A Contribution to the Pharmacology of Cannabis Indica

[Jacob Bell]

BY C.R. MARSHALL, M.D.


Notwithstanding the large amount of labor which has been
expended on Indian hemp, we know comparatively little of
its pharmacology. The active principle, it is true, has been
isolated, in a more or less impure form, by O'Shaughnessy,
Robertson, the brothers Smith, and more 'recent investigators,
but the more important question of the changes this
undergoes has not, as far as I am aware, until recently, been
attempted. To me this is the most interesting part of the
inquiry. Apart from the great financial loss entailed by the
growing inertness with age of the drug, the variability in the
strength, its preparation has led to numerous misfortunes in
medical practice, and a distrust in its use as a therapeutic
agent. The isolation of the active principle of the drug would
not matter if we could only insure our preparations being of
constant strength. But, without knowing the cause of the
increasing inertness, this it is impossible to do. With this
cause, among other questions, I intend to deal in this paper.
As I have dealt elsewhere' with the history of the active
principles of Indian hemp, I shall confine myself in this
communication to the work of the most recent observers.
Two .and a half years ago three Cambridge chemists-Wood,
Spivey and Easterfield-commenced a re-investigation of the
chemistry of Indian hemp. They worked with charas, as being
the most active preparation of the plant, and by extraction
with organic solvents (alcohol, ether, petroleum ether, etc.)
and subsequent fractional distillation, they isolated a monoand
sesqui-terpene, a crystalline paraffin and a resinous body
(cannabinol); an indistillable pitch and an insoluble sandy
residue were left behind.2 The proportions of these substances
are shown in the subjoined table, taken from a
communication by Easterfield and Wood to the Cambridge
Philosophical Society.3
Other samples more recently examined have not been
found to be so good as this. A second lot contained only 15
per cent. cannabinol; and a third only 10 per cent. Furthermore,
the cannabinol from these samples was not so pure as
that obtained from the first sample and from the cannabinol
obtained from the last the acetyl derivative of a higher
homologue of the pure substance has been prepared. This
homologue was present to the amount of lo-20 per cent.
The products (with the exception of the paraffin) and
certain impure intermediate substances were passed on to me
for pharmacologic examination. I naturally turned my attention
first to the resin. The terpenes were present in too small
an amount, and their chemic constitution and physical
character were not such as to suggest a cannabis-like action.
Personne,4 it is true, attributed the activity of the drug to an
oily liquid, cunnabene (Cl8 H,, ), which Valenti,' and more
recently Vignola,6 have shown to be an impure sesquiterpene;
but Roux ' has proved physiologically that cannabene
is not the active principle. On the other hand, numerous
investigators had shown that the active principle is of a
resinous nature. The paraffin was only present in very small
amounts, and from its constitution and properties it is easy
to infer that it possesses no marked physiologic properties.
The resin was found to be active. It possessed, as far as I
could see, all the peculiar effects of the hemp plant. The
question to be settled was its purity. As it boils at 265 to 270
degrees C, under 20 m.m. Hg pressure, and possesses a
constant composition, the presence of an impurity seemed
improbable. At least it could only be due to a stereo-chemical
isomer or a substance with closely allied composition and
properties. The possible presence of an alkaloid was avoided
by treating the crude drug with dilute sulphuric acid before
commencing the investigation. But no alkaloid has been
found in charas.
In a more or less impure form cannabinol has been isolated
from various commercial preparations, viz.: Merck's cannabinon,
extractum cannabis Indicae ethereum, resina cannabis
Indicae. and T. & H. Smith's cannabin.
Physiologic Experiments have been carried out on cats, dogs, rabbits
investigations. and myself, and the investigations have been mainly confined
to the administration of the various substances by the
mouth-a condition necessitated by the comparative insolubility
of the drugs. With the experiments in detail I do not
intend to deal-admirable descriptions have been given by
various observers, both in this and other countries-but in
appendix I will be found types of experiments and in
appendix II a synopsis of the experiments made. By combining
these and referring to the text, little difficulty will be
experienced in forming mental pictures of the condition in
each individual experiment.
Most of my experiments were made upon two dogs. One
was a mongrel puppy something like an Airedale terrier in
breed; the other was a young adult fox-terrier. Later a third
dog, an English terrier, was added. The first two dogs were of
very different temperament; the one (Airedale terrier) was
self-reliant and intelligent; the other was affectionate, but
nervous to an extreme degree. The English terrier, although
timid, possessed much more character than the last one. This
question of temperament, I believe, is of considerable importance
in dealing with the finer effects of cannabis indica. The
cats were adults; the rabbits young, usually three to four
months old.
The terpene in the comparatively small doses in which I
was able to give them, produced no noteworthy symptoms
beyond slight diuresis. In rabbits there seemed to be slight
transient excitement, but the compound given to these
animals was impure. On myself 0.5 cc. produced no effect; 2
cc. (sesqui-terpene) slight and transient listlessness and heaviness
of the head.
The resin, cannabinol, in dogs constantly produced the
same qualitative effect, although it varied slightly in the
different animals and in the same animal from time to time.
The first noticeable symptom (one-half to two hours) was
slight lassitude and an appearance of heaviness about the
eyes. Gradually the depression increased and sleepiness and
usually sleep followed; yawning and sighing were not infrequent; the body when standing swayed from side to side and
this gradually increased until the animal fell over or suddenly
pulled himself up with an effort. Usually, after falling, he
remained in the position and went to sleep. Sometimes the
rocking motion occurred in an antero-posterior direction,
especially in the fox-terrier. In this animal, too, the standing
position was more characteristic, the hind legs being half
bent. In this position and markedly unsteady he usually
stood gazing into the fire. Distinct ataxia during walking was
present or absent according to the dose. After large doses the
attention was blunted, but after small ones no effect in this
direction was noticed. After three to six hours the animals began
to improve. At this period the larger sometimes became
extremely frolicsome and if played with would run about
barking in a high-pitched voice. Usually both animals slept
or lay before the fire until taken to the kennel for the night.
When under the influence of the drug, the pupils were
sometimes slightly dilated, sometimes unaffected., occasionally
contracted; the pulse and respiration were slowed, but
whether more than could be accounted for by the condition
of rest it was often difficult to decide. My general impression
is that the pulse was slower than during ordinary sleep. The
temperature, with one exception, invariably fell; at the most
not more than 3 degrees C., usually not more than 1 or 2
degrees C. The fall naturally varied with the temperature of
the room. It was most marked in the fox-terrier, and in this
dog trembling was not an infrequent symptom. The reflexes
were always present and the sense of pain was doubtfully
blunted; the olfactory sense, however, seemed depressed.
Vomiting was a frequent symptom; salivation, independent
of any emesis, a rare one. In the fox-terrier, increased
micturition was occasionally obtained. The influence of dose
was not marked. Generally speaking, the symptoms were
fairly constant; but owing to the insolubility of the material
complete absorption was difficult to insure. Consequently, in
dogs at least, a strictly quantitative comparison could not be
made. Occasionally a small dose produced more marked
symptoms than a larger one, but this was rare, and in the
fox-terrier the onset of the symptoms as a rule was later and
they lasted longer than in the other dogs. On the whole,
however, the symptoms were fairly proportioned to the
amount given. After small doses (0.02 g. per kg.) quietude,
heaviness about the eyes, sleepiness and usually slight unsteadiness
occurred; attention was not appreciably affected,
and the symptoms almost passed away in five or six hours. In
the English terrier this dose produced a very marked effect,
the ataxia being as severe as after much larger doses to other
dogs. After large doses (0.1 g. per. kg.) there were marked
depression, ataxia, vomiting and sleepiness, although sleep
was not an invariable symptom. In the evening food was
refused, but the following morning they seemed quite well.
In cats effects similar to those occurring in dogs were
obtained, but the action was more severe and prolonged.
After a dose of 0.058 g. per. kg. improvement did not
commence until after twenty-five hours. The depression and
muscular weakness were more marked than in dogs, and
salivation was a more constant symptom. Total anorexia and
consequent loss of weight occurred after large doses. A
detailed description of an experiment will be found in
appendix I.
On rabbits preparations of cannabis indica exert comparatively
little effect. This was observed by O'Shaughnessy, and
it has been noted by more recent investigators. The same
effect was obtained in my own experiments with cannabinol.
But I am inclined to believe that the immunity is more
apparent than real. After large doses, slight depression and
quietude are the only observable symptoms, but on further
examination a fall in the number of heart-beats and respiration
and the temperature was found to occur; the animal
refuses to eat and death usually ensues. The low cerebral
development of these animals prevents them showing unmistakable
signs of cannabis poisoning, and these are only found
in observations on the vegetative functions. The lethal dose,
however, is much larger than for dogs or cats.
The effect on myself was very similar to that described by
other observers as peculiar to Indian hemp. After large doses
(0.1 g.) there was a sensation of dryness of the lips, and of
increased viscidity of the buccal mucus, a pleasurable tingling
throughout the body, muscular weakness, slight ataxia, risibility
and loss of time sensation. My pulse was said to be
increased in frequency, sensation was somewhat blunted, and
the pupils were not often forthcoming.
After intermediate doses (0.05 g.) the ability to work was
lost altogether. I usually sat before the fire doing nothing,
almost thinking of nothing. There was a marked unwillingness
to move. Pleasurable tingling in the limbs, very slight
ataxia and other symptoms similar to those obtained after a
larger dose were present. Time passed quickly. Sleepiness was
sometimes, but not always, present. As an early symptom a
peculiar indistinctness of the periphery of the visual field
occurred, and later it was found that the point of regard was
made to travel with greater difficulty, as along the line of a
page. Depression usually continued throughout the following
day.
The residual pitch, when dissolved in oil, was active, but
much less so than cannabinol. The symptoms were the same.
Given in the solid form it exerted little effect. In all
probability the activity was due to unchanged cannabinol
present. Certain intermediate impure products were tried, but
none of these was as active as cannabinol. The insoluble
residue was inactive.
Thus, by a process of elimination, cannabinol was found to Theactive
be the most active ingredient of the charas products. But in princip'e*
order to determine its comparative activity, control experiments
were made with the crude material and extracts
obtained from it. The natural product exerted much the same
action as cannabinol, but both spirituous and oily extracts
were somewhat more active; a similar result was obtained
with Merck's cannabinon. This raised the question as to
whether cannabinol is the sole active ingredient of the plant.
I think we must assume that it is, at least, the active
principle. The symptoms produced by the natural product
and the resin are practically the same, and this is an
important point. It suggests that we must look for changes
occurring in the resin either during its manufacture or
subsequently; or to a diminished absorbability as compared
with extracts of the crude product. That faulty manufacture,
etc., will produce a more or less inert substance, will be seen
from evidence given later; but I am inclined to attribute to
the lessened absorption the more important role. The terpenes
probably increase the rapidity of absorption of crude
extracts, but this I have not yet been able to put to the test.
That cannabinol does not possess all the activity of the hemp
plant I am prepared to admit; but this is the case with most
other crude drugs and their so-called active principles. In the
case of charas the terpenes probably aid in its physiologic
action, as the crude drug seemed to produce more excitement
than pure cannabinol; and when the drug is smoked it is
possible that pyrodene and other bases, which are produced
by the destructive distillation of the substance, may aid in its
intoxicating effects. If any other substance aids in its action,
we have at present no indication of it. Moreover, that
cannabinol is the chief active ingredient is supported by the
fact that the activity of different products is roughly proportionate
to the amount of cannabinol they contain, and that
the growing inertness of Indian <hemp can be explained by
changes occurring in this resin.
The question of the purity of cannabinol can only be
settled by further research, and this, I may add, is being
undertaken. The only demonstration of its purity in the
present state of our knowledge, viz: the reconversion of the
crystalline acetylized derivative into cannabinol, failed. The
acetyl derivative was not crystalline, and the reconverted
cannabinol was much less active, physiologically, than the
parent substance. This might be explained in many ways, but
at present it is idle to speculate.
The last and worst sample of charas yielded a substance
which contained a higher homologue of pure cannabinol.
This homologue regenerated from its acetyl compound was
physiologically inactive. Whether it is active previous to
acetylizing is at present impossible to say.
The cause of The different samples of the same preparation of Indian
of *Ihnediniaanc* ihvei*mvp. hemp possess varying physiologic effects, and that good
samples darken and deteriorate in keeping has long been
known; but until recently no satisfactory explanation of this
has been offered. In 1894 Leib Lapin,* by means of fractional
precipitation prepared a substance which he termed
cannabindon. This presented the appearance of "a beautiful
dark cherry-red mass of thick consistency, which took the
form of the vessel in which it stood, and showed a smooth
horizontal surface." Its formula he gives as C8H,, 0. It
possessed distinct reducing properties, and rubbed up with
chocolate and left a week, its physiologic action was in great
part lost. The latter he explains as being due to an oxidation
of the preparation resulting from its finely divided state and
its contact with fat and air; and he strengthens his position
by a reference to the similar behavior of ergot, which
undergoes oxidation less readily than cannabindon. The
oxidation product he states "is inactive or very slightly
active."
Although I was aware of Leib Lapin's views, my own
researches were carried out independently. What first drew
my attention to the matter was the gradual darkening which
cannabinol underwent when left exposed to the air in a
test-tube; the darkening commenced on the surface and
gradually extended downward; the superficial layers being
affected rapidly, the deeper layers very slowly. In order to
determine whether this was due to oxidation, and whether in
consequence the activity was affected, oxygen was slowly
passed through cannabinol kept fluid by immersion in a
sulphuric acid bath at 150 to 160 degrees C. The material
rapidly darkened and the consistency increased. After passing
the oxygen through for six hours the activity was found to be
decidedly less. It was then bubbled through for thirteen
hours more, the temperature toward the end of the experiment
being raised to 185 degrees C. in order to keep the
substance fluid. On cooling, the substance set to a hard,
brittle mass, exactly resembling pitch in appearance. No loss
or gain of weight, within the limits of experimental error
occurred. This pitchy material given in the solid form
possessed scarcely any action, but this in part is due to the
lessened solubility and higher melting-point, for if previously
discolored in oil, a distinct, though comparatively slight,
effect is obtained. Dr. Easterfield, who has made all the
analyses in connection with the charas research kindly undertook
one of the oxidized cannabinol. The percentages obtained,
compared with those of cannabinol, were:
Calculated for C18Hz402
(cannabinol)
Found Calculated for C18Hz203
c = 79.4 c = 77.7 c = 75.0
H = 8.8 H= 7.5 H= 8.3
The product obtained was therefore not completely oxidized,
and the activity it retained was in all probability due
to unchanged cannabinol. As a control experiment carbon
dioxide was passed through a similar sample of cannabinol
similarly treated. Very slight darkening, probably owing to
slight admixture with air occurred, but there was no increase
in consistency. Only a slight diminution in activity was
observed.
The influence of temperature was tried. Cannabinol distilled
at 400 degrees C. under atmospheric pressure was
found to be slightly less active than cannabinol distilled at
265 degrees C. under 20 M.m. Hg. pressure, but when the
substance was heated in sealed tubes at 220 to 260 degrees C.
for twenty-four hours, no very great loss of activity occurred,
although this was distinct. As slight oxidation may have
resulted during the process, the influence of temperature per
se may be disregarded. The action of aqueous vapor has not
been determined.
It would therefore seem as if the loss of activity of Indian
hemp was due to oxidation of the active ingredient. The
terpenes, like other members of this class, readily hydrolyze,
and this, doubtless, exerts some effect in the deterioration of
the crude drug. The obvious remedy is to keep cannabis
preparations in air-tight vessels until they can be used. For
practical purposes a well-corked bottle seems to be sufficiently
protective but hermetically sealed packages, especially
for transport purposes, are to be prepared. In sealed tubes we
have kept cannabinol for seventeen months without the
slightest change.
The limitation of the oxidation to the superficial layers
probably explains many of the accidents occurring in practice.
If the preparation has been long in stock and imperfectly
protected, these may have become comparatively inert,
and scarcely any effect may be produced, while a renewal of
the prescription from deeper parts-or the substitution of a
more recent preparation-may produce very marked effects. I
am certain that the accidental administration of superficial
and deep layers of cannabinol will explain some discrepancies
in my own results, which previously were inexplicable.
As regards a chemical test for the physiologic activity of
cannabis compounds, none exists; and the only indication at
present is in the direction of their reducing power. This will
probably give us some information, and I hope to deal with
the question later. As far as cannabinol is concerned, the
transparency is the best ready indication of its purity. When
placed in an ordinary test-tube print ought to be read
through it with ease; any blackening is due to admixture with
oxidized material. If not carefully prepared impure products
are readily obtained, and such gives no more constant
results than the ordinary preparations on the market. The
transparency, however, is not an absolute indication of its
purity, for the higher homologue of cannabinol, which, when
derived from its acetyl compound is inactive, is almost as
transparent as cannabinol itself. What the physiologic effect
of this compound is in the natural state, it has not been
possible to determine.
But the variation in activity of the preparations of Indian Susceptibilit
hemp will not account for all the differences in effect
produced. A difference in individual susceptibility also exists.
What this is due to we do not know. It is probable that
certain types of men are more susceptible than others, and
that certain habits, such as the alcoholic, have an inhibiting
influence on this direction. The subject is a difficult one to
treat from a purely experimental point of view. In the dogs
the greatest effect seemed to be connected with greatest
mental stability, but how much of this was due to variability
of absorption and how much to individual differences it is
difficult to say.
The following case which recently came under my notice is
of interest in this connection, as it enabled me to compare
the effect of the same dose on myself. A gentleman suffering
from neuralgia took % grain extractum cannabis indicae (B.
P.) in the form of a pill. The pills were made up by a
well-known London druggist. The following account was
written by the patient himself: "At about 4:30 on Sunday,
feeling neuralgic pain in the right eye, I took one of the pills.
I then had tea and read aloud for some time, feeling nothing
unusual. But about 7:30, when dressing for dinner, I began to
suffer from very curious feelings. I felt giddy and seemed to
lose command of my actions; thoughts seemed to pass
rapidly through my brain and I hardly felt responsible for
myself. I went to my wife's room and described my feelings.
She was alarmed at my appearance and said I was very white.
I felt a sort of burning uncomfortable feeling inside and I
tried to make myself vomit by drinking several tumblerfuls of
hot mustard and water. This was partially successful, but I
felt very ill and a doctor was called in. When he came I was
unable to speak coherently; sentences were disjointed, and
my memory partially failed me. I was ordered to bed and
undressed with difficulty. I then shook violently all over, and
my hands were cold and tended to contract. I was given some
brandy and water and gradually I became more natural.
Afterward I took some soup and fish. During my sleep I felt
inclined to laugh, but I do not think I actually did so. The
next morning I was comparatively well, but throughout this
day and the next I did not feel quite well; there was a
numbness and coldness in my legs and I feared I was in for an
attack of influenza, but my temperature was normal." The
neuralgia was cured, but afterward he told me he would
rather bear the pain than the effects of the remedy. The
ramainder of the pills were given to me and on two occasions
I tried them on myself.On both occasions the usual effects of
Indian hemp were produced, viz., paresthesia in the extremities,
inability to do mental work, and sleepiness, but not the
giddiness and other symptoms produced in the case cited.
The less effect may in part be due to my previous experience,
and the absence of fear in consequence, but this is insufficient
to account for all the difference. The prescription was
dispensed by a first-class pharmacist and there was no reason
to believe that the extract was unequally shared.
The absorption
of cannabinol.
For all practical purposes, cannabis preparations may be
regarded as being quite insoluble in water. They are soluble in
fats and organic solvents generally, but with the exception of
fats these are not common constituents of the contents of
the alimentary canal. It is even doubtful what part fats play
in the absorption of the drug. If Moore and Rockwood's
view of fat absorption be accepted, the only influence they
could have would be a physical one-the substance would be
brought into a state of finer division and thereby rendered
more susceptible to other agencies. When given dissolved in
oil, the onset of the symptoms is not distinctly earlier than in
other cases, but as absorption probably only occurs from the
intestine this observation is of little consequence. The more
important question is the solubility of the active principle in
dilute acids and alkalies respectively. According to Kionka"
the resin of Indian hemp is insoluble in alkalies. From the
therapeutic point of view Germain Se'e" states that cannabis
is the peculiar sedative of the stomach. Both these statements
suggest that the active principle is soluble in an acid medium,
and this is supported by the fact that cannabinol is actually
soluble in strong sulphuric acid and glacial acetic acid. But
my results for dilute acids are opposed to this view, and
contrary to the statement of Kionka, I find it soluble in
dilute alkalies. The following experiment proves this: Two
Erlenmeyer's flasks were taken; into one (A) was put 2.127
grammes cannabinol; into the other (B) put 2.3 3 5 grammes.
Both were left over sulphuric acid until they attained a
constant weight; 100 c.c., 1 per cent. caustic soda solution
was then added to A and 100 c.c., 1 per cent. hydrochloric
acid (gas) to B. Both were shaken occasionally and left
twenty-four hours. The alkaline solution soon became of a
purplish color, which deepened; the acid solution remained
perfectly clear. After standing twenty-four hours, both solutions
were poured off and the remaining cannabinol was
rapidly washed with distilled water until the washings were
free from acid and alkali respectively. The flasks were again
put over sulphuric acid and left until the weight became
constant. The alkali-containing flask (A) had lost 0.03
gramme cannabinol; the acid-containing flask (B) 0.005
gramme, the latter being within experimental error.
It is therefore probable that the cannabis resin is absorbed
under the influence of the alkaline juices of the upper part of
the intestine. In the mouth, solution occurs to a slight extent,
as is evidenced by the peculiar unpleasant taste, but this can
not be of practical importance. The influence of other
alimentary conditions has not been determined.
The condition of the stomach, however, plays an important
part in the time of appearance of the symptoms,
probably by hastening or retarding the course of the drug to
the intestines. Thus in one case, when the drug was taken on
an almost empty stomach, four hours passed before the onset
of the symptoms, whereas if taken just before a meal, the
first symptoms invariably occurred within one and a half
hours. Taken after meals the appearance of the first symptoms
is variable. In atony and dilatation of the stomach
cannabis is said to be inactive (as a gastric sedative). The
small solubility of the drug, even in alkalies, probably
accounts for the insidious onset of the symptoms and its
prolonged effect.
In order to determine roughly the influence of continued
dosage on the activity of cannabinol, the two dogs were given
very large doses every day for a week. A small dose, similar to
one given just before the experiment, was then adminisered
and its effects watched. The influence was certainly less than
on the previous occasion, but the diminution was not
marked. Whether habituation to this remedy occurs less
readily than with other hypnotics can only be determined by
practical experience. I know of no reliable observations on
the subject, although it must be well known. In any case the
tolerance is not likely to be so great as in the case of opium.
During my experiments with the two dogs, this question of
tolerance often presented itself, and it was on this account
that a third dog was obtained. Of the greater susceptibility of
this there could be no doubt; but to a certain extent it was
only apparent. The experience was new to him; he walked
about and stumbled when the other dogs would have laid
down. The same thing happened in the earlier experiments
with these dogs; the ataxia was marked; later, they learned
wisdom by experience, and laid down soon after the drug was
given. It was often difficult to get them to stand sufficiently
long for any indications to develop.
Although my experiments did not show any great amount
of tolerance, they seemed to me to show some mental
depression; the normal physical life of the animals seemed to
run on a lower level, although this was difficult of proof.
That cannabis indica exerts a powerful depressing influence,
on some individuals at least, there can be no doubt, and from
experiments on myself I have little hesitation in joining the
ranks of those clinicists who regard Indian hemp as a causal
factor of insanity. But this point, and others, I hope to
develop in a later communication.
Effects on Owing to the insolubility of cannabis preparations and the
special organs. pressure of other work, exact experiments on the different
organs have not been carried out. A solution of cannabinol
was made by heating an excess of the substance in a 1 per
cent. solution of sodium bicarbonate on a water bath, but the
resulting product, which was of a brownish color and probably
contained about 1 in 1000 cannabinol, had no distinct
influence on blood-pressure. A solution of cannabinol phosphate
(8 per cent.) in one experiment caused a slight fall and
subsequent rise of blood-pressure, but from other points of
view this substance was but slightly active.
Cannabinol is, however, somewhat depressant to the heart.
A fall in the number of beats was constant, and in many cases
this seemed greater than could be accounted for by the rest
and sleep. Thus, in the largest dog, a pulse of 108 fell to one
of 48, and a slight irregularity, also noticed in rabbits,
occasionally occurred. That the blood-vessels were not dilated
was inferred from a comparison with the action of
chloral. After this drug, there was not the same marked fall in
the number of the heart-beats, and the character of the beat
was slightly different. After a large dose of cannabinol my
own pulse increased in frequency; after a small dose no effect
was noticed; after ,intermediate doses I invariably forgot to
take it. No distinct effect on the respiration was observed. It
was slower and deeper, as in ordinary sleep.
In the fox-terrier increased micturition was not infrequent;
but this was not observed in the other dogs. Constipation was
not an obvious symptom. After continued dosage some
evidence of it existed, but this was not seen after single doses.
In myself it was rarely present. Salivation was an occasional
symptom, but as this occurs in dogs and cats after the
exhibition of drugs possessing no specific properties in this
direction, it is not probable that cannabinol exerts any
specific action in this way. In my own case dryness of the
mouth was a more constant feature.
The main action of cannabinol, however, is on the nervous
system, and probably on the cerebral cells. From introspective
analysis it is difficult to avoid the conclusion that some
peripheral action exists, but as all the symptoms can be
explained by a central influence, it is simpler, in absence of
proof, to accept this.
One of the most prominent physical symptoms is the loss
of time-sensation. This is mentioned by most writers. But it is
not peculiar to Indian hemp, as it occurs after mescal button
and other drugs of a similar nature. Its explanation, to my
mind, is simple. The estimation of time is a complex act and
dependent upon our calling to consciousness a series of
events. When the physical state is depressed by Indian hemp a
succession of ideas cannot be maintained; time ceases to
exist, and it can not therefore be estimated. Even the
apparently slowly travelling second hands of a watch, which
is observed when under the influence of Indian hemp, may be
explained in a similar way. The power of conception is more
or less lost; current events are rapidly forgotten, while those
fixed in the memory by older associations may still be
recalled. Under the full influence of the drug, even those too
are forgotten, and one's whole previous existence seems to be
blotted out.
A most interesting condition, after large doses, is the
occurrence, alternately, of loss of control and lucid intervals.
During the latter, all the elements of complete sanity are
present, but the physical state is below the normal level. In it
the processes on which consciousness depends are readily
exhausted, and the condition of irresponsibleness develops.
Slight mental strain during the lucid periods seems to hasten
the occurrence of a state of irresponsibility. A more complete
rest from thought brings back the rational intervals. The
over-estimation of distance was never distinctly observed by
me, except to a slight degree on one occasion. The effect is
probably connected with the increased effort made to accommodate
the ocular muscles to the required distance, and is
dependent on deficient will-power. Hallucinations, too, of a
very slight character, were only present in one instance-a
result probably attributable to my lack of imagination. In
dogs, after large doses, the attention was blunted, and they
became less obedient. As far as I can see, there seems to be
no selective influence on any psychical phenomenon. All
such processes are depressed, but whether to an equal degree
I am not prepared to state. With this question, however, I
hope to deal at some future time.
111 effects. The most common ill effect, or rather after effect, I have
experienced, has been depression, lasting the whole or greater
part of the following day, after a large dose (O.lg.) This, and
the accompanying mental exhaustion, were decidedly painful,
and the effect was markedly prolonged by attempts to do
an ordinary day's work.
In dogs, vomiting was not an uncommon symptom but this
was much less marked than with morphine. A slight, occasional
irregularity of the heart in these animals and rabbits,
has been mentioned; and a similar condition, viz: an increase
in the cardiac irregularity of heart disease has been observed
by Prior" after cannabis preparations, in men These have been investigated in connection with experi- Derivativesof
ments on the constitution of this body. Oxycannabin cannabinoI.
(C,, H,, N04) is inactive, at least in moderate doses. Acetylcannabinol
and the cannabinol regenerated from it were but
slightly active. The acetyl compound of the higher homologue
of cannabinol, as well as the substance (regenerated
from the acetyl compound) itself, was inactive.
Tri-brom-cannabinol, a brownish powder, was found to
possess hypnotic properties. In dogs the action was very
slight, but on myself (after O.lg) sleep and depression were
marked, and three days of mental exhaustion followed.
Attempts were made to obtain a more soluble preparation
of cannabinol, and this was best accomplished by making a
phosphoric ester. Cannabinol was heated to 100 degrees C.
with phosphoric anhydride. The melt was boiled out with
alkalies, which dissolved nearly the whole of it, and this was
then neutralized by hydrochloric acid. An amorphous substance
was obtained, which, on analysis, gave results agreeing
with the supposition that is was cannabinol phosphate.
Physiologically, however, the substance was not very active
and injected subcutaneously into a dog produced an abscess.
Therapeutically, cannabinol is likely to be a valuable Therapeutic
hypnotic. It is purer and more reliable than the cannabis indications.
preparations on the market, but it does not appear to possess
any other advantages over them. It is not a powerful cerebral
depressant (except in relation to its dose), and belongs rather
to the substances termed "sleep producers" than "sleep
forcers." Owing to its comparative insolubility its action is
prolonged, and this in my own case leads to depression. Its
advantages are, that its lethal dose is considerable; it does not
inhibit secretory activity; and it does not readily induce
habituation. Its disadvantages are, the excitement produced
by early doses and the depression which follows its use. It
appears to be a slight analgesic, but how far its activity goes
in this direction it is impossible, in the absence of experiments
in which pain is present, to say. This can only be
proved by clinical observation. Purely pharmacologic investigations
do not support any other actions of this drug, but so
far as they have been carried they do not deny their existence.
In conclusion, I express my thanks to Messrs. Wood,Spivey and Easterfield, for the material supplied me, and
especially to Dr. Easterfield for the help he has given me during
the progress of the work.

Appendix I.
Descriptions of personal experiments will be found in the Lancet. P
= heartbeat; R = respiration; T = respiration; T = rectal temperature.
Dog (English terrier); wt. 7180 grams; P., 102; R., 16; T., 38.2
degrees C.; (room temperature 20 to 22 degrees C.); 12:lO o'clock,
0.14 gram cannabinol; 12:40, slight depression, distinct unsteadiness;
12:45, ataxia more marked, head unsteady, eyes heavy; 12:55, very
unsteady, will not lie down, pricked up ears when cart passed window,
no dilatation of pupils; 1 :lO, extremely unsteady, continually falling
over; will not touch milk, P. 96, T. 37.7 C.; 1:40, ataxia rather worse,
still walking about; 1:50, vomited small quantity, mainly yellowish
fluid; 1:.54, vomited again; 2:10, condition same, constantly falling
over, P. 108, T. 38.6 C.; 2:20, vomited again; 2:30, circus movements,
then sat down, got up and repeated several times; 2:40, vomited; 2:50,
vomited; 3:10, slightly better; but still falling over, P. 108, T. 38.9 C.;
3 :40, been laid down last twenty minutes, slept partly, just got up,
ataxia very much better at first but soon developed again; 4: 10, sleepy,
P. 96, T. 38.5 C.; 4:40 still marked ataxia but much better; 5:15,
further improvement, still unsteady and depressed, P. 96, T. 38.9 C;
following morning, apparently well. This was the only case in which a
rise of temperature was noted.
Dog (Airedale puppy), wt. 6500 grams. lo:30 o'clock, 0.5 gram
cannabinol given in bread, P. 192; 11:30, lively, no obvious effect;
11:45,, sleepy, lay down; 12:30, still in same position, yawning, came
when called but seems rather stupid; 1 :OO, walking about, when played
with commenced to run about and bark in a higher pitched voice; 2:00,
been asleep for last half hour, does not answer to name so readily, weak
on legs, can not stand steadily; 3 :OO, condition same, asleep, P. 96;
4:00, still asleep, occasionally wakes up, yawns and stretches, will not
answer to name; 5 :30, condition much the same, still weak on legs and
tired, sent to kennel, would not eat; following morning, apparently
normal.
Cat, wt. 3600 grams. 1:30 o'clock, 0.15 gram cannabinol given in
meat; 2 :30, no apparent effect; 3 :OO, sleeping; 3 :45, awakened, rather
weak on legs, gait slightly unsteady; 5 :OO, much worse, distinct
into-ordinate gait but does not move about much, has been laid down
mostly, with chin on ground, passed a loose motion, would not drink
milk although seemed eager for it and only ate two small pieces of
meat.
Second day, 9: 30 o'clock, no apparent alteration, still stupid, would
not come when called, distinct muscular weakness, gait still unsteady,
pupils somewhat dilated, would not drink milk although a little had
been drunk during the night; 2:30, slightly better, gait less unsteady;
5 :30, still better, looks up when called, ataxia still present; following
morning, seemed quite normal.
Rabbit, wt. 620 grams; P., 300; R., 76; T., 38.4 C.
First day, 2:25 o'clock; 2.4 grams cannabinol given in mucilage;
5:2.5, has been quiet since drug was given, eyelids partially closed,
slightly depressed, doubtful muscular weakness; P. 216, R. 30, T. 34.1
Second day, 10:00 o'clock, somewhat worse, head trembles slightly,
sensation blunted but kicks on being handled, has not eaten any food,
P. 204, R. 54, T. 3 1.4 C., placed before fire; 5 :45, seems slightly better,
P. 150, R 30, T. 32.7 C.
Third day, 12:15 o'clock, condition much the same, trembling of
head present, eyes half closed, P. 168, R. 60, T. 29.1 C.; 5:30, slightly
increased muscular weakness, pupils more dilated, been laid before the
fire all day. P. 204, R. 36, T. 3 1.8 C.
Fourth day, 1l:OO o'clock, no noticeable change. P. 138, R. 39, T.
30.6 C.; 6:00 much worse, trembling very marked.
Fifth day, 9:00 o'clock, found dead, rigor mortis, cold; afternoon,
few small petechia in stomach, otherwise normal, stomach and cecum
full of food.
.Appendix II.
This appendix contains a summary of the experiments made on
which the foregoing account is based. Only the briefest description is
given, but some attempt has been made to indicate the comparative
value of the experiments. The experiments are given in the order they
were made. The time in parentheses indicates the period after
administration of the drug at which the preceding symptom was noted;
m., minute; h., hour.
Three dogs were used; at first only two. All were fed at 9 o'clock Experiments
P.M. Unless otherwise indicated the individual substances were given in on dogs.
gelatine capsules by the ,mouth.
1. May 5, 1897; Airedale terrier; weight 3100 gms.; 0.4 g.
cannabinol phosphate; slight depression and sleepiness.
2. June 4, 1897; Airedale terrier, 4400 gms.; 0.4 g. cannabinol
phosphate hypodermically; slight depression and sleepiness, fall in pulse
rate; longer effect than in last case.
3. June 16, 1897; Airedale terrier, 5400 gms.; 1.1 g.
acetyl-cannabinol; sleepiness and depression (30 m.), unsteadiness,
occasional slight excitement, vomiting.(3 h.), dilatation of pupils. Quite
well next morning.
4. July 1, 1897; Airedale terrier; 0.5 g. cannabinol; slight
sleepiness (75 m.), stupidity, muscular weakness and unsteadiness; slept
most of day; normal next morning; effect more marked than 3.
5. July 15, 1897; Airedale terrier; 7520 gms.; 1 g. charas; tired,
yawning (30 m.), sleepy, ataxia, etc., pupils somewhat dilated, very
much excited (6 h.); seemed normal next day; effect somewhat greater
than 4.
6. July 22, 1897; Airedale terrier; 0.3 C.C. l/6 alcoholic extract
charas; depression (60 m.), temporary excitement (100 m.), weakness
and unsteadiness (most marked 5 to 6 h.), shivering, involuntary
micturition; slightly excited next morning; very marked effect.
7. July 28, 1897; Airedale terrier; 1 C.C. l/6 alcoholic extract
charas; lay down (75 m.), but excited if played with; sleepiness,
unsteadiness, etc., as in 6, but symptoms less severe; normal next
morning.
8. July 30, 1897; Airedale terrier; 0.9 C.C. mono-terpene from
charas; no effect.
9. Aug. 2, 1897; Airedale terrier; 1.1 cc. sesqui-terpene from
charas; no effect.
10. Aug. 3, 1897; Airedale terrier; 0.5 g. cannabinol distilled at
406 degrees C. (atmospheric pressure); lay down (30 m.), vomited (55
m.), depressed, head falling to one side (75 m.), afterward sleepiness,
unsteadiness, etc., vomited twice (6 h.); effect almost as marked as 4.
11. Aug. 11, 1897; Airedale terrier; 1 C.C. greenish oil,
intermediate between sesqui-terpene and cannabinol, unpleasant smell,
vomited (45 m.); no effect beyond slight depression.
12. Oct. 19, 1897; Airedale terrier, 9650 gms,; 9.97 .g.
intermediate product between sesqui-terpene and cannabinol (distils
below 300 degrees C.); slight depression, increased micturition; no
other effect.
13. Fox-terrier, 7550 gms.; 0.75 g. intermediate product between
sesqui-terpene and cannabinol (distills below 300 degrees C.); vomited
four times (70 to 100 m.), increased micturition; no other effect.
14. Oct. 27, 1897; Airedale terrier, 10,700 gms.; 1.15 g.
cannabinol, from Merck's cannabinon; depression (40 m.), sleepiness,
muscular yeakness and unsteadiness, dilated pupils, vomiting (140 m.,
240. m., 255 m.); somewhat better, but still severely affected (5% h.):
would not touch food; apparently well next morning. Most marked
effect yet.
1.5. Fox-terrier, 7950 gms.; 1.04 g. cannabinol, from T. and H.
Smith's cannabin. Unsteadiness (3 5 m.), which increased; became tired
and sleepy but walked about much, vomited (4% h.); more unsteady
but less depressed than other dog; would not touch food; well next
morning.
16. Nov. 11, 1897; Airedale terrier, 11,250 gms.; 0.99 g. Merck's
cannabinon. No effect (30 m.), usual symptoms marked (60 m.),
continued to 180 m., afterward gradual improvement, very much better
(6% h.), salivation (2 h. continued 1 h.), vomiting (2 h.); depression and
unsteadiness more marked than 14 but more transient.
17. Fox-terrier, 8100 gms.; 1.04 g. ext. cannab. indic. ether
(Merck). Slight effect (60 m.), unsteadiness (75 m.), vomited (3% h.),
ataxia main symptom; not much better (6% h.); very little sleep,
apparently well next morning-; effect about the same as 15.
18. Nov. 18, 1897; Airedale terrier; 0.19 g. ext. cannab. indic.
ether (Merck). Depression (45 m.), marked unsteadiness (60 m.), slight
salivation (90 m.), sleepy, excited, vomited (3 h.), ataxia not much
better when left (4 h.).
19. Nov. 22, 1897; Airedale terrier; 1.95 g. cannabinol. Slight
effect (30 m.): unsteadiness, sleepiness, etc., developed, but symptoms
not more severe than 18.
20. Fox-terrier; 1 g. ext. cannab. indic. (Merck). Commencing
weakness (45 m.), more marked (60 m.), afterward became very severe;
incontinence of urine, vomited (130 m., 135 m.), trembling from cold;
slight improvement (3% h.).
21. Nov. 26, 1897; Airedale terrier; 0.19 g. cannabinon (Merck)
given in a piece of meat. Slight effect (2 h.); distinct unsteadiness (2%
h.), subsequently worse, depressed but not sleepy.
22. Fox-terrier; 0.55 g. extract cannab. indic. Sicc. (Merck). No
distinct effect.
23. Dec. 1, 1897; Airedale terrier, 12,400 gms.; 0.15 g. alcohol
ether extract charas [previously heated three times with dil. H2S04].
Sleep main symptom, depression (60 m.), unsteadiness (90 m.),
vomiting (2% h. 3% h.); distinct improvement (5 h.).
24. Fox-terrier; 8800 gms.; 0.15 g. alcohol ether extract charas
[previously heated three times with dil. H2S04] . Slight depression (35
m.), slight unsteadiness (75 m.), afterward very distinct; slept, salivation
(3 h.), vomited (4 h.), not much improvement (6 h.); well next
morning.
25. Dec. 3, 1897; Airedale terrier; 0.15 g. alcohol-ether extract
charas [previously heated 14 hours at 260 degrees C.] . Effects similar
to 23, but somewhat less marked and delayed-no obvious action
except slight depression and sleepiness for three and one-half hours.
26. Fox-terrier; 0.21 g. alcohol-ether extract charas [previously
heated 14 hours at 260 degrees C.] . Slight depression (60 m.), slight
unsteadiness (3 h.), much more marked (3% h.); improvement (4% h.).
27. Dec. 6, 1897; Airedale terrier; 0.15 g. cannabinol rapidly
distilled from alcohol-ether extract. No apparent effect (70 m.), later,
usual symptoms developed, very distinct unsteadiness.
28. Fox-terrier; 0.54 g. pitch from extract, contains a little cannabinol.
Slight depression; no other distinctive action.
29. Dec. 9, 1897; Airedale terrier; 0.15 g. distillation fraction previous
to cannabinol than latter. Depression (30 m.), sleepiness, unsteadiness
(85 m.), but not marked; attention good, excited (5% h.).
30. Fox-terrier; 0.21 g. distillation fraction previous to cannabinol
than latter. Mostly laid down at first; slight unsteadiness (2 h.), worse
(3% h.), slight sleepiness; symptoms not marked.
31. Airedale terrier; 0.21 g. charas extract, further heated for 60
hours at 220 to 260 degrees C. (c. 25). Depression (60 m.), unsteadiness
(105 m.), slept fairly well, much better (5% h.); symptoms more
marked than 25 but less than 23.
32. Fox-terrier; 0.39 g. charas extract, further heated for 60 hours
at 220 degrees C. (c. 25). Slight depression and unsteadiness (90 m.),
much more marked (2 h.), still severe (5% h.), sleepy, symptoms about
equal to 24.
33. Dec. 28, 1897; Airedale terrier; 1.07 g. cannabinol (oldest).
Laid down at first, could not be induced to stand long; very slight
unsteadiness (3 h.) and depression, more severe (5 h.) but still fairly
well; normal next morning.
34. Fox-terrier; 1.03 g. cannabinol (oldest); Slight depression (60
m.), unsteadiness (90 m.), still distinct (5 h.); depressed following
morning.
35. Dec. 29, 1897; Airedale terrier; 0.92 g. cannabinol, distilled
from another sample of charas. Asleep (55 m.), very unsteady (90 m.),
continued as long as observed (6 h.); slept mostly.
36. Fox-terrier; 0.96 g. cannabinol, distilled from another sample
of charas. Unsteadiness (55 m.), became very marked afterward,
vomited (65 m. and 5 h.); slight improvement (6 h.).
37. Dec. 31, 1897; Airedale terrier; 1.1 g. cannabinol (oldest).
Slight depression and unsteadiness (70 m.), increased later, slept
mostly; more marked effect than 33.
38. Fox-terrier; 0.97 g. cannabinol (oldest). Unsteadiness (70 m.),
which increased, still marked (5% h.); effect greater than 34.
39. Jan. 3, 1898; Airedale terrier; 0.97 g. cannabinol, distilled
from another sample of charas. No effect (60 m.), afterward slept, very
slight unsteadiness, (2 h.), did not increase, lay down occasionally; slept
remainder of day, playful when aroused.
40. Fox-terrier; 0.95 g. cannabinol, distilled from another sample
of charas. No effect (60 m.), very slight unsteadiness (2 h.), soon became
more marked, continued as long as observed, slept somewhat;
slightly depressed next morning.
41. Jan. 4, 1898; Airedale terrier; 1.1 g. cannabinol, distilled from
another sample of charas. Slight depression; no marked symptoms.
42. Fox-terrier; 0.99 g. cannabinol, distilled from another sample
of charas. Depression and unsteadiness (2 h.) not very marked; slight
depression next morning.
43. Jan. 5, 1898; Airedale terrier, 12,llOgms.; 1.03 g. cannabinol,
distilled from another sample of charas. Slight depression (60 m.), slight
unsteadiness, slept mostly; unsteadiness increased, vomited (125 m.),
awakened to be taken to kennel, very unsteady.
44. Fox-terrier, 8210 gms.; 0.97 g. cannabinol, distilled from
another sample charas. Slight depression and unsteadiness (60 m.), became
more marked and continued as long as under observation (6% h.),
vomited a little (5% h.), slept partly; apparently normal next morning.
45. Jan. 6, 1898; Airedale terrier; 1.01 g. cannabinol, distilled
from another sample of charas. Slight depression (60 m.), slept mostly,
unsteadiness less marked than 43; apparently well the following morning.
46. Fox-terrier; 0.97 g. cannabinol, distilled from another sample
of charas. Slight depression (60 m.), unsteadiness (70 m.), effects similar
but ataxia less marked than 44.
47. Jan. 7, 1898; Airedale terrier; 0.98 g. cannibinol, distilled from
another sample of charas. Depression (30 m.), unsteadiness (60 m.),
became very distinct, laid down mostly, slept partly; very slight depression
next morning.
48. Fox-terrier; 0.97 g. cannabinol, distilled from another sample,
of charas. Depression (30 m.), unsteadiness (60 m.), became very distinct,
laid down mostly, slept partly; very slight depression next morning.
49. Jan. 8, 1898; Airedale terrier; 1.04 g. cannabinol, distilled
from another sample of charas. Depression (60 m.), unsteadiness (90
m.), not further observed.
50. Fox-terrier; 0.97 g. cannabinol, distilled from another sample
of charas. No apparent effect (90 m.); not further observed; apparently
normal next morning.
51. Jan. 9, 1898; Airedale terrier; 1.02 g. cannabinol, distilled
from another sample of charas. Not observed.
52. Fox-terrier; 1 g. cannabinol, distilled from another sample of
charas. Not observed.
53. Jan. 10, 1898; Airedale terrier; 1.02 g. cannibinol, distilled
from another sample of charas. Depression, distinct ataxia, but not
marked; slept most of the time.
54. Fox-terrier; 1 g. cannabinol, distilled from another sample of
charas. Sleepiness, depression and slight unsteadiness, symptoms less
marked than usual; slight depression next morning.
55. Jan. 11, 1898; Airedale terrier; 0.22 g. cannabinol (as 31). No
evident effect (60 m.), later transient depression, but no ataxia
developed. Compare with 3 1.
56. Fox-terrier; 0.4 g. cannabinol (as 31). No effect (60 m.), later
depression and unsteadiness but less than 32.
57. Jan. 25, 1898; Airedale terrier, 13,150 gms.; 0.21 g. cannabino1
(as 31). Slight depression (60 m.), afterward sleepiness, unsteadiness,
excited (5 h.).
58. Fox-terrier, 7980 gms.; 0.42 g. cannabinol (as 31). No effect
(60 m.), later sleepiness, slight unsteadiness and depression.
59. Feb. 11, 1898; Airedale terrier; 0.16 g. third fraction cannabino1
dissolved in .64 g. olive oil. Depression (30 m.) followed by sleep,
no distinct unsteadiness, excited at times, vomited a little (4% h.); still
depressed (5% h.).
60. Fox-terrier; 0.18 g. third fraction cannabinol dissolved in .64 g.
olive oil. Depression (35 m.) and sleep, no ataxia observed but could
not be induced to stand long; still depressed (5 h.).
61. Feb. 15, 1898; Airedale terrier; 0.16 g. second fraction
cannabinol in .64 g. olive oil. Symptoms similar to 59.
62. Fox-terrier; 0.18 g. second fraction cannabinol in .64 g. olive
oil. Slight depression and unsteadiness (2% h.) but less marked than 60,
vomited (5 h.).
63. Feb. 17, 1898; Airedale terrier; 0.16 g. first fraction
cannabinol in .64 g. olive oil. Depression somewhat more marked than
6 1 but no unsteadiness, vomited slightly (3 h.).
64. Fox-terrier; 0.18 g. first fraction cannabinol in .64 g. olive oil.
Some depression and slight unsteadiness, but doubtful if as marked as
62.
65. Feb. 22, 1898; Airedale terrier; 0.21 g. cannabinol distilled at
atmospheric pressure, then heated 5 hours at boiling point. Slight
depression and sleepiness, no ataxia observed; much better (5% h.).
66. Fox-terrier; 0.23 g. cannabinol distilled at atmospheric
pressure, then heated 5 hours at boiling point. Slight depression, no
sleep; almost well (5% h.).
67. Feb. 24, 1898; Airedale terrier; 2.1 g. cannabinol distilled at
atmospheric pressure, then heated 5 hours at boiling point. Depression
and unsteadiness, but. symptoms not very marked, slept somewhat,
vomited (3% h., 4% h.), slight improvement (6 h.).
68. Fox-terrier; 2.2 g. cannabinol distilled at atmospheric pressure,
then heated 5 hours at boiling point. Depression and distinct
unsteadiness, did not sleep; somewhat better (5% h.).
69. Feb. 28, 1898; Fox-terrier; 0.43 g. acetyl-derivation of higher
homologue of cannabinol. No effect (2% h.).
70. March 1, 1898; Airedale terrier; 0.2 g. cannabinol distilled in
vacua. Depression, sleep and unsteadiness, more marked than 67;
decided improvement (5% h.).
71. Fox-terrier; 0.22 g. cannabinol distilled in vacua. Distinct
unsteadiness (60 m.), slight depression; symptoms similar to 68; much
better (5% h.).
72. March 3, 1898; Airedale terrier; 0.45 g. pitch dissolved in 1.5
g. olive oil containing some cannabinol. Slight depression and
unsteadiness; much better (4% h.).
73. Fox-terrier; 1.03 g. cannabinol regenerated from old acetyl
compound. Slight depression and sleepiness, no obvious ataxia.
74. March 8, 1898; Airedale terrier; 0.06 g. morphin acetate in
capsule. Vomited frothy mucous-like vomit (12 m., 14 m., 17 m.),
marked depression, much worse than any previous observation, retching
(22 m.), rapid breathing, quick pulse, head-nodding (40 m.), salivation
(44 m., continued to 120 m.), still much depressed, constant moaning,
slight myosis (130 m.), fall of temperature 1.1 degrees C., sleepiness,
slight unsteadiness; improvement (4 h.), but still depressed (5% h.).
75. Fox-terrier; 0.1 g. morphin acetate in capsule. No effect (20
m.), head nodding (30 m.), retching and vomiting of frothy colorless
fluid (35 m., 38 m., 50 m., 55 m., 90 m., 105 m.), salivation,
unsteadiness, depression (130 m.), not sleepy, salivation stopped (3%
h.), fall of temperature 2.3 degrees C; could not be induced to stand up,
somewhat better (4% h.).
76. March 16, 1898; 0.93 g. olive oil extract of charas, containing
about .2 to .25 g. soluble charas products. Slight depression and
unsteadiness (60 m.), sleepiness, vomiting (160 m.), ataxia more
marked, excited (3% h.), slight improvement (5% h.).
77. Fox-terrier; 1.86 g. olive oil extract of charas, containing .4 to
.5 g. soluble charas products. Sleepiness and depression (30 m.), distinct
unsteadiness (60 m.), which became more marked later, vomited (105
m.); no obvious improvement (5% h.).
78. March 18, 1898; Fox-terrier, 8840 gms.; 0.15 g. extract
cannab. indic. (B.P.) in pills (from London chemist). No effect (90 m.),
afterward depression and marked ataxia, vomited (2% h.).
79. March 22, 1898; Airedale terrier, 13,580 gms.; 1.03 g. partly
(%) saponified acetyl derivative of higher homologue of cannabinol. No
distinct effect.
80. Fox-terrier; 0.35 g. oxycannabinol. No obvious effect.
81. March 25, 1898; Airedale terrier; 1.02 g. cannabinol.
Depression, very distinct unsteadiness (60 m.), sleepiness, vomited (2
h., 3% h.), no distinct improvement (4% h.).
82. Fox-terrier; 0.99 g. cannabinol. No obvious effect (60 m.),
depression (75 m.), vomiting (105 m., 115 m., 130 m., 135 m., 255
m.), slight unsteadiness (120 m.), symptoms increased; no improvement
(4% h.).
83. March 30, 1898; Airedale terrier; 1 g. chloral hydrate in
capsule. Sleepiness (15 m.), very slight ataxia, somewhat more marked
(30 m.); fall of temperature 0.4 degrees C., apparently normal (4 h.).
84. Fox-terrier; 1 g. chloral hydrate in capsule. Sleepiness (15 m.),
slight muscular weakness but no distinct ataxia; fall of temperature 0.4
degrees C., apparently normal (4 h.).
85. April 5, 1898; Airedale terrier; 0.5 g. chloralose in capsule.
Slight depression and sleepiness, transient; fall of temperature 0.5
degrees C.
86. Fox-terrier; 0.0195 g. hyoscine hydrochlorid. Uneasiness (30
m.) followed by whining, dryness of the tongue, dilatation and less
marked reaction of pupils to light, increased rapidity of heart beat (60
m.), improvement commenced (2 h.); no fall of temperature.
87. April 11, 1898; 0.21 g. cannabinol. Slight depression,
sleepiness and unsteadiness, continued 6 hours.
88. Fox-terrier; 0.2 g. cannabinol. Slight depression (30 m.) but
not much affected until (90 m.), became very unsteady, sleepiness,
incontinence of urine, trembling, vomiting (2 h.); fall temp. 3 degrees
C; most marked effect obtained with this dose.
89. English terrier, 7180 gms.; 0.15 g. cannabinol. Less reserved
(20 m.), slight depression (30 m.), sleepiness chief symptom, no
obvious ataxia; slight improvement (5 h.).
90. April 15, 1898; Airedale terrier; 0.2 g. cannabinol kept in
sealed tube since Dec. 12, 1896. Slight depression and sleepiness (45
m.), became much more marked; unsteadiness developed, attention
became impaired, vomited (5 h.), then improved.
91. English terrier; 0.14 g. cannabinol kept in sealed tube since
Dec. 12, 1896. Slight depression and very distinct unsteadiness (30 m.),
gradually increased until fell over every few steps, vomited (100 m.,
104 m., 150 m., 200 m.), slept a little (3% h.), much better but still
markedly depressed (5 h.), temperature fell 0.5 degree C., then rose 1.2
degree C.
92. Fox-terrier; 0.39 g. cannabinol, through which oxygen has
been passed 3 to 4 hours at 150 degrees C. Slightly depressed (45 m.),
very slight unsteadiness (60 m.), became somewhat more marked, slight
sleepiness; symptoms not severe but temperature fell 1.4 degrees C.
93. April 19, 1898; Airedale terrier, 12,840 gms.; 0.22 g.
cannabinol (as in 90), subjected to oxygen for 6 hours at 150 to 160
degrees C. Slight depression and sleepiness (30 m.), increased, distinct
unsteadiness; not much improved (6 h.).
94. English terrier; 0.16 g. cannabinol (as in 93). Depressed,
restless (20 m.), sleepy (30 m.), slight unsteadiness (40 m.), gradually
became worse, but not so bad as in 91; vomited (55 m., 115 m.),
somewhat better (4% h.), but no further improvement (5% h.).
95. Fox-terrier, 8270 gms.; 0.21 g. cannabinol (as in 90). Slight
depression (30 m.), but not much affected during first hour, afterward
much depressed, slight unsteadiness; no improvement (5% h.).
96. April 23, 1989; Fox-terrier; 0.19 g. cannabinol (as in 90).
Asleep (30 m.), but no marked symptoms for three hours, then slight
unsteadiness, which increased, distinct (6% h.).
97. Airedale terrier; 0.22 g. cannabinol through which CO, has
been passed for 20 hours at 150 to 185 degrees C. Slight depression and
sleepiness (30 m.) became more marked, unsteadiness (60 m.), vomited
(105 m.); afterward improved but still under influence (6% h.).
98. English terrier; 0.2 g. cannabinol through which oxygen has
been passed for 20 hours at 150 to 185 degrees C., pitchy appearance.
Very slight depression and restlessness (30 m.) which quickly (1 h.)
passed away; no ataxia.
99. April 27, 1898; English terrier, 7760 gms.; 0.2 g.
tribrom-cannabinol. Depressed (60 m.), slight sleepiness but no distinct
unsteadiness, apparently normal (4 h.).
100. Dec. 11, 1895; 2500 gms.; 3.5 g. charas given in mucilage (65 Experiments
c.c.), chloroformed during injection. Vomited most of the substance on cats.
(about 50 c.c.) after recovery from chloroform, depression, weakness,
narcosis and death (4 h.); no characteristic macroscopic changes.
101. June 20, 1896; 2600 gms.; 0.15 g. cannabinol in meat.
Sleepiness (90 m.), muscular weakness, marked ataxia, stupidity;
commencing improvement (25 h.), complete recovery (44 h.).
102. May 26, 1896; 2700 gms., same cat; 0.27 cannabinol as pills
with starch. Quiet (90 m.), restlessness and micturition, then salivation
(3% h.), muscular weakness and unsteadiness, anorexia; improvement
(25 h.), almost well (28 h.).
103. June 2, 1896; 1.3 g. cannabinol in capsules. Tired, quiet (60
m.), salivation and unsteadiness (100 m.), marked ataxia, sleepiness,
dilated pupils: improvement (30 h.), almost well (53 h.).
Experiments Substances were made into an emulsion with gum and injected
on rabbits. through a catheter into the stomach.
104. Nov. 1, 1895; 1730 gms.; 0.895 g. impure (sesqui) terpene.
Slight excitement.
105. Nov. 4, 1895; 1730 gms.; 0.895 g. charas with sodium
bicarbonate. Slight excitement.
106. Nov. 5, 1895; 1730 gms.; 0.876 g. petroleum ether extract.
Slight excitement.
107. Dec. 17, 1895; 1440 gms.; 1.44 g. charas. No distinct effect.
108. Jan. 16, 1896; 1500 gms.; 3 g. petroleum ether extract.
Became quieter; number of heart beats and respiration, and
temperature fell; death occurred on third day.
109. June 5, 1896; 1100 gms.; 2.2 g. cannabinol. Depression (60
m.), sleepiness, fall in pulse (252 to loo), respiration (142 to 18) and
temperature (40.4 to 35.7 degree C.), diminished reflexes; improvement
(20 h.), much better but not normal (29 h.).
110. June 10, 1896; 930 gms.; 2.2 g. charas. Quieter (90 m.), fall in
pulse, respiration and temperature; died on fourth day, cold and
marasmus.
111. April 5, 1898; 620 gms.; 2.3 g. cannabinol. Depressed, slight
muscular weakness, sleepiness, fall in pulse, respiration and
temperature ; death, 3 % days.
Personal 112. Feb. 1, 1895; 0.1 g. cannabinol, taken about 2:45 P.M.
experiments. 113. Feb. 8, 1985; 0.1 g. cannabinol in 0.05 C.C. alcohol and 20 C.C.
water. Slight mental depression.
114. March 9, 1895; 0.5 C.C. monoterpene in 20 C.C. water. No
effect.
115. March 10, 1896; 0.05 g. cannabinol in 0.1 C.C. alcohol and 20
C.C. water. No distinct effect for 4 hours, then feeling of dryness in
mouth, pleasant tingling, slight unsteadiness, happiness, unpleasant
visions on closing eyes, time relation not completely lost, feeling of
tiredness but no marked tendency to sleep.
116. March 28, 1897; 0.05 g. cannabinol regenerated from acetyl
compound. Taken at 8 P.M., retired to bed at lo:30 feeling a little tired,
slept soundly till 6 P.M., no distinct effect.
117. April 5, 1897; 0.05 g. cannabinol regenerated from acetyl
compound. Taken at lo:30 A.M., slightly depressed in afternoon, no
other effect.
118. April 5, 1897; 0.1 g. cannabinol regenerated from acetyl compound.
Taken at 11 P.M., tired and sleepy in afternoon.
119. April 10, 1897; 0.2 g. cannabinol regenerated from acetyl compound.
Taken at 1 P.M., slight dryness of mouth and paresthesia (160
m.) followed by sleepiness, depressed during evening, retired at 11:30.
120. April 13, 1897; 4 cannabinol tablets (a commercial preparation)
= g. cannabinol. Taken at 5 :08 P.M., feeling of lightness in head
(5 :55), dinner 6:00, afterward felt sleepy and slightly intoxicated; time
relations altered but not annulled.
121. June 7, 1897; 0.2 g. cannabinol phosphate. Taken at lo:30
P.M., Retired at 12 M., no evident effect.
122. June 9, 1897; 0.4 g. cannabinol phosphate. No distinct action.
123. June 6, 1897; 0.8 g. cannabinol phosphate. Taken at lo:45
P.M., 11:40 very sleepy, retired, awoke at 7:20 A.M., feeling very
sleepy, depressed all the morning.
124. March 17, 1898; 0.05 g. oily extract of charas, containing .013
g. soluble products. Dinner at 6:20, taken at 8:00, slight sleepiness and
mental exhaustion followed.
125. March 18, 1898; 0.105 g. oily extract of charas, containing
.013 g. soluble products. Taken at 6:25 P.M., dinner 6:50, 7:35 peculiar
feeling of lightness in head, continued to work, 8:00 rather better,
11:OO retired feeling sleepy.
126. March 20, 1898; 0.016 g. (% grain) ext. cannab. Ind. (B. P.)
pill. Tea 5 P.M;, slight indigestion, pill taken at 7:30, 10:30no evident
effect, 10: 35 slight light-headedness, warmth of face and mental exhaustion,
afterward fell asleep.
127. March 21, 1898; 0.14 g. partly (%) saponified acetyl derivative
of higher homologue of cannabinol. Taken at 5 : 30 P.M., no effect.
128. March 22, 1898; 0.1 g. third fraction cannabinol. Taken at
5 :45 P.M., dinner 6:30, 8:25 feeling of lightness in head and mental
exhaustion, continued working, effect passed off in about 30 m.
129. March 23, 1898; 0.1 g. second fraction cannabinol. Taken at
5:45 P.M., dinner 6:45, 7:20 no effect, 9:25 slight dryness of lips and
lightness in head, seemed to pass off but worse again at 7:45, happy,
have difficulty in reading, sleepy, 10:00 just awakened from a short
nap, read a little but soon exhausted, 11:20 retired, 6:45 P.M., awoke,
felt well.
130. March 24, 1898; 0.1 g. first fraction cannabinol. Taken at 5:45
P.M., dinner 6:45, 7:45 no effect, 7:50 feeling of slight dryness of lips
and lightness of head, 8:00 somewhat more depressed, not working
well, 8:45 working better. 10:00 still somewhat depressed, 11:30 retired
but did not succeed in sleeping for some time.
131. March 25, 1898; 0.1 g. cannabinol (oldest). Taken at 5:45
P.M., dinner at 6:30, 7:30 peculiar light-headedness and dryness of the
lips, 7:45 slightly unsteady, paresthesia in head and legs, heaviness of
eyelids, no correct estimation of time, 9: 30 awakened from short sleep,
10:00 rather better but unable to work, lo:30 retired, somewhat depressed
the following morning.
132. March 27, 1898; 0.35 g. acetyl derivative of higher homologue
of cannabinol. Taken at 7: 30 P.M., no effect.
133. March 29, 1898; 0.05 g. cannabinol pill made 18 months ago.
Taken at 5 :5 0, dinner at 6: 30, 8: 30 unsteady symptoms, cannot work,
estimation of time not so good, 9:15 worse, energyless, 10: 30 went out
for a few minutes, improved, 11:OO can read moderately well, but
eyelids heavy.
134. March 30, 1898; 0.09 g. Merck's cannabinon. Taken at 5:45,
dinner 6:30, 7:20 lightness in head, loss of time relation, happy,
an-&ed, pleasant tingling, etc.; sleepy, 8:00 lay down, slept till lo:30
then retired, awakened (7:OO A.M.) feeling dull and depressed, lasted
the whole morning.
135. April 14, 1898; 0.05 g. opium. Taken at 9:00 P.M., 10:00 no
obvious action, IO:05 slight heaviness of eyelids, very slightly tired,
lo:20 rather better, 11:lO feel somewhat tired, head rather heavy,
slight sense of "well-being," 12 :00 still heaviness of eyes and tiredness
of head but have worked fairly well last half hour, not sleepy; retired,
soon fell asleep, awakened at 7:00 A.M. feeling well, pleasant sense of
gravity, which continued most of morning; no constipation.
136. April 15, 1898; 0.1 g. cannabinol through which oxygen
passed 3 to 5 hours at 150 to 160 degrees C. Taken at 5:45, dinner at
6:30, 9:15 slight visual indefiniteness, slight and transient paresthesia,
afterward felt slight incapacity for work but no marked effects, 11:45
not sleepy but retired.
137. April 17, 1898; 0.05 g. cannabinol sealed up since Dec. 28,
1896. Tea 4:30, drug taken 5:45, 6:50 slight mental exhaustion and
feeling of lightness in head, 7:20 rather sleepy, 8:00 trying to read but
have little energy for anything, 9:00 condition same, no estimation of
time, feeling of warmth in face and head, 10:00 sleepy, retired.
138. April 21, 1898; 0.065 g. same cannabinol treated with oxygen
for 20 hours at 150 to 185 degrees C. Taken at 5:45, dinner 6:40,8:05
slight feeling of lightness in head, 9:30 have been reading some time, at
first had a little difficulty, now feel quite normal.
139. April 22, 1898; 0.05 g. same cannabinol treated with COa for
20 hours at 150 to 185 degrees C. Taken at 5:50, dinner 6:30, 7:00
commencing light-headedness, 8:00 more distinct, a want of energy,
9:45 condition same, trying to read, 10:00 not able to do any work,
10:45, no improvement, retired.
140. April 24, 1898; 0.1 g. tribrom-cannabinol. Taken at 8:00 P.M.,
supper at 8: 30, 9: 30 slightly sleepy, 1l:OO sleepy, no other peculiar
effect of cannabinol, retired, slept till 6:45, depressed, suffered from
mental exhaustion during three following days.
141. May 4, 1898; 0.065 g. oxycannabinol (as in 138) dissolved in
oil. Taken at 5 :45, dinner at 6:30. 7: 15 went out for a walk, 8:15
arrived home, slightly tired, peculiar feeling in eyes and head grew
slightly worse and continued the whole evening, but was insufficient to
prevent me writing; 11: 10 retired, slept soundly, 6:40 A.M. got up, felt
sleepy.
142. May 6, 1898; 0.1 g. charas (best). Taken at 5:45, tea at 4:30,
dinner at 7 :OO, 7:00 slight effect in head, worked in garden, felt want
of energy, 8: 30 influence more marked, agreeable heaviness of eyelids,
very little energy, 10:00 retired, condition same, slept well, depressed
following morning.
143. May 12, 1898; 0.016 g. (% grain) ext. cannab. Indic (B. P.) in
pill (cp. 126). Taken at 5:50, dinner at 6:30, 7:25 lightness of head,
peculiar feeling about eyes, 7:50 pleasant tingling in face and feet, no
other marked effect, reading fairly well, 8:40 tingling still present, unable
to read with benefit, cannot calculate time very well, symptoms
continued throughout evening, became sleepy but managed to do some
copying. 12: 30 retired, 7: 30 got up feeling tired but soon well.
144. May 19, 1898; 2 C.C. sesqui terpene taken in weak mucilage.
Taken at 12 :45, lunch 1: 10, 1: 15 slightly listless and slight heaviness of
head, which soon passed away.


Source: A Contribution to the Pharmacology of Cannabis Indica