College, Cambridge. first three series of ergograms after an injection of 1 mgm. of sulphate

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1 EFFECT OF STRYCHNINE ON MUSCULAR WORK. BY P. C. VARRIER-JONES, B.A., Late Scholar of S. John's College, Cambridge. (From the Psychological Laboratory, Cambridge.) STRYCHNINE has been the subject of only a few experiments to determine its effect on muscular work. It was therefore suggested to me by Dr Rivers that further experiments would be useful and that they should be carried out with Kraepelin's improved ergograph. To previous experiments I have found only two references. Rossil in his researches on fatigue included strychnine in the number of the drugs he examined. He found that there was a remarkable increase in the amount of work done by the muscles after an injection of strychnine, and that although there was an increase in the quantity of work done, yet the heights of the different contractions were in no way augmented. He continued his series of ergograms for one hour, at the end of which time he had completed seven. Only an increase in the amount of work performed under the influence of strychnine is shown, no reference being made to any decrease. This is probably due to the fact that the ergograms did not extend over a sufficiently long period. The dose (1 milligram sulphate of strychnine) was injected hypodermically. F4rd2 found that the amouint of work done was increased during the first three series of ergograms after an injection of 1 mgm. of sulphate of strychnine-i.e. during roughly three quarters of an hour. Later, however, the amount of work performed was diminished, remaining below the normal till the end of the experiment (about an hour and a half the time of the dose). The meth6d used for this experiment is identical with that employed by Rivers and Webber in their work on caffeine3, sets of six ergograms being taken separated by two minute intervals. A period of half 1 Ro ssi. Rivista sper. di Freniatria, xx. p Fere. Travail et Plaisir. Paris, Felix AlMan This Journal, xxxvi. p

2 436 P. C. VARRIER-JONES. an hour was allowed between sets I and II and also between II and III. Between each of the later sets an hour wvas allowed to elapse. During the half hours typewriting of a simple kind was done, the left hand only being used. Gentle wvalking exercise occupied the hour intervals with the exception of the second (between sets IV and V), during which dinner was taken. The conditions of life were kept as constant as possible during the experiment in both mental and physical work. No alcohol or other stimulant was taken during this time, save the usual cup of coffee at breakfast. Smoking was not indulged inl. The midday meal was of a light nature and the experiment was begun at 4 p.m., being continued for abouit five hours. The doses consisted of 3 and 7 minims of liquor strychninae hydrochloridi, i.e. of 1-8 and 4 2 mgm. of strychnine hydrochloride, and of a simple infusion ofgentian indistinguiishable in taste from the strychnine solutions. These doses were administered in half a tumbler of water in an order unknown to the subject, whose only information was that there were three solutions, one with no strychnine, the second with a small amount, and the third with a full amount of the drug. At the actual time the dose was taken there was no indication as to its nature2, but the large increase in the work done after the stronger dose of strychnine rendered concealment impossible later in the day, as well as revealing to some slight extent the plan of the experiment since each dose was expected to occur an equal number of times. Though the increase at first may be looked on as practically a pure drug effect, it is probable that the interest aroused by so definite an alteration in muscular capacity tended to increase the work still further. The amnount of this increase would, however, be small compared with that directly due to the dose. The actual experiment was begun after about a week's training, the daily total of six sets being reached at the end of that time. A small experiment for another purpose had been carried out a couple of months earlier. Now to turn to the actual figures of the experiment it will be seen by reference to Table I (which gives the work for each day) that there is a great fall of muscular capacity in the later days of the experiment. The change is very nmarked after August 2nd but it is present to a slight extent before that date. In order to make a comparison of the drug effects 1 The subject is usually a very moderate smoker. 2 A slight headache followed the taking of the strychnine on more than one occasion, and once it was noted that objects were seen as blue.

3 STRYCHNINE AND MUSCULAR WORK. 437 TABLE I. WVork in kilogrammetres for each day of experiment. July Aug No No No Ergogram dose dose 7 m. Control 3 m. 7 m. Control 3 m. Control 3 m. 7 m. Control 3 m. 7 m. dose I 1 4'8 3'0 41 3'1 2'5 2'6 1'1 0'3 0' '2 0'1 0'1 2 1' ' '6 09 1'3 0'3 0'2 0'2 0'2 3 2'5 2' '3 2'3 2'3 3'6 2'4 3'1 1P7 2'3 0'7 0' '3 4 1P7 2'3 2'1 1'6 2' '5 2'6 2'2 2'7 0' '7 0'7 5 1'7 2'7 1'5 1'2 2'0 2'4 51 2'2 1' '8 0'9 0'8 0'5 6 2'3 1'5 1'6 1'2 1'4 2' '1 1'7 21 4'2 1'1 0'5 0'9 0'8 Total '9 10'8 13' '3 11'3 11' ' '9 2'6 II 1 3'3 3'2 4'2 3'2 4' '3 1' '3 0'4 0'1 0'3 2 1'9 25 3'8 1'8 3'0 3'0 3'0 2'7 2'0 1' '3 0'7 0'7 0'7 3 2'2 2'4 2'4 1'5 2'6 2'6 3' '4 1P ' '0 0'9 4 2' '0 1'7 1'8 2' '0 13 3'2 0'6 1'1 1' P ' '6 2'9 2'7 2'3 2' '3 1'0 1'7 1'3 6 1'7 2' '9 2'0 2'9 2'9 1' P9 2'9 0'3 0'3 1'6 1 1 Total 13'2 15'2 17'6 10'6 16' '7 12'7 12'3 8'8 21'2 2' '4 5-4 III 1 2'5 2' ' *9 1P ' '2 0'4 0'3 0'6 2 2' '9 2'1 3'0 2'5 3'0 1P8 2'8 1P5 4'1 0'3 0'8 0'9 1P P5 2'1 1P8 2'1 2' P P8 4'5 0'8 0'6 0'9 1P0 4 2'3 1'7 2'1 1P '2 1P6 3'5 2'4 4'1 0'7 1P1 0'8 0' P '0 19 3'2 3'0 19 2'6 1P '4 0'9 0'9 0'9 6 1P8 1P5 2'2 1P2 2'5 3'2 2'2 1' P7 3'2 0'5 10 0'8 1P4 Total 13'1 11' '9 16'2 19'9 19'6 10'5 17' '5 2'9 4'8 4'6 5'8 IV 1 2'3 3' '1 7'1 4' '3 3'6 0'3 2' ' '8 2'7 2' ' '8 0'9 2'5 0'5 0'2 0'8 1P6 3 1p7 2'3 2'7 0'9 3'2 2'7 2'9 2'5 2' '7 0'9 1P2 1P0 2'4 4 0'9 2'5 2'1 1P6 2'8 1P7 3'2 2'4 2'5 2' P0 1P4 0'9 2'2 5 1P '1 1P5 2'5 2'0 2'7 2'1 2'1 1'9 2'8 0'9 1'2 1'3 1P7 6 1P '5 1' '3 2'7 1P7 2'1 1P7 2' P4 1P0 1P3 Total '8 10'6 20'0 15'8 18'2 12'7 16'9 9'3 16' '2 9-6 V ' * '0 19 1'1 01 0'5 01 0'2 0'3 0'7 2 1'0 2'1 2'9 2'3 2'1 2'6 2'7 2'5 5'1 1P7 1P8 0'2 0'8 0'7 1P6 3 1P6 2'2 1P9 2'7 2'9 2'2 2'7 2' '0 2'3 0'8 0'8 0'8 1P8 4 1P '3 2'9 1P8 2S5 1P2 2'0 2'6 1P7 2'2 0'7 0'9 0'8 2' P8 2'2 2'2 2'0 2'3 1P8 2'5 1P7 1P9 0'9 1'5 0'9 1P8 6 0' '1 2'5 2' P8 2'1 1P7 2'6 1'0 0'7 0'7 2'0 Total P2 15'3 16'0 16'1 14'1 14'5 12'4 16' ' '2 10'1 VI 1 2'6 1P7 2'7 2'6 5'6 2'6 1P3 0'7 1P8-3 0' '1 0'3 0'6 2 0'8 1P '4 19 2' '8 0' ' '2 2'7 2'3 2'3 2'7 1' '7 0' ' ' '6 1'9 2'6 1' '9 0' '6 5 1' '2 1'9 1'4 2'4-2'2 1'0 0'7 0'9 1' p4 2'4 2' '3 2'4 1'1 2'5-1'8 0'6 0'9 09 2'0 Total 9' '3 16'S 17'7 11'2 13' '3-9' ' '4 1 Ergogram incomplete; drum clockwork out of order. 2 Perhaps incomplete; weight lifted beyond scale, four minutes occupied in readjustment (see p. 443, footnote 2). 3 Through a breakdown in the ergograph after Set I the first two intervals were of an hour's duration and the last set was omitted.

4 438 P. C. VA RRIER-JONES. t.s s b Ce bmr > H _ < Q- cq :4 co_ C 0. _ o e O _l CN D o CQ q oo_ q _ - -q _lu: r- s Sem X > z - _ b ;l ;l P-4 ~ ~ Cq _-4 C;l I _ s H co ~~~~~~~~~~~~~~~~1-4 ( a t^ 0 o o fd t w ib it t N X I,-s t C) X H p a f a o o z g=^ > to ~ ~ ~~~~~~ H-4 r- cca eo r _ O_ c cq H cs cq P c cq H o >H Xc 0. * 0 o- 0 0 C)s cd0 Ca CB z 1 0 o ED s Q ct _l C> ; t- 3 k o,- 00 u: Cq r- to-- > H az. _ e CO _ e > _ t O - 0 Q W o cz o ss c-?- ^ c;l-4 cq" cqcq cq cq v- 1:4-{ b abc tes a: ch S I E H. s _ 3.t t V. oo -1 o V- C t CO X Ho * cq 1-4 os 1: - 0 I- CQ CO o a4 C sec9 10~~~~~ -

5 STRYCHNINE AND MUSCULAR WORK. 439 in the two conditions the experiment has been divided into two halves. The 'Work for the first six days and that for the last six days have been taken separately-the average daily work under the different doses being shown for the first half of the experiment in Table II, for the second half in Table III. In order that the drug effects may not be concealed by the changes in capacity from day to day, the figures of any day are referred to the first set of that day as a standard, the relative rise or fall being thus obtained. The first set is taken as 600, so that the average ergogram in that set is always 100-the figures are given in brackets in Tables II and III. This device is due to Dr Rivers and is here greatly preferable to the comparison of all ergograms with the initial ergogram of the first set, more especially as in this experiment the early ergograms of a set are subject to abnormalities to be described later. It has this disadvantage, however, that the later ergograms of the supposed normal set may be influenced by the dose taken between the first and second ergograms. Unfortunately no accurate data can be given as to the rate of absorption of the strychnine taken; it is known that it is slow in the stomach and rapid in the intestine, so that the absorption depends chiefly on the rapidity of passage from the stomach. The first set occupied as a rule about twelve minutes after the dose was taken; the time was never less than eleven minuites. Many different experiments have shown that a period of from five to ten minutes is long enough for some drugs, such as potassium iodide, to reach the general circulation and even to be excreted in the saliva, urine, etc. in quantities large enough to be recognised. We might therefore expect that after ten to twelve minutes the tracings would show some effect of the strychnine. Glancing at Table I we see that the first set of July 25 is about normal in size as compared with those of previous days (i.e. days on which no dose was taken) but slightly larger than those of the succeeding days. That of July 28 is rather larger than normal. Compared with the surrounding days, August 2nd is considerably larger, and possesses the peculiarity of a sudden increase in the last ergogram, which cannot be referred to any external cause. This set lasted in all 14 minutes, owing to a large number of submaximal contractions. There is some possibility, therefore, that this is a strychnine increase. The first sets of the later days of the experiment, however, show a tendency to increase

6 440 P. C. VARRIER-JONES. h JKI at O > O 3 O < O ~~~~~~~~~~~~O _l COeR CO.).-- a2~~~~~~~~~~~~~~~~~a Oo Co CO CC O U O 0 -e - ~ -,*t e X O4 Cq 0Q Ir- X S Q g ~~~~~~ ^ ' ~~~ aa C O at - mtx *C co pq r-4 o-4o4 y. ; l g s g W N e b N > s -la00 r4 N l Xq ZtS o e o C~~~~~C ~~~~~~iq o km cq m g 00~~~~~~~~~~~~~~~~~~~~0 4 t a 0 O H 9 O~~km t NO t : ^ N-; 0 r co JHeNqX> 2 r- t r- 00 t 2 4 gts t t ~~ SN N CO 4 t t s s 7- q *00 e < t A O H H X X t X > > > ; > _ H- & 0 Q ~ > ~ < N ~ o e Co C o 0 cq Co t4 co C O aao > O t H H HH~~~~~q cqco H H H H od aq cot 0 E kmt C2 O H g Q H X H X t oot j eo r4 o4eqol cl eq P-4 I"

7 STR YCHNINE AND MUSCULAR WORK. 441 with the progress of the set, but much stress cannot be laid on variations of this kind, as relatively large differences are possible under conditions outwardly the same. The differences in the first and following sets of the two days when no dose was taken (viz. July 23 and 24) form an extreme instance of this kind of variation'. We see, therefore, that although the possibility of a drug effect in the first set of any day cannot be excluded, yet it is by no means certain. Moreover, if present it would merely serve to diminish the apparent amount of the increase due to the drug-so that the percentages given may be taken to represent not unfairly the real course of events. The percentages shown at the foot of Tables II and III are ISo - 9C / 150 AV;TL9eCHtiV%t Avcecr HeLlkt CIO Iqo...- so N 4mtero CotvLractcoqs Nu6rr1Ur of Cortractio>s ;, ISo o ~ ~ ~ ~ : o 130 N W Iso *o 80 Wortk "* V Wok 7 OT I T 11 Fig. 1. Percentage figures to show the effect of strychnine on sets of ergograms. I for the first half, II for the second half of the experiment. P, control mixture; Q, 1-8 mgm. dose; R, 4-2 mgm. dose. The arrow shows when the dose was administered. 1 It is very unlikely that such large differences would occur- on succeeding days, owing to improvement in training and method.

8 442 P. C. VARRJER-JONES. graphically represented in Fig. 1 (the numbers being divided by six for convenience). Taking those dealing with the smaller dose of strychnine-1p8 mgm. -we see that, compared with the normal curve, the work done (in the earlier set of days) is increased until set IV, there being a slight fall in set III (due to one only of the two days concerned when the conditions were not quite normal). The figures are as follows. The first set being taken as 600, there is an increase in the second to 688, a slight fall in the third to 639, a big rise in the fourth to 803 which falls again in the fifth and sixth sets to 685 and 590 respectively, the latter being below the normal. The greatest rise therefore is in the fourth set, in which alone is the absolute amount of work done definitely greater than on the normal days. Now the stronger dose shows a similar but smaller rise. It attains its maximum in the seconid set instead of in the fourth set and gradually falls to a condition much more below normal than the original increase was above it. There is in fact a rise in the second set to 712, then a gradual fall through 701, 636,.573, to 479 in the last set, both the fifth and sixth sets being nmuch less than the normal amounts, which are 682 and 677 respectively. The curves above that for work in Fig. 1 represent numbers of contractions and average height (that is the total lift divided by the number of contractions), both treated in exactly the same way as the figures for work. The curve of the number of contractions is practically a reproduction of that for work and shows that the increase and the decrease are mainly due to alterations in the numbers of the contractions in the ergograms concerned. At the same time the top curve (of the average heights of these contractions) shows tl-hat the initial rise for both doses, and the second or continued one for the weaker dose, are associated with sonme increase in length, while the final fall is similarly associated with a slight decrease. Whether this effect is more than is that due to the different proportion the usual end fractions bear to the whole number of contractions in a longer and a shorter ergogram respectively is difficult to say, but probably there is some drug effect. The condition of things in the second half of the experiment is different, but here again there is at first an increase followed by a decrease. The percentage figures for the weak dose show an increase reaching its maximum in the fourth set (Fig. 1 and Table III), the total being 829 to the normal 786. The absolute amount of work done is however below that of the normal day throughout. The stronger dose has its maximum in the second set, with the

9 STRYCHNINE AND MUSCULAR WORK. 443 tremendous increase from 600 to 1127 (the normal being 491). The absolute amouint of work for this and the succeeding sets (III and IV) is very much larger than that for the corresponding totals of either the control or the small dose, being for the second set 13-8 to 7-1 and 6-6 kgm. respectively'. Following on the increase with both doses of strychnine is a depression, but while that for the strong dose is more than that for the weak one, the difference is much less than that in the first half of the experiment. The amounts are subnormal in the fifth and sixth sets. It must be remembered that the absolute increase in this half is very much smaller than that in the earlier days though relatively larger. Also associated with this there is great iltegularity of the work in the later days. The most pronounced difference between the two groups is seen on inspection of the curves for numbers of contractions, and the average heights. The number of contractions is increased slightly at first and falls in both cases below normal imnmediately after. The average heights on the other hand are very definitely above normal for the remainder of the experiment and for sets II-IV enormously above with the strong dose. This means that though slightly due to increase in the number of contractions, the real source of the gain in the power to work is in the obtaining of larger contractions, while when the reaction sets in giving a smaller efficiency, the amount is saved from a greater fall by the continued condition of the improved length of contraction. The effect of the strychnine is not to increase the contractions to normal dimensions, but to restore them from an extremely reduced condition to something approaching normal. The process by which they have become reduiced is a graduial one and is associated with the diminution in muscular capacity, both illustrating the cumulative effect of the doses used. The amount of work possible seems to diminish after the first strong dose of strychnine; the total for the first set of the 26th July is smaller than those for previous days. There is some recovery on the 27th July and on the 28th. The totals for the 29th July are larger than for any other day during the experiment2. On this day, however, a new I Set I for the strong dose will be noticed to be larger than that for the other doses. 2 The size of the first set of ergograms is abnormal from the fact of a disturbance occurring in the 4th of the set, thus giving a slightly incomplete ergogram but a large increase in the 5th and 6th due to the mental stimulus of the disaster.

10 444 P. C. VARRIER-JONES. condition is found in the arrangement of the work in the set. Until this day (July 29th) each set of ergograms, almost without exception, runs a similar course. The first ergogram is the largest-often by a considerable amount-and the following five with more or less regularity tend to grow smaller. The 29th July, hlowever, begins its first set with a small ergogram (Table I) and improves in the second, and again in the third. The second set is similar, with an increase to maximum at the third ergogram. The samie condition obtains in set VI, but the intervening sets are after the old pattern. This condition becomes more noticeable from day to day and the progress from a minimal amount (02 kgm. for example) up to 2-0 kgm. or more may occupy four ergograms, as in set I of the 30th July, or in extreme cases even five, as in set I of the 1st Aug. There is a slight suggestion of the beginning of this process in the first sets of July 27th and 28th, but it is only marked on July 29th. Fig. 2. A, a normal set of six ergograms. B, showing the effect of strychnine on the first ergogram of the set'. C, showing the extension of this effect to the later ergograms of the set. It becomes more prominent with the course of the experiment, until the total becomes minimal throughout the whole set. The old condition persists longest in the central sets of the day, i.e. after 1 The 1 8 mgm. dose was taken after the first ergogram of this set, but, as explained earlier, was probably without effect on the work done in the set, so that A, B and C may be considered free from any immediate external stimulus.

11 STRYCHNINE AND MUSCULAR WORK. considerable practice has been obtained but before fatigue has definitely set in. Thus it is seen in sets III, IV, V of the 29th of July (Table I): III, IV of July 30, III of the 31st July with equality of ergograms 1 and 2 if not predominance of the former. Even the stimulus of the drug is unable to reproduce the old condition in the second set of Aug. 2nd and 5th. Associated with the increase in this condition is the decrease in work done which follows the admninistration of the 4-2 mgm. quite accurately, the third time (Aug. 2) leaving only a minimal capacity (Aug. 3-5). There is also a change in the contractions, which become minimal, so that their number falls off much less than the amount of work done. This is similarly progressive and two stages are shown in Fig. 2. Subjectively there was a feeling of great incapacity, one can hardly call it weakness, there seemed to be plenty of power present, but a something lacking which by its absence prevented the power from becoming effective. The weight seemed intolerably heavy. This wore off as the day progressed, but later the whole business became very laborious, though there was no muscular fatigue in the ordinary sense. There was no feeling of increased muscular tone. SUMMARY. 445 From the above description it will be seen that there is an irnmediate and a cumulative effect of strychnine taken in doses of 3 and 7 minims of liquor strychninae hydrochloridi (1-8 and 4-2 mgm. of strychnine hydrochloride). The immediate effect is to produce an increase in the capacity for muscular work. With the smaller dose the increase is gradually produced with its maximum about three hours after its ingestion. With the 4-2 mgm. dose the maximum is obtained in about half an hour. In either case a fall follows and the capacity becomes subnormal-a condition which continued until the end of the experiment, a period of considerably over five hours. The cumulative effect sbows itself in a great diminution in muscular capacity which is to a certain extent gradual, but which reaches its final stage suddenly after the third strong dose (Aug. 2). This diminution is mainly due to a shortening of the individual contractions, and is seen first in the initial ergograms of the various sets, but more especially in the first and last sets of a day's work. It then spreads until the totals are minimal for the whole day.

12 446 P. C. VARRIER-JONES. The increase in the work done, which is the immediate result of a dose of strychnine, is produced differently according as it is taken early or late in the series of days. The early doses effect an increase by adding to the number of normal contractions made. The later doses tend to increase the submaximal contractions to their normal condition, though their number is also somewhat augmented. Strychnine acts essentially on the spinal cord and medulla; indeed it is remarkable that its action is so clearly defined on this tissue alone, for even in poisonous doses it does not appear to affect the cerebrum or peripheral nervous structures. Moreover we now know that the drug acts peripherally on the sensory or receptor cells, through which it may be regarded as producing a change whereby impulses can pass through more easily and, instead of being localised to a relatively few efferent nerves, may break down the resistance, so as to spread to all efferent fibres supplied from the spinal cord. I conclude then that the effects described are produced by the action of strychnine in diminishing the resistance to afferent impulses on the sensory side of the cord. The after effect may be due either to a poisonous effect of the drug or to pure fatigue. My cordial thanks are due to Dr W. H. R. Rivers for his constant help and advice during this work, as well as to Dr W. E. Dixon for kindly preparing the solutions used.