THE EFFECTS OF DEXTROAMPHETAMINE ON PHYSIOLOGICAL
RESPONSES AND COMPLEX PERFORMANCE
DURING SLEEP LOSS

I. Introduction.

Dextroamphetamine sulfate is among those
drugs (Schedule IT) requiring strict controls
because of their abuse and addiction potential.
Currently, the main use of this and related drugs
is as an aid to weight reduction, and then only
under certain closely controlled conditions. It
js also used in combination with scopolamine as
an anti-motion-sickness drug. A combination
of scopolamine and dextroamphetamine is in use
by the National Aeronautics and Space Admin-
istration for the astronauts, Six capsules were
used by the crew of Apollo 11.*

The literature on amphetamines has been re-
viewed extensively by Weiss and Laties,’* who
concluded that amphetamines have their most
beneficial effect in counteracting or preventing
performance deterioration that results from fa-
tigue and/or sleep loss. They concluded that
amphetamines not only were more effective than
caffeine, but also produced fewer and less severe
side effects.

Although amphetamines promote a sense of
alertness and well-being, little has been reported
on the physiological aftereffects resulting from
their withdrawal. They also may promote a
false sense of performance capability, a condi-
tion that could have detrimental effects on skilled
performance.

The purpose of this experiment is twofold:
First, to identify and clarify possible differences
between the subject’s appraisal of his perform-
ance and objective test scores (test scores will
also be related to his physiological responses
while under the influence of dextroamphetamine
sulfate), and second, to evaluate the subject’s
performance for several hours after withdrawal
of the drug as well as during the use of it.

The results of this study are not to be inter-
preted as advocating the use of dextroampheta-

mine sulfate to ameliorate the effects of fatigue
or sleep loss. It is representative of a drug type
(stimulant), others of which might be as effec-
tive without the same degree of abuse and addic-
tion potential.

Il. Method.

Ten male paid volunteers (ages 20 to 28 years)
served as subjects. Preceding the actual experi-
ment, they spent 2 days in indoctrination and
training on the Civil Aeromedical Institute
Multiple Task Performance Battery (MTPB).?
The battery included tasks that involved moni-
toring, group problem solving, mental arithmetic,
pattern discrimination, and two-dimensional com-
pensatory tracking. The subjects were tested in
2-hour sessions every 4 hours for a total of seven
sessions. The task schedules for the first and
second hours of each session were identical. The
basic 1-hour task schedule required performance
of the combinations of tasks shown in Table 1.
Two different kinds of analyses were carried out.
The first analysis was an appropriate expansion
of a Lindquist Type VII analysis of variance
design applied -to each of the individual per-
formance task measures. The second analysis,
also an expanded Lindquist Type VII design,
was applied to composite scores derived as fol-
lows: The measures taken during a given 15-

TABLE 1. One-Hour Task Schedule
Tine {n Minutes
gos 15-30 30245 45-60
Warning Lights x x x x
Meters x x x x
Artthmette x x
Pattern Identification x
Problen Solving x x x
‘racking x

Note; X indicates task active



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2000 2400 0400 0800 1200 1600 2000
TIME (CLOCKHOURS)
Freure 7. Urinary norepinephrine excretion rates
through time (X+8.E.M., n=10). Mean urinary ex-
eretion of dextroamphetamine (broken line) is read
on the right ordinate.

than fatigue per se. In any event, the checklist
failed to reveal differences under conditions in
which objective measures of performance re-
vealed substantially significant differences.

B. Subjective Performance Estimates. The
accuracy of the subjects’ estimates of their per-
formance is difficult to ascertain because the
method for computing the “true” score necessar-
ily contained some arbitrary elements. Whereas
the true score was based on an equal-variance
measure of overall performance, it is very un-
likely that the subjects had precise feedback on
the monitoring tasks; further, since the estimates
were made at the end of a session, we would not
expect the subjects to remember with any great
accuracy the levels of performance maintained.
Tt is likely that, with appropriate feedback and
sufficient training, the subjects could learn to
produce rather good estimates during the earlier
periods of the session. Thus, the term “overesti-
mate” should be interpreted in a relativistic
manner. However, the estimates were generally
accurate in that, under both conditions, as the
level of performance decreased, the estimate also
decreased. Overall, the very small difference in
the accuracy of the estimates under the two con-
ditions implies that the drug did not lead to
overestimation of performance capabilities.

C. Complex Performance. If we think of the
totality of the different task combinations of the
MTPB as being a “job” (as the term “job” is

used in everyday discourse), then the overall
composite score may be thought of as an index
of how well that job is performed. Thus, the
general finding was that performance of the job
was better under the dextroamphetamine condi-
tion than under the placebo condition. As shown
in Figure 2, performance under the drug condi-
tion was better than under the placebo condition
from 0400 until the end of the experiment, even
though the last drug capsule was ingested at
0400. The continued, though not statistically
significant, superiority of the drug condition at
1600 and 2000 may have resulted from the con-
tinued presence of the drug in the subjects? sys-
tems, or it may have been the result of the drug’s
having allowed a less fatiguing night without
sleep. The data do not allow an assignment of
weight to the contribution of these two possible
factors.

If we consider the elements of the task com-
plex, we see that there is a large variation in the
susceptibility of the individual tasks to the pos-
sible deleterious effects of sleep loss and, by in-
ference, the alleviation of those effects by
dextroamphetamine. The most sensitive tasks
appear to be the lights and meters tasks, both of
which involve performance of monitoring. In
addition, the tracking task and the pattern iden-
tification task were performed significantly bet-
ter under the drug condition than under the
placebo condition. Considering first the moni-
toring tasks, it should be noted that. these tasks
require systematic scanning of the performance
panel to achieve good performance. Good moni-
toring performance generally depends on the
ability of the subject to divert his attention from
ongoing tasks requiring relatively sustained at-
tention (such as mental arithmetic) and his
ability to rapidly detect and respond to “ab-
normal states” of the monitoring tasks, The
structure of the pattern identification task re-
quires a good sense of timing. ‘The standard
pattern (a six-bar histogram graph) is present
for 5 seconds and each of two comparison pat-
terns is present for only 2 seconds. Thus, the
subject must divert his attention from whatever
other tasks are active to the pattern identification
display at specific times if the briefly presented
problem elements are to be seen and identified.
Similarly, the subject must be able to shift his
attention back and forth between the tracking
task display and the other tasks in order to


TABLE 2. Comparisons of True Composite MTPB Scores with Estimated MIPB Scores

PLACEBO pes
ited Scores a

Session | Pros Georgy Eeeigen, i ae ae
2000 72.5 41.52 83.3 4 3.38 10,8 3.10% 72.2 41.41 81,8 4 2,22 9.6 3.75ee
2400 71.8 4 1.68 81.4 4 2.97 9.6 2.72% 72.4 + 1.63 81.6 + 2.54 9.2 2.85*
0400 67.8 4 2.91 71.6 4 3.22 3.8 1,18 72.9 + 1.84 80.8 4 1.85 7.9 3.5166
0800 65.1 4 3.53 62.5 4 5.44 2.6 0.67 70.6 + 2.15 75.3 « 2.72 a7 1.45
1200 66.1 4 2.44 63.5 4 3.50 2.6 0.68 70.6 + 2.35 75.3 4 1,66 4.7 1.58
1600 67.1 4 3.35 70.5 4 4.44 3.4 0.64 69.8 4 2:66 70.0 4 4,22 0.2 0.03
2000 68.5 4 2,09 74.8 3.45 6.3 1.56 70.4 4 2.32 73.3 4 4,29 2.9 0.66
x 68.4 + 2,50 72.5 4 3.77 4.1 71.3 4 2.05 76.9 + 2.78 5.6
n= 10
* p< .05
wep s 01

son of the subjects’ estimates of their relative
performance levels and their calculated perform-
ance; calculated performance is expressed as the
obtained composite score divided by the theoreti-
cal maximum score, this quotient then being
multiplied by 100. When the drug was used, the
subjects’ estimates of performance were signifi-
cantly higher than the calculated performance
scores during the first three sessions. When only
the placebo was used, the subjects’ estimates were
significantly higher during the first two sessions
but decreased as the period without sleep in-
creased, whereas when the drug was used, their
estimates remained consistently higher than the
calculated performances. However, when differ-
ences between estimated and calculated scores
over the total testing period are considered, there
was no statistically significant difference between
the two conditions.

C. Complea Performance. Performance on
the MTPB and the mean urinary excretion rate
of dextroamphetamine are shown in Figure 2.
The subjects’ MTPB performance js expressed
as overall composite score, with each point on
the curve representing the average for each of
the Q-hour sessions. An abbreviated summary
of the results of the analysis of these and other
data is shown in Table 3. In the analysis of the
data shown in Figure 2, the main effects of drug
condition and sessions were significant. In ad-
dition, the interaction of drugs with hours (first
vs. second hour of a session) was significant.

Figure 2 presents the data relevant to the first
of these interactions; namely, the drug by ses-
sions interaction. Although the overall effect of
sessions was significant, it is clear that this is an
average effect, and the important performance
characteristic is the decline associated with the
placebo condition. Individual “t” tests showed
the difference between the drug and placebo con-
ditions to be significant (p<.05) at 0400, 0800,
and 1200.

The analyses of the other composite perform-
ance measures show essentially the same effect

4 PEnroRMANce- RUG CONDITION 2
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580 r+-=-0 DEXTROAMPHETAMINE EXCRETION

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2000 2400 0400 0800 1200 1600 2000
TIME (CLOCKHOURS)

Ficure 2. Standard_ composite MTPB scores through
seven sessions (X+S8.E.M. n=10). Mean urinary
excretion of dextroamphetamine (broken line) is read
on the right ordinate.



minute interval were combined so that each
contributed equal variance to the resultant com-
posite score. (See Chiles, Jennings, and West?
for a more detailed description of the method of
computation of the composite scores.) These
composite scores were analyzed separately for
each interval, and, in addition, the mean of the
15-minute composite scores for each hour of test-
ing was analyzed. At the end of each test ses-
sion, the subject was asked to estimate his level
of performance during the preceding session,
expressed as a percent of what he thought his
“best” performance would be. At that same
time, the subject was to indicate a subjective
estimate of his state of fatigue by completing
the 10-item Subjective Fatigue Checklist.1t

Physiological responses consisted of heart rate
(HIR), which was obtained by using dry silver
electrodes with a CM; lead’? and measured con-
tinuously with an Electrocardiocorder (Avionics,
Model 400), and rectal temperature (T;.), which
was measured by an indwelling thermistor probe
read from a portable bridge.

Urine samples were collected periodically, pre-
served with 1.2 N sulfuric acid, and frozen for
later analyses. Biochemical analyses of the 17-
ketogenic steroids (17-KGS) were made by a
method described by Few,‘ and values were
measured with a colorimeter in a Technicon
Autoanalyzer system. Values for urinary epine-
phrine (E) and norepinephrine (NE) were
made by using an automated differential fluoro-
metric technique reported by Fiorica and Moses.*
Urine dextroamphetamine was determined by a
modified colorimetric method of Keller and
Ellenbogen’ and read from a Zeiss Spectropho-
tometer at a wavelength of 508 mp. All concen-
trations were multiplied by the urine volume
measured for each to obtain the total output.

After the training period, the 10 subjects were
arbitrarily divided into two groups of five sub-
jects each. Each group was tested twice, at
1-week intervals, in a double-blind design. For
one test the subjects ingested only sugar (lactose)
placebos at 4-hour intervals for a total of six
capsules beginning at 2000. In the other test
dextroamphetamine sulfate capsules were admin-
istered in three 5-mg doses at 2000, 2400, and
0400 and placebos in identical capsules were ad-
ministered at 0800, 1200, and 1600. One group

Days Land 2 0830 - 1630 Training on the Couplex Perforaence Task
Day 3 1630 Report to chaaber a
1700
1800 - 2000
No. 1, stare recording
”
2000 - 2200
2200 - 2400 Complex per foreance
2400 Fatigue checklist, estimation of performance,
urine sample No. 2, capsule No. 2
Dey 4 0001 - 0200 Free tine
0200 - 0400 Conplex per formance
0400 Fatigue checklist and estimation of
Performance, urine saaple No. 3, capsule
No. 3
(0400 - 0600 Free cime
0600 - 0800 Complex performance

‘0800 Fatigue checklist and eatimacton of
Performance, urine sample No. &, capsule
No. &

0800 - 1000 Breakfase

1000 - 1200 Coaplex per formance

1200 Fattgue checklist and estimation of
Performsnce, urine sample No. 5, capsule
No. 5

1200 + 1400 Lunch

1400 - 1600 Complex performance

1600 Fatigue checklist and estimation of
performance, urine sample No, 6, capsule
No. 6
1600 - 1800 Supper
Complex performance
2000 Fatigue checklist and estiaation of

Performance, urine sample No, 7, unhook
release subjects

Ficure 1. Schedule of events.

was tested first with the placebo and the other
group was tested first with the dextroampheta-
mine,

Figure 1 shows the schedule of events that
each of the two groups completed, once with the
placebo and once with the drug. Subjects re-
ported at 1630, at which time ECG electrodes
were attached and the rectal probe was inserted.
Subjects voided and discarded the first urine at
1700. Measurements were initiated directly after
the first complex performance session at 2000.
These were continued at 4-hour intervals for the
ensuing 24-hour test period with the exception
of HR and T,. observations, which were read
each hour. Subjects did not sleep throughout
the test period.

Il. Results.

A. Fatigue Checklist. The Subjective Fatigue
Checklist. provided a scale of 0 to 20, with 0
representing extreme fatigue and 20 representing
the condition of being totally refreshed. When
only the placebo was used, the mean score was
8.9; when the dextroamphetamine was used, the
mean score was 9.8. The numerical difference
between the two conditions was not statistically
significant.

B. Subjective Performance Estimates. The
summary data for the performance estimates are
shown in Table 2, These data present a compari-


RECTAL TEMPERATURE

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o” o—* PLACEBO CONDITION
O 364 > = DRUG ADMINISTERED

wiht iit, —
2000 2200 2400 0200 0400 0600 0800 1000 1200 1400 1600 1800 2000
TIME (CLOCKHOURS)
Fsaune 4, Hourly rectal temperature as a function of
time (K+S.EM,, n=10).

Excretion of 17-KGS and dextroamphetamine
is shown in Figure 5. Although the peak for
the steroid fraction under the drug condition
appears earlier and at a level about 0.1 mg/hr
lower than the peak for the placebo condition,
the only significant difference for this measure
is for time (p<.001). This generally reflects
the expected diurnal rhythm effect.

The curves for urinary excretion of E and the
excretion of dextroamphetamine during the drug
condition are shown in Figure 6. Epinephrine
excretion rates for the drug condition are ele-
vated over those for the placebo condition
(p<.001). The degree of elevation increases
over time (p<.05) for the drug condition but,
drops to the level of the placebo condition by the

1.4 @——— I7-KGS EXCRETION- DRUG CONDITION 7 28
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2000 2400 0400 0800 1200 1600 2000
TIME (CLOCKHOURS)

Ficure 5. Urinary 17-ketogenic steroid excretion rates
through time (X+S.E.M., n=10). Mean urinary ex-
cretion of dextroamphetamine (broken line) is read
on the right ordinate.

end of the 24-hour period. The drug condition
by time interaction was also significant (p <.001).
Figure 7 shows the curves of NE excretion
rates for the two conditions and the urinary ex-
cretion rate for dextroamphetamine. The curves
show the NE excretion levels to be, on the aver-
age, higher under the drug condition than under
the placebo condition. Although the difference
is significant (p<.05), the excretion pattern is
variable. The time course of NE excretion in
the drug condition is biphasic, with one peak at
2400 and a second, slightly higher peak at 1200.
None of the interaction effects among drugs,
groups, and time was statistically significant.

3500 - @———®_ E EXCRETION - DRUG CONDITION 28
TE tacneron-rsceno covorion ]
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3000 A -onve aoumnstenco V4
g
= 2800 4.20
Ss
z
2000 + 4.16
w
z
£ is00 + 4.2
a
Z
= 1000 + 4.08
w
500} 4.04

2000 2400 0400 0800 1200 1600 2000
TIME (CLOCKHOURS)

Ficure 6. Urinary epinephrine excretion rates through
time (X+S.E.M, n=10). Mean urinary excretion of
dextroamphetamine (broken line) is read on the right
ordinate.

IV. Discussion.

A. Fatigue Checklist. The period without
sleep led the subjects to describe their general
condition as being characterized by moderate
fatigue under both the drug and the placebo
conditions. The difference of less than one unit
on the 20-point scale is small (less than 5 per-
cent). It is of interest that the drug did not,
appear to result in a measurable difference on
the fatigue parameter, especially since perform-
ance was maintained at a significantly higher
level under the drug condition than under the
placebo condition. Perhaps the subjective pa-
rameter being assessed by the scale was not di-
rected at the proper domain; ie. greater
emphasis should have been placed on the detec-
tion of feelings, alertness, or sleepiness rather

(4H/97) 3NINVLEHdNVONLX3G



Technical Report Documentation Page

T. Report No. 2. Government Accession No. 3, Recipient's Catalog No.
FAA-AM-75~-14
%, Title ond Subtitle 3, Report Date

November 1975

©. Performing Organization Code

THE EFFECTS OF DEXTROAMPHETAMINE ON PHYSIOLOGICAL
RESPONSES AND COMPLEX PERFORMANCE DURING SLEEP LOSS

[B. Performing Organization Report No.

7. Author's) Ey Aw Higgins, W. D, Chiles, J. M, McKenzie,
phe" Tampietro,; Jd, A. Vaughan, G. B. Funkhouser,
Mi J A, B.S dé

Burr. ennings, an West
9. Performing Organization Nome and Address 10. Work Unit No. (TRA!S)
FAA Civil Aeromedical Institute
P. 0. Box 25082 TT, Contract or Grant No.

Oklahoma City, Oklahoma 73125

TS. Type of Report and Period Covered

12. Sponsoring Agency Name ond Address

Office of Aviation Medicine OAM Report
Federal Aviation Administration
800 Independence Avenue, S.W. 14. Sponsoring Agency Code

Washington, D.C. 20591

15. Supplementary Notes

Work was performed under Task AM-A-74-PHY-65.

16. Abstract

On two separate occasions, performance of 10 male subjects was measured on the
Civil Aeromedical Institute Multiple Task Performance Battery at 4-hour intervals
for a period of 24 hours without sleep. Each subject received a capsule at 4-hour
intervals beginning at 2000. On one occasion, the first three doses contained

5 mg each of dextroamphetamine sulfate followed by placebos for the remaining
three capsules. On the other occasion, all capsules were placebos. Results of
the experiment demonstrated that the dextroamphetamine sulfate sustained a high
level of proficiency and alertness and delayed the effects of fatigue for 8 to 12
hours after the ingestion of the third and final drug capsule. Heart rate, rectal
temperature, and urinary excretion rates of catecholamines were elevated with this
drug. These increases could support the enhancement of proficiency and alertness
demonstrated with amphetamines. Neither the subjects’ feelings of fatigue nor the
accuracy of their estimates of performance capabilities differed significantly in
these two test conditions.

17, Key Words 78. Distribution Statement
Dextroamphetamine, Sleep loss, Complex Document is available to the public throug!
performance, Urinary stress indicators, | the National Technical Information Service,|
Body temperature, Heart rate Springfield, Virginia 22151
19. Security Classif. (of this report) WO. Security Cloasif. (of this page) 2 No. of Pages | 22. Price
$3.00 PC
Unclassified Unclassified +95 MF

Form DOT F 1700.7 (6-72) Reproduction of completed page authorized



heat, and also because it increases muscle tone
for greater heat production. Further, relatively
large amounts of NE may be released from the
hypothalamus, the site of central regulation of
body temperature. The myocardium contains
numerous sympathetic nerve endings and can
take up significant quantities of catecholamines.
The elevated HR (Figure 3) with dextroamphe-
tamine may reflect the role of the catecholamines
in augmenting cardiac output under stress,

Differences in the excretion patterns of E and
NE may be traced to the anatomical sites at
which each was secreted. Most of the E origi-
nates in the adrenal medulla, where it is secreted
sporadically, the quantities related to the in-
tensity of the stimulus, while most of the NE is
stored in adrenergic vesicles located in the several
organs containing sympathetic innervation. Thus,
the rate of release and subsequent excretion of
NE may differ from one organ to another, re-
sulting in the irregular pattern through time.

Dextroamphetamine has little apparent effect
on 17-KGS excretion (Figure 5), since the ex-
cretion rate with the placebo is not different from
that with the drug and excretion pattetns under
both conditions are probably the result of diurnal
variation.

V. Summary and Conclusions.

Performance of a complex task was maintained
at a significantly higher level during a period of
24 hours without sleep when subjects were given
15 mg of dextroamphetamine sulfate in three
5-mg doses at 4-hour intervals. However, sub-
jective measures showed that neither feelings of
fatigue nor the accuracy of self-estimates of per-
formance efficiency were significantly affected by
the administration of the drug as compared to a
placebo control condition. Increases were found
in the levels of HR, T,., and urinary catechola-

mine excretion. Excretion of urinary dextro-
amphetamine reached a peak about 4 hours after
administration of the third and final drug cap-
sule, but excretion levels were still quite elevated
at the end of the study. Presumably because of
the continued presence of the drug, the various
biochemical and physiological parameters showed
effects for 8 to 16 hours after the last drug cap-
sule was administered, and performance was also
maintained at a higher level throughout the
withdrawal period.

The results of this study should not be inter-
preted to suggest that the detrimental effects of
sleep loss can be prevented by the administration
of dextroamphetamine sulfate. Although the
difference between the presleep loss and the sleep
loss conditions was not statistically significant,
performance under the drug condition during
the morning and afternoon hours of the second
day suggested some loss of efficiency. The only
inference permitted by a strict interpretation of
the results is that performance would be expected
to be maintained at a higher level under dextro-
amphetamine than without it. It should also be
noted that, since dextroamphetamine is generally
regarded as one of the most effective stimulants,
more common, legal stimulants (such as caffeine)
would not be expected to insure satisfactory per-
formance levels under conditions of sleep loss.

In the realm of methodology, the detailed
analysis of the performance data suggests that
monitoring tasks embedded in a task complex
provide the most sensitive indicators of the im-
pact of stresses such as sleep loss. The implica-
tion of this finding is that tasks that would
typically be regarded as peripheral to the main
duties of the operator, and are thus assigned a
lower priority, are likely to suffer even though
the major, high priority tasks appear to be un-
affected by sleep loss.


maintain good performance. In contrast, the
presentation of a problem on the arithmetic task
js accompanied by a rather loud noise produced
by the resetting of the keys of the response mech-
anism as well as the onset of the nine, rather
bright Nixie tubes used to present the problem
elements. On the group problem-solving task,
although the feedback lights are no more visible
than the monitoring lights, the group nature of
the task tends to compel the typical subject to
attend to this task with some care; namely, all
of the subjects are—or, if they pay attention,
can be—aware of how each individual subject is
performing on this task. Thus, a certain amount
of group pressure is exerted on individual sub-
jects to perform well. In fact, occasionally a
subject is found who, if he is poor on one or
more of the other tasks, will simply let those
tasks go in order not to be obviously poor on the
group problem-solving task. Another factor to
be considered in evaluating the individual tasks
is the consistently observed tendency of subjects
to attach different priorities to the different
tasks, As noted above, the problem-solving task
is given rather high priority, as is the arithmetic
task; in this latter case the reason is, perhaps,
that many people feel a need to demonstrate that
they are reasonably proficient at carrying out
simple addition and subtraction.

Performance of the task complex as a whole
requires skill in the domain of time sharing.
The subject, to perform well, must be able to
shift his attention rapidly from one type of
activity to another. In this sense, the monitoring
tasks can be thought of as providing an index
of the “channel capacity” that the subject has to
spare after giving what he considers to be ade-
quate attention to the major tasks; ie. those
tasks to which he gives priority, Pursuing this
line of reasoning to its conclusion, then, we would
say, at the descriptive level, that the dextro-
amphetamine mitigates the performance effects
of the period of sleep loss by preventing the
reduction of the subject’s channel capacity.

These general findings are clearly in line with
those of previous investigators as reviewed by
Weiss and Laties.* Thus, the major contribu-
tion of the present study, with respect to per-
formance measurements, lies in the methodologi-
cal refinement permitted by the MTPB; namely,
the MTPB brought out the differential effects

of sleep loss as affected by dextroamphetamine
in relation to the nature of the task demands.

D. Physiological and Biochemical Effects.
Stolman and Stewart" report that the ampheta-
mines reach a maximum excretion rate between.
3 and 12 hours after ingestion and that an aver-
age of 29 percent of the dose is excreted in 24
hours, but there is a wide individual variation in
excretion rate. The mean total excretion of
dextroamphetamine for the subjects in this ex-
periment was 15.6 percent, ranging from a low
of 2.6 percent to a high of 43.3 percent in the
24-hour period for which measurements were
made. The average rate of excretion of the drug
remained at an elevated level throughout the
study, and the post-drug Jevels did not go below
that observed in the samples taken 4 hours after
ingestion of the first capsule. When this finding
is considered in conjunction with the data of
Stolman and Stewart, it would appear that (on
the average) substantial amounts of the un-
metabolized drug could remain in the subjects’
systems at the end of the experiment.

The data indicate that dextroamphetamine is
sympathomimetic, particularly evidenced by the
cardiovascular and the temperature regulation
systems. Wurtman,? in reviewing the results of
a number of investigators, describes the role of
the catecholamines in the mechanisms of the
physiological effects of amphetamine on the cen-
tral nervous system. Amphetamine liberates
stored NE from nerve endings in the brain.’*
However, the amine thus released is not metab-
olized before it leaves the nerve ending, and thus
it is able to exert, continuing physiologic effects.°
The uptake of H®-norepinephrine is plocked by
amphetamine.s® Since uptake appears to be a
major mechanism for catecholamine inactivation
in adrenergic nerves, this blockade in the brain
probably lengthens the period that NE molecules
released at central synapses remain effective.
Amphetamine may also interfere with the me-
tabolism of catecholamines by monoamine oxi-
dase” The definitive increases in urinary E
(Figure 6) and NE (Figure 7) levels with
dextroamphetamine over those of the placebo-
condition level lend support to this interpreta-
tion. The substantially higher value of T;.
under the drug condition than under the placebo
condition (Figure 4) probably occurs because
the amphetamine decreases perspiration and in-
creases vasoconstriction, both of which conserve



TABLE 3.

Abbreviated Summary of Analyses of Performance Measures

Days Drugs Periods Sessions

Individual Measures

Red Lights Ns s s s Ns

Green Lights 8 s s s 8

Meters Ns NS 8 8 s

Arithmetic Time NS NS s Ns NS

Arithmetic Percent NS Ns 8 s NS

Pattern Identification Time NS NS NS NS NS

Pattern Identification Percent NS s 8 NS NS

Problem Solving Time 8 NS s 8 NS

Problem Solving Percent NS NS s Ns NS

Days Drugs Sessions Hours Drugs x Sessions Drugs x Hours

Tracking Vector

Absolute Error Ns s 8 NS NS NS
Tracking RMS

Vector Error NS Ns s NS Ns Ns
Composite Measures

ist 15 min. s s 8 Ns s NS

2nd 15 min, NS 8 s NS 8 NS

3rd 15 min, NS s s Ns s Ns

4th 15 min. s 8 s NS s s

Overall NS s Ss NS Ss Ss

Note:

and do not warrant separate comment. How-
ever, the analyses of the individual measures do
suggest a different emphasis. Specifically, it is
noted that the significant drug effects were found
on only two of the individual measures other
than the monitoring task measures. These two
measures were “percent correct” on the pattern
identification task and “vector absolute error”
on the tracking task.

D. Physiological and Biochemical Data. The
physiological and biochemical data were analyzed
by the randomized block factorial method. The
paired “t” test was employed to evaluate data
during given time intervals. The hourly meas-
urements of HR are shown in Figure 3. Mean
rates for the dextroamphetamine condition were
significantly higher than the rates for those re-
ceiving the placebo only (p<.001). Although
both curves showed evidence of a circadian
rhythm, there were no significant differences
over time for either condition.

Rectal temperature as a function of time and
drug condition is shown in Figure 4. The drug
condition produced internal body temperatures
that were significantly higher than those pro-
duced by the placebo condition. (p<.001). The
curves for both conditions clearly indicate a 24-
hour rhythm, as T,. decreased in the early morn-

§ indicates significant at .05 level of confidence or better; NS indicates not significant.

ing hours even though the subjects were awake
and active. The curves began to merge at about
1600 and were at normal levels by the end of the
test period. The interaction between drug con-
dition (drug/placebo) and time was significant
(pS.01).

HEART RATE

‘© DRUG CONDITION
88} *—* PLACEBO CONDITION

4 onus aoministeRED

“0

BEATS PER MINUTE

t .

60 1 1
2000 2200 2400 0200 0400 0600 0800 1000 1200 1400 1600 1800 2000
TIME (CLOCKHOURS)

Ficure 3. Hourly heart rate as a function of time
(X+S.E.M.,, n=10).







ACKNOWLEDGMENT

The authors express their appreciation to the personnel of the Stress
Analysis Research Unit for the biochemical analyses of the urinary cate-
cholamines and 17-ketogenic steroids. They also thank Mr. Peter Nelson of
the Biostatistical Section for the statistical analyses of the physiological and
biochemical data and the Medical Illustration staff for preparing the graphs.





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