition. Thus, in general, these results confirmed those of earlier studies with similar levels of THC.
In the second study, by Hindrik, Robbe, and O'Hanlon (1999), the participants' performance was evaluated in terms of subjective ratings as well as objective measures of lane tracking, maintaining a fixed speed (100 km/hr) and car following headway. The participants were eighteen 20-28 years old Dutch drivers who were moderate drinkers and marijuana smokers. The design was a double-blind crossover, in which each driver received all of the following six combinations of alcohol and marijuana: alcohol placebo+THC placebo, alcohol placebo+100 g/kg THC, alcohol placebo+200 g/kg THC, .04 BAC alcohol+THC placebo, .04 BAC alcohol+100 g/kg THC, and .04 BAC alcohol+200 g/kg THC. The results showed that THC impaired performance on both tasks, and that the effects were synergistic with alcohol. Thus, there was dose-dependent deterioration in lane tracking (both in standard deviation of lateral position and in total time out of lane), which was further exacerbated exponentially with alcohol. Finally, as observed before, the self rating of performance decreased with increasing levels of THC, but was not affected by the alcohol.
Hobi, Gastpar, Gastpar, et al. (1982) studied a group of twenty depressive patients during a 3-4 month course of antidepressant therapy, comparing them with a healthy control group for subjective assessment of their depressive mood and performance as well as objective measurement of variables relating to driving behavior. The measurements were taken 2-4 weeks after a pre-treatment period (day 1) and after 2-3 months of further therapy (day 2). During therapy, all patients felt "less depressive" and "more capable" in subjective terms. All patient groups made learning progress in the objectively-measured variables (psychomotor co-ordination and attentiveness tests). By day 2, the patient groups had almost reached the performance level of the control group, providing they received antidepressant therapy (regardless of the action profile) which was suitable for the basic disorder and the symptoms, and therapy was successful in the opinion of the physician. The authors concluded that depressive patients, assuming suitable antidepressant treatment and good response, are more capable of driving while under maintenance therapy than driving while not under maintenance therapy.
Hindmarch, Subhan, and Stoker (1983) described the development of an objective measure of car driving performance, brake reaction time, and compared the effects of amitriptyline and zimeldine on this measure in a placebo-controlled, acute, single-dose, volunteer study. The effects of treatment on laboratory tests of critical flicker fusion threshold, choice reaction time and tracking accuracy and on self-assessments of sedation were also examined. At 2 hours post-treatment, amitriptyline produced a significant increase in brake reaction time when compared to both placebo and zimeldine. At 4 hours post-treatment, a significant reduction in "tracking accuracy" and a significant increase in choice reaction time was observed after treatment with amitriptyline, while no such effects were seen with zimeldine. Measures of critical flicker fusion threshold and self-ratings of sedation also revealed that amitriptyline produced a significant degree of sedation at 4 hours when compared to zimeldine and placebo. In contrast, zimeldine produced elevated critical flicker fusion threshold, but did not affect self-ratings of sedation.
Judd (1985) noted that, despite the extremely widespread use of antipsychotic medications, there is little evidence from the surveys conducted to date that this class of psychoactive medications is significantly implicated in vehicular crashes or deaths. He quoted epidemiologic evidence that, in five major surveys of vehicular fatalities in which drug and alcohol analyses were obtained, only two of over 800 victims studied involved detection of antipsychotic medications. He concluded that the acute administration of antipsychotics in normal individuals does induce sedation and performance decrements in visual-motor coordination and specific attention behaviors, which have a deleterious effect on driving behavior. On the other hand, he emphasized that antipsychotics are rarely used on an acute basis and tolerance to the sedation and decreased alertness does occur during chronic treatment. He noted that antipsychotic drugs have the capacity to potentiate the effects of alcohol, sedative hypnotics, narcotics and antihistamines, and therefore, combination of antipsychotics with these substances increases the impairment of driving behavior.
Judd also concluded that there is an indication that the less sedating piperazine phenothiazines and the butyrophenones may have little or no effect on psychomotor performance, and antipsychotic drugs of these two subclasses may have a distinct advantage, at least in terms of driving performance, over the other more sedating drugs. Judd noted that antipsychotic drugs are almost never used for recreational or abuse purposes; therefore, the effect that antipsychotics may have on the driving behavior of those seriously disordered mentally ill patients who require continued maintenance on these medications should be of primary concern. Judd found good agreement in the literature suggesting that schizophrenic patients demonstrate improved psychomotor performance during chronic treatment with antipsychotic drugs. Thus, it is possible that despite the fact that antipsychotics have been shown, on an acute basis, to impair driving performance in normals, they may have a beneficial effect on driving behavior in schizophrenics. Unfortunately, Judd found no study in the literature that focuses on the effect of long-term maintenance of antipsychotic drugs on driving performance of schizophrenic patients.
Linnoila and Seppala (1985) concluded that, although some impairment of skills due to antidepressants has been observed clinically, the impact of antidepressants on traffic safety is at present [circa 1985] unknown. They observed that antidepressants (especially sedative antidepressants) and alcohol may have additive deleterious effects on skilled performance, and that combined effects are most prominent in the initial phase of treatment and diminish during prolonged treatment. They stated that the interaction with alcohol is mainly pharmacodynamic and indicated that major increases in the blood alcohol or antidepressant levels are uncommon in humans in social drinking situations, and minor changes are masked by individual pharmacokinetic variations. They concluded that an interaction between antidepressants and alcohol as well as the effect of untreated depression may be more important for traffic safety than drug effects alone.
Ramaekers, Swijgman, and O'Hanlon (1992) studied the acute and subchronic effects of moclobemide and mianserin on driving and psychometric performance, and compared these effects to those of placebo in a double-blind, crossover study involving 17 healthy volunteers. Mianserin, moclobemide and placebo were administered for 8 days. Subjects' performance was measured on days 1 and 8 of each treatment series; subjective sleep parameters, mood, and possible side-effects were recorded each treatment day on questionnaires or visual analog scales. Mianserin affected most of the performance measures, while moclobemide affected none; mianserin also impaired driving and tracking performance and decreased critical flicker fusion. While receiving mianserin, subjects reported depressed levels of alertness, calmness, and contentment; together with feelings of drowsiness and fatigue during the day. No statistical interactions between the factors "drugs" and (treatment) "days" were found, indicating that little pharmacological tolerance developed over time during mianserin treatment. Mianserin's sedative properties were held responsible for all performance and subjective effects of the drug. It was concluded that moclobemide 200 mg once a day has no important sedative properties.
Ramaekers, van Veggel, and O'Hanlon (1994) combined results from two separate studies that were used to compare the acute and subchronic effects of two monoamine oxidase-A (MAO-A) inhibitors, moclobemide and brofaromine, on actual driving performance and sleep. Both studies were conducted according to a double-blind, crossover design involving 18 patients receiving moclobemide and 16 patients receiving brofaromine. Patients were administered either moclobemide 200 mg b.i.d., mianserin 10 mg t.i.d., and placebo (study 1), or brofaromine 50 and 75 mg b.i.d., doxepin 25 mg t.i.d., and placebo (study 2) for 8 consecutive days (3). A standardized driving test was conducted on day 1 and day 8 of treatment. Daily logs of estimated sleep duration and quality were obtained. Neither moclobemide nor brofaromine impaired driving performance. Some indication, although statistically not significant, was found that moclobemide improved driving performance on day 1. Brofaromine 75 mg significantly improved driving performance of day 8 of treatment.
The researchers found no significant difference between the effects of both drugs in a cross-study comparison. Moclobemide did not affect any sleep parameter, whereas brofaromine shortened sleep duration and decreased sleep quality. On day 1, mianserin and doxepin impaired driving. Impairment dissipated after 8 days of treatment with doxepin, but not during treatment with mianserin. Sleep duration was prolonged during treatment with both drugs, whereas sleep quality remained unaffected. It was concluded that both MAO-A inhibitors are safe drugs with respect to driving.
Ramaekers, Muntjewerff, and O'Hanlon (1995) examined the acute and subchronic effects of dothiepin 75-150 mg and fluoxetine 20 mg on critical flicker fusion frequency (CFF), sustained attention and actual driving performance, and compared the results with those of placebo in a double-blind, crossover study involving 18 healthy volunteers. Drugs and placebo were administered for 22 days in evening doses. Fluoxetine doses were constant but dothiepin doses increased on the evening of day 8. Performance was assessed on days 1, 8 and 22 of each treatment series. Subjective sleep parameters and possible side effects were recorded on visual analogue scales on alternate treatment days. The authors found that dothiepin reduced sustained attention on day 1 by 6.7% and CFF on day 22 by 1.1 Hz. Fluoxetine reduced sustained attention days 1, 8 and 22 of treatment by 7.4, 6.7 and 6.5% respectively. CFF decreased linearly over days during fluoxetine treatment and significantly differed from placebo on day 22 with 1.2 Hz. Neither drug significantly affected driving performance. While receiving dothiepin, subjects complained of drowsiness on days 1-3 of treatment and slept 43 minutes longer.
van Laar, van Willigenburg, and Volkerts (1995) examined the acute and subchronic effects of two dosages of a new serotonergic antidepressant nefazodone, and those of the tricyclic imipramine in a double-blind, crossover, placebo-controlled study. Twenty-four healthy subjects from two age groups (12 adults and 12 elderly from both sexes) received the four treatments (nefazodone, 100 and 200 mg twice daily, imipramine 50 mg twice daily; and placebo) for 7 days with a 7-day washout period. Measurements were performed after the morning doses on day 1 and day 7. These included a standard over-the-road highway driving test, a psychomotor test battery, and sleep latency tests. Blood samples were taken on both days and analyzed to determine concentrations of parent drugs and their major metabolites. It was found that the reference drug, imipramine, had a detrimental effect after a single dose on lateral position control in the driving test, primarily in the adult group, that diminished after repeated dosing. Minor impairment on psychomotor test performance was found on both days. On the other hand, a single administration of both doses of nefazodone did not impair highway driving performance (even showed some improvement) and had no or only minor effects on psychomotor performance. After repeated dosing, nefazodone (200 mg twice daily, but not the 100-mg dose) produced slight impairment of lateral position control; dose-related impairment of cognitive and memory functions also was found. The effects of nefazodone were generally in the same direction in both age groups. Significant correlations were found between steady-state concentrations of nefazodone in plasma (200-mg, twice-daily condition) as well as imipramine, and reaction time changes in a memory scanning task. Neither drug appeared to induce daytime sleepiness as measured by the sleep latency tests.
Ramaekers, Annseau, Muntjewerff, et al. (1997). Studied parallel groups of depressed (DSM III-R) outpatients who received moclobemide (n=22) and fluoxetine (Prozac) (n=19), double-blind, for 6 weeks. Respective starting doses were 150 mg twice a day and 20 mg q.a.m. (every morning). These could be doubled afer 3 weeks for greater efficacy. Chronic users of benzodiazepine anxiolytics continued taking them as co-medication. Therapeutic and side effects were assessed using conventional rating scales. Actual driving performance was assessed during the week before therapy and at 1, 3 and 6 weeks thereafter using a standardized test that measures standard deviation of lateral position (SDLP). Similar remissions in depressive symptoms and side effects occurred in both groups. Patients drove with normal and reliable (r=0.87) SDLPs before treatments. Most continued to do so but a few drove with progressively rising SDLPs and the overall trends were significant in both groups (p<0.03). A post-hoc multiple regression analysis was applied for identifying factors that correlated with SDLP in separate tests after the beginning of therapy. At 3 and 6 weeks there were significant (p<0.03) relationships involving the same factor; patients who drove with progressively higher SDLPs appeared to be those using benzodiazepines that are metabolized by a P450 isozyme subject to inhibition by their particular antidepressant.
O'Hanlon, Robbe, Vermeeren, et al. (1998) studied the effects of venlafaxine, an antidepressant acting by selective serotonin and norepinephrine re-uptake inhibition with a potency ration of 51, in a standardized, actual driving test, a battery of psychomotor tests (critical flicker fusion frequency, critical tracking, divided attention), and a 45-minute vigilance test. Thirty-seven healthy volunteers, 22 of whom completed the study, received venlafaxine in fixed (37.5 mg twice a day) and incremental (37.5-75.0 mg twice a day) doses as well as mianserin (10-20 mg three times a day) and placebo according to a 4-period (15 days each), double-blind, crossover design. Testing occurred on days 1 and 7 and after dose increments, on days 8 and 15. The results indicated that venlafaxine does not generally affect driving ability and should be safe for use by patients who drive.
Histamine mediates numerous processes in nearly all organs and tissues. Too much histamine can create allergic reactions and other physical problems, and antihistamines restrict the release of histamine to the cells. Histamines are categorized according to the three types of cell-surface receptors (called H1, H2, and H3 receptors) the histamine bind to. The most pertinent of these to this review are the H1 receptors, and H1 antihistamines restrict the release of histamines to the H1 receptors. Older H1 antihistamines (1st generation H1 anti-histamines) have been found to cause side effects such as drowsiness, which are greatly reduced by the newer, 2nd generation H1 antihistamines.
Betts, Markman, Debenham, et al. (1984) conducted a double-blind, placebo, controlled experiment measuring the effects of 1st generation antihistamine triprolidine and the and the 2nd generation antihistamine terfenadine on actual driving performance in a group of experienced women drivers. They found that triprolidine greatly impaired driving behavior, whereas terfenadine did not. Triprolidine also impaired subjective and objective measures of mood and arousal, and despite an awareness that their driving was impaired while they were taking this agent, subjects could not correct their performance. The researchers concluded that this study suggests that drivers who need antihistamine drugs should avoid those that act centrally.
Starmer (1985) reviewed available evidence that antihistamine-induced impairment of human psychomotor performance constitutes a traffic hazard. He noted that there were two distinct classes of histamine antagonists, which act at different receptors (H1 and H2), and that they should be considered separately. H1 antagonists are freely available to the public and are widely consumed. He also noted that they are a rather heterogenous group of drugs which share the common property of antagonizing some of the effect of histamine. Starmer indicated that other effects, particularly sedation, are prominent with many of the older members of the H1 group, and these drugs can be shown to impair performance in laboratory tasks and to interact additively with alcohol and other central nervous system depressant drugs. Despite this potential for impairment of driving ability, Starmer observed that they are seldom suggested as causative factors in traffic crashes. He pointed out that a number of new histamine H1 antagonists have been developed recently which only gain limited access to the central nervous system and appear to be less likely to cause impairment of performance skills. Histamine H2 antagonists have a much more restricted and closely supervised use in medicine, and of the two agents currently available (cimetidine and ranitidine), only cimetidine appears to pose traffic safety problems, largely because of its ability to interfere with the metabolism of other drugs which depress the central nervous system. He recommended appropriate prescribing to eliminate this problem. Starmer concluded that, with both classes of histamine antagonist, it is now possible for the prescriber to select from the available drugs one with a minimal potential for disrupting driving ability.
In a later review (limited to H1-receptor antagonists), Simons (1994) also observed that 1st generation histamine H1-receptor antagonists frequently cause drowsiness or other CNS adverse effects, but that 2nd generation H1-antagonists have a relative lack of such effects. He noted that even the 2nd generation drugs can create some risk and recommended that "the magnitude of the beneficial effects of each H1-antagonist should be related to the magnitude of the unwanted effects, especially in the CNS and cardiovascular system, and a benefit-risk ratio or therapeutic index should be developed for each medication in this class."
Moskowitz and Wilkinson (2003) have just completed a review of the scientific literature on the effects of H1-antagonist antihistamines on driving and driving-related performance. Studies relating to five 1st generation drugs (chlorpheniramine, clemastine, diphenhydramine, hydroxyzine, and triprolidine) and five 2nd generation drugs (astemizole, cetirizine, fexofenadine, loratadine, and terfenadine) were included in the review. The authors found that 88% of the studies of 1st generation antihistamines found some impairment in driving related skills, but that only 22% of the 2nd generation antihistamines found such impairments. However, the percent of drugs within each generation and the percent of studies showing impairment varied widely among specific drugs within each generation.
Performance of driving tasks was impaired in 13% of the 32 studies that examined driving behavior. When the tasks are limited to actual driving, only 10% of the 20 studies showed impairment. Analysis of studies focusing on cognitive and psychomotor skills yielded similarly low rates. Most 1st generation drugs resulted in a feeling of sedation and a change in the EEG, whereas the overwhelming majority of the 2nd generation antihistamines did not result in such feelings or physiological changes. Consistent with these findings, most studies of 1st generation drugs showed impairments on visual functioning, divided attention, vigilance, and tracking, while studies of the studies of 2nd generation antihistamines rarely showed any impairments on any of the tasks studied. Furthermore, the authors note that in many cases where impairment was shown, the dose levels greatly exceeded the recommended therapeutic levels. In conclusion, the authors note that "it would appear that proper selection of a 2nd generation antihistamine would produce little skills performance impairment. Therefore, one would not anticipate a significant effect on traffic collisions." (p. 20).
Selected experimental studies of both H1- and H2- receptor antagonist drugs published since the late 1980s are summarized in the remainder of this section. Some of the studies reviewed by Moskowitz and Wilkinson are included.
O'Hanlon (1988) reported that the results of two placebo-controlled driving performance studies confirmed prior laboratory data showing that terfenadine does not adversely affect the driving performance of users. The amplitude of vehicle weaving calculated for drivers who received this agent did not differ from control values. Neither terfenadine nor loratadine, another nonsedating antihistamine, potentiated the adverse effects of alcohol on driving performance.
Ramaekers, Uiterwijk, and O'Hanlon (1992) report the results of a study in which 16 healthy male and female volunteers took part in a 6-way, double-blind crossover trial to compare the effects of single doses of the 2nd generation H1-receptor antagonists cetirizine (10 mg) and loratadine (10 mg), with placebo, with and without alcohol (0.72 g/kg, lean body mass). Performance was measured in two repetitions of a psychometric test battery, and a standard, over-the-road driving test. EEG was also measured during driving. Alcohol significantly affected almost every performance measure and altered the EEG energy spectrum during driving while the blood concentrations declined from 0.37 to 0.20 mg/ml. The effects of cetirizine on driving performance resembled those of alcohol. It caused the subjects to operate with significantly greater variability in speed and lateral position ("weaving" motion). The effects of alcohol and cetirizine appeared to be additive. Certain cetirizine-placebo differences in subjective feelings and test battery performance were also significant. Loratadine had no significant effect on any performance parameter. The authors concluded that cetirizine, but not loratadine, generally caused mild impairment of performance after a single 10 mg dose.
Ramaekers and O'Hanlon (1994) conducted another study of antihistamines following a nine-way observer- and subject-blind, crossover design. Its purpose was to compare the single-dose effects of the following drugs on driving performance acrivastine (8, 16 and 24 mg); the combination of acrivastine (8mg) with pseudoephedrine (60mg); terfenadine (60, 120 and 180 mg); diphenhydramine-HCI (50mg); and placebo. The subjects were 18 healthy female volunteers. Drug effects were assessed in two repetitions of two driving tests (highway driving and car-following) after each treatment. The study indicated that the normal therapeutic dose of acrivastine (8 mg) had little effect on driving performance, and virtually none when that dose was given in combination with pseudoephedrine (60 mg). Higher doses of acrivastine severely impaired driving performance. Terfenadine had no significant effect on driving performance after any dose while diphenhydramine strongly impaired every important driving parameter.
Vuurman, Uiterwijk, Rosenzweig, and O'Hanlon (1994) compared the acute effect of doses of mizolastine 5, 10, 20 and 40 mg, an active control (clemastine 2mg) and placebo on actual car driving and psychomotor performance. Twenty four healthy volunteers were treated according to a doubt-blind, 6-way crossover design. In the driving test, lasting about 1 hour, lateral position control and speed were continuously measured; the psychomotor test battery, lasting 50 minutes, comprised critical flicker fusion frequency, critical instability tracking, divided attention, memory search and choice reaction time, and vigilance studies; and mood changes and possible adverse effects were rated on visual analogue scales. The results showed a dose-response relationship. Mizolastine 40 and 20 mg impaired driving and psychomotor performance. The effect of mizolastine 40 mg on driving was strongly correlated with that of clemastine (r=0.78) and was comparable to the effect of a blood ethanol level of 0.8 mg/ml. Mizolastine 5 mg and 10 mg did not have a significant effect on driving performance and psychomotor tests. It was concluded that at a 10 mg dose of mizolastine, the therapeutic dose, it could be considered a safe antihistamine, although individual adverse reactions cannot be completely ruled out.
O'Hanlon and Ramaekers (1995) reviewed the major results of eight double-blind placebo-controlled, volunteer studies undertaken by three independent institutions for showing the effects on actual driving performance of "sedating" and "nonsedating" antihistamines (respectively, triprolidine, diphenhydramine, clemastine and terfenadine; and loratadine, cetirizine, acrivastine, mizolastine, and ebastine). A common, standardized test was used that measures driving impairment from vehicular "weaving" [i.e., standard deviation of lateral position (SDLP) ]. Logical relationships were found between impairment and dose, time after dosing, and repeated doses over 4-5 days. The newer drugs were generally less impairing, but differences existed among their effects, and none was unimpairing at doses 1-2 times the currently recommended levels. One or possibly two of the newer drugs possessed both performance-enhancing and impairing properties, depending on dose, suggesting two mechanisms of action.
Vermeeren and O'Hanlon (1998) studied the effects of fexofenadine on performance for the purpose of determining its safety of use by patients who engage in potentially dangerous activities, especially car driving. (Fexofenadine is the hydrochloride salt of terfenadine's active metabolite.) Fexofenadine was administered in daily doses of 120 or 240 mg. each in single and divided units given over 5 days. Two milligrams of clemastine given twice daily and placebo were given in similar series. Twenty-four healthy volunteers (12 men, 12 women; age range 21 to 45 years) participated in a double-blind six-way crossover study. Psychomotor tests (critical tracking, choice reaction time, and sustained attention) and a standardized actual driving test were undertaken between 1.5 to 4 hours after administration of the morning dose on days 1, 4, and 5 of each series. On day 5, subjects received a moderate alcohol dose before testing. Fexofenadine did not impair driving performance. On the contrary, driving performance was consistently better during twice daily treatment with 120 mg fexofenadine than during treatment with placebo, significantly so on day 4. Both of the 240 mg/day regimens significantly attenuated alcohol's adverse effect on driving on day 5. Effects in psychomotor tests were not significant, with the exception of the critical tracking test in which the first single doses of fexofenadine, 120 and 240 mg. had significantly impairing effects. It was concluded that fexofenadine has no effect on performance after being taken in the recommended dosage of 60 mg twice daily.
Finally, Weiler et al. (2000) compared the effects of fexofenadine, diphenhydramine, alcohol, and placebo on driving performance. They used a randomized, double-blind, double-dummy, four-treatment, four-period crossover trial conducted in the Iowa Driving Simulator. The trial involved 40 licensed drivers with seasonal allergic rhinitis who were 25 to 44 years of age. One dose of fexofenadine (60 mg), diphenhydramine (50 mg), alcohol (approximately .10 blood alcohol concentration), or placebo, was given at weekly intervals before participants drove for 1 hour in the Iowa Driving Simulator. The main objective was to measure coherence, defined as "a continuous measure of participants' ability to match the varying speed of a vehicle that they were following." The study also measured subject drowsiness and other driving variables, including lane keeping and response to a vehicle that unexpectedly blocked the lane ahead. Participants had significantly better coherence after taking alcohol or fexofenadine than after taking diphenhydramine. Lane keeping (steering instability and crossing the center line) was impaired after alcohol and diphenhydramine use compared with fexofenadine use. Mean response time to the blocking vehicle was slowest after alcohol use (2.21 seconds) compared with fexofenadine use (1.95 seconds). Self- reported drowsiness did not predict lack of coherence and was weakly associated with minimum following distance, steering instability, and left-lane excursion. The authors concluded that the participants had similar performance when treated with fexofenadine or placebo, and that driving performance was poorest after taking diphenhydramine. The authors also found that drowsiness ratings were not a good predictor of impairment, "suggesting that drivers cannot use drowsiness to indicate when they should not drive."
In a study by Klebel, Saam, and Hoffman (1985), 21 hypertensive patients received (after a one-week placebo period) a 4-week treatment with a once daily dose of 300 mg of the antihypertensive celiprolol hydrochloride (Selectol). Twenty-one normotensive subjects receiving placebo during the whole trial period and 20 normotensives receiving no treatment at all served as comparative groups. Prior to the treatment, the hypertensive subjects showed a marked lack in acquisition and reproduction of complex visual information, and their subjective emotional condition was more negative than that of the healthy subjects. A one-week placebo treatment had no influence on the parameters under test. One single dose of celiprolol had no influence on the specific capacity of driving a motor vehicle and on the emotional condition. Long-term medication of celiprolol did not impair the driving ability. The subjective emotional condition improved as desired. Another study (reviewed on page 31) also found that mepindolol sulphate, a beta blocker without sedating properties, did not impair driving or driving-related performance (Willumeit, Ott, Neubert et al., 1984).
Betts, Harris, and Gadd (1991) examined the effects of the antivertigo drug betahistine on driving. In the study, 72 mg were taken three times daily, prochlorperazine 5 mg were taken three times daily, and placebo was taken for 3 days before testing. Then, the subjects were compared on two actual driving tasks (weaving and gap estimation) and two psychomotor tasks (reaction time and kinetic visual acuity) in normal subjects. The results showed that the psychomotor effects of betahistine could not be distinguished from those of placebo and that prochlorperazine impaired driving performance causing increased carelessness and slowing on the weaving test. Also, there was little subjective appreciation of impairment during taking prochlorperazine.
Wylie, Thompson, and Wildgust (1993) noted that patients who are prescribed psychotropic medication may be expected to have some impairment in general attention and concentration and in measures of psychological and motor performance. These impairments may be due to the illness itself, the medication or the combination of both. In this study, 22 patients who were receiving injections of neuroleptics for chronic schizophrenia were compared with 16 control subjects in their performance on simulated driving tests. The researchers found a significant decrement in driving performance in the index group compared with a normal control group.
Vuurman, Muntjewerff, Uiterwijk, et al. (1996) performed studies to determine whether mefloquine, a quinoline anti-malarial drug, affects psychomotor and actual driving performance when given in a prophylactic regimen, alone or in combination with alcohol. Forty male and female volunteers were randomly assigned in equal numbers to two groups, and were treated double-blind for one month with mefloquine and placebo. The medication was taken in a 250 mg dose on the evenings of days 1, 2, 3, 8, 15, 22 and 29. Testing was done on days 4, 23 and 30, the latter after repeated doses of alcohol sufficient to sustain a blood concentration of about .35 mg/ml. Two real driving tests were used to measure prolonged (1 hour) road tracking and car following performance; critical flicker fusion frequency, critical instability tracking, and body sway were also measured in the laboratory. Mefloquine caused no significant impairment in any test at any time relative to placebo. It significantly improved road tracking performance on day 4. A significant interaction between prior treatment and alcohol was found in the body sway test, as the alcohol-induced change was less after mefloquine than placebo. The sensitivity of the driving test and the critical flicker fusion frequency test were shown by the significant overall effect of alcohol which did not discriminate between the two prior treatments.
Ellingrod, Perry, Yates, et al. (1997) examined the driving effect of anabolic steroids in the form of physiologic (100 mg/wk) and supraphysiologic (250 and 500 mg/wk) doses of testosterone cypionate (TC). The Iowa Driver Simulator was used in the study. Six normal subject volunteers were studied off TC and on TC once steady-state concentrations were achieved after at lease three weeks of dosing. Despite the administration of supraphysiologic testosterone doses, an increase in aggressive driving behavior was not detected. Likewise, corresponding psychometric testing was unable to detect any change in aggression in the test subjects. Although aggressive driving behavior may be increased by testosterone administration, the drug itself may not be responsible for these effects. Supraphysiologic doses greater than 500 mg/wk and a semi-controlled research environment may be necessary to produce this effect, since case reports of anabolic steroids abuse causing altered driving behavior may be multifactorial in nature.
Grant, Murdoch, Millar, and Kenny (2000) studied psychomotor performance in 10 healthy volunteers during recovery after a target-controlled infusion of propofol anaesthesia. Choice reaction time, dual task tracking with secondary reaction time and a within-list recognition task were assessed at target blood propofol concentrations of 0.8, 0.4 and 0.2 mg/ml. Performance was impaired most at the highest blood propofol concentration (choice reaction time increased by a mean of 247 ms and secondary reaction time by a mean of 178 ms). Choice reaction time and dual task tracking with secondary reaction time were the most sensitive and reliable methods of assessment [significant difference from baseline (p<.05) at a propofol concentration of 0.2 mg/ml with choice and secondary reaction time testing]. Within-list recognition assessment of memory was not sufficiently sensitive at very low propofol concentrations. The impairment in choice and secondary reaction time with a blood propofol concentration of 0.2 mg/ml was less than that observed with a blood alcohol concentration of .05 and no greater than that observed with a blood alcohol concentration of .02 in a previous study involving healthy volunteers.
Selected literature on the effects of a wide range of drugs on performance of driving-related tasks and performance of actual driving tasks was reviewed. Classes of drugs considered were:
The amount of research in these classes varied widely, with the most attention given to CNS depressants and the least given to narcotics. We found essentially no experimental research on some other classes of drugs not listed above, for example, hallucinogens and inhalants.
With respect to narcotics, one laboratory study of a synthetic opioid (fentanyl) showed impairment on a tracometer task, another finding no difference in the performance of chronic users of methadone and non-users in driving-related tasks, and a third finding that the only significant effect of codeine on signs and symptoms in NHTSA 's DEC program was a reduction in pupil size. However, a 1974 simulator study found that acute codeine use resulted in more crashes, more instances of leaving the road, and more ignoring of instructions. Lastly, a simulator study of persons using narcotics in the treatment of chronic non-malignant pain found no significant impairment. These sparse results suggest that acute use of narcotics can definitely impair driving performance, but that chronic therapeutic use need not cause impairment.
For CNS depressants, two sub-classes, benzodiazepines and barbiturates, have received the bulk of the attention in the literature. Of these, the benzodiazepines have generated most of the studies. The variety of benzodiazepines is wide, with most of them falling into two categories, those with effects having a short half-life (peaking at two to three hours) and those with effects having a long half-life (lasting nine or more hours). Tested benzodiazepines classified as short half-life included flurazepam, temazepam, and triazolam. Tested long half-life benzodiazepines included alprazolam, diazepam, flunitrazepam, lorazepam, and nitrazepam.
Nearly three-fourths of the experiments on benzodiazepines of all types found impairments of one or more tasks or functions. Interestingly, a larger percentage of driving experiments than laboratory experiments indicated significant impairment (79% vs. 70%, respectively). The research indicates that the impairing effects of benzodiazepines can vary wide for different members of the drug class: for example, diazepam consistently impaired performance in two-thirds of the pertinent experiments, while clobazam caused impairment in only one very high-dose experiment. Not surprisingly, the research indicates a clear dose-response relationship for benzodiazepines - 87% of experiments using high dosages found impairment. A few experiments tested the effect of chronic and sub-chronic use of benzodiazepines, with the results suggesting impairments in some tasks after a week or so of usage. Residual ("hangover") effects of several benzodiazepines used as hypnotics were also found. In sum, the research indicates that most benzodiazepines can cause significant impairment of driving and driving-related tasks, especially at high dosages. However, it has been argued that therapeutic dosages create impairments that may be less hazardous to driving than the illnesses they are treating.
Only three studies were found dealing with barbiturates alone, all indicating impairment of one or more tasks over a range of dosages. The tasks included those that were both cognitive and psychomotor in nature, including eye movements, digit symbol substitution, and card sorting. In one study, it was concluded that pentobarbital produced dose-related effects similar to those of alcohol on all psychomotor and cognitive measures.
While the research on the effects of CNS depressants indicate a high potential for impairment of driving and driving-related tasks, the very sparse experimental literature indicates that the opposite is true for CNS stimulants. Laboratory tests of acute effects showed either no impairment or improvement on various psychomotor and cognitive tasks, but a test of chronic users indicated impairment of card sorting and memory tasks.
Experimental research on the effects of cannabis have produced mixed results, indicating that any effects (slightly over half of the experiments we examined showed impairment) dissipate quickly after one hour, so that a day after ingestion they are no longer significant. Furthermore, while drivers feel high, they actually tend to compensate for their feelings. Of the behavioral measures studied, marijuana seems to effect the encoding of information and its short-term storage. It has been found that marijuana impairs digit span (forward and backward) and time estimation. While alcohol causes an underestimate of time, marijuana causes an overestimate of time, and consequently an under-production in time-production tasks. Impairments in tracking and reaction time have also been noted, but in a much less consistent manner than with alcohol impairment. Experiments in actual driving tasks indicated impairment in a range of such tasks, including maintaining lateral position, headway, and speed: negotiating turn-offs; avoiding crashes; and performing secondary tasks. [Ward and Dye (1999) present an excellent summary of the effects of cannabis on various aspects of driving and driving-related performance.]
A considerable body of literature on the behavioral effects of antihistamines has been created in recent years. So-called H1 antihistamines (which restrict the release of histamines to cells) have been the subject of nearly all of this research. Older H1 antihistamines (1st generation H1 antihistamines) have been found to cause side effects such as drowsiness, which are greatly reduced by the newer, 2nd generation H1 antihistamines.
The recent review by Moskowitz and Wilkinson (2001) examined 130 articles on the effects of five "key" 1st generation and five key 2nd generation H1 antihistamines on driving and driving-related performance. They found that 88% of the studies of 1st generation antihistamines found some impairment in driving related skills, but that only 22% of the studies of 2nd generation antihistamines found such impairments. Performance of driving tasks was impaired in 13% of the 32 studies that examined driving behavior. Studies of cognitive and psychomotor skills yielded similarly low percentages. Most 1st generation drugs created a feeling of sedation and caused impairments of various psychomotor tasks, but few 2nd generation antihistamines resulted in such feelings or impairments. Most important, the dose levels causing impairment very often greatly exceeded the recommended therapeutic dosages. Our own examinations of a number of laboratory and driving experiments involving H1 antihistamines produced findings that were consistent to those of Moskowitz and Wilkinson. We found no studies of the effects of H2 or H3 antihistamines on driving and driving-related performance.
Several anti-depressant drugs have been tested in a few studies to determine their effects on driving and driving-related tasks. These drugs include: amitriptyline, brofaromine, doxepin, fluoxetine, mianserin, moclobemide, venlafaxine, and zimeldine. Of these, only amitriptyline, doxepin, and mianserin have been found to impair driving. It is believed that such impairment is due primarily to the sedative effects of these three drugs.
Finally, the experiments dealing with six other drugs not in any of the above categories (an anti-hypertensive drug, an anti-vertigo drug, an injected neuroleptic drug for treating schizophrenia, an anti-malarial drug, an anabolic steroid, and propofol anaesthesia) found impairment for only two of the drugs. Schizophrenics undergoing treatment involving chronic use of the neuroleptic were more impaired than a group of normals not using a neuroleptic, but it could not be said whether the drug or the illness or both caused the impairment. And the impairment by propofol was during recovery after anaesthesia when driving would not be likely.
It is difficult to generalize further about such a diverse group of drugs, but a few broad conclusions seem warranted. With respect to acute effects, it appears that the following drug classes have a high potential for significant impairment of driving and driving-related performance:
Drugs classes with a relatively low potential for significant impairment after acute usage are CNS stimulants (which actually may improve performance in some instances), 2nd generation H1 antihistamines, and most other anti-depressants. In addition, the literature suggests that acute use of cannabis has a moderate potential for impairment.
Very few studies examined the chronic and sub-chronic use of the above classes of drugs, and most of those that did suggest little effect on driving and driving-related performance. Interestingly, one study finding a clear effect (on card sorting and memory) involved a stimulant, d-amphetamine. Also, another study found that the anti-depressant mianserin impaired actual performance after eight days of use.
All-in-all, the literature supports the common-sense notion that drugs with a strong sedative action taken in the highest doses have the highest potential for significant impairment, while others have the lowest potential. Other meta-generalizations about which tasks and functions are impaired by which doses of which drugs cannot be made on the basis of the literature we examined.
2This would amount to about 2.2 ounces of alcohol for a 160 pound man and about 1.4 ounces for a 120 3b.i.d
3 b.i.d is an abbreviation for “twice a day,” and t.i.d. is an abbreviation for “three times a day.