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Comparison
of
five
commonly
abused
stim ulants
which are used to reduce fatigue
D.J. Mascord, A. Dean, J.Gibson, J. Springall, G.A. Starmer & M.J. Christie
Psychopharm acology Research Unit, Pharm acology Departm ent,University o f Sydney. N SW .
Australia.
ABSTRACT
The effects o f five stimulants, which are commonly used by long distance truck drivers, were
evaluated to compare their ability to reduce fatigue. The stimulants were caffeine (200 m g),
ephedrine hydrochloride (60 m g), pseudoephedrine hydrochloride (60 m g), phentermine (30
mg) and diethylpropion hydrochloride (75 mg). The com parison data were derived from three
experiments which were carried out in our laboratory and shared a comm on m ethodology
(Gibson et al., 1995; Dean et al., 1996 and Springall, 1996). N o significant differences in
performance were found among the five drug treatments on the 4th hour o f a 3-way divided
attention task or during a post-testing session (2 -way divided attention, digit sym bol coding,
critical flicker fusion frequency). Systolic blood pressure and oral temperature were not
differentially affected by the drugs but a significant (p <
0
.0 1 ) treatment difference was found
for diastolic blood pressure. Pseudoephedrine caused the greatest increase in diastolic blood
pressure, w hen compared with diethylpropion and phentermine. Ephedrine produced the
second largest increase, which significantly exceeded that after diethylpropion. Heart rate (HR)
was found to be significantly lower after caffeine (p <
0
.0 1 ) than after ephedrine,
pseudoephedrine, phenterm ine or diethylpropion. H eart rate variability (s.d. o f HR) was found
to be significantly (p <
Caffeine was
0
.0 1 ) greater after ephedrine than after phentermine o r diethylpropion.
significantly (p < 0.001)
less likely than ephedrine, pseudoephedrine,
phentermine or diethylpropion to cause a reduction in the spectral pow er o f the blood pressure
com ponent (0.08 - 0.15 Hz) o f the cardiac frequency signal. These results suggest that none of
the five stimulants, when taken in normal therapeutic doses, differ greatly in their capacity to
improve performance and that differences among the drugs are mainly related to their effects on
the cardiovascular system.
INTRODUCTION
Fatigue, speeding and alcohol are considered to be the m ajor causal factors in Australian traffic
collisions. N ot surprisingly, fatigue appears to assume a m uch greater prom inence in crashes
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involving long-distance drivers. In an attempt to delay the onset o f fatigue, m any long-distance
drivers habitually resort to the use o f stimulant drugs. W illiamson et al. (1992) found that
16.6% o f their heavy vehicle driver sample thought that stimulant use was the best w ay to
alleviate fatigue. In other research, 40% to 50% o f Australian drivers admitted the use o f
stimulants, at least on some trips (Linklater, 1977; H ensher et al., 1991; H enderson, 1994).
Stimulants are well known to produce an elevation o f m ood, a sense o f increased energy and
alertness, enhanced performance and a decrease in appetite. H ow ever, Mehrabian (1986)
suggested that when stimulants are used frequently and/or in high doses, they have the
paradoxical effect o f inducing an emotional undertone o f low arousal which is evident in
feelings o f listlessness, fatigue, lack o f ability to concentrate and remain alert, and low energy.
In a m ajor collision between a passenger bus and a truck in northern New South W ales in 1989,
in which the truck driver and 17 bus passengers were killed, ephedrine-induced hallucination
was considered by the Coroner to have been a factor in the collision. Other possibilities
included a fatal cardiac arrhythmia o r a cerebrovascular accident, both o f which could have been
expressions o f ephedrine toxicity. The driver o f the truck was found to have an blood ephedrine
concentration which was 80 times the normal therapeutic level.
In a recent study (Bock et al., in press), truck drivers (n = 494), bus drivers (n = 199), longhaul (n = 523) and short-haul m otorists (n = 472) were questioned about their experiences of
fatigue. Saliva samples were taken from the participants and were analysed for a num ber of
drugs. The incidence o f illicit and licit stimulants was much higher in truck drivers than in bus
drivers or other m otorists. Stimulants detected in the saliva o f truck drivers included caffeine
(83%), cotinine (18%), ephedrine and pseudoephedrine (8 %), phenterm ine (7% ), amphetamine
(4%) and methylamphetamine (4%). Diethylpropion could not be assayed and other drugs
comprised less than 2%. Hall (1995) reported several studies which investigated the incidence
o f stimulants and other drugs in truck drivers in the U .S.A . In the first study (Insurance
Institute for Highw ay Safety), illicit stimulants were found in 12% and licit stimulants were
found in 5% o f drivers. In the second study (National Transportation Safety B oard),
methylamphetamine and other amphetamines were found in 7% and other stimulants in
8
% of
fatally-injured truck drivers.
The aim o f the present study w as to examine whether caffeine and a num ber o f commonly
abused stimulants (ephedrine, pseudoephedrine, phentermine and diethylpropion) differed in
their ability to reduce fatigue w hen taken at therapeutic levels. The data were obtained from
three experiments (see Table 1 below). Previous research in this area has been limited by a
rather narrow focus on cocaine and the amphetamines so that the effects o f a large num ber of
closely-related com pounds, which are also used to ‘im prove’ driver perform ance, have been
largely ignored.
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Table I : Studies included in the analysis.
Experiment
Stimulant
1. G ibson et al., 1995
caffeine
2. D ean et al., 1996
ephedrine (60 mg) and pseudoephedrine (60 mg)
3. Springall, 1996
phentermine (30 mg) and diethylpropion (75 mg)
mg)
(2 0 0
METHODS
All three experiments used essentially the same m ethodology. Subjects had to m onitor a 4-hour,
3-way divided attention task, which consisted o f a central tracking task, a secondary peripheral
visual discrim ination task and a random visual 'emergency' signal (presented as a red light). An
infra-red m onitor w as clipped to the subjects' ear lobe and heart inter-beat-interval was recorded
during the four hours on task. Oral tem perature, blood pressure, perform ance on a short battery
o f tests ( 2 -way divided attention, digit symbol coding, critical flicker fusion frequency) and
subjective estimates o f fatigue (sedation, boredom , co-ordination and w illingness to drive a
m otor vehicle) were recorded both before and after the four hour 'fatigue' m onitoring task. A
full description o f the m ethods is contained in Gibson et al., 1995 and D ean et al., 1996.
Caffeine (200 m g), ephedrine hydrochloride (60 mg) and pseudoephedrine hydrochloride (60
mg) were given to subjects after two hours on task while phentermine (30 m g) and
diethylpropion (75 mg) were given at the beginning o f the four hour task because they were
only available as slow-release formulations. All the studies were placebo-controlled.
RESULTS
Since interest was restricted to between-treatment effects rather than time effects, only data from
the 4th hour o f the 3-way divided attention task and the post-test battery were analysed because
it was expected that any differences between the stimulants w ould have been at their greatest at
this time. A common score (drug m inus placebo) was derived and differences between the
effects o f the drugs were tested by ANOVA.
N o significant differences in performance was found among the five stimulant drugs for
tracking control (F 4 7
5
= 0.825; p > 0.05), peripheral detection reaction time (F 4 7
> 0.05) or 'em ergency' reaction time (F 4
divided attention task. In the post-testing session, tracking control (F 4
peripheral detection reaction time (F 4
7 5
5
= 0.756; p
= 0.286; p > 0.05) on the 4th hour o f the 3-way
75
75
= 0.788; p > 0 .0 5 ),
= 0.655; p > 0.05), digit sym bol coding (F 4
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101
-
75
=
1.953; p > 0.05) and critical flicker fusion frequency (F 4
75
= 1.538; p > 0.05) were also not
significantly different.
N o significant differences in systolic blood pressure (F 4
temperature (F 4
75
7 5
= 1.83 = p > 0.05) or oral
= 1.04; P > 0.05) were found among the drug treatments, but there was a
significant difference (F 4
75
= 4.11; p < 0.01) in diastolic blood pressure. P ost-hoc analysis
(Newm an-Keuls) indicated that pseudoephedrine caused the largest increase in diastolic blood
pressure w hen compared with diethylpropion and phentermine. Ephedrine caused the second
largest increase, which was significant when com pared with diethylpropion.
H eart rate w as found to be significantly lower after caffeine (F 4
75
= 7.52; p < 0.01) than after
ephedrine, pseudoephedrine, phentermine and diethylpropion. H eart rate variability (s.d. o f
HR) was also found to be significantly greater after ephedrine (F 4
7 5
= 4.07; p < 0.01) than
after phentermine and diethylpropion. Caffeine was found to be significantly (F4
0
.0
0 1
75
= 17.2; p <
) less likely than ephedrine, pseudoephedrine, phentermine and diethylpropion to cause a
reduction in the spectral pow er on the blood pressure component (0.08 - 0.15 Hz) o f the cardiac
frequency signal.
DISCUSSION
W e have consistently been able to demonstrate a progressive development o f fatigue in placebo
groups in this experimental paradigm. A deterioration in performance coupled with an increase
in the spectral pow er o f the blood pressure com ponent (0.08 - 0.15 H z) o f the heart rate pow er
spectrum and a slowing of heart rate over time were found. An increase in signal pow er for the
0.08 - 0.15 H z frequency band is considered to provide a reliable indicator o f fatigue (Mascord
& H eath, 1993). W hen caffeine, ephedrine, pseudoephedrine, phentermine or diethylpropion
was administered to subjects, the effects o f fatigue were either reversed or stabilised. The
results from the current analysis between the individual stimulants suggests that none o f the five
drugs differ in their capacity to improve performance and that the differences between drugs
were mainly related to their cardiovascular effects.
It is commonly believed that caffeine is a stimulant which increases heart rate. In fact, caffeine
has complex, varied and often antagonistic effects on the cardiovascular system , depending on
the dose and caffeine tolerance o f the subject (Myers & Reeves, 1991). In the study by Gibson
et al., (1995), caffeine had no significant effect on heart rate. It w as found in this study that
both heart rate and the spectral pow er o f the blood pressure component (0.08 - 0.15 Hz) were
lower after caffeine than after ephedrine, pseudoephedrine, phentermine and diethylpropion.
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Ephedrine, pseudoephedrine, phentermine and diethylpropion are all sympathomimetic amines.
The principal pharmacological actions o f these stimulants on the central nervous system are
direct and those on the cardiovascular system are exerted indirectly via catecholamine release
from peripheral sympathetic nerves. In therapeutic doses, ephedrine increases blood pressure
by increasing cardiac output and causing peripheral vasoconstriction. Tachycardia may also
occur. Pseudoephedrine is a stereoisomer o f ephedrine with a similar pharmacological profile.
Although capable o f producing a typical spectrum o f sympathomimetic cardiovascular effects,
pseudoephedrine is four times less potent than ephedrine (Drew, et al., 1978). The effects of
increased sympathetic stimulation induced by phentermine and diethylpropion on
the
cardiovascular system are manifested as a rise in diastolic blood pressure, palpitations,
hypertension and cardiac arrhythmias (Douglas et al., 1983), but such effects normally only
occur after supra-therapeutic doses. In this study, it was found that diastolic blood pressure was
higher after pseudoephedrine and ephedrine than after phentermine and diethylpropion. The
heart rate variability (s.d. o f HR) after ephedrine was also greater than for the other stimulants.
These results appear to be consistent with current knowledge o f the individual stimulant drugs
but are o f limited predictive value for effects which might occur after large doses taken by
tolerant individuals.
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