Psychopharmacology (2012) 222:401411

DOI 10.1007/s00213-012-2744-7

ORIGINAL INVESTIGATION

Effects of d-amphetamine on simulated driving performance

before and after sleep deprivation
Magnus Hjlmdahl & Anna Vadeby & sa 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 also
used to promote wakefulness, yet their effects on driving
performance during sleep deprivation have not been thoroughly researched in experimental studies.
Objectives The aims were to assess the effects on fundamental driving parameters during simulated driving of two
doses of d-amphetamine and further to assess the interaction
between d-amphetamine and sleep deprivation.
Methods A double-blind, placebo-controlled experiment including 18 healthy male volunteers was conducted.
Results The participants felt more alert when taking a dose
of 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 the
subjects from becoming successively sleepier during the
night. A significant main effect of the dose was found for
three out of the five primary indicators where the lower dose
led to improved driving. These indicators were crossing-car
reaction time, and coherence and delay from a car-following
M. Hjlmdahl (*) : A. Vadeby : . Forsman : C. Fors
Swedish Road and Transport Research Institute,
SE-581 95 Linkping, Sweden
e-mail: magnus.hjalmdahl@vti.se
G. Ceder : R. Kronstrand
Department of Forensic Genetics and Forensic Toxicology,
National Board of Forensic Medicine,
SE-587 58 Linkping, Sweden
P. Woxler
Department of Psychiatry, University Hospital,
SE-581 85 Linkping, Sweden
R. Kronstrand
Division of Drug Research, Linkping University,
Linkping, Sweden

event. Regarding sleep deprivation, a main effect was found

for four of the primary indicators and three of the secondary
indicators. The results showed overall impaired driving with
respect to standard deviation of lateral position and delay in
reaction time when the sleep-deprived conditions were compared to the alert condition. We found no interactions between dose and sleep deprivation for any of the performance
indicators.
Conclusions Our results suggest that administration of damphetamine does not compensate for impairment of driving due to fatigue. The positive effects of 10 mg were not
further improved or even sustained when increasing the
dose to 40 mg.
Keywords Amphetamine . Sleep deprivation . Driving
performance . Simulator . Stimulants

Introduction
Amphetamine is a central nervous system stimulant used in
medicine to treat attention deficit disorders and narcolepsy.
Amphetamine is also commonly abused and is frequently
found to be present in forensic toxicological investigations
of 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). In
a recent study of apprehended drivers in Sweden, more than
50 % were positive for amphetamine (Holmgren et al.
2007), whereas in a 5-year survey of drivers killed while
driving, 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).

402

This could be interpreted to mean that amphetamine has a

low crash risk, and some experimental studies have even
shown that low doses of amphetamine may improve some
cognitive processes, such as attention and psychomotor
functioning (de Wit et al. 2002; Silber et al. 2006). On the
other hand, case studies have shown that amphetamines
negatively influence driving performance (Logan 1996;
Logan et al. 1998) and that stimulant use increases the crash
risk by two to three times (Drummer et al. 2004; Movig et
al. 2004). The differences between the outcome of the
experimental studies and epidemiological data can be
explained by the complexity of the tasks involved. In isolation, cognitive processes may be improved at low doses of
stimulants, but when divided attention is needed, the performance is impaired. This has been described as tunnel
vision or an inability to gather information from different
sources (Mills et al. 2001). Experiments performed in advanced driving simulators offer the opportunity to create and
in detail study and measure operational behaviour such as
lateral position, speed control, and headway, or strategic
behaviour including speed choice, as well as tactical behaviour 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 epidemiological data may also be the result of differences in
doses administered. Doses used in experiments range from 5
to 40 mg of amphetamine, considerably less than those
administered for recreational use (Lia et al. 2009; Silber et
al. 2005). For example, the median concentration of amphetamine in apprehended drivers was reported to be
0.80 mg/L (Jones et al. 2008), much higher than concentrations up to 0.1 mg/L plasma concentrations reported in
experimental 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 terms
of both physiological, subjective psychological, and cognitive measures (Asghar et al. 2003; Jones 2007; Lia et al.
2009). Since amphetamine can be repeatedly administered
around the clock over several days, followed by exhaustion
and long sleep, the lack of correlation between blood concentrations and signs of influence can be a result of fatigue
from sleep deprivation (Jones et al. 2008).
Direct investigations of how d-amphetamine affects driving performance in simulators or during real-life driving are
very limited, and the only study so far reported was performed 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 perceptual
narrowing.
Besides the intake of drugs, sleep deprivation in itself is
considered a risk factor for road traffic accidents (Anund

Psychopharmacology (2012) 222:401411

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; Vakulin et al. 2007).
Amphetamine influences the function of the central nervous
system by releasing and blocking the reuptake of catecholamines 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 performance during sleep deprivation have also been studied
with a focus on caffeine (Biggs et al. 2007; De Valck and
Cluydts 2001; De Valck et al. 2003; Reyner and Horne
2000). Investigations regarding the use of amphetamines
to prolong wakefulness and overcome sleep deprivation
have primarily been directed towards aviation (Caldwell
and Caldwell 2005; Caldwell et al. 2003; Emonson and
Vanderbeek 1995; Gore et al. 2010). The results showed
that amphetamine maintained flight skills, psychological
mood, and physiological activation in sleep-deprived pilots.
Thus, amphetamine by itself may not only impair driving
skills, but may also improve driving skills when the subject
is sleep deprived.
Identifying this paucity of data, we aimed to assess the
effects of two doses of d-amphetamine on fundamental
driving parameters during simulated driving and, further,
to assess the interaction between d-amphetamine and sleep
deprivation in a double-blind, placebo-controlled experiment conducted in a moving-base driving simulator.

Methods
Subjects
The experiment was approved by the Regional Ethics
Committee in Linkping (Dnr M91-07) and granted authorization by the Swedish Medical Products Agency (EU-nr
2007-002500-18, Dnr 151:2008/14592). Based on experience from earlier trials, it was decided that 18 subjects were
required 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 to
5,000 km per year and having held a valid driving licence
for at least 5 years). Exclusion criteria were ADHD according to DSMIV, and the subjects were screened for that
diagnosis using ASRS-v1.1. Other exclusion criteria were
problems with motion sickness, history of alcohol or drug
abuse, and regular use of prescription medications. The
criteria were no use of drugs in the previous 12 months
and less than 14 standard drinks per week. The reason for

Psychopharmacology (2012) 222:401411

403

only using male participants was that it was of interest to

keep variability low; thus, gender was taken out of the
equation. Male was chosen before female because it is in
general 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 examination, urine drug testing (for amphetamines, opiates, cannabinoids, cocaine, and benzodiazepines), as well as an
interview with a psychiatrist. A few weeks after the experiment was completed, all subjects had a follow-up medical
examination, including an interview.
Procedure
A randomized, double-blind, placebo-controlled, crossover
design was used. Three different doses were combined with
three levels of sleep deprivation, resulting in a total of nine
conditions. Each subject participated in the experiment at
three occasions, at 7-day intervals. At each occasion, the
subjects were given one of three doses: placebo, or 10 or
40 mg of d-amphetamine. Each test occasion lasted overnight, from afternoon to next morning, and included four
subjects, who had three driving sessions each: one in late
afternoon, one at night, and one in the morning. Each
subject had his driving sessions at the same day and time
each week. The timetable for the first subject to arrive on
each test occasion is given in Table 1. The timetables for the
three other subjects were delayed 1, 2, and 3 h, respectively.
Otherwise, the procedure was the same. The subjects were
not allowed to eat anything from the time they arrived until
after the first driving session. They were not allowed to
Table 1 Timetable for the subjects at each test occasion

T0

Arrival. Tests: breath alcohol, blood pressure, pulse, blooda, urineb, KSS
Drug intake
No food intake was allowed before the first drive.
Tests: blood pressure, pulse, blooda
Driving session 1. KSS before and after
Tests: blooda, questionnaire
Dinner and free time
Tests: blood pressure, pulse, blooda
Driving session 2. KSS before and after

T0 + 6:45
T0 + 7:00

d-amphetamine

pH, cannabis, opiates, cocaine,

amphetamine, benzodiazepines

There were a number of tests carried out before, between,

and after each driving session. The timeline for each session
is shown in Table 1. Upon arrival, the subjects were asked to
rate their sleepiness level using the Karolinska Sleepiness
Scale (KSS) (Akerstedt and Gillberg 1990). The KSS ranges
from 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 administration of d-amphetamine (or placebo), the subjects were tested
for ethanol using a breathalyser and drugs of abuse using a
urine-screening test. At this point, the subjects blood pressure and pulse were also registered, and a pre-dose blood
sample was taken. After drug administration, the subjects
filled 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, sleepiness was self-rated, and blood samples were obtained. After
the first driving session (which lasted for approximately
45 min), a KSS rating was given, blood pressure and pulse
were measured, and a blood sample was taken. The subjects
then filled out a questionnaire regarding the driving session.
Four hours after the first driving session, it was time for the
second session, and blood pressure, pulse, and KSS were
registered before the drive. Also, a blood sample was taken.
After the second drive, there was no test except for KSS and

Event

T0 + 1:45
T0 + 2:00
T0 + 2:45

Tests

Time

T0 + 0:30

Note that T0016:00, 17:00,

18:00, or 19:00 for the four
subjects each night. This means
that they arrived and drove with
one hour time offset

sleep or to drink any caffeine-containing beverages during

the whole test occasion. The time between the driving sessions was spent in a room next to the simulator room, where
the subjects could eat, talk to each other, watch television, use
the Internet, etc.

T0 + 7:45
T0
T0
T0
T0

+
+
+
+

11:45
12:00
12:45
13:00

Questionnaire
Sandwich and free time
Tests: blood pressure, pulse, blooda
Driving session 3. KSS before and after
Questionnaire
Taxi home

404

a questionnaire. For the third and last drive (4 h after the

second drive), the procedure was the same as for drive
number two. After the last drive of the final week, the
drivers were given an extended questionnaire to take home
and fill out. This questionnaire covered their experience
throughout the whole experiment.
Driving simulator scenario
The study was carried out on VTIs driving simulator III,
which is a moving-base driving simulator with interchangeable cabins. In this experiment, a Saab 9-3 cabin was
mounted on the motion platform. The simulator is situated at VTIs head office in Linkping, Sweden. The
moving-base system is a unique solution that has been
designed and constructed by VTI. It is used to generate
forces felt by the driver while driving. It can be divided into
three separate parts: a large linear motion, tilt motion, and a
vibration table.
The route designed for this experiment covered both rural
and urban roads with speed limits of 50 and 70 km/h. In the
urban sections, there were both signal-controlled intersections and intersections with rights of way. All in all, the
route was 44.6 km long and took approximately 45 min to
drive. The subjects were instructed to consider the drive as
their daily route to work and to drive as they normally
would during these conditions. The experimental design in
this study required that the test subjects drive the same
scenario on nine occasions, which meant that large learning
effects 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 experiments (Fors et al. 2010; Ljung Aust et al. 2011; Vaa et al.
2006). In an attempt to minimize the learning effects, we
had all subjects conduct a test drive before the experiment
started, so that to some extent, they familiarized themselves
with the route and the scenario. To further minimize the
learning effects, the events the subjects encountered did not
occur at the same spot every time but happened at several
different places. For a description of the events, see
Performance indicators and events section below. At the
end 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. In
this event, roads with a speed limit of 90 km/h were also
included.
Performance indicators and events
A number of performance indicators based on driving data
were calculated for the analysis. These were based on both
normal driving, such as mean speed and standard deviation
of lateral position (SDLP), and also on specific situations or

Psychopharmacology (2012) 222:401411

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 crossing
the roadway in front of the driver, traffic lights turning
yellow and then red, a bus turning out from a bus stop
in 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, all
drivers had the same time to respond to these events
to avoid colliding, or driving against a red light, regardless of their driving speed. In addition to these events,
some normal driving situations were also studied. These
were mean speed, standard deviation of speed, standard
deviation 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 from
this 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 between the studies; these are labelled as primary performance
indicators in the text and tables of this study. The measures
that may be unique to this study are labelled as secondary
performance indicators.

Statistical analysis
To study the overall treatment effect, the data were analysed
using analysis of variance (ANOVA), and the models were
chosen to correspond with the design of the study. The main
objective of the study was to investigate the subjects driving performance, but we also studied how different doses of
d-amphetamine affected the subjects self-reported sleepiness. Each treatment was given to each subject, and to
control for variability between people, a repeated measures
design was used. This implies that the factor subject was a
random factor, and the other factors were regarded as fixed
factors (Montgomery 1991). The following factors were
used in the models:
0dose (00placebo, 1010 mg, 2040 mg)
0plasma concentration of d-amphetamine (0, 020,
2040, 4060, 6080, 80+ng/ml)
0test occasion (1, 2, or 3)
0drive (0, SD1, and SD2; reflects three levels of sleep
deprivation)
0subject (1, , 18)
To refine the data analysis, two different models were
used. The first model used dose of d-amphetamine as the

Psychopharmacology (2012) 222:401411

405

Fig. 1 Distribution of plasma

concentration of d-amphetamine
(in nanograms per millilitre) for
each dose (0, 10dose 10 mg,
20dose 40 mg) and drive. For
the first drive, plasma concentration was measured both before
and after the driving session, and
a mean of these concentrations
was used in the analysis. For the
second and third drives, plasma
concentration was measured
only before the driving sessions

main factor of interest, while the second model used plasma

concentration of d-amphetamine instead of dose.
1.
Yijklm ai bj g k z l ag il "ijklm
2.
Yijklm i b j g k z l "ijklm
where was the mean effect and 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 performance, occasion and drive reflected the learning effects due
to repeated driving sessions. Moreover, drive also reflected
the different states of alertness. Subject is entered to
account for individual differences. The interaction
was added to model 1 to account for temporal changes
in 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 as
response variables; see Performance indicators and events
section for a description. The performance indicators were
divided into primary and secondary indicators, and the

Table 2 Results from variance of

analysis on sleepiness (KSS)
p values for tests of factor effects

Intercept
KSS before drive

<0.001

primary indicators were studied in more detail. The primary

performance indicators were crossing-car reaction time and
SDLP at 70 km/h from the first part of the experiment and
coherence, gain, and delay from the car-following event. If the
factor of interest, dose or plasma concentration, was
significant in the ANOVA analysis, pairwise comparisons 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 comparisons was used.

Results
The whole experiment was carried out in 3 weeks starting
each week at four oclock Sunday afternoon and ending at
eight oclock Friday morning. Four subjects were present
every night giving 20 subjects in total. Eighteen subjects
completed 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 data
for another two drivers who fell asleep during the carfollowing event on the last drive when driving with placebo.

Dose
<0.001

Occasion

Drive

Subject

Dose drive

0.07

<0.001

<0.001

0.53

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Psychopharmacology (2012) 222:401411

Table 3 Mean level of sleepiness (KSS) for different doses of damphetamine

Dose

Mean level

0 mg

10 mg

40 mg

5.47

5.00

4.07

The mean levels are adjusted for unbalance in the design

Thus, these two drives ended a few minutes earlier than

planned. For the first drive, plasma concentration was measured both before and after the driving session, and a mean
of these concentrations was used in the analysis. For the
second and third drive, plasma concentration was measured
only before the driving session. Figure 1 illustrates how the
actual 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 Sleepiness
Scale. The results from the analysis of variance showed a
significant difference in sleepiness between different doses,
between subjects as well as between driving sessions
(Table 2). The effect of different doses is shown in
Table 3, and a higher dose led to increased alertness.
Pairwise comparisons showed a significant difference between all pairs of doses. The effect of dose and drive is
illustrated in Fig. 2. The subjects experienced an increased
sleepiness 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 and
ten secondary performance indicators described in the
Performance indicators and events section above.

Fig. 3 Mean levels of crossing-car reaction time(s) for different doses

and sleep deprivation. The mean levels were adjusted for imbalance in
the design

Primary performance indicators

The results for the primary indicators and how they were
affected by different doses of d-amphetamine are shown in
Figs. 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 significant effect of dose. These indicators were crossing-car
reaction time and two of the indicators from the carfollowing 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 experience
that 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 in
Table 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 0
and 10 and between 0 and 40 were significant. Considering

Mean level of KSS

7
6

Dose
0 mg
10 mg
40 mg

5
4
3
2
1
0
0

Drive

Fig. 2 Mean levels of sleepiness (Karolinska Sleep Scale) before each

drive. The mean levels were adjusted for imbalance in the design

Fig. 4 Mean levels of SDLP (in centimetres) for different doses and
sleep deprivation. The mean levels were adjusted for imbalance in the
design

Psychopharmacology (2012) 222:401411

Fig. 5 Mean levels of coherence (car following) for different doses

and sleep deprivation. The mean levels were adjusted for imbalance in
the design

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 the
analysis instead of dose did not yield other results. As with
dose, crossing-car reaction time, coherence, and delay showed
significant effects.

Secondary performance indicators

Results for the secondary performance indicators and how
they were affected by different doses of d-amphetamine are
summarized in Tables 6 and 7. Table 6 shows the p values
for the tests of factor effects and Table 7 shows the mean
levels. None of the secondary performance indicators
showed a significant effect of dose, and only one, a significant effect of drive. The same was found when using
concentration instead of dose in the analysis.

Fig. 6 Mean levels of gain (car following) for different doses and
sleep deprivation. The mean levels were adjusted for imbalance in the
design

407

Fig. 7 Mean levels of delay (car following) for different doses and
sleep deprivation. The mean levels were adjusted for imbalance in the
design

Questionnaire results
All subjects could correctly state at what occasion they were
given the high dose. Sixteen out of 18 could also distinguish
the low dose from placebo. The experience of damphetamine differed somewhat among the subjects.
Several described that they felt high: they became alert,
talkative, social, and excited. Some described the effect as
positivethey felt relaxed and comfortablewhile others
felt restless. Almost all subjects thought the medicine made
them less drowsy. A few stated that the medicine only
caused an absence of drowsiness, without increased alertness or any other effects. The experiences of the low dose
were about the same as those of the high dose, but the
effects were much weaker and lasted for a shorter period
of 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 medicine had any influence on their driving performance. Some
subjects commented that since the d-amphetamine made
them alert, they probably drove better after taking the drug
compared 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 also
reported that the medicine made them more attentive, focused, 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 as
they 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 a
risky and egocentric behaviour. More than half of the subjects had difficulties falling asleep the day after the highdose occasion. Some felt drowsy for a couple of days
following the test, mainly after the high dose. Some reported

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Psychopharmacology (2012) 222:401411

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

Intercept

Crossing-car reaction time

Road 70 km/h, SDLP

Dose

Occasion

Drive (sleep deprivation)

Subject

Dose drive

<0.001
<0.001

0.001
0.85

0.01
0.37

0.01
0.02

<0.001
<0.001

0.95
0.36

Car following: coherence

<0.001

<0.001

0.08

0.01

<0.001

0.23

Car following: gain

Car following: delay

<0.001
<0.001

0.68
0.04

0.22
0.001

0.97
0.01

<0.001
<0.001

0.81
0.89

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

that the dry mouth/throat and reduced appetite persisted on

the 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 damphetamine on fundamental driving parameters during
simulated driving and to assess the interaction between damphetamine and sleep deprivation. The results showed that
participants in the study felt more alert when taking a dose
of 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
been reported (Berridge et al. 1999; Emonson and
Vanderbeek 1995; Gore et al. 2010). However, the data did
not show any evidence that taking d-amphetamine prevented the subjects from becoming successively sleepier
during the night. The results for driving performance indicators 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 to
improved 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 agreement with another study on driving-related tasks where a
low dose of d-amphetamine was administered (Mills et al.
2001). On the other hand, Silber et al. performed studies
with a higher dose (0.42 mg/kg) similar to the high dose in
our study and found a decrease in overall driving ability in
the 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 improvement. However, our driving scenarios also included sleep
deprivation, and the simulator facilities were very different
from those of Silber et al.; a direct comparison of outcomes
might be difficult. A significant finding in our study was
that the positive effects of a low dose (10 mg) were not
further improved or even sustained by increasing the dose to
40 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. The
results showed overall impaired driving with respect to SDLP
and delay when the sleep-deprived conditions were compared
to the alert condition. However, improved driving was also
found, with respect to crossing-car reaction time. It is notable
that no interactions were found between dose and sleep deprivation for any of the performance indicators, indicating that
there was no evidence in our data that taking a dose of damphetamine compensated for the impairment of driving. The

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
Alert

Crossing-car reaction time

Road 70 km/h, SDLP
Car following: coherence
Car following: gain
Car following: delay

2.30
0.21
0.73
1.07
3.89

Dose 10 mg
SD1

(0.07)
(0.01)
(0.02)
(0.04)
(0.33)

2.14
0.21
0.72
1.04
4.04

SD2
(0.08)
(0.01)
(0.02)
(0.04)
(0.33)

2.07
0.25
0.66
1.09
4.57

The mean levels are adjusted for unbalance in the design

(0.07)
(0.01)
(0.03)
(0.04)
(0.39)

Dose 40 mg

alert

SD1

SD2

alert

SD1

SD2

2.08 (0.08)
0.22 (0.01)
0.82 (0.02)
1.06 (0.04)
3.05 (0.31)

1.91 (0.08)
0.20 (0.01)
0.80 (0.02)
1.08 (0.04)
3.24 (0.31)

1.95 (0.08)
0.23 (0.01)
0.71 (0.02)
1.04 (0.04)
4.07 (0.33)

2.05 (0.08)
0.22 (0.01)
0.74 (0.02)
1.07 (0.04)
3.72 (0.32)

1.94 (0.08)
0.21 (0.01)
0.76 (0.02)
1.09 (0.04)
3.40 (0.32)

1.87 (0.08)
0.22 (0.01)
0.75 (0.02)
1.09 (0.04)
4.29 (0.32)

Psychopharmacology (2012) 222:401411

409

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

Bus reaction time

<0.001
<0.001

0.14
0.98

<0.001
0.01

0.51
0.93

<0.001
<0.001

0.21
0.84

Intersections: minimum speed

<0.001

0.42

<0.001

0.72

<0.001

0.16

Road 50 km/h, mean speed

Road 50 km/h, SDLP

<0.001
<0.001

0.13
0.77

0.01
0.41

0.84
0.09

<0.001
<0.001

1.00
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

Road 70 km/h, SD

<0.001
<0.001

0.86
0.55

<0.001
0.18

0.14
0.21

<0.001
<0.001

0.37
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

results did not change when the actual plasma concentration

rather than the dose was considered.
There are several limitations of our study that may have
affected the results of the experiment. For example, the
subjects drove the same route ten times (three conditions
at three levels of sleep deprivation, plus one familiarization
drive). There was a large risk for learning effects, and the
analyses also showed a learning effect from week to week
on several performance indicators. This effect is unfortunately common in simulator experiments and needs to be
accounted for in the analysis (Fors et al. 2010; Ljung Aust et
al. 2011; Vaa et al. 2006). This effect might also have
influenced the sleep deprivation condition, in which the
driver became more and more sleep deprived at the time
as also becoming more familiar with the driving scenario.
Learning effects were minimized by ensuring that the events
encountered did not occur at the same spot during each
drive. Apart from the learning effect, there was also a large
Table 7 Mean levels of driver performance measures (secondary) for
different doses of d-amphetamine
Response variable

Bus min TTC

Bus reaction time
Intersections: minimum speed
Road 50 km/h, mean speed
Road 50 km/h, SDLP
Road 50 km/h, SD
Road 70 km/h, mean speed
Road 70 km/h, SD
Speed passing moped_no wait
Traffic light reaction time

Dose
0 mg

10 mg

40 mg

2.82
1.27
38.99
56.70
0.20
2.20
75.39
2.34
61.70
1.13

2.81
1.26
39.08
55.75
0.19
1.93
75.22
2.59
61.56
1.11

2.73
1.26
38.30
57.60
0.19
2.08
75.03
2.55
62.10
1.15

The mean levels are adjusted for unbalance in the design

individual variation in the way the subjects responded to the

treatment, which further complicated the analysis (I felt
focused, attentive and alert, I didnt feel anything at all,
I felt hyperactive and drove badly). In an effort to account
for pharmacokinetic differences, blood samples were used
to measure the actual d-amphetamine concentration at the
different driving sessions. Finally, it should also be acknowledged that the present study only included male participants. We cannot exclude the possibility that damphetamine effects would differ in females due to gender
difference in drug sensitivity or drug metabolism.

Conclusions
We found few significant results, and those showed both
improved and worsened driving performance. We found no
interactions between dose and sleep deprivation for any of
the performance indicators, which suggests that administration of d-amphetamine does not compensate for impairment
of driving due to fatigue. In addition, the positive effects of the
low dose were not further improved or even sustained when
the dose was increased to approximately 0.5 mg/kg. This
might indicate that at still higher doses, there are few or no
positive effects of d-amphetamine. More research is needed
on the doseeffect relationship for amphetamine as well as
more research including the possibility to better capture the
individual differences that were noted in this study.
Acknowledgments This study was carried out within the European
project DRUID, coordinated by BASt, Germany. DRUID provided
50 % of the funding for the study; 35 % was contributed by VTI,
Sweden, and 15 % by VINNOVA, Sweden. The study is one of several
coordinated studies within DRUID WP1, methodology and research
led 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 Skopp
at Universttsklinikum Heidelberg, Germany.

410

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