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ORIGINAL INVESTIGATION

Effects of d-amphetamine on simulated driving performancebefore and after sleep deprivation

Magnus Hjälmdahl   & Anna Vadeby   & Åsa Forsman   &

Carina Fors   & Gunnel Ceder   & Per Woxler   &

Robert Kronstrand

Received: 31 May 2011 /Accepted: 8 May 2012 /Published online: 26 May 2012# Springer-Verlag 2012

Abstract

 Rationale  Stimulant drugs are commonly abused and alsoused to promote wakefulness, yet their effects on driving

 performance during sleep deprivation have not been thor-oughly researched in experimental studies.Objectives  The aims were to assess the effects on funda-mental driving parameters during simulated driving of twodoses of d-amphetamine and further to assess the interaction

 between d-amphetamine and sleep deprivation. Methods  A double-blind, placebo-controlled experiment in-cluding 18 healthy male volunteers was conducted. Results  The participants felt more alert when taking a doseof d-amphetamine than when taking placebo, and the effect 

was stronger for the higher dose. However, the data did not show any evidence that taking d-amphetamine prevented thesubjects from becoming successively sleepier during thenight. A significant main effect of the dose was found for three out of the five primary indicators where the lower doseled to improved driving. These indicators were crossing-car reaction time, and coherence and delay from a car-following

event. Regarding sleep deprivation, a main effect was found

for four of the primary indicators and three of the secondaryindicators. The results showed overall impaired driving withrespect to standard deviation of lateral position and delay inreaction time when the sleep-deprived conditions were com-

 pared to the alert condition. We found no interactions be-tween dose and sleep deprivation for any of the performanceindicators.Conclusions   Our results suggest that administration of d-amphetamine does not compensate for impairment of driv-ing due to fatigue. The positive effects of 10 mg were not further improved or even sustained when increasing thedose to 40 mg.

Keywords   Amphetamine . Sleep deprivation . Driving performance . Simulator  . Stimulants

Introduction

Amphetamine is a central nervous system stimulant used inmedicine to treat attention deficit disorders and narcolepsy.Amphetamine is also commonly abused and is frequentlyfound to be present in forensic toxicological investigationsof drivers and fatalities (Holmgren et al.  2007; Jones 2005,

2007; Jones and Holmgren  2005; Jones et al.  2007, 2008,2009; Lia et al. 2009; Logan 1996; Simonsen et al. 2011). Ina recent study of apprehended drivers in Sweden, more than50 % were positive for amphetamine (Holmgren et al.2007), whereas in a 5-year survey of drivers killed whiledriving, the percentage of positive cases was less than 3 %,with ethanol detected as the predominant substance in 22 %of the cases (Jones et al.  2009). Also, a 10-year study of drivers killed in road traffic crashes in Australia showed that only 4.1 % had stimulants present (Drummer et al.  2003).

M. Hjälmdahl (*) : A. Vadeby : Å. Forsman : C. ForsSwedish Road and Transport Research Institute,SE-581 95 Linköping, Swedene-mail: magnus.hjalmdahl@vti.se

G. Ceder : R. KronstrandDepartment of Forensic Genetics and Forensic Toxicology,

 National Board of Forensic Medicine,SE-587 58 Linköping, Sweden

P. Woxler Department of Psychiatry, University Hospital,SE-581 85 Linköping, Sweden

R. KronstrandDivision of Drug Research, Linköping University,Linköping, Sweden

Psychopharmacology (2012) 222:401 – 411

DOI 10.1007/s00213-012-2744-7

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This could be interpreted to mean that amphetamine has alow crash risk, and some experimental studies have evenshown that low doses of amphetamine may improve somecognitive processes, such as attention and psychomotor functioning (de Wit et al.  2002; Silber et al. 2006). On theother hand, case studies have shown that amphetaminesnegatively influence driving performance (Logan   1996;

Logan et al. 1998) and that stimulant use increases the crashrisk by two to three times (Drummer et al. 2004; Movig et al.   2004). The differences between the outcome of theexperimental studies and epidemiological data can beexplained by the complexity of the tasks involved. In isola-tion, cognitive processes may be improved at low doses of stimulants, but when divided attention is needed, the perfor-mance is impaired. This has been described as   “tunnelvision” or an inability to gather information from different sources (Mills et al.  2001). Experiments performed in ad-vanced driving simulators offer the opportunity to create andin detail study and measure operational behaviour such as

lateral position, speed control, and headway, or strategic behaviour including speed choice, as well as tactical behav-iour such as risk taking and the ability to gather and interpret information in the traffic situation (Michon 1985).

The different outcomes of experimental studies and epi-demiological data may also be the result of differences indoses administered. Doses used in experiments range from 5to 40 mg of amphetamine, considerably less than thoseadministered for recreational use (Lia et al. 2009; Silber et al.   2005). For example, the median concentration of am-

 phetamine in apprehended drivers was reported to be0.80 mg/L (Jones et al.  2008), much higher than concen-

trations up to 0.1 mg/L plasma concentrations reported inexperimental studies (Silber et al. 2005). On the other hand,there seems to be little correlation between the amphetamine

 blood concentration and the degree of impairment in termsof both physiological, subjective psychological, and cogni-tive measures (Asghar et al.  2003; Jones  2007; Lia et al.2009). Since amphetamine can be repeatedly administeredaround the clock over several days, followed by exhaustionand long sleep, the lack of correlation between blood con-centrations and signs of influence can be a result of fatiguefrom sleep deprivation (Jones et al.  2008).

Direct investigations of how d-amphetamine affects driv-

ing performance in simulators or during real-life driving arevery limited, and the only study so far reported was per-formed by Silber et al., who concluded that a dose of 0.42 mg/kg affected daytime driving only (Silber et al.2005). The behaviours that contributed to this finding were“incorrect signalling”,   “failing to stop at a red light ”, and“driving slowly”, results that are consistent with perceptualnarrowing.

Besides the intake of drugs, sleep deprivation in itself isconsidered a risk factor for road traffic accidents (Anund

2009; Barrett et al.  2004; Biggs et al.  2007; Desai et al.2006; Hack et al.  2001; Jackson et al.  2008; Lenne et al.1998; Orzel-Gryglewska   2010; Philip et al.   1999,   2004;Reynolds and Banks   2010; Va k u l in e t a l .   2007).Amphetamine influences the function of the central nervoussystem by releasing and blocking the reuptake of catechol-amines and has been shown to improve cognitive and motor 

function in sleep-deprived subjects (Magill et al. 2003). The possible positive effects of stimulant drugs on driving per-formance during sleep deprivation have also been studiedwith a focus on caffeine (Biggs et al.  2007; De Valck andCluydts   2001; De Valck et al.   2003; Reyner and Horne2000). Investigations regarding the use of amphetaminesto prolong wakefulness and overcome sleep deprivationhave primarily been directed towards aviation (Caldwelland Caldwell   2005; Caldwell et al.   2003; Emonson andVanderbeek   1995; Gore et al.   2010). The results showedthat amphetamine maintained flight skills, psychologicalmood, and physiological activation in sleep-deprived pilots.

Thus, amphetamine by itself may not only impair drivingskills, but may also improve driving skills when the subject is sleep deprived.

Identifying this paucity of data, we aimed to assess theeffects of two doses of d-amphetamine on fundamentaldriving parameters during simulated driving and, further,to assess the interaction between d-amphetamine and sleepdeprivation in a double-blind, placebo-controlled experi-ment conducted in a moving-base driving simulator.

Methods

Subjects

The experiment was approved by the Regional EthicsCommittee in Linköping (Dnr M91-07) and granted autho-rization by the Swedish Medical Products Agency (EU-nr 2007-002500-18, Dnr 151:2008/14592). Based on experi-ence from earlier trials, it was decided that 18 subjects wererequired for the experiment (Fors et al.  2010). The set-up of the experiment, however, allowed for four persons per day,which led to the recruitment of 20 persons (four persons per night during 5 days). The subjects were recruited from the

VTI test subject database. Inclusion criteria were male, 23 – 40 years old, and experienced drivers (driving 1,000 to5,000 km per year and having held a valid driving licencefor at least 5 years). Exclusion criteria were ADHD accord-ing to DSM – IV, and the subjects were screened for that diagnosis using ASRS-v1.1. Other exclusion criteria were

 problems with motion sickness, history of alcohol or drugabuse, and regular use of prescription medications. Thecriteria were no use of drugs in the previous 12 monthsand less than 14 standard drinks per week. The reason for 

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only using male participants was that it was of interest tokeep variability low; thus, gender was taken out of theequation. Male was chosen before female because it is ingeneral more difficult to recruit female subjects to simulator experiments. Smoking was not an exclusion criteria, but they were not allowed to smoke during the testing session.Prior to the experiment, the participants were subjected to an

examination including a physical and psychiatric examina-tion, urine drug testing (for amphetamines, opiates, canna-

 binoids, cocaine, and benzodiazepines), as well as aninterview with a psychiatrist. A few weeks after the exper-iment was completed, all subjects had a follow-up medicalexamination, including an interview.

Procedure

A randomized, double-blind, placebo-controlled, crossover design was used. Three different doses were combined withthree levels of sleep deprivation, resulting in a total of nineconditions. Each subject participated in the experiment at three occasions, at 7-day intervals. At each occasion, thesubjects were given one of three doses: placebo, or 10 or 40 mg of d-amphetamine. Each test occasion lasted over-night, from afternoon to next morning, and included four subjects, who had three driving sessions each: one in lateafternoon, one at night, and one in the morning. Eachsubject had his driving sessions at the same day and timeeach week. The timetable for the first subject to arrive oneach test occasion is given in Table 1. The timetables for thethree other subjects were delayed 1, 2, and 3 h, respectively.Otherwise, the procedure was the same. The subjects werenot allowed to eat anything from the time they arrived untilafter the first driving session. They were not allowed to

sleep or to drink any caffeine-containing beverages duringthe whole test occasion. The time between the driving ses-sions was spent in a room next to the simulator room, wherethe subjects could eat, talk to each other, watch television, usethe Internet, etc.

Tests

There were a number of tests carried out before, between,and after each driving session. The timeline for each sessionis shown in Table 1. Upon arrival, the subjects were asked torate their sleepiness level using the Karolinska SleepinessScale (KSS) (Akerstedt and Gillberg 1990). The KSS rangesfrom 1 to 9, where 10very alert, 50neither sleepy nor alert,70sleepy but no effort to remain awake, and 90very sleepy,an effort to stay awake, fighting sleep. Prior to administra-tion of d-amphetamine (or placebo), the subjects were testedfor ethanol using a breathalyser and drugs of abuse using aurine-screening test. At this point, the subjects’ blood pres-sure and pulse were also registered, and a pre-dose bloodsample was taken. After drug administration, the subjectsfilled out a background questionnaire (only at the first test occasion). Immediately prior to their first driving sessions,

 blood pressure and pulse were measured once again, sleep-iness was self-rated, and blood samples were obtained. After the first driving session (which lasted for approximately45 min), a KSS rating was given, blood pressure and pulsewere measured, and a blood sample was taken. The subjectsthen filled out a questionnaire regarding the driving session.Four hours after the first driving session, it was time for thesecond session, and blood pressure, pulse, and KSS wereregistered before the drive. Also, a blood sample was taken.After the second drive, there was no test except for KSS and

Table 1  Timetable for the sub- jects at each test occasion

 Note that T0016:00, 17:00,18:00, or 19:00 for the four subjects each night. This meansthat they arrived and drove withone hour time offset a d-amphetamine b pH, cannabis, opiates, cocaine,amphetamine, benzodiazepines

Time Event  

T0 Arrival. Tests: breath alcohol, blood pressure, pulse, blooda , urine b, KSS

T0 + 0:30 Drug intake

 No food intake was allowed before the first drive.

T0 + 1:45 Tests: blood pressure, pulse, blooda 

T0 + 2:00 Driving session 1. KSS before and after  

T0 + 2:45 Tests: blooda , questionnaire

Dinner and free time

T0 + 6:45 Tests: blood pressure, pulse, blooda 

T0 + 7:00 Driving session 2. KSS before and after  

T0 + 7:45 Questionnaire

Sandwich and free time

T0 + 11:45 Tests: blood pressure, pulse, blooda 

T0 + 12:00 Driving session 3. KSS before and after  

T0 + 12:45 Questionnaire

T0 + 13:00 Taxi home

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a questionnaire. For the third and last drive (4 h after thesecond drive), the procedure was the same as for drivenumber two. After the last drive of the final week, thedrivers were given an extended questionnaire to take homeand fill out. This questionnaire covered their experiencethroughout the whole experiment.

Driving simulator scenario

The study was carried out on VTI’s driving simulator III,which is a moving-base driving simulator with interchange-able cabins. In this experiment, a Saab 9-3 cabin wasmounted on the motion platform. The simulator is situ-ated at VTI’s head office in Linköping, Sweden. Themoving-base system is a unique solution that has beendesigned and constructed by VTI. It is used to generateforces felt by the driver while driving. It can be divided intothree separate parts: a large linear motion, tilt motion, and avibration table.

The route designed for this experiment covered both ruraland urban roads with speed limits of 50 and 70 km/h. In theurban sections, there were both signal-controlled intersec-tions and intersections with rights of way. All in all, theroute was 44.6 km long and took approximately 45 min todrive. The subjects were instructed to consider the drive astheir daily route to work and to drive as they normallywould during these conditions. The experimental design inthis study required that the test subjects drive the samescenario on nine occasions, which meant that large learningeffects could be expected. Learning effects in simulator studies with repeated measures are common and need to

 be handled in both the design and the analysis of the experi-ments (Fors et al.  2010; Ljung Aust et al.  2011; Vaa et al.2006). In an attempt to minimize the learning effects, wehad all subjects conduct a test drive before the experiment started, so that to some extent, they familiarized themselveswith the route and the scenario. To further minimize thelearning effects, the events the subjects encountered did not occur at the same spot every time but happened at severaldifferent places. For a description of the events, see“Performance indicators and events” section below. At theend of the drive, there was a car-following event. Before that event, the driver stopped the vehicle and was given new

instructions, which were to follow the vehicle in front. Inthis event, roads with a speed limit of 90 km/h were alsoincluded.

Performance indicators and events

A number of performance indicators based on driving datawere calculated for the analysis. These were based on bothnormal driving, such as mean speed and standard deviationof lateral position (SDLP), and also on specific situations or 

events. These events were designed to trigger behaviour that would indicate a change in behaviour, reaction, and risk taking.

The events included in this study were a car crossingthe roadway in front of the driver, traffic lights turningyellow and then red, a bus turning out from a bus stopin front of the driver, and a moped driving slowly while

oncoming traffic made overtaking somewhat difficult.These events were all triggered on time, that is, alldrivers had the same time to respond to these eventsto avoid colliding, or driving against a red light, regard-less of their driving speed. In addition to these events,some normal driving situations were also studied. Thesewere mean speed, standard deviation of speed, standarddeviation of lane position on 50- and 70-km/h roads,and minimum speed when driving through intersections.There was also a specific car-following test used in this study(Brookhuis et al. 1994; Waard and Brookhuis 2000), and fromthis test, the measures car following: coherence, gain, and

delay were extracted.Since the work carried out in this study is one of several

coordinated experiments within the EU project DRUID,there are measures that are coordinated and compared be-tween the studies; these are labelled as primary performanceindicators in the text and tables of this study. The measuresthat may be unique to this study are labelled as secondary

 performance indicators.

Statistical analysis

To study the overall treatment effect, the data were analysedusing analysis of variance (ANOVA), and the models werechosen to correspond with the design of the study. The mainobjective of the study was to investigate the subjects’ driv-ing performance, but we also studied how different doses of d-amphetamine affected the subjects’  self-reported sleepi-ness. Each treatment was given to each subject, and tocontrol for variability between people, a repeated measuresdesign was used. This implies that the factor  subject  was arandom factor, and the other factors were regarded as fixedfactors (Montgomery   1991). The following factors wereused in the models:

α0dose (00 placebo, 1010 mg, 2040 mg)θ0 plasma concentration of d-amphetamine (0, 0 – 20,20 – 40, 40 – 60, 60 – 80, 80+ng/ml)β 0test occasion (1, 2, or 3)γ 0drive (0, SD1, and SD2; reflects three levels of sleepdeprivation)ζ 0subject (1,  …, 18)

To refine the data analysis, two different models wereused. The first model used dose of d-amphetamine as the

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main factor of interest, while the second model used plasmaconcentration of d-amphetamine instead of dose.

1.

Y ijklm  ¼ μþ a i þ b  j þ g k  þ z l þ ag il þ "ijklm

2.

Y ijklm  ¼ μþ θi þ b  j þ g k  þ z l þ "ijklm

where   μ  was the mean effect and   ε  was an error term.  Y could be either a driving performance indicator or KSS.Sleepiness was analysed by the first model and driving

 performance by both models. When analysing driver perfor-mance, occasion and drive reflected the learning effects dueto repeated driving sessions. Moreover, drive also reflectedthe different states of alertness. Subject is entered toaccount for individual differences. The interaction   αγ 

was added to model 1 to account for temporal changesin plasma concentration during the night for different doses. To measure the driving performance for the different 

test subjects, a number of performance indicators were used asresponse variables; see  “Performance indicators and events”section for a description. The performance indicators weredivided into primary and secondary indicators, and the

 primary indicators were studied in more detail. The primary performance indicators were crossing-car reaction time andSDLP at 70 km/h from the first part of the experiment andcoherence, gain, and delay from the car-following event. If thefactor of interest, dose or plasma concentration, wassignificant in the ANOVA analysis, pairwise compari-sons between different levels of the factors were made.The comparisons were based on the estimated marginal

means, which compensate for an unbalanced design, if that was the case. The Bonferroni adjustment for multiple compar-isons was used.

Results

The whole experiment was carried out in 3 weeks startingeach week at four o’clock Sunday afternoon and ending at eight o’clock Friday morning. Four subjects were present every night giving 20 subjects in total. Eighteen subjectscompleted the whole experiment, one subject got ill in the

simulator, and one asked to not participate due to discomfort when taking blood samples. There was a partial loss of datafor another two drivers who fell asleep during the car-following event on the last drive when driving with placebo.

Fig. 1   Distribution of plasmaconcentration of d-amphetamine(in nanograms per millilitre) for each dose (0, 10dose 10 mg,20dose 40 mg) and drive. For the first drive, plasma concen-tration was measuredbothbeforeand after the driving session, anda mean of these concentrations

was used in the analysis. For thesecond and third drives, plasmaconcentration was measuredonly before the driving sessions

Table 2   Results fromvariance of analysis on sleepiness (KSS)

 p values for tests of factor effects

Intercept Dose Occasion Drive Subject Dose × drive

KSS before drive <0.001 <0.001 0.07 <0.001 <0.001 0.53

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Thus, these two drives ended a few minutes earlier than planned. For the first drive, plasma concentration was mea-sured both before and after the driving session, and a meanof these concentrations was used in the analysis. For thesecond and third drive, plasma concentration was measuredonly before the driving session. Figure  1 illustrates how theactual plasma concentration (in nanograms per millilitre)varied between subjects for each dose and drive.

Effect of dose on sleepiness

Sleepiness was measured by the Karolinska SleepinessScale. The results from the analysis of variance showed asignificant difference in sleepiness between different doses,

 between subjects as well as between driving sessions(Table   2). The effect of different doses is shown inTable   3, and a higher dose led to increased alertness.Pairwise comparisons showed a significant difference be-tween all pairs of doses. The effect of dose and drive isillustrated in Fig.  2. The subjects experienced an increasedsleepiness during the night, which was lowered, the higher 

the dose of d-amphetamine.

Effect on variables reflecting driver performance

The driver performance was studied using five primary andten secondary performance indicators described in the“Performance indicators and events” section above.

Primary performance indicators

The results for the primary indicators and how they wereaffected by different doses of d-amphetamine are shown inFigs.  3,  4, 5, 6, and 7  and summarized in Tables  4 and 5.Table  4  shows the   p   values for the tests of factor effects.Three of the primary performance indicators showed a sig-nificant effect of dose. These indicators were crossing-car reaction time and two of the indicators from the car-following event, coherence and delay. All indicators except gain showed significant effects of drive. The most consistent result is the significant effect of subject for all variables.This was expected, since we know from previous experiencethat there are large inter-individual differences in driver 

 performance (Ingre et al.   2006a,   b). The mean levels for different doses and levels of sleep deprivation are shown inTable 5. The mean reaction time for the event crossing car was 2.17 s for placebo and just below 2.0 s when 10 or 40 mg was given. The pairwise differences between dose 0and 10 and between 0 and 40 were significant. Considering

Table 3  Mean level of sleepiness (KSS) for different doses of d-amphetamine

Dose

0 mg 10 mg 40 mg

Mean level 5.47 5.00 4.07

The mean levels are adjusted for unbalance in the design

0

1

2

3

4

5

6

7

8

0 1 2

Drive

   M  e  a  n   l  e  v  e   l  o   f   K   S   S

0 mg

10 mg

40 mg

Dose

Fig. 2   Mean levels of sleepiness (Karolinska Sleep Scale) before eachdrive. The mean levels were adjusted for imbalance in the design

Fig. 3   Mean levels of crossing-car reaction time(s) for different dosesand sleep deprivation. The mean levels were adjusted for imbalance inthe design

Fig. 4   Mean levels of SDLP (in centimetres) for different doses andsleep deprivation. The mean levels were adjusted for imbalance in thedesign

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the performance indicator coherence, a significant difference between placebo and 10 mg of d-amphetamine was shown,with a lower value of coherence for placebo. The indicator 

delay (which reflects reaction time) also showed a significant difference between placebo and 10 mg, with a higher value for  placebo (see Table  5). Using plasma concentration in theanalysis instead of dose did not yield other results. As withdose, crossing-car reaction time, coherence, and delay showedsignificant effects.

Secondary performance indicators

Results for the secondary performance indicators and howthey were affected by different doses of d-amphetamine are

summarized in Tables 6  and  7. Table 6  shows the  p  valuesfor the tests of factor effects and Table  7 shows the meanlevels. None of the secondary performance indicatorsshowed a significant effect of dose, and only one, a signif-icant effect of drive. The same was found when usingconcentration instead of dose in the analysis.

Questionnaire results

All subjects could correctly state at what occasion they weregiven the high dose. Sixteen out of 18 could also distinguishthe low dose from placebo. The experience of d-amphetamine differed somewhat among the subjects.Several described that they felt   “high”: they became alert,talkative, social, and excited. Some described the effect as

 positive — they felt relaxed and comfortable — while othersfelt restless. Almost all subjects thought the medicine madethem less drowsy. A few stated that the medicine onlycaused an absence of drowsiness, without increased alert-ness or any other effects. The experiences of the low dosewere about the same as those of the high dose, but the

effects were much weaker and lasted for a shorter periodof time. Common side effects of the drug were dry mouth/ throat, reduced appetite, and a tingling sensation in the body.About a third of the subjects did not believe that the med-icine had any influence on their driving performance. Somesubjects commented that since the d-amphetamine madethem alert, they probably drove better after taking the drugcompared to driving while in a sleep-deprived condition, but they did not think the d-amphetamine led to increased risk taking or impaired driving performance. Some subjects alsoreported that the medicine made them more attentive, fo-cused, and alert. During the high-dose drive, some subjects

had a feeling that their driving performance was really good.However, afterwards, they had doubts and were afraid that their driving performance might not have been as good asthey had thought. About a fourth of the subjects thought that the drug had a negative influence on their driving. They

 believed that the high dose led to increased speed and arisky and egocentric behaviour. More than half of the sub-

 jects had difficulties falling asleep the day after the high-dose occasion. Some felt drowsy for a couple of daysfollowing the test, mainly after the high dose. Some reported

Fig. 5  Mean levels of coherence (car following) for different dosesand sleep deprivation. The mean levels were adjusted for imbalance inthe design

Fig. 6   Mean levels of gain (car following) for different doses andsleep deprivation. The mean levels were adjusted for imbalance in thedesign

Fig. 7  Mean levels of delay (car following) for different doses andsleep deprivation. The mean levels were adjusted for imbalance in thedesign

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that the dry mouth/throat and reduced appetite persisted onthe day after the test. Two subjects reported having gastric

 pain. About a third of the subjects did not feel any effects at all the day after the test.

Discussion

The aims of the present study were to assess the effects of d-amphetamine on fundamental driving parameters duringsimulated driving and to assess the interaction between d-amphetamine and sleep deprivation. The results showed that 

 participants in the study felt more alert when taking a doseof d-amphetamine than when taking placebo, and the effect was stronger for the higher dose. This is in line with what could be expected of this substance and what has previously

 be en re po rt ed (B er ri dg e et al .   1999; Emonson andVanderbeek  1995; Gore et al. 2010). However, the data didnot show any evidence that taking d-amphetamine pre-vented the subjects from becoming successively sleepier 

during the night. The results for driving performance indi-cators were less clear. There was no significant effect of dose on any of the ten secondary performance indicators.However, a significant main effect of dose was found for three out of the five primary indicators. The low dose led toimproved driving performance with respect to crossing-car reaction time, coherence, and delay, whereas the results for the high dose were less clear, with the only significant difference from placebo being in relation to crossing-car 

reaction time. The performance improvements are in agree-ment with another study on driving-related tasks where alow dose of d-amphetamine was administered (Mills et al.2001). On the other hand, Silber et al. performed studieswith a higher dose (0.42 mg/kg) similar to the high dose inour study and found a decrease in overall driving ability inthe daylight sessions (Silber et al.   2005). We could not verify this in our study, where only one main effect was

different from placebo; in that case, it was also an improve-ment. However, our driving scenarios also included sleepdeprivation, and the simulator facilities were very different from those of Silber et al.; a direct comparison of outcomesmight be difficult. A significant finding in our study wasthat the positive effects of a low dose (10 mg) were not further improved or even sustained by increasing the dose to40 mg or approximately 0.5 mg/kg. This might indicate that at doses commonly taken by recreational users or addicts,there are few or no positive effects of d-amphetamine.

Regarding sleep deprivation (alert, slightly sleep deprived,sleep deprived), a main effect was found for four of the

 primary indicators and three of the secondary indicators. Theresults showed overall impaired driving with respect to SDLPand delay when the sleep-deprived conditions were comparedto the alert condition. However, improved driving was alsofound, with respect to crossing-car reaction time. It is notablethat no interactions were found between dose and sleep dep-rivation for any of the performance indicators, indicating that there was no evidence in our data that taking a dose of d-amphetamine compensated for the impairment of driving. The

Table 4   Results from analysis of variance on driver performance for primary performance indicators

Response variable Intercept Dose Occasion Drive (sleep deprivation) Subject Dose × drive

Crossing-car reaction time <0.001 0.001 0.01 0.01 <0.001 0.95

Road 70 km/h, SDLP <0.001 0.85 0.37 0.02 <0.001 0.36

Car following: coherence <0.001 <0.001 0.08 0.01 <0.001 0.23

Car following: gain <0.001 0.68 0.22 0.97 <0.001 0.81

Car following: delay <0.001 0.04 0.001 0.01 <0.001 0.89

The analysis is based on the model with dose as a factor.  p  values for tests of factor effects

Table 5   Mean levels (standard deviation) of driver performance measures (primary) for different doses of d-amphetamine and different levels of sleep deprivation (alert, SD1, SD2)

Response variable Dose 0 mg Dose 10 mg Dose 40 mg

Alert SD1 SD2 alert SD1 SD2 alert SD1 SD2

Crossing-car reaction time 2.30 (0.07) 2.14 (0.08) 2.07 (0.07) 2.08 (0.08) 1.91 (0.08) 1.95 (0.08) 2.05 (0.08) 1.94 (0.08) 1.87 (0.08)

Road 70 km/h, SDLP 0.21 (0.01) 0.21 (0.01) 0.25 (0.01) 0.22 (0.01) 0.20 (0.01) 0.23 (0.01) 0.22 (0.01) 0.21 (0.01) 0.22 (0.01)

Car following: coherence 0.73 (0.02) 0.72 (0.02) 0.66 (0.03) 0.82 (0.02) 0.80 (0.02) 0.71 (0.02) 0.74 (0.02) 0.76 (0.02) 0.75 (0.02)

Car following: gain 1.07 (0.04) 1.04 (0.04) 1.09 (0.04) 1.06 (0.04) 1.08 (0.04) 1.04 (0.04) 1.07 (0.04) 1.09 (0.04) 1.09 (0.04)

Car following: delay 3.89 (0.33) 4.04 (0.33) 4.57 (0.39) 3.05 (0.31) 3.24 (0.31) 4.07 (0.33) 3.72 (0.32) 3.40 (0.32) 4.29 (0.32)

The mean levels are adjusted for unbalance in the design

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results did not change when the actual plasma concentrationrather than the dose was considered.

There are several limitations of our study that may have

affected the results of the experiment. For example, thesubjects drove the same route ten times (three conditionsat three levels of sleep deprivation, plus one familiarizationdrive). There was a large risk for learning effects, and theanalyses also showed a learning effect from week to week on several performance indicators. This effect is unfortu-nately common in simulator experiments and needs to beaccounted for in the analysis (Fors et al. 2010; Ljung Aust et al.   2011; Vaa et al.   2006). This effect might also haveinfluenced the sleep deprivation condition, in which thedriver became more and more sleep deprived at the timeas also becoming more familiar with the driving scenario.

Learning effects were minimized by ensuring that the eventsencountered did not occur at the same spot during eachdrive. Apart from the learning effect, there was also a large

individual variation in the way the subjects responded to thetreatment, which further complicated the analysis (“I felt focused, attentive and alert ”,  “I didn’t feel anything at all”,

“I felt hyperactive and drove badly”). In an effort to account for pharmacokinetic differences, blood samples were usedto measure the actual d-amphetamine concentration at thedifferent driving sessions. Finally, it should also be ac-knowledged that the present study only included male par-ticipants. We cannot exclude the possibility that d-amphetamine effects would differ in females due to gender difference in drug sensitivity or drug metabolism.

Conclusions

We found few significant results, and those showed bothimproved and worsened driving performance. We found nointeractions between dose and sleep deprivation for any of the performance indicators, which suggests that administra-tion of d-amphetamine does not compensate for impairment of driving due to fatigue. In addition, the positive effects of thelow dose were not further improved or even sustained whenthe dose was increased to approximately 0.5 mg/kg. Thismight indicate that at still higher doses, there are few or no

 positive effects of d-amphetamine. More research is neededon the dose – effect relationship for amphetamine as well as

more research including the possibility to better capture theindividual differences that were noted in this study.

Acknowledgments   This study was carried out within the European project DRUID, coordinated by BASt, Germany. DRUID provided50 % of the funding for the study; 35 % was contributed by VTI,Sweden, and 15 % by VINNOVA, Sweden. The study is one of severalcoordinated studies within DRUID WP1, methodology and researchled by Dr. Anja Knoche at BASt. The specific task within WP1 is Task 1.2, experimental studies led by Dr. Jan Ramaekers of Maastricht University. The analysis of blood was carried out by Dr. Gisela Skoppat Universtätsklinikum Heidelberg, Germany.

Table 6   Results from analysis of variance on driver performance for secondary performance indicators

Response variable Intercept Dose Occasion Drive (sleep deprivation) Subject Dose × drive

Bus min TTC <0.001 0.14 <0.001 0.51 <0.001 0.21

Bus reaction time <0.001 0.98 0.01 0.93 <0.001 0.84

Intersections: minimum speed <0.001 0.42 <0.001 0.72 <0.001 0.16

Road 50 km/h, mean speed <0.001 0.13 0.01 0.84 <0.001 1.00

Road 50 km/h, SDLP <0.001 0.77 0.41 0.09 <0.001 0.59

Road 50 km/h, SD <0.001 0.22 0.16 0.01 <0.001 0.97

Road 70 km/h, mean speed <0.001 0.86 <0.001 0.14 <0.001 0.37

Road 70 km/h, SD <0.001 0.55 0.18 0.21 <0.001 0.52

Speed passing moped_no wait <0.001 0.93 0.56 0.65 <0.001 0.65

Traffic light reaction time <0.001 0.66 0.52 0.09 <0.001 0.15

The analysis is based on the model with dose as a factor.  p  values for tests of factor effects

Table 7   Mean levels of driver performance measures (secondary) for different doses of d-amphetamine

Response variable Dose

0 mg 10 mg 40 mg

Bus min TTC 2.82 2.81 2.73

Bus reaction time 1.27 1.26 1.26

Intersections: minimum speed 38.99 39.08 38.30

Road 50 km/h, mean speed 56.70 55.75 57.60

Road 50 km/h, SDLP 0.20 0.19 0.19

Road 50 km/h, SD 2.20 1.93 2.08

Road 70 km/h, mean speed 75.39 75.22 75.03

Road 70 km/h, SD 2.34 2.59 2.55

Speed passing moped_no wait 61.70 61.56 62.10

Traffic light reaction time 1.13 1.11 1.15

The mean levels are adjusted for unbalance in the design

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