REPORT BY BRIGADE-SURGEON-LIEUTENANT-COLONEL D. D. CUNNINGHAM, F.R.S., C.I.E., ON THE NATURE OF THE EFFECTS ACCOMPANYING THE CONTINUED TREATMENT OF ANIMALS WITH HEMP DRUGS AND WITH DHATURA.

Three distinct experiments were conducted in the Biological Laboratory attached to the Zoological Garden in Calcutta on the effects following the continued administration of hemp drugs and of dhatura to monkeys.

In the first of them a monkey (Macacus rhesus) was subjected to frequent inhalations of the smoke of ganja during a period of many months ; in the second, two monkeys (Af. eynomolgus) were treated with almost daily doses of charas for more than two months ; and in the third a second specimen of JIJ. rhesus was caused to inhale the smoke of the seeds and leaves of dhatura periodically during a period of about six weeks.

I regret that no experiment on the effects following inhalation of smoke derived from a mixture of ganja and dhatura was carried out. On learning that the Hemp Drugs Commission were desirous that such an experiment should be tried, I gave instructions for its immediate initiation, but as I was obliged to leave Calcutta almost immediately after doing so, my orders were apparently forgotten, and, on my return to Calcutta in July, I ascertained that DO continuous administration of dhatura had been begun until the receipt of reiterated instructions from Europe reached the laboratory in the end of May, and that then dhatura alone and not a mixture of dhatura and ganja was made use of.

Whilst regretting that the wishes of the Commission have not been fully complied with in this respect, I do not feel sure that the results of the experiments, conducted as they have been, are not really more instructive than they would have been had the mixed drugs been made use of in the third, seeing that, in so far as isolated instances are capable of furnishing grounds for inference a comparison of the phenomena present in the first and third experi- ments appears to indicate that, whilst prolonged, habitual inhalation of the smoke of gania alone fails to give rise to any appreciable morbid effects on the cerebral nervous centres, a comparatively brief exposure to the influence of habitual inhalation of the smoke of dbatura alone is accompanied by conspicuous injury to them.

In carrying out the experiments there was no difficulty in securing the administration of charas so long, at all events, as the animals did not dislike the drug, as it can be mixed with milk, and mixture was for some time freely partaken of. In order, however, to secure
efficient inhalation of smoke of ganja or dhatura, it was necessary to provide a special apparatus, the nature of which is illustrated in the accompanying photograph.*

It consisted of a chamber which could be hermetically closed at all points, save where a supply and a discharge tube were connected with its opposite extremities. The walls of the chamber were composed of wood covered externally by a coating of zinc, and contained two windows closed with plate glass, one in either of the lateral walls. At one end there was a sliding door fitting accurately into a brass lined groove. The supply-tube entered near the bottom of one of the terminal walls arid the discharge one emerged towards the top of the opposite one so as to secure an even diffusion of the smoke throughout the interior of the chamber as far as possible. The supply-tube was connected distally with a large wash-bottle, through which the smoke from a chillum of ignited ganja or dhatura passed, and the discharge one with two large water-aspirators, which served to draw the smoke through the entire apparatus.

The great difficulty was to secure that no leakage should take place at any of. the numerous joints which were present throughout the apparatus, but this was overcome by the liberal application of cerate and clay, and it then worked most satisfactorily ; the only trouble which was encountered lying in the tendency which the portion of the supply-tube nearest the wash-bottle had to become choked by resinous matter which had not been completely removed from the smoke during its passage through the water.
The following notes indicate the details of procedure and results in the individual experiments.

EXPERIMENT I.

On the effects of the systematic inhalation of the smoke of ganja.

Nature of the animal employed : Macacus rhesus (3` weighing 16 lbs.

The first inhalation was administered on the 7th of November 1893 and the 12th of July 1894, so that the experiment extended over more than eight months. During this period one hundred and eighty one inhalations were administered. Durino. the greater rart of the period the administrations were repeated almost daily save on Sundays, but during March they were repeated only on alternate days, and during April and May only at irregular intervals owing to the fact that at that time the animal was suffering from a mild but prolonged attack of dysentery.

During the earlier part of the course of the experiment the animal apparently disliked the treatment as he violently resisted introduction into the inhalation-chamber, was restless when the smoke began to enter it, and not unfrequently attempted to prevent its entrance by plugging the orifice of the supply-tube. As time went on, however, and the experience lost its strangeness, his objections gradually diminished and were ultimately, replaced by a positive desire for the treatment. He then readily entered the chamber, resisted any attempts to remove him from it before he had had a full dose, was restless and uneasy on days on which the treatment was omitted, and on two occasions on which he managed to make his escape from his cage, showed an evident desire to enter the chamber on his own account.

The symptoms attending the process.of inhalation were not invariably of precisely uniform character. As a rule they came on quietly and insensibly and consisted in steadily increasing drowsiness, leading on to quiet sleep. Durino.° the course of exposure the conjunctiva:I and eyelids frequently became considerably congested, but this may, of course, have been merely dependent on direct irritation incident on their contact with the smoke. When removed from the chamber ere profound sleep had supervened the animal was evidently intoxicated. In many cases he was incapable of sitting up without supporting himself by means of grasping the bars of his cage, and, when less profoundly affected, being very unsteady on his legs. On being introduced into his cage, he not unfrequently either at once or after a short delay lay down and slept quietly for some time. On awaking from such sleep, as well as in those cases where sleep did not intervene, he almost invariably showed symptoms which appeared to indicate that he was for some time the subject of optical delusions. He gazed about attentively in directions in which nothing which seemed likely to excite his curiosity was present, and carefully scrutinised the floor of his cage for objects which did not exist. Suchsymptoms continued to persist for a considerable time after all other indications of intoxication had disappeared, continuinerb to manifest themselves in greater or less degree during the entire course of the latter portion of any day on which the treatment had been administered in the morning

On a certain number of occasions, however, the symptoms did not follow this normal course. On these the onset of signs of drowsiness was greatly delayed and had hardly began to show itself ere the animal was suddenly seized with violent general convulsions and immediately thereafter became profoundly unconscious. The symptoms on the recovery of consciousness in no way differed from those in cases where the earlier ones had followed the normal course. No satisfactory explanation of the occurrence of such exceptional phenomena could be arrived at, and it must remain uncertain whether they are to be regarded aethe consequence of certain temporary subjective peculiarities on the part of the animal or of variations in the quality of the drug.

In no instance was there any appreciable indication of the development of any cerebral excitement either during the administration of the drug or after intoxication had been fully established.

The normal symptoms were those of simple drowsiness and loss of will-power accompanied by optical delusions—those characterising the exceptional cases of temporary abnormal• activity of the spinal cord and basal ganglia which may very probably have been dependent on diminution in the inhibitory power of the higher cerebral centres.

The general health of the animal remained excellent during the entire course of the experiment save for a period during the months of April and May, in which he suffered from dysenteric symptoms. The occurrence of these, however, cannot be in any way definitely ascribed to the use of the drug as they are of frequent occurrence among monkeys in confinement apart from any special treatment. The only permanent appreciable effect resulting from the treatment manifested itself in the form of a very considerable diminutbn in appetite for food, which set in shortly after the initiation of the experiment and thereafter remained per, sistent throughout its entire course.

At the desire of the Hemp Drugs Commission the experiment was brought to a close on the day following my return to Calcutta on the 12th of July 1894. Death was induced by mehns of prolonged administration of chloroform, and a post-mortem examination was conducted immediately it had occurred. The results of this were as fogow in so far as mere casual naked-eye-inspection goes, for, as I have already pointed out, the detailed histological examination of thecondition of the various organs and tissues is a matter not of a few hours' but of many weeks' work, so that it has been impossible for me to carry it out and at the same time to meet the wish of the Commission for the immediate submission of a report. Specimens of all the more important organs have, however, been carefully preserved and will form the subject of detailed histological examination hereafter.

Results of post-mortem examination of the animal.—The body weighed 13 lb. 7 oz., indicating a loss in weight of 2 lb. 9 oz. during the eight months of treatment. This, or at all events, the whole of this loss, is certainly not fairly creditable to the treatment, seeing that for a considerable period not long before the close of the experiment the animal had been subject to an attack of dysentery, which would alone have been sufficient to occasion considerable loss of weight.

On laying the body open the phenomenon which at once attracted attention as unlike any ordinarily present in caged monkeys, was the great amount of fat accumulated in the omentum, the mesentery and the visceral and parietal pericardium. This was specially noteworthy in connection with the markedly diminished ingestion of food which had characterised the subject of the experiment during the greater part of its course, and with the coincident considerable reduction in body-weight which had occurred.

The body generally appeared to be fairly well-nourished and a considerable amount of subcutaneous fat was present.

The lungs were quite exceptionally healthy for a caged monkey; neither of them being in the least degree adherent to the thoracic walls, the left one being apparently perfectly healthy, and the right merely showing a few, patches of deep congestion towards the base.

Under the influence of the osrnie acid contained in the fixing solution in which .specimens of it were immersed, the muscular tissue of the heart showed unequivocal signs of the presence of a certain amount of interstitial fat. Whether, however, these were due to true fatty degeneration of the muscular elements proper, or, as is more probably the case, to mere fatty accumulation in the connective tissue, must remain an open question until the detailed histological examination of the tissues has been carried out.

The liver, spleen and pancreas appeared to be perfectly normal, save that, as in the case of the cardiac muscle, a slight excess of interstitial fat made its appearance under the influence of osmic acid.

The kidneys, the stomach, the large and small intestines and the cerebro-spinal nervous centres were all apparently perfectly healthy.

The only peculiar features in the body, then, which could in any way be rationally regarded as connected with the treatment to which the animal had been exposed, were the excessive accumulation of fat in the tissues of the omentum, peritoneum, and pericardium, and the tendency to the establishment of a similar accumulation in the cardiac muscle, the liver, the pancreas and the spleen.

But the only persistent symptom attending the treatment during life was a considerable diminution in appetite for food, so that, in so far as the results of a single experiment afford any ground for inference, it would appear that the most important effect of the habitual employment of inhalations of the smoke of ganja is to give rise to diminution in the normal processes of tissue-waste to such a degree that local accumulations of fat are liable to occur even in spite of the coincident and similarly originating diminution in the ingestion of food. The diminution in activity of the normal processes of tissue-waste tends, on the one hand, to give rise to decreased ingestion of food and on the other to local accumulations of fat in spite of this. But, if the habitual practice of inhalations of the drug really do produce such effects, it is clear that, in place of being hurtful, it may be positively beneficial to people who are obliged to undergo exertions without having the means of procuring a diet fully adapted to make good the amount of tissue-waste normally associated with these. As has been already pointed out, it is necessary to exercise extreme caution in coming, to any definite conclusions from the experiment, first, because it is an isolated one, and, second, because the post-mortem examination has not yet been histologically completed, but the evidence which it has afforded, is, in so far as it goes, rather in favour of the use of the drug under certain conditions than adverse to it.

EXPERIMENT II

On the ejects of habitual ingestion of charas.

In this experiment two small monkeys (M. qnomolgus) were employed. One of them, A, weighed 5 lb 7 oz., and the other, B, 4 lb 1 oz.

A standard globule of the drug, representing the amount of his ordinary dose, Was obtained from a habitual ebaras-eater. It weighed 1'05 grain and at the outset of the experiment one-twentieth part of that amount was daily administered to A, and one-twentyfourth part to B, as approximately proportionate doses weight for weight, as compared with those of the man and his ordinary doses.

The drug was rubbed up with a little milk and the animals readily partook of the mixture. Doses of the above amount were daily administered for some time, but, as they failed to produce any appreciable symptoms, the quantity was then gradually increased, until towards the close of the experiment as much as 3 grains, was given daily to each of the animals.

The experiment was begun on the 31st October 1893 and continued until the 6th January 1894, and during this period doses were administered on 62 days. The original small doses were employed until the 12th November when the amount was somewhat increased. On the 25th November the dose was raised to 0.52 grain, on the 28th December to 2 grains and on the 30th December to 3 grains.

No conspicuous effects manifested themselves during the entire course of the experiment. At the outset the animals appeared for a time to be somewhat quieter than they had been previous to the administration of the drug, but, if this were in any way a consequence of the treatment, it was one of very transitory nature as it soon wore off, ani during the whole of the latter part of the course of the experiment they appeared to be entirely unaffected in any way, and were quite lively. Their appetite for food underwent no appreciable alteration throughout.

The rapid and considerable increases in the amount of doses of the drug which were latterly made unfortunately had the effect of bringing the experiment to an abrupt and untimely termination, for after they had for a few days partaken of doses of 3 grains both animals simultaneously absolutely declined to touch the milk containing the drug, and, in spite of repeatedly renewed attempts to induce them to resume the habit, they have persistently refused to do so up to the present time. They were therefore only under treatment from the 31st October until the 6th of January, which was the last day on which they could be induced to partake of the milk, and the only noteworthy phenomenon which presented itself during the entire course of the experiment was the abruptness with which an extreme distaste for the drug set in. This is the more remarkable when compared with the phenomena which presented themselves in connection with continued treatment by inhalations of ganja. In the case of the ingestion of charas continued treatment was accompanied with the development of a distaste for the treatment, whilst in the case of ganja-inhalation it led to the acquisition of an abnormal craving for it.

EXPERIMENT III.

On the effects of habitual inhalations of the smoke of Me seeds and leaves of dhatura.

The subject of experiment, as in the case of that on the effects of the inhalation of the smoke of ganja, was a fair-sized specimen of Macaens rhesus. The treatment was initiated on the Ist June and continued until the 11th July, so that the experiment lasted for a period of about six weeks. In its conduct the same inhalation-apparatus was employed as in the first experiment. At the outset the seeds of dhatura were made use of as the source of smoke, but as the latter appeared to be undesirably potent, leaves were presently substituted for them and were persistently employed throughout the rest of the experiment.

The symptoms attending the treatment were not invariably quite uniform in character. On some occasions indications of a certain amount of cerebral excitement were present for some time, but as a rule drowsiness and gradually increasing intoxication manifested themselves from the outset, either alone or associated with symptoms of irritation of the respiratory apparatus as indicated by coughing.

The animal was killed by means of prolonged administration of chloroform on the morning of the 14th July and a post-mortem examination conducted at once with the following results :

The lungs were not adherent to the thoracic walls, but were both deeply congested almost everywhere, and specially towards their apices in which numerous tubercular nodules and small cavities were present. Such phenomena are, of course, very frequent in the lungs of monkeys in confinement, but it remains possible that the general pulmonary congestion may have been partially due to irritation incident on the inhalation of the smoke. The visceral pericardium was almost devoid of fat and was somewhat thickened and opaque, especially over the region of the right auricle. The omentum and mesentery were also very free from fat. The spleen appeared to be rather anemic and was somewhat fibroid in texture. The liver, pancreas, stomach, large and small intestines, and kidneys presented no abnormal appearances.

On opening the cranium the dura-mater was found to be somewhat thickened and, especially in the neighbourhood of the superior longitudinal sinus, very conspicuously congested. In this region, too, the membrane in the occipital region was fixed to the cranial walls by soft, very vascular adhesions. The pia-mater was thickened and so highly injected throughout that the cerebral surface had a generally diffused pink tint. The cerebral substance was everywhere abnormally soft and so friable as to render any immediate removal of the membranes impossible without the occurrence of much destruction of the nervous tissue. Like the surface, although in minor degree, it was of a pinkish tinge owing to abnormal accumulation of blood. Conditions of this kind appeared to be universally diffused throughout the whole of the cerebral centres, the texture of the hemispheres, of the cerebellum and of the basal ganglia being alike soft, and the evidences of abnormal congestion universally distributed. In spite of this, however, the spinal cord and its membranes were to all appearance perfectly healthy.

In so far as a single experiment goes the results in this case would, then seem to show that the habitual inhalation of the smoke of dhatura, even when only practised for a relatively brief period, is sufficient to establish serious morbid changes in the cerebral nervous centres, and that it therein differs from the habitual inhalation of the smoke of ganja extending over a much more prolonged period. This clearly indicates the necessity of distinguishing between cases in which ganja alone is employed from those in which a mixture of ganja and dhatura is substituted for it, as otherwise certain prejudicial effects which are really due to the use of the latter drug may be erroneously credited to the former one.

The 21st July 1894.    D. D. CUNNINGHAM.