THE PHYSIOLOGICAL ACTION 
OF 
COCAINE 
AND OF ITS 
ANALOGUE, BRUCINE. 
BY j,.. 
THOMAS J. MAYS, M.D, 
PHILADELPHIA. 
[Reprinted from the Therapeutic Gazette, June, 1885.] 
DETROIT, MICH. : 
GEORGE S. DAVIS, PUBLISHER. 
1885. THE PHYSIOLOGICAL ACTION 
OF 
COCAINE 
AND OF ITS 
ANALOGUE, BRUCINE. 
OUITE recently I undertook to investigate 
the physiological action of cocaine, not 
with a view of adding anything new to its al- 
ready extensive literature, but chiefly for the 
purpose of personal familiarization with the 
physiological behavior of the drug. Its action 
in many respects was so striking and so dif- 
ferent from most other drugs previously in- 
vestigated, that it seemed to me to stand 
isolated in the experimental world, as it actu- 
ally did in the clinical field. Further inquiry, 
however, showed that there is another agent 
which behaves very much in the same manner, 
and which shares the anaesthetic property of 
cocaine, although probably to a less degree. 
I have no doubt that further research with 
the same, or perhaps other and superior 
methods, will succeed in showing that there 
are still other drugs which have the power of 
allaying local sensibility in common with co- 
caine. The agent alluded to is brucine, an 
alkaloid contained in the seeds of strychnos 
nux vomica, and a twin sister of strychnine. 
To give the data of the investigation in their 
true order, the necessary points in the action 
of cocaine bearing on that of brucine will 
first be given, after which the experimental 
details of brucine will be presented. 
hydrochlorate of cocaine. 
Action on Frog's Ventricle.-Its action on 
the isolated ventricle agrees in some and 
differs in other respects with many of the 
agents which I had previously investigated.* 
In its minimum dose, which was ascertained 
to be i to 160,000,-i.e., 1 part of cocaine to 
160,000 parts of a two per cent, blood solu- 
tion,-it gives stronger and more vigorous 
pulsations than the two per cent, solution of 
blood alone can give, as is shown by a and b 
of Fig. 1. 
It also affects the conductivity of the ven- 
tricle like ammonia, soda, digitaline, caffeine, 
morphine, delphinine, etc.,-i.e., in minimum 
doses it enhances the nervous irritability, and 
in maximum doses, or in continued minimum 
doses, the nervous irritability is reduced to 
zero; but then, unlike the above-named 
agents, it arrests the heart in diastole, and 
not in systole, as they do, or cause the heart 
to become wild and unmanageable, as some of 
them do, but it gently calms the heart down 
until it is completely arrested, when, as soon 
as it is liberated from the influence of poison- 
ous doses, it rebounds and pulsates as before. 
In Fig. 2 is shown the characteristic arrest of 
the heart by maximum doses of cocaine (1 to 
1000) and by maximum doses of digitaline, 
the latter being selected as a fair specimen 
of those agents which cause systolic arrest. 
The tracing (a) given by cocaine maintains 
a parallel position to the abscissa, while 
(/$) that given by digitaline rises far above 
the abscissa, showing that during the pro- 
cess of arrest the heart is most firmly con- 
tracted. 
Another characteristic of cocaine is the 
suddenness with which it depresses the ner- 
vous irritability of the heart. In the space 
of a few minutes the minimum stimulus of 
the induction apparatus sinks many centi- 
metres, showing that it blunts the impressi- 
bility of the heart in a manner similar to that 
with which it is known to blunt the sensibility 
of man. 
* See my article on the " Action and Antagonism of 
some Drugs on Frog's Ventricle," Therapeutic Ga- 
zette, February, 1885. 2 
THE PHYSIOLOGICAL ACTION OF COCAINE 
Fig. 1.-a, tracing given by two per cent, blood solution alone. 
b, tracing given by 1 part of cocaine added to 160,000 parts of two per cent, 
blood solution. 
Fig. 2.-a, tracing of cocaine arrest of the frog's heart. 
b, tracing of digitaline arrest of the frog's heart. 
General Action on the Frog.-My observa- 
tions on the general action of cocaine on the 
frog tally with those of other observers. Sub- 
cutaneous introduction of 1.0 ccm. of one- 
half per cent, solution is followed in a few 
minutes by general convulsions, and after- 
wards by general hyperaesthesia. The con- 
vulsions are undoubtedly spinal, since they 
are produced and continued after the me- 
dulla is divided. The general action of 
cocaine does not diminish general sensibility. 
When smaller doses are given, a stage of 
motor paralysis precedes that of convulsions. 
In still smaller doses the convulsions are 
hardly pronounced, or do not exist at all. 
Respiration ceases before cardiac action. 
In order to make an intelligent comparison 
between its general action and that of bru- 
cine, a few experiments will be detailed here. 
Experiment 1.-Made for the purpose of 
testing the general influence of cocaine on 
the frog. Frog small, but active. Respiration 
56 per minute. 
9.35 A.M. Injected 1 ccm. of one-half per cent, so- 
lution of cocaine (grain subcutane- 
ously. 
9.40 A.M. Respiration 42; jumps on being touched. 
9.41 A.M. Left anterior foot stretched to one side. 
9.42 a.m. Begins to drag posterior extremities; an- 
terior legs normal. 
9.43 A.M. Remains on back and croaks. 
9.44 A.M. Respiration 32; moves legs on pinching, 
and makes unsuccessful efforts to get oft 
back. 
9.45 A.M. Lies with outstretched legs. 
9.47 A.M. Still has power to raise body with anterior 
extremities, but posterior extremities are 
outstretched and motionless. 
9.50 A.M. No motion on pinching hind legs, but 
moves hind legs and whole body when 
anterior legs are pinched; croaks; be- 
comes convulsed. 
10.00 A.M. Posterior extremities are paralyzed; re- 
spires only occasionally. 
10.02 A.M. Motion only in anterior extremities. 
1.10 P.M. Heart arrested in diastole; filled with 
black blood. 
Experiment 2.-To test large doses of co- 
caine injected subcutaneously. Frog medium 
size. Respiration 50 per minute. 
9-37 A-M- Injected 2 ccm. of one-half per cent, solu- 
tion of cocaine (y& grain) in left back. 
9.40 A.M. Spontaneous convulsions. 
9-45 A-M. Convulsions continue; respiration spas- 
modic. 
9.50 a.m. Spasms not continuous, but occur at in- 
tervals of twenty or thirty seconds. 
10.00 A.M. Touching any part of body produces 
spasm. 
10.10 A.M. Lies flat on belly. 
11.00 A.M. Lies helpless in any position. 
11.30 A. m. Occasional spasms only; respiration ceased. 
12.00 m. Division of medulla; spasms continue. 
12.15 P-M- Tendency to spasms disappearing. 
12.25 P-M- Spasms ceased; completely paralyzed. 
12.30 p.m. Heart pulsations, 22. 
Local Action on Frog.-At the seat of hypo- 
dermic injection or of local application reflex 
sensibility is always diminished. 
Local Action on Man.-The invariable im- 
pairment of local sensibility in man is too 
well known to have attention directed to it 
here. AND OF ITS ANALOGUE, BRUCINE. 
3 
Fig. 3.-a represents tracing given by two per cent, solution of blood alone. 
b represents tracing given by I part of brucine added to 160,000 parts of 
two per cent, blood solution. 
Fig. 4.-a indicates the brucine and b the digitaline arrest. 
BRUCINE.* 
The action of this drug was always regarded 
as being identical in kind to that of strych- 
nine, only differing in degree. When I first 
tested its action on the frog's ventricle it 
behaved so similarly to the action of cocaine 
on the same organ that I ventured to give it 
a more thorough trial, with a view of ascer- 
taining whether it had any power like cocaine 
to deaden sensibility. It was soon found, 
however, that the ordinary preparations in 
the market were worthless for the purpose 
sought, since they invariably brought out the 
strychnine effects soon after the beginning or 
near the termination of the experiment, no 
matter how small the quantity used, although 
in most instances there was some evidence of 
anaesthesia. After confronting considerable 
difficulty I succeeded, through the advice of 
Dr. Squibb, of Brooklyn, in obtaining a very 
pure specimen of the drug from the Chas. T. 
White Chemical Company, of New York 
City, to whom my thanks are due for the 
kindness and aid which they extended to me 
throughout this investigation. 
Its Action on the Frog's Ventricle.-Its 
effects in minimum doses of i to 160,000-/.<?., 
1 part of brucine to 160,000 parts of a two 
per cent, blood solution-were markedly stim- 
ulant, as is shown in Fig. 3 : a shows the 
tracing which was given by the two per cent, 
blood solution alone, while b marks the action 
of 160,000 parts of same blood with one part 
of brucine superadded. 
Nearly all the agents previously investi- 
gated which had a special affinity for the 
conductivity of the heart arrested it in sys- 
tole, while brucine, contrary to this observa- 
tion, and in consonance with the action of 
cocaine, influences conductivity, but arrests 
the heart in diastole. This is illustrated in 
Fig. 4, where the brucine arrest is contrasted 
with that of digitalme. The heart was first 
arrested with brucine (a) and immediately 
afterwards with digitaline (£). 
Again, the suddenness with which it de- 
presses the conductivity or blunts the re- 
ceptivity of the heart is similar to the action 
of cocaine, as well as its transient disturb- 
ing influence on the heart in maximum or 
in continued minimum doses. These ob- 
servations led me to believe that its local 
and general action may be analogous to 
that of cocaine, and I am able to state 
that this assumption has been confirmed 
both by clinical and further physiological 
research. 
* The literature on brucine is very meagre, and I am 
only able to give the following references: 
Prevost: "Action physiologique de la Brucine." 
C. R. Soc. de Biol., 14 Octobre, 1882. L. Wintzen- 
ried: " Recherches experimentales relatives & 1'Action 
physiol, de la Brucine." Diss. Genfeve, 1882. Brunton: 
Amer. Assoc. Jour., May 2, 1885, in London letter. 4 
THE PHYSIOLOGICAL ACTION OF COCAINE 
General Action on the Frog.-In my obser- 
vations on the general action of brucine a 
number of experiments were made, but only 
two, which are typical of the rest, will be 
given here. 
Experiment 3.-Made for the purpose of 
testing the influence of brucine on the frog 
when subcutaneously injected. Frog small, 
but active. Respiration 58 per minute. 
11.21 A.M. Injected in left back 0.05 ccm. of one per 
cent, solution of brucine (% mg. orb- 
grain). 
11.28 A.M. Respiration 30; frog active. 
11.34 A.M. Repeated the same dose in right back. 
11.35 A-M> Fess active; head inclines to droop. 
11.36 A.M. Respiration 28. 
11.37 A.M. Croaks, and is slightly paralyzed in pos- 
terior extremities. 
11.38 A.M. When leg is drawn out allows it to remain 
in that position for a minute. 
11.39 A-M> Left hind leg lies outstretched and par- 
alyzed, but is withdrawn slowly when 
touched sharply. 
11.42 A.M. Respiration 14. 
11.43 A-M- Both hind legs lying outstretched and flac- 
cid; the right only withdrawn when 
touched. 
11.44 A-M- Remains on back and croaks. 
11.45 A-M- Neither leg moved when touched. 
11.47 a.m. Lies flat on belly. 
11.52 A.M. Respiration 8. 
11.53 A-M- Slight twitches over whole body when legs 
or webs are touched; hyperaesthesia. 
11.55 A-M- Strong blow of breath on body will also 
call forth a general twitch; respiration 
ceased. 
12.15 P-M- Slight spontaneous momentary spasms. 
2.00 p.m. Spasms more pronounced and general. 
3.00 p.m. Medulla divided. 
3.15 p.m. Spasms still continue. 
3.30 p.m. Spasms ceased. 
4.00 p.m. Pithed; pulsations of heart 48. 
Experiment 4.-Made for the purpose of 
testing a somewhat larger dose of brucine 
given subcutaneously. Frog small, and ac- 
tive. Respiration 60 per minute. 
4.22 p.m. Injected 0.2 ccm. of one per cent, solution 
of brucine (2 mg. or b gr.) in left back. 
4.23 p.m. Symptoms of motor paralysis in posterior 
extremities. 
4.25 p.m. Respiration 54. 
4.26 p.m. Decided loss of motion in posterior ex- 
tremities. 
4.27 p.m. Convulsions; legs outstretched and stiff; 
rolls on back; respiration ceased. 
4.30 p.m. Spasm can be induced by touch; general 
hyperaesthesia. 
4.35 p.m. Lies outstretched and flaccid on belly, and 
a very slight spasm can only be induced 
by touch; tendency to spasm greatly 
lessened. 
4.45 P.M. Legs twitch when pinched hard; lies flac- 
cid and paralyzed. 
4.55 P.M. No response to touch or pinching. 
5.55 p.m. Heart arrested in diastole. 
These experiments point out that in its 
general action brucine provokes a short 
period of at least motor paralysis, which is 
succeeded by convulsions ; that the loss of 
motion first affects the posterior extremities ; 
that the convulsions are spinal; that there is 
no marked impairment of general sensibility, 
but, on the contrary, preceding and during the 
convulsive stage there is confirmed hyperees- 
thesia, which is succeeded by complete motor 
and sensory paralysis ; and, finally, that respi- 
ration ceases before the heart is arrested. 
Action on Reflex Frog.-In these ex- 
periments the secondary coil of an induction 
apparatus is joined to a Du Bois key, this is 
connected with a Pohl's commutator, and 
from here two wires were joined to each foot 
by means of a rubber band, thus bringing 
each foot into a separate electric circuit. In 
due time, after the brain of the frog was de- 
stroyed, the irritability of each leg was tested 
with single induction shocks, and the mini- 
mum stimulus required to call forth reflex 
motion noted. After which the leg was from 
time to time immersed in a solution of brucine, 
or enveloped with blotting-paper saturated 
with same solution, and-the minimum reflex 
irritability tested at intervals. 
Experiment 5.-Reflex frog ; medium size ; 
four per cent, solution of brucine employed. 
Minimum reflex irritability of Left Leg. Right Leg. 
8.46 a.m. Before immersion 10.o 9.0 
8.56 a.m. Left leg immersed in solu- 
tion for eight minutes. 
9.00 9.0 9.0 
9 03 8.5 9.0 
9.06 8.5 9 o 
909 7-5 9-0 
9.12 7.0 9.0 
9i5 7-o 9.0 
9-J8 6.5 9.0 
9.21 6.0 9.0 
9.24 6.0 9.0 
9.27 6.0 9.0 
9.30 6.0 9.0 
Left leg immersed again for five 
minutes. 
9-36 5-5 9° 
9-39 4-5 90 
9-43 40 8.5 
946 3-5 8.0 
9-49 3° 8.0 
9-51 30 8.0 
9-53 2.5 8.0 
956 2.0 7.5 
9-59 i-5 7-5 
10.02 1.0 3.5 
10.05 0.0 3.5 
10.08 No reflex 0.0 0.0 
10.09 A-M- No reflex when posterior, but when an- 
terior legs are pinched both hind legs 
are withdrawn, showing that they still 
have reflex power when the afferent im- AND OF ITS ANALOGUE, BRUCINE. 
5 
pulse is carried to the spinal centre 
through the sensory nerves of the an- 
terior extremities. 
10.18 A.M. Reflex action completely paralyzed; no 
motion on pinching any part of the 
body; frog lies flaccid and motionless 
on glass plate. 
9.20 A.M. (Next day.) No reflex action; heart's 
pulsations 18. 
12.00 P.M. Heart arrested in diastole; no spasms 
throughout. 
Experiment 6.-Reflex frog ; medium size ; 
ten per cent, solution employed by means of 
saturated blotting-paper. 
Minimum reflex irritability of Left Leg. Right Leg. 
6.09 P.M. Before application of bru- 
cine 8.5 8.5 
Blotting-paper applied now, and 
during intervals of observation. 
6.11 P.M 8.5 8.5 
6.13 8.0 8.5 
615 7-5 8.5 
6.17 70 8.5 
6.19 6.5 8.5 
6.21 6.5 8.5 
6.23 6.0 8.5 
6.25 6.0 8.5 
6.27..... 6.0 8.5 
6.29 5-5 8.5 
6.31 5-° 8.5 
6- 4-5 8.0 
6.35 40 8.0 
6.37 3-5 8.0 
6.39 30 8.0 
6.41 2.5 8.0 
6.43 2.0 8.0 
6.45 2.0 8.0 
6.47 2.0 8.0 
6.49 2.0 8.0 
6.51 1.5 8.0 
6.53 1.0 8.0 
6.55 °-5 8.0 
6.57 °-5 8.0 
6.59 °-5 7-5 
7.01 0.0 7.5 
7- o.o 7.5 
7-05 °-° 7-5 
7.07 Partial reflex 0.0 7.5 
7.09 " " 0.0 7.0 
7.11 " " 0.0 7.0 
7.13 " " 0.0 7.0 
7.15 " " 0.0 7.0 
7.17 Noreflex 0.0 7.0 
7.21 " 0.0 7.0 
7.30 " 0-0 0-0 
7.31 P.M. Pinching web of left foot calls forth no re- 
sponse, but on pinching anterior legs both 
hind legs are drawn up and flexed. 
7.33 P.M. Very sensitive in anterior part of the body; 
both hind legs are stretched out and para- 
lyzed ; both are drawn up when anterior 
extremities are pinched. 
8.15 P.M. No reflex motion in posterior extremities 
when strongly stimulated or pinched, but 
only slight reflex motion in them when 
anterior legs are pinched. 
8.20 p.m. Electric stimulus, which is not able to call 
forth any motion when applied to poste- 
rior extremities, will cause contraction in 
them when applied in same strength to 
anterior extremities; no spasm or convul- 
sion throughout the whole experiment, al- 
though the brucine was certainly absorbed 
during the experiment. 
These experiments prove without a doubt 
that reflex action is disturbed not by virtue 
of motor, but of sensory paralysis, when 
brucine is locally applied ; that it not only 
produces sensory paralysis in the leg to 
which it is applied, but by gradual absorp- 
tion through the skin it also affects the sensi- 
bility of the opposite leg, and, finally, that of 
the whole body; and that paralysis of motion 
follows that of sensation. 
Other experiments, the details of which it 
is not necessary to give here, also showed 
that the local application of five per cent, so- 
lution to skin of frog in other parts of the 
body diminished sensibility. 
Local Action on Man.-The benumbing action 
of brucine on the mucous membrane in health 
is not so prompt as that of cocaine in the same 
strength. I cannot account for this unless the 
former is more rapidly absorbed and diffused 
than the latter. A ten per cent, solution will 
relieve the scalding on the tongue caused by 
the application of Cayenne pepper ; and a five 
per cent, solution acts very readily in aphthae 
of the mouth, applied with a camel's-hair brush. 
The same solution also cured a toothache in an 
old stump in a very few minutes. 
It is, however, on the cutaneous surface 
where its action is the most decided and defi- 
nite. On the back of the hand even the 
weaker solutions produce a benumbing effect, 
while a ten or a twenty per cent, solution 
causes a very marked impairment of sensi- 
bility. This is best demonstrated if it is ap- 
plied to a hairy part of the hand or arm, and 
allowed to remain for ten or fifteen minutes, 
and then the sensibility of the spot compared 
with that of a neighboring one by pulling the 
hair. Applied croton oil liniment to arm, 
and in the course of six hours two applica- 
tions of a five per cent, solution of brucine 
to the part affected relieved the itching 
shortly, and the pustulation also seemed to 
disappear from that time on. The same so- 
lution applied to an intense superficial cuta- 
neous pain, caused by a too lengthy applica- 
tion of a mustard-plaster, brought immediate 
ease to the patient. I applied a five per cent, 
solution in two cases of pronounced cutaneous 
pruritus,-which was in all probability a re- 6 
THE PHYSIOLOGICAL ACTION OF COCAINE AND BRUCINE. 
fleeted condition dependent on some uterine 
irritation,-with marked relief in both of 
them. The two cases were nearly identical, 
and hence I will only detail one, as follows : 
May 13, 1885.-Mrs. H., aged 36, has been 
suffering with a violent itching of the skin, 
only during the night, for the last year and a 
half. It is worst just before menstruation. It 
began in the groins and loins, then extended 
down both lower limbs, and finally up to 
her head. She says the itching is terrible, 
and comes on every night about bedtime, 
and often keeps her awake nearly a whole 
night; and so she gets up in the morning as 
tired as she was when she lay down. 
Treatment.-Ordered a five per cent, solu- 
tion of brucine to be brushed over the affected 
parts on going to bed, and to be repeated 
every half-hour until relief is afforded. 
J/izy 15.-She reports to-day that she ap- 
plied the brucine for the last two nights,-the 
first night three times, and the second night 
only once,-and it relieved the itching en- 
tirely. She says she had not slept so well for 
a long time as she did the last two nights. 
May 19.-She reports that one application 
on going to bed sufficiently allays- all itching 
for that night. 
J/tzy 21.-Still improving. 
General Remarks.-To obtain the full an- 
aesthetic property of brucine it is important 
to possess a pure article, and it is needless to 
point out that almost all the commercial speci- 
mens of the drug contain a large percentage 
of strychnine, and are therefore worthless, and 
may be even dangerous for this purpose. I 
do not wish to maintain that absolutely pure 
brucine, even if it can be obtained in this 
state, is entirely harmless, especially since 
some chemists hold that it is very difficult, if 
not impossible, to get brucine entirely free 
from strychnine; but I am convinced that 
there is a marked difference in the purity of 
the various preparations which I used, and 
that the one which gave the best results 
brought out the anaesthetic property of bru- 
cine in direct proportion to the absence of 
the strychnine or convulsive effects. 
My opportunity for testing its clinical value 
has been limited to the above detailed ob- 
servations, but it will probably prove to be a 
valuable agent in the treatment of irritable 
and superficial affections of the skin, and, 
perhaps, also of the mucous membranes. Of 
this last I would speak guardedly, for it seems 
to act more promptly on the outer than on the 
inner coverings of the body. 
It is very readily applied with a small 
sponge or camel's-hair brush, and from ten 
to fifteen drops can be employed at a time, 
and even more if the affected spot is exten- 
sive. If the weaker solutions are inefficient 
the stronger ones can be used. It shows 
its effects in from five to ten minutes. In 
making a solution of the alkaloid five drops 
of hydrochloric or of sulphuric acid must 
be added to each gramme. It is preferable 
to use either the nitrate or the sulphate of 
the alkaloid. 
151 N. Fifteenth St., May 21, 1885.