T I M E RELATIONS O F OBJECTIVE AND SUBJECTIVE REACTIONS T O

D-AM PHETAM I N E AND PE N T O BARB I T O N E

MARIANNE FRANKENHAEUSER and BIRGITTA POST

Psychological Laboratory, University of Stockholm, and Laboratory of Aviation and Naval Medicine, Karolinska institutet,

Stockholm, Sweden

FRANKENHAEUSER, M. & POST, B. Time relations of objective and subjective reactions to d-amphetamine and Pentobarbitone. Scand. J. Psychol., 1964, 5, gg-~o~.-Successive measurements of pulse rate, blood pressure, objective and subjective reaction speed, and six mood variables were made on 12 healthy subjects during 135 min. periods following the intake of either 15 m g d-amphetamine, zoo mg Pentobarbitone, or a placebo. It was shown that (I) the two drugs had essentially opposite effects on all objective and most sub- jective variables; (2) after d-amphetamine subjective effects appeared earlier and reached their maximum more rapidly than objective effects; (3) both types of reaction were less pronounced after Pentobarbitone than after d-am- phetamine under the present dose conditions; and that (4) after Pentobarbi- tone maximum objective effects were attained at an earlier point in time.

Psychological and physiological reactions of normal subjects to drugs that stimulate or depress the activity of the central nervous system have been extensively studied. It is well known that stimulants in appropriate doses may improve performance in a variety of tasks, in particular in fatigued subjects, while depressants in moderate doses impair performance (e.g. Kornetsky & Humphries, 1958; Mirsky & Rosvold, 1960; Nash, 1962). Subjective changes in mood often appear more striking than performance changes, stimulants gene- rally producing feelings of efficiency and elation, and depressants drowsiness and a mild euphoria. Physiological functions such as circulatory reactions (see e.g. review by Trouton & Eysenck, 1960) and catecholamine excretion (Frankenhaeuser & Post, 1962), are also affected in opposite directions by the two types of drugs.

While the general pattern of objective and subjective effects of stimulants and depressants is relatively well known, information as to the time relations of these effects is scanty. Measurements have generally been made at one single point in time after administration of the drug. Hence, little is so far known about the times for onset, increase, decline, etc., of the various reactions. The present experiments were designed to examine the time pat- terns of objective and subjective reactions following the intake of d-amphetamine and Pentobarbitone.

METHODS

Subjects, drug administration, and general design Twelve male students of psychology participated in the experiments. Their ages ranged

between 20 and 24 years (mean Z Z . ~ ) , and their body weights and heights between 60 and 98 kg (mean 69.2), and 173 and 188 em (mean 180.9). Before being accepted as subjects they were given a medical examination.

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I00 MARIANNE FRANKENHAEUSER AND BIRGITTA POST

Each subject came to four sessions, one for general orientation and preliminary training on a reaction-speed test, and three drug sessions spaced at intervals of about one week. In each drug session the subject was given two capsules containing either zoo mg Pentobarbitone, 15 mg d-amphetamine, or a lactose placebo. All capsules were identical in appearance and neither the experimenter, nor the subject, knew which was being given. The order of admini- stration of drug and placebo capsules was rotated so that each kind of capsule was given first, second, or third an equal number of times.

The subjects had been informed that the purpose of the experiments was to examine their reactions to a number of drugs that were in common clinical use and were known not to have any long-lasting side effects. They were told that some of the drugs might produce sleepiness, some alertness, whereas others might not produce any mental symptoms at all. T o counteract directional effects of anticipation, care was taken to convey the impression that one and the same subject would receive either the same drug in each session (though possibly in different doses) 01, which was actually the case, that the capsules may have a different content each time.

Instructions were also given not to drive a car on the day of an experiment, not to have any other drugs on the same or the previous day, and not to eat or drink anything in the morning prior to an experiment. All experiments were carried out between 8 a. m. and I p. m., and the subjects were served a light meal (a glass of milk and two pieces of bread and butter) when they arrived in the laboratory.

Objective variables

Pulse rate was measured by palpation of the radialis artery and systolic and diastolic blood pressure by the sphygmomanometric method. Measurements were made once before and four times after the capsules had been taken.

Reaction speed was measured by recording the time taken to press a key in response to an auditory signal of 0.1 sec. duration. The signals had been recorded on magnetic tape and were presented to the subject through earphones. Each trial lasted 15 min. and comprised 300 signals separated by irregular intervals of z to 4 sec. The time between signal and response was recorded by an electronic counter. These time measures were transformed into measures of speed and expressed as the mean number of responses per sec. There was one trial before the capsules were given, and four trials during the subsequent period.

Subjective variables

Measurements of subjective reactions were obtained by the method of magnitude estima- tion, which is the simplest direct scaling method. The application of this scaling method to the measurement of mood variables has been described in detail in reports of earlier investiga- tions (e.g. Ekman, Frankenhaeuser, Goldberg, Bjerver, Jiirpe & Myrsten, 1963). The sub- jects gave self-estimates in respect of the following variables: subjective reaction speed, ‘sleepy’, ‘alert’, ‘tired’, ‘happy’, ‘tense’, and ‘relaxed’.

After the capsules had been taken four sets of estimates were made, each immediately after the reaction-speed trials. For the first estimates the standard state of comparison was defmed as the subjective state, in terms of each variable, at the time of the reaction-speed test that preceded the intake of capsules. For each of the following sets of estimates the standard was changed, so that the subjective state at the time when the previous estimates were made, ser- ved as the standard. Thus, the subject estimated changes in his subjective reactions from one trial to the next, always using his state at the previous trial as his standard of comparison. The standard states were always denoted 10. Before giving his estimate the subject was asked if he felt more or less of a given variable after which he assigned a number to it. If he felt, for example, twice as alert as his conception of his own degree of alertness during the previous trial, he should report 20, if he felt 25 per cent more alert he should report 12.5; if, on the other hand, he felt only half as alert his estimate should be 5 , etc.

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REACTIONS TO D-AMPHETAMINE AND PENTOBARBITONE I01

Procedure

After the subject had had his light meal and had relaxed in a chair for about 10 min., his pulse rate and blood pressure were measured and he had a 15-min. reaction-speed trial. He was reminded that his subjective state during this trial would serve as the standard of compari- son for his first subjective estimates. After this he was given the capsules assigned to him for that day. Then his pulse rate, blood pressure and reaction speed (Is-rnin. trial) were mea- sured, after which he estimated his subjective reactions. Then followed a 15-min. pause during which he relaxed and read magazines. The same procedure was repeated three times. Thus, altogether four measurements were obtained for each variable after the intake of capsules. These four trials were spaced over 135 min. A full session lasted about three hours.

RESULTS Lhug and placebo treatments

The results are presented in Figs. I , 2, and 3, which show the mean successive measure- ments of all variables in the d-amphetamine, Pentobarbitone, and placebo conditions. Subjective estimates in trials 3, 4, and 5 have been transformed and expressed as units of the pre-treatment state which, for each variable, was denoted 10. Data from each of the three conditions will be reviewed in turn, and then the effects of the different treatments will be compared.

D-amphetamine. Following the intake of the drug there was a rather consistent increase in pulse rate; at the two last trials (from about 80 min. after the drug had been taken) there was also a rise in blood pressure (Fig. I). Objective and subjective reaction speed both increased (Fig. 2). Estimates of the mood variables showed that the subjects felt less sleepy and tired, and more alert, happy, and relaxed as the experiment progressed (Fig. 3 ) .

Pentobarbitone. After the intake of Pentobarbitone blood pressure decreased during the experimental period, while pulse rate remained relatively unchanged (Fig. I). Objective and subjective reaction speed both decreased (Fig. 2). The time-patterns of the subjective estimates of mood showed some irregularities, but the main trends were that the subjects felt progressively more sleepy, tired, and relaxed, and less alert and tense (Fig. 3 ) .

Placebo. The data obtained after the intake of the placebo illustrate the effects of the ex- perimental situation as such on the variables examined. There were pronounced changes in several variables. Pulse rate and blood pressure as well as objective and subjective reac- tion speed decreased during the experiment (Figs. I and 2). The estimates of mood showed that the subjects felt more sleepy, tired, and tense as the experiment progressed (Fig. 3). These control data show that, on the whole, the experimental situation as such affected the subjects in much the same way as did Pentobarbitone, although to a lesser degree.

Comparison between drug effects

When evaluating the effects of d-amphetamine and Pentobarbitone, the reactions occur- ring in the placebo situation have to be taken into account. The influence of factors other than the drugs have been eliminated by expressing each of the scores in the d-amphetamine and Pentobarbitone conditions as percentages of the corresponding measurements in the placebo condition.

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I02 MARIANNE FRANRENHAEUSER AND BIRGITTA POST

a s - , I 4 I I I 1 2 0 , . , 8 U ,

Pulse rale SYSl. pnss.

- 115 - 80 - m I E 7 5 - E

70 - E

85 ' ' ' ' ' ' 100 - -30 0 30 60 90 120

Diast. press. Time in mlnutes af tor treat ment

75 -30 0 30 60 90 120

Time In minutes a f t or t rea t men t

FIG. I . Successive mean measurements of pulse rate and blood pressure after d-amphetamine (0-O), Pentobarbitone (0-o), and a placebo ( X- x).

The results thus obtained are shown in Figs. 4, 5 , and 6. The main characteristics of the data may be summarized as follows: (a) most variables were affected in opposite directions by the two drugs; ( b ) both drugs, however, made the subjects feel less tense and more re- laxed; (c) after d-amphetamine subjective effects appeared earlier and reached their maxi- mum more rapidly than objective effects; ( d ) under the present dose conditions both types of reaction were less pronounced after Pentobarbitone than after d-amphetamine, and after Pentobarbitone maximum effects were attained at an earlier point in time.

I ' I ' " I I " " '

16 Subj.reaclion speed -

01 14 - U

2 a

> 10

3 a -

.- U 0 01

7 u)

6 -

L " " " -30 0 30 60 90 120

Time in minutes a f t e r treatment FIG. 2. Successive mean measurements of objective and subjective reaction speed after d-amphetamine

( 0-o), Pentobarbitone (0-o), and a placebo ( x - x).

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REACTIONS TO D-AMPHETAMINE AND PENTOBARBITONE '03

12

10 - 8 -

SLeepy

6 ' ' " ' * -30 0 30 60 90 120

1 - , I

0 14 - 1 2 -

Y

zi u a! x 8 - a u) fired

6- -30 0 30 60 90 120 I

14

12

10

9

6- -30 0 30 60 90 120

I ' " " ' i

-30 0 30 60 90 120

Happy

" " " -30 0 30 60 90 120

6- -30 0 30 60 90 120

Time i n minutes after treatment

FIG. 3. Successive mean estimates of subjective mood variables after d-amphetamine (0-o), Pentobarbitone (O-O), and a placebo ( x- x) .

Statistical analyses

0;lferences between drug and placebo data were analysed by applying the t-test to mean intxa-pair differences between scores obtained after the intake of the placebo and each of the two drugs. These comparisons were based on the individual means of the three last trials after the capsules had been taken, the first trial being omitted because it was started immediately after administration of the drugs, i.e. before the pharmacological effects had appeared. Table I shows that significant differences were found (a) between d-amphetamine and placebo in the variables pulse rate, subjective reaction speed, 'sleepy', and 'tired', and (b) between Pentobarbitone and placebo in the variables 'sleepy' and 'alert'.

Lhyerences between pre- and post-treatment data for all conditions were analysed by app- lying the t-test to mean intra-pair differences between scores obtained before and after (means

S d . 1. PJycbol., Vol. 5,1964

I04

0) 3

w 0

8 8

m 110 - Sys!. press. - 110 - Diast. press.

n

2 105

-

- L 100 100

2 95 95

C 0) 0 L

MARIANNE FRANKENHAEUSER AND BIRGITTA POST

110 -!--6: 100 90 -- Subj.reaclion speed

80

115 -

2 110 -

pulse rate 3

> - m a 0

0

L

d 95 ' ' ' ' ' '

-30 0 30 60 90 120

Time in minutes after treatment

FIG. 4. Successive mean measurements of pulse rate andxblood pressure after d-amphetamine ( 0-0) and Pentobarbitone (0-0) in per cent of placebo scores.

: 110 - m > 0

0 5 105 m n - b 100 Y E a, 0 L 95 2

90 - -30 0 30 60 90 120 150

Time in minutes af ter treatment

FIG. 5. Successive mean measurements of objective and subjective reaction speed after d-am- phetamine (0-0) and Pentobarbitone (0-0) in per cent of placebo scores.

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REACTIONS TO D-AMPHETAMINE AND PENTOBARBITONE

I t 0 -

100 --

120: 80 Alert c: 60 ' I ' ' I '

' 0 5

:-x: Tired

'iii gF-- - - - l > 140

0

0 m a

0 U

n Q) 120

- .c 100

5 80 0 L

a" 60 -30 0 30 60 90 120

140

120

100

80

60

i Relaxed

- 3 0 0 30 60 90 120 60

Time in minutes after treatment

and Pentobarbitone (@-a) in per cent of placebo scores. FIG. 6. Successive mean estimates of subjective mood variables after d-amphetamine ( 0 - 0 )

of three last trials) the intake of d-amphetamine, Pentobarbitone, and the placebo. Table 2

shows that significant changes were found (u) after d-amphetamine in the variables sub- jective reaction speed, 'sleepy', 'tired', 'tense', and 'relaxed'; (b) after Pentobarbitone in systolic and diastolic pressure, objective reaction speed, and in the subjective variables 'sleepy', 'alert', 'tired', and 'tense'; (c) after the placebo in pulse rate, systolic pressure, and the variable 'sleepy'.

COMMENTS

The present data illustrate some interesting discrepancies between objective and subjec- tive drug effects as produced by the doses used in the present experiments. Following intake of Pentobarbitone both objective and subjective reactions appeared in less than 40 min.

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106 MARIANNE FRANKENHAEUSER AND BIRCITTA POST

TABLE I. t-values for mean intra-pair differences between scores obtained after (means of three last trials) d-amphetamine, Pentobarbitone, and a placebo.

t-value

Variable d-amph-placebo Pentobarb.placebo

Pulse rate + 2.487* - 0.221 Systolic pressure + 1.679 - 0.995 Diastolic pressure + 1.063 - 0.129 Obj. reaction speed + 1.292 - 0.667 Subj. reaction speed + 2.231~ - 0.558 ‘Sleepy’ - 3.260*+ f 1.917* ‘Alert’ + 1.449 - I.907* ‘Tired’ - 3.100** 4- 0.043 ‘Happy’ + 0.849 - 0.822 ‘Tense’ - 1.286 - 1.261 ‘Relaxed’ 4- 1.054 + 0.469

Pco.05; ** Pco.01. df= I I; one-tailed t .

Peak effects seem to have been reached well within the period of observation, for some vari- ables in less than 90 min. In some cases a return towards normal levels was seen at the end of the experimental period.

After intake of d-amphetamine the subjective reactions followed a time pattern similar to that of the Pentobarbitone reactions. The objective effects, however, appeared con- siderably later and were still increasing when the experimental period ended.

TABLE 2. t-values for mean intra-pair diferences between scores obtained after (means of three last trials) d-amphetamine, Pentobarbitone, and a placebo.

t-value

Before-after Before-after Before-after Variable d-amph. Pentobarb. placebo

Pulse rate - 1.608 + 0.3 15 f 2.395, Systolic pressure + 0.402 + 3.227** + 2.82821 Diastolic pressure Obj. reaction speed Subj. reaction speed ‘Sleepy’ ‘Alert’ ‘Tired’

‘Tense’ ‘Relaxed’

‘Happy’

+ 0.649 - 1.333 - 1.936* + 1.984, - 1.107 + 2.389’ - 1.170 + 2.720**

- 1.940*

+ 4.333- + 1.955* + 1.167 - 3.8612’ + 3.641” - I.833* + 0.280 + 2.~46~ - 1.000

f 1.709 + 1.273 + 0.469 - 2.783”* + 1.193 - 1.735

- 0.684 - 0.714 - 0.907

* Pco.05; #* P < O . O I .

df- XI; one-tailed t .

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'07

The influence of the drugs on objective as compared with subjective performance is of particular interest. Results from some earlier investigations with drugs, for instance adre- naline and noradrenaline (Frankenhaeuser, J ape & Matell, 1961; Frankenhaeuser & J w e , 1963), show that actual performance may be relatively unimpaired, or even improved, while the subjects feel that they perform less well. In experiments with alcohol a tendency in the reverse direction was noticed at a point in time when objective performance was at a mini- mum, subjective working capacity was at a maximum (Ekman et al., 1963). It would be important to find out more about the factors affecting an individual's ability to judge accu- rately his own level of performance, so that the direction and extent of discrepancy between actual and estimated performance could be predicted. The present data suggest that the objective impairment following Pentobarbitone is accurately estimated, while the improve- ment after d-amphetamine is overestimated (Fig. s). These questions are being further explored in experiments now under way which cover longer time periods within which it will be possible to examine the effects of d-amphetamine more fully.

The reactions occurring in the placebo situation are likely to have been associated mainly with the nature of the experimental situation (cf. DiMascio & Merman, 1960). Since the instructions given to the subjects before the experiments were phrased so as to prevent them from expecting effects in definite directions, it seems unlikely that the intake of the capsules should have played a major role in producing the reactions. It is, however, not surprising that monotonous and boring experiments such as these give rise to symptoms resembling those produced by Pentobarbitone.

REACTIONS TO D-AMPHETAMINE AND PENTOBARBITONE

We are indebted to Dr. G. Matell, who carried out the medical examinations, to Mr. R. Hagdahl and Mr. B. Wrangsj6, who assisted in the experiments, and to Miss G. Johansson who helped with the computational work. The investigation was supported by a grant from the Swedish Council for Social Science Research.

REFERENCES

DIMASCIO, A. & KLERMAN, G. L. (1960). Experi- mental human psychopharmacology: the role of non-drug factors. In G. J. SARWER-FONER (Ed.), The dynamics of psychiatric drug therapy. Springfield, 111: Thomas. Pp. 5-0.

EKMAN, G., FRANKENHAEUSER, M., GOLDBERG, L., BJBRVER, K., JKRPE, G. & M m m , A. L. (1963). Effects of alcohol intake on subjective and objective variables over a five-hour period. Psychopharmacologia, 4 , 28-38.

FRANXENHAEUSER, M. & JARPB, G. (1963). Psy- chophysiological changes during infusions of adrenaline in various doses. Psychophannaco-

FRANI<ENHAEU~~, M., J ~ P E , G. & MATELL, G. (1961). Effects of intravenous infusions of adrenaline and noradrenaline on certain psy- chological and physiological functions. Acta physiol. scand., 51, 175-186.

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FRANKENHAJJUSER, M. & POST, B. (1962). Cate- cholamine excretion during mental work as modified by centrally acting drugs. Acta physiol. scand., 55, 74-81.

KORNWSKY, C. & HUMPHRIES, 0. (1958). Psycho-' logical effecta of centrally acting drugs in man. J. ment. Sci., 104, 1093-1099.

MIRSKY, A. F. & ROSVOLD, E. (1960). Psycho- active drugs in studies of attention. In L. UHR & J. G. MIL- (Eds.), Drugs and be- hawior. New York Wiley. Pp. 375-392.

NASH, H. (1962). Psychologic effects of ampheta- mines and barbiturates. J. n e w . ment. Dis.,

TROUTON, D. & EYSENCK, H. J. (1960). The effects of drugs on behaviour. In H. J. EY- SENCK (Ed.), Handbook of abnormal psychology. London: Pitman. Pp. 634-696.

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