Colloid Chemistry of the Nervous Systems. IV

THE COLLOID CHEMISTRY O F T H E NERVOUS SYSTEMS. IV* BY WILDER D. BANCROFT, ROBEcRT S. GUTSELL,

** AND JOHN E.

RUTZLER, JR.

* **

More than thirty-two years ago MacLeod found that morphinism could be cured by the use of bromides,’ still practical advantage has not been taken of this discovery. The fact that MacLeod’s work made no useful impression seems to be due to the utter lack of understanding of why sodium bromide should help drug addicts. I n the light of the theory of reversible agglomeration intelligent use can be made of MacLeod’s facts. The natural attack upon the problem, bearing in mind the work with sodium bromide and the theory of reversible agglomeration, is to attempt to cure drug addiction by the use of sodium rhodanate which is a better peptizing agent than sodium bromide. Since no drug addicts were available who cared to undergo a purely experimental treatment, and since the general medical profession is loath to act upon a theory, it became necessary to perform experiments on addicted dogs. Tatum, Seevers, and CollinsZ say: “An experimental study of morphine poisoning, both acute and chronic, has for its goal the elucidation of the corresponding conditions in man. A direct study of morphine poisoning in man is complicated by the state of mind of the subject, consequently that aspect of the problem approachable by the methods of the physiological laboratory is more safely based on controlled laboratory experimentation.” So, it would seem that in some respects it was well that our first experiments were made on dogs. Plant and Piercea say that there is quite a bit of variability in the withdrawal symptoms when a group of dogs is withdrawn from morphine abruptly. The withdrawal symptoms of the dogs as a group gave a composite picture which is similar to that obtained in man. These writers conclude that the dog is the best laboratory animal for the study of morphine addiction. Tatum, Seevers, and Collins believe that the monkey is more suitable for such studies than the dog. The dog was used in our work because they are easier to obtain, less expensive, and more hardy. Since dogs cannot administer morphine to themselves, the only way to test the validity of the theory that reversible agglomeration is responsible for many, if not all, of the symptoms of drug addiction and withdrawal is to withdraw the animals abruptly under the influence of a peptizing agent. Mental rehabilitation can hardly be studied to advantage with dogs. *This work is done under the programme now being carried out at Cornel1 University and sup orted in part by a grant from the Heckscher Foundation for the Advancement of Reaearcg established by August Heckscher a t Cornell University.

**M. D. ***Eli Lilly Fellow. 1 Bancroft and Rutzler: Proc. Nat. Acad. Sci., 17, 186 (1931). * J. Phmm. Exp. Ther., 36, 447 (1929). a J. Pharm. Exp. Ther., 33, 329 (1928).

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WILDER D. BAXCROFT, ROBERT S . GUTSELL, JOHN E. RUTZLER, JR.

With the work of the above five authors as a guide, the experiments reported in this paper were made in order to determine whether or not sodium rhodanate will control the symptoms produced by the abrupt withdrawal of morphine from addicted tissues. Six dogs were used in this work. Before the experiments were started the animals were allowed to become acclimatized to their new surroundings. This procedure eliminates such things as depression due to homesickness and physiological upsets due to change of food and habits. This collection of dogs included one male collie, designation CI, about two years old, one female collie, designation Cz, about two years old; one female mixed hound, designation HI, about one year old; and three female beagles, designations B I , B2, and B3. The beagles were litter-mates, and were about two and one-half months of age. During the period of acclimatization the dogs were studied so that some of their peculiarities could be observed and used for comparison later on. CI was a wild, brainless dog; he was neither malicious nor interested in human beings. Affection did not seem to appeal to him. When chained up outside, this dog would bark continuously a t the sky for long periods a t a time. Cz was a thoroughbred; she was very quiet and ladylike, with a tendency to be shy. She was not cowardly, and responded gratefully to human company. H I was vivacious, and continually sought human affection. B I , Bz, and B3 were typical puppies; they were full of life and interested in everything. They banded together when allowed outside. None of these animals showed any tendency whatsoever to be mean; although it was not easy to impress things upon C I . Others who have experimented on morphine addiction in dogs used large doses of morphine (30 mg. per kg. to more than IOO mg. per kg.). The smallest dosage used by Plant and Pierce was 30 mg. per kilogram; this corresponds to about 32 grains a day for an average-sized man, and is a large dose. They say, p. 342, that “there was no distinct relationship between the size of the dose at withdrawal and the severity of the symptoms although the two animals that showed very marked symptoms were withdrawn at a low dosage level (30 and 40 mgm. per kilogram).” I t will be clear, in the light of the theory which will be discussed later, that any continued dosage of morphine sufficient to produce a physiological effect will bring about addiction to the drug. So, in addicting our dogs, small doses of morphine were administered a t the start and the dosage level was never increased greatly. The dosage increase per unit of time in the case of Cz, B I , Bz, and B3 was the same, 0.0032 gram every other day from the 12th to the 41st day. The mode of addiction of these four dogs was therefore identical, disregarding variations in weight. In this manner it was hoped that the dogs could be addicted without profoundly disturbing their physiological processes. Likewise inherent physiological weaknesses should not play such an important rtile in the behavior of the animals on small doses of morphine as on large doses. Therefore the initial amount of morphine used was carefully made small enough SO that the dogs were not deeply narcotized by the drug. The dosage was never increased rapidly enough to bring about narcosis.

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“Abstinence’ phenomena are more marked after a progressive rise in dosage than on a constant small or moderate dosage.” I t is a well-known fact that the morphinist requires more and more of the drug to “keep him comfortable” as the time during which he is addicted becomes longer. This fact is easily explained on the basis of the theory of reversible agglomeration. This corresponds to the well-known cases2 in which more of a salt is necessary to cause agglomeration if the salt is added slowly to the sol. So, for both practical and theoretical reasons the dogs were given increasing doses of

morphine during this study. Fig. I shows the amount of morphine injected subcutaneously each day during the course of these experiments. A detailed record of the behavior of the dogs during addiction and withdrawal follows. This is useful because it shows a complete behavior picture which includes many mental reactions not hitherto described. First Day The addiction period was initiated on Wednesday, September 16, 1931. BI, Bz, and B3 were given one quarter of a grain of morphine sulphate each a t 10:15 a. m. The alkaloid was dissolved in sterile distilled water, a procedure which was followed throughout. I n less than ten minutes the three dogs quieted down markedly; and each of them vomited. They did not seem to be in great distress; the vomiting was not severe. The two collies, C I and Cz were given one half grain of morphine apiece. These dogs quieted down and vomited just as the puppies did. All of the dogs were quiet and sleepy during the afternoon; they refused food a t night. Second Day, September 17th The dogs were injected at 9:30 a. m. They refused food a t the morning feeding hour. Each of the dogs appeared to know that something was going ‘Taturn, Seevers, and Collins: J. Pharm. Exp. Ther., 36,452 (1929). Bancroft: “Applied Colloid Chemistry,” 296 (1926).

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WILDER D. BANCROFT, ROBERT 8. GUTSELL, JOHN E. RUTZLER, JR.

to happen to them when the experimenters appeared. The animals became markedly quieted after the injections; all of them vomited. The effects of the morphine seemed to be manifested more quickly than on the first morning. The dogs did not appear to be so lethargic this afternoon as during the first afternoon. Their appetites were better a t night.

Third Day, September 18th The dogs accepted food this morning; they were very lively before the injections which were made a t I O a. m. This provoked vomiting within a very few minutes. All of the dogs except C2 again were depressed by the morphine. Since Cz was naturally quiet and well behaved, the depressing effect of the morphine was not so noticeable. Before noon the dogs were very quiet. CI,the hyperexcitable collie who always before had barked a t automobiles, did not even move when an automobile drew up. During the afternoon the dogs slept as much as they did on the.afternoon of the second day. Their appetites were somewhat improved. Fourth Day, September 19th The injections were made at I O : I S a. m. Vomiting resulted as usual; all of the animals quieted down after the injections. The hind legs of B I , B2, and B3 moved with an ataxic gait. According to Sollmann‘ this ataxia is not an unusual reaction of dogs to morphine. The animals refused their evening meal; in general they acted the same as during the third day.

Fifth Day, September 20th The dogs were injected at 10:30 a. m. Before the injections were made, a study of the dogs showed them not to be so lively as they have been in the mornings. This may be due to the fact that it was a damp rainy day. It seemed to require a longer time for the morphine to bring about vomiting this morning. The drug quieted the dogs, as usual. The dogs are fed a t 6 a. m. and 6 p. m. They have been refusing the evening meal and accepting the morning meal. The animals were more or less somnolent all day. For the last two days CI has been salivating a great deal. Cz salivated after vomiting today. Sixth Day, September 21st Before the injections this morning all of the dogs were more animated than on the fifth day. The dogs were weighed for the first time today. Fig. z, which will be discussed a t different places in this paper, shows how the weights of the dogs varied during the course of the experiment. Morphine was injected a t 10:oj a. m. today. The animals did not seem to quiet down so much after the injections today; but they all vomited as usual. CI salivated profusely when observed during the afternoon. He was very “dopey,” and his gait was distinctly ataxic. Cz salivated slightly, and was very quiet. B I , Bz, and B3 were salivated, and hardly depressed a t all. By and large, the dogs were affected less by the morphine today than on other days. The dogs’ appetites continued to be poor. “A Manual of Pharmacology,” 219 (1917).


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FIQ.2 Curve I , dog Cr Curve z, dog Cz Curve 3, dog H I

Curve 4, dog BI Curve .s, dog Bz Curve 6, dog B3

Seventh Day, September 22nd BI, Bz, and B3 were quite active this morning, as usual. Cz was quiet, but was interested in the events occurring around her. C I was disinterested this morning. The addiction period of H I was started this morning. The onset of vomiting after the administration of morphine was somewhat delayed today. C I , Cz, and H I vomited; while B I , Bz, and B3 were not observed to vomit a t all, H I was not depressed much by the morphine. The drug definitely did not quiet down B I , Bz, and B3 so much as it had heretofore. It can be seen from the behavior of the dogs as a group that they have acquired a tolerance for morphine. During the afternoon C I was disinterested and exhibited a very ataxic gait. This was a hot day, and CI may be affected more by the heat than the other dogs. He went out of his way to avoid human beings. Cz was quiet, but acted much brighter than she did yesterday afternoon. B I , Bz, and B3 appeared to be unaffected by the morphine that was administered during the morning. H I was neither vivacious nor badly depressed by the morphine. Eighth Day, September 23rd This morning all of the dogs were much livelier than they were on the previous few mornings. Cz seemed very shy and quiet; this is probably the natural temperament of Cz for she is a bright dog, and while shy and quiet she was by no means disinterested. The dogs were unusually friendly toward the experimenters this morning. Morphine was injected a t 10:35 a. m. BI, Bz, B3, and C I lost their vivacity after they were injected, No signs of vomiting were noticed. This morning it was possible to inject all of the dogs except H I without holding them tightly. B I , Bz, and B3 no longer appear to be constipated. During the afternoon CI was more animated than he was yesterday; also, his gait was less ataxic. He appeared to be less afraid of

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WILDER D. BANCROFT, ROBERT

s.

GUTSELL, JOHN E. RUTZLER, JR.

people than he has been. C2 did not exhibit any depression in the afternoon from the injection. The morphine has changed the character of this dog. While she is very friendly when approached, she appears to be seclusive, quieter, and more shy than she was. She does not seem to care for human company any more; but she does not attempt to repel it. B I , Bz, and B3 were not excessively quiet this afternoon. Whereas they followed the experimenters around without coaxing this morning before the morphine was administered, they ran away when approached this afternoon. H I was quieter than during the previous afternoon; but she was not depressed much by the drug. Ninth Day, September 24th The dogs were quite lively this morning. C I appeared to both expect and want the drug. B I , Bz,and B3 were very salivated. C2 was brighter today. Since tolerance to the vomiting reaction, and to a lesser degree to the depressing action, has apparently been established, the dosage of morphine was raised this morning. The dogs were weighed before they were injected. All of the dogs vomited fdlowing the injections with the exception of H I ; they were all quieted by the drug. It is interesting to note that HI is so constituted that her vomiting center is not stimulated by nxrphine like the other dogs. When the experimenters appeared in the afternoon all of the dogs were quiet and very salivated. Upon being released, they were as animated as they were yesterday. Although HI was more depressed than she was yesterday she was not salivated. All of the animals whined this afternoon. The ataxia exhibited by CI persisted today.

Tenth Day, September 25th The dogs acted as usual this morning; they were neither more nor less lively than on the preceding few mornings. However, they are not nearly so lively in the mornings now as they were on the first few mornings of the addiction period. Morphine solution was’injected a t IO:OO a. m. The dogs became quiet after the injections. HI vomited for the second time. All of the other dogs vomited. At noon the dogs were still quiet; they were not somnolent or greatly depressed. I n general, the morphine has not caused the dogs to be “dopey” and dispirited. Their reactions are better characterized as being less vivacious and somewhat slowed down. Eleventh Day, September 26th All of the dogs were quite animated this morning. B I , Bz, and B3 began to salivate when the experimenters appeared; they were not salivated beforehand. Cz acted quite differently today. She showed more interest in things, was much less shy, and more interested in human company. The morphine did not cause B2 and HI to vomit. Twelfth Day, September 27th The dogs were fairly lively this morning. B I , B2, and B3, and H I were especially lively. C2 continues to be less shy and more interested in things. CI has quieted down in a most striking manner. At the beginning of the


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experiment he was wild and scatter-brained. Now he is calm and does not evidence his brainless makeup so positively. Morphine was administered at I I :OO a. m. today. H I did not vomit and was not quieted much by the drug. C2 vomited after the injection and then became rather quiet. C I vomited also. CI and C2 commenced to salivate immediately after being injected. B I , B2, and B3 exhibited some interesting reactions this morning. Upon the appearance of the experimenters they all began to salivate profusely. So profuse was the salivation that the animals soon became wet all over their bodies. While B I was being injected, B3 looked on and vomited before the injection of BI was completed. B3 immediately consumed the vomitus showing that she was hungry and probably not nauseated. B2 vomited so quickly after the morphine was injected that the mechanism probably was not a stimulation of the vomiting center; she consumed the vomitus also. Reach’ considers that salivation before and after the injection of morphine is a withdrawal symptom. Pavlov2 and Collins and Tatum3 call it a conditioned reflex. Pavlov also describes reflex vomiting similar to that just pictured. There does not seem to be much question but that Pavlov is right; because, as will be seen later increasing the dosage of morphine failed to stop the salivation. Also, all of the dogs began to salivate when the experimenters appeared, no matter what time of day it was, or whether before or after the injections of morphine were made. I t was determined definitely that visitors did not induce this reaction. Thirteenth Day, September 28th The dogs were just as lively this morning as they were yesterday morning. They began to salivate shortly after seeing the experimenters, with the single exception of H I . The morphine dosage was increased today for all dogs except H I . The injections were made a t IO:OO a.m. B I , B2 and B3 vomited; but the other dogs did not. The larger dosage did not cause the dogs to become more quiet than usual. During the afternoon the animals acted no differently, so far as general appearance goes, than they did on the smaller dosage. They were not particularly quiet.. C2 was shy and self-contained, thus reverting to her earlier condition. B I , Bz, B3 and CI salivated profusely when the experimenters came in sight. The dogs’ appetites are better than they have been so far during the experiment. Fourteenth Day, September 29th Cz was less shy again today. When one of the experimenters came into the cage she prostrated herself at his feet. CI is becoming quieter and quieter. HI still acts very animated in the morning. BI, B2, and B3 have quieted down in the last few days so that they are not nearly so animated in the morning as they were during the first week of addiction. B I , B2, B3 and C I salivated profusely when the experimenters appeared. AMorphinewas ad‘2.exp. Path. Therap., 16, 321 (1914). 2 “Conditioned Reflexes,” 35 (1927). a Am. J. Physiol., 74, 14 (1925).

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s.


ministered a t IO:OO a.m. C I , B2, and B I vomited within 15 minutes after the injections. To date HI has been comparatively refractory to the drug; for it has not affected her as much as the other dogs. Fifteenth Day, September 30th Profuse salivation commenced today when the experimenters appeared. C2 exhibited a different reaction again today. The cloak of shyness has fallen once more; and she was more investigative. For the past few days this dog has submitted to the injection very undemonstratively. She appears to be ready for it when the experimenters approach her. H I was vivacious this morning. C I walked up to the experimenters as though he desired to be injected. When one of the beagles was taken out of the cage and into a room to be weighed and injected, the two other beagles began to howl. All of the dogs submit to the injections quietly so that extremely little restraint is necessary during the manipulation. The injections were made a t I O : I S a.m. Each of the dogs was examined for tenderness in the regions where the injections have been given. Since no tenderness was found, the conclusion is drawn that the dogs are not suffering from abscesses. No vomiting was witnessed after the morphine was administered today. Also, there was little, if any depression produced by the drug. To date the dogs have been on a diet of bread and milk. Sixteenth Day, October 1st The dogs presented the same general behavior picture this morning as they have for the last two mornings. The dogs salivated profusely, as usual. Morphine was administered a t 10:30 a.m. Bz was taken out of her cage and into a room to be injected. The other two dogs, B I and B3, howled almost as soon as the room door was closed. The morphine had very little affect on H I ; she did not vomit or become depressed. C I and Cz did not vomit. B I , B2, and B3 did vomit. CI, Cz, and H I were fed a pound of raw hamburg each; B I , Bz, and B3 were each given one-half pound of the raw meat at the evening meal time. Cz refused to eat hers at the time, but ate it during the night. Seventeenth Day, October 2nd B I , B2, and B3 were considerably more animated today; C2, H I , and C I acted as they have for the last few mornings. None of the dogs appears to be constipated. All of the dogs, except H I , salivated when the experimenters appeared. Morphine was administered at 10:3o a.m. The drug did not have any quieting effect on any of the dogs, with the exception of H I . She became only slightly less lively. About ten minutes after being injected C I began to whine and bark. He was not barking a t anything in particular; he turned his head away from the experimenters when he barked. The bark was a peculiar explosive halfhearted yelp. So far as could be determined there was no external cause for pain. This description of the behavior of C I illustrates the psychiatric abnormality of the dog which will be considered in detail later.


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The dogs were not seen vomiting today. At no time, before or after this day, during the experiment have any of the dogs growled, snapped, or acted mean in any way either during, before, or after the injections. During the afternoon H I was quiet and retiring. The other dogs acted the same as they have for the last few mornings before being given morphine. C I , C2 , and H I were each given a pound of raw hamburg. H I and Cz refused to eat the meat. C2 made vomiting movements when the meat was presented; she consumed the meat during the night. H I did not eat the meat a t all. Cr ate the meat hungrily; he was extraordinarily quiet and gentlemanly in the way he took the meat. B I and B3 were given three-quarters of a pound of meat. Bz refused the meat.

Eighteenth Day, October 3rd With the exception of H I , all of the dogs were livelier this morning than they have been during the past week. They all salivated prior to the administration of the drug; this is the first time that H I has salivated. The injections of morphine were made at IO:OOa.m. B I , Bz and B3 were taken, one at a time, into the weighing room to be given the hypodermic. When B I was taken into the room, Bz and B3 began t o howl. B3 began to howl when Bz was taken into the room. This reaction on the part of the dogs left behind being repeated, as it has, signifies either one of two things; either they wanted the injection of morphine, or they did not want their sister dog taken away from them. In the light of the behavior of the dogs later in the experiment, the former reaction seems to be the more likely. None of the dogs vomited after their dosage of morphine; likewise they were quieted very little by the drug. Of course, the dogs are not now so animated before the drug is injected as they were during the earlier part of the experiment. C I was more excitable this morning, and would not stand still while being injected. On the whole, the dogs seem very lively for the amount of morphine that must be in them. Nineteenth Day, October 4th Again this morning the dogs seemed a little more lively than they have been for the past week. The experimenters drove up to, and then 30 yards past the door of the experimental barn, and stayed there for about ten minutes. In a few minutes the dogs in the barn began to bark and howl. The loud baying of B I , Bz, and B3 could be distinguished clearly. Upon entering the experiment station none of the addicted dogs barked; whereas three other dogs continued to make a disturbance. C I was profusely salivated at this time. B I , B2, B3, Cz, and H I commenced to salivate upon seeing the experimenters. C I balked at being injected today, as he did yesterday. The drug did not quiet the dogs, with the exception of H I . She did not show much effect from the injection. Each of the three beagles was given its morphine just outside of the cage in the sight of the others. While B I was being injected B2 and B3 bayed loudly. Likewise B3 bayed while B2 was being injected. These dogs now stand still

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without being restrained at all while being given the hypodermic; they wag their tails during the process. C2 and HI do not have to be held either. All of the dogs were fed Calo dog food a t night. With the exception of H I they ate well. Twentieth Day, October 5th The process of driving past the door of the experiment station was repeated today with the same result as yesterday. The addicted dogs apparently become restless during the middle of the morning before they are given morphine. The restlessness subsides when the drug is given. The hypodermics were given at I I :ooa.m. Prior to this all of the dogs salivated. The morphine did not provoke vomiting. B I , Bz, and B3 repeated their baying performance of yesterday. The drug no longer seems to quiet the dogs after the injections. Twenty-first Day, October 6th The dogs did not make a commotion when the experimenters arrived today. Morphine was administered at I I :oo a.m. All of the dogs were salivated this morning. B I , Bz, and B3 repeated their act of the last two days. With the exception of CI, all of the animals stand still without being held while the injections are made. There were no evidences of vomiting after t h e morphine was administered today. C I is somewhat rebellious while being injected; his high degree of excitability is maintained. C z , CI, and H I appear to be constipated. Twenty-second Day, October 7th Again today the dogs did not make a commotion when the experimenters waited outside of the experiment station. All of the dogs salivated profusely before being injected; B I , Bz, and B3 were quite a good deal more salivated than the other dogs. This has been the case ever since these three dogs began to salivate. Morphine was administered at IO:ISa.m. The three puppies did not repeat the baying act. None of the dogs vomited after being given morphine. C z was somewhat less shy this morning; she was bothered by diarrhea. C I had diarrhea also. Twenty-third Day, October 8th Another interesting reaction was observed this morning. The day was dark and wet; and all of the experimental dogs were noticeably more quiet than usual. Three other dogs at the experiment station acted no differently than on other days. This same reaction has been observed several times. Quite independently of this the authors have been told by addicts who are not using the drug, but whose nervous systems have not returned to normal, that on dark, damp days they feel depressed. So, there seems to be an analogy here between the behavior of man and dogs. Morphine was administered at 10:30 a.m. B I and CI both vomited after the drug was given. The reaction was not so severe as usual. C I did not struggle while being injected. His hyperexcitability has disappeared. Neither

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C I nor Cz was bothered by diarrhea today. B I , B2, and B3 are not constipated. Most of the animals now wag their tails while being injected. Twenty-fourth Day, October 9th

It was cold today, and the addicted dogs were quiet. The other dogs were noisy. All of the experimental dogs began to salivate profusely before being injected. The drug was administered at 10:30 a.m. Only C I had to be held while this was done. None of the dogs came of their own accord into the room where the injections were made. CI and B I vomited after being given the morphine. KOsigns of diarrhea were seen. Cz was less shy than she has been. When the experimenters appeared in the afternoon all of the dogs began to salivate. There were other persons observing the animals when the experimenters came; but they did not cause the dogs to salivate. The degree of salivation was not nearly so great as it is in the morning before the dogs are given morphine. The dogs were fed Ken-L Ration during the afternoon. C I , BI, Bz, and B3 consumed it voraciously; the latter three dogs pranced around and fought for it. Yet the dogs refuse bread and milk, which they formerly liked. C2 ate the Ken-L Ration in a very lady-like manner. The experimental dogs have refused all but very appetizing food for the last two weeks. Twenty-fifth Day, October 10th All of the dogs salivated profusely this morning, when the experimenters appeared. While the animals were being observed, and before any preparations whatever were made for the injections, C I and BI vomited. This was in all probability reflex vomiting. Morphine was administered at IO:OO a.m. None of the dogs vomited after the injections. They were fed Ken-L Ration during the afternoon. Twenty-sixth Day, October 11th The experimenters arrived late in the morning. Despite the cold wet day, there was a great deal of barking and excitement. Upon entering the experiment station the addicted dogs became quiet, and showed no signs of excitement. The dogs salivated as usual. H I was bothered by diarrhea. None of the animals vomited after the morphine was administered at 12 :30 p.m. Twenty-seventh Day, October 12th The dogs began to salivate soon after the experimenters arrived. Morphine was injected a t I O : I S a.m. I t has been noticed that a short time after the drug is given the dogs stop salivating. CI was restless and hyperexcitable while being injected. He protested physically, but did not growl or snap. The other dogs did not have to be held while being injected. None of the animals vomited after being injected; further, they were livelier than usual after the drug was exhibited. Twenty-eighth Day, October 13th When the experimenters arrived the dogs salivated, as usual. C I is almost as scatter-brained and crazy as he was before the experiment was started.

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Morphine was administered at 9:15 a.m. C I again protested against being injected. He vomited shortly after the injection. This was probably reflex vomiting for he consumed the regurgitated material. None of the other dogs vomited. Twenty-ninth Day, October 14th In order to observe the reactions of the dogs if the exhibition of morphine were delayed, the animals were not injected until 5:30 p.m. After midmorning the addicted dogs were markedly uneasy and barked almost continuously until the experimenters came to inject them. The dogs became quiet and began to salivate when we arrived. Cz did not salivate until the injection was started. BI, Bz, and B3 were slightly restless and wandered around their cage in an aimless manner. None of the dogs vomited after having morphine. C I did not protest nearly so much as he did yesterday when given the drug. So it can be assumed that the dogs now have a physical need for morphine. At times several of the dogs have been bothered by conjunctivitis. Thirtieth Day, October 15th All of the dogs were salivated before they were given morphine. The drug was administered at IO:Ij a.m. The animals did not vomit after being injected. The morphine quieted the dogs more than usual today; this is probably due to the fact that a shorter time than usual elapsed between the last two injections. The conjunctivitis noticed in H I and C2 was treated with argyrol. C I protested strongly against the injection this morning. For the past week it has been noticed that the dogs attempt to defecate shortly after morphine is administered. Thirty-first Day, October 16th Each of the addicted dogs began to salivate when observed by the experimenters. CI remains scatter-brained and senseless; he protested against being injected. The dogs were quieted by the morphine somewhat more than usual. None of the animals vomited after morphine was exhibited. The conjunctival condition of Cz and H I is better today; it was treated again with argyrol. Thirty-second Day, October 17th Despite the fact that it was a cold and rainy day, the dogs were a little more lively; all salivated prior to receiving the drug. Morphine was injected a t IO:OOa.m. B I , Bz, and B3 wagged their tails while being injected. This has occurred for several days. It was definitely determined that the animals wag their tails much harder while the solutaon i s running out of the needle. The phenomenon commences during t h e pre-injection handling of the dogs; they do not wag their tails harder when the needle is thrust under the skin. H I and Cz are no longer suffering from conjunctivitis. CI presents a strange figure; during the injection he acted in a weird, scatter-brained manner. Then he vomited. Following this, for the second time in the last two days, he stood motionless with his head in a corner of the

I533


cage for quite a while. Further, during the last few days he has gnawed a two by four inch timber almost half in two. Plant and Pierce' consider this to be a withdrawal symptom. Therefore the dosage of morphine was raised more rapidly from this day on. The dogs were depressed extremely little by the morphine today. Thirty-third Day, October 18th The dogs began to salivate as usual this morning upon the appearance of the experimenters. Morphine solution was injected a t I I :oo a.m. CI protested wildly against the injection; in doing so he was not either mean or ugly in any way. He vomited after being given the morphine. B I , Bz, and B3 repeated their tail wagging episode. C I has a maniacal look. The dogs were fed Ken-L Ration during the afternoon. C I , B I , Bz, and B3 took this food voraciously. Cz refused to accept the food while being observed or coaxed. As soon as the experimenters were out of sight, she ate heartily. H I refused food entirely. A neutral, uninstructed observer remarked casually that CI looks like a maniac; it should be stressed that this dog has never cared for human society since coming to the experiment station. This afternoon it was again demonstrated that only the experimenters elicit the salivation reaction. A stranger watched the dogs for five minutes, and saw no salivation. Yet, a minute or two after the approach of one of the experimenters the dogs began to salivate. The secretion was not so profuse as it has been on other afternoons. All of the addicted dogs have undergone a change of character. They slink and act as though they have done something wrong, when they are approached. Thirty-fourth Day, October 19th H I and Cz failed to salivate when the experimenters watched them. C I was somewhat more quiet this morning. Morphine was administered a t 10:30 a.m. Cz vomited severely after the injection. H I , B I , Bz, and B3 began to wag their tazls only when the morphzne solutzon began to r u n through the hypodermzc needle. All of the dogs except H I seemed hungry when fed Ken-L Ration. C I balked at being injected so strongly that it was not advisable to try to administer the morphine while he was being held tightly. The dog quieted down when he was soothed, stroked, and talked to; this was continued, and he submitted t o the injection without protesting. I t was not necessary to restrain him at all. Thirty-fifth Day, October 20th With the exception of HI, the dogs salivated when the experimenters appeared. She did not salivate either before or after the injection. She has conjunctivitis again; it was treated with argyrol. As has been the rule for the past couple of weeks the dogs were quiet before morphine was administered. Cz was difficult to inject again this morning; he stopped making a fuss when he was soothed. J. Pharmacol. Proc., 31,

2 1 0 (1927);

J. Pharm. Exp. Therap., 33, 343

(1928).

1534

WILDER D. BANCROFT, ROBERT 6 . GUTSELL, JOHN E. RUTZLER, JR.

None of the animals vomited after being given morphine. H I and Cz became much more quiet after the drug was given. H I and Bz wagged their tails when the liquid ran out of the hypodermic needle. Thirty-sixth Day, October 21st There were no unusual occurrences today except the following. Cz vomited after being injected. H I and Cz were treated with argyrol for conjunctivitis. H I was not salivated. CI was difficult to inject. All of the dogs except CI, wag their tails when the morphine solution flows from the needle. Thirty-seventh Day, October 22nd Morphine was not administered until 6:oo p.m. The dogs were noisy all afternoon. They were quiet when the experimenters arrived. They became noisy when the experimenters did not enter the barn. It was obvious that the dogs were distinctly more friendly to the experimenters than they usually are. H I and Cz, in particular, came up to us in an extremely friendly manner. C I began to salivate before he saw the experimenters. H I did not salivate at all. CI was not quite so difficult to inject as he has been in the last few days. None of the dogs vomited after morphine was administered. It was decided that the dogs show sufficiently definite signs of addiction to morphine for them to be prepared for withdrawal. Accordingly Cz and B3 were selected for abrupt withdrawal without sodium rhodanate. The other dogs with the exception of C I are to receive daily doses of sodium rhodanate for a period of four days prior to abrupt withdrawal. During this time morphine will be continued in increasing doses. C I will be given sodium rhodanate today and be withdrawn abruptly tomorrow. CI was given 0.4 grams of sodium rhodanate in a gelatine capsule buried in a small ball of meat. BI and B2 were given one capsule each containing 0.2 gram of sodium rhodanate in a similar manner. A capsule containing 0.2 gram of sodium rhodanate was forced down the throat of H I . Sodium rhodanate was followed in ten or fifteen minutes by the injection of morphine. The dogs that were given sodium rhodanate seemed to become more quiet than the others after morphine was administered. Thirty-eighth Day, October 23rd When observed this morning Cz and B3 did not seem to be quite as bright as the other dogs. All of the dogs except H I began to salivate when the experimenters appeared. C I objected strenuously to being injected. Since raising the dosage of morphine more rapidly, this dog has not stopped gnawing the timbers of his cage. It seems therefore that gnawing is not necessarily a withdrawal symptom. In this case it is considered to be a nervousness which parallels his general peculiar character changes. The injections were made at 10:30 a.m., dosage with morphine being continued. B I , Bz, and B3 were not given morphine first this morning; they whined while the other dogs were being injected. H I made vomiting motions after the drug was given.


1535

Sodium rhodanate was given again this morning. The doses administered were: HI, 0.2 gram in a capsule per os, C I , 0.4 gram in a capsule in meat per os, BI, 0.2 gram in a capsule in meat per os, Bz, 0.2 gram in water by subcutaneous injection.

Thirty-ninth Day, October 24th All of the dogs salivated when the experimenters appeared, except HI. The dogs were quiet as has been usual in the morning for the past few weeks. C I did not look so maniacal today. Morphine was injected a t IO:Ij a.m., none of the dogs vomited afterward. C I was withdrawn abruptly today, that is he received no morphine. Sodium rhodanate was administered again today. C I was given 0.4 gram in a capsule in meat per os. H I , B I , and B2 were given 0.2 gram each in water solution by subcutaneous injection. The injection was quite painful to B I , it did not pain Bz or H I . Fortieth Day, October 25th Cz salivated more profusely than ever today; HI did not salivate a t all, and Bz salivated very little. For the last few days Bz has not salivated

much. This dog acts more nearly normal than she has for some time. Morphine was administered at I I :oo a.m. None of the dogs vomited after the injections. The behavior of C I deserves special mention. He looks definitely less maniacal than he has lately. This morning he was more friendly than he has been for three or four weeks. He did not act so brainless and crazy as he has during the entire course of the experiment. He was lively in a normal way, which is most unusual. These changes were sharp and well-defined. He still gnaws at the supports of his cage. He passed a soft stool today. Sodium rhodanate was administered as follows: C I , 0.6 gram in a capsule in meat per os; H I , B I , and Bz, 0 . 2 gram in water solution by subcutaneous injection. These injections did not pain any of the dogs today.

Forty-first Day, October 26th Morphine was administered at 3:30 p.m. The dosages of sodium rhodanate given were: C I , 0.4 gram in a capsule per os in meat; H I , and Bz, 0.2 gram in water solution by subcutaneous injection; B I , 0.3 gram in water solution by subcutaneous injection. C I continues to gnaw industriously at the wood supports of his cage. For the first time in many weeks he showed interest in another dog. He does not show signs of diarrhea. The dog salivated less than usual. He showed definite signs of interest in human affection; he sought stroking by the experimenters. When led from place to place he did not balk as he does usually. A rapid, nervous opening and shutting of the jaws was noticed. The action did not last long, and was probably an effort to free his mouth and lips of saliva. This animal is improved much today; remarkable improvement in his general behaviour has been noticed in the last few days.

1536


H I is in very poor physical condition; she is, and has been, losing weight rapidly. She did not salivate today. Her nose is stopped up by dried mucus; the nasal passages are very dry. The conjunctivitis has disappeared. The injection of sodium rhodanate did not appear to pain her. This dog and B3 have been and are more interested in other dogs than are any of the experimental animals. H I sprawled out on the floor of her cage and gave the appearance of being drowsy after the injections. She is markedly tender over the hips. C2 salivated today, as usual. For the last few days she has turned over on her back when the experimenters came to her cage. This may be an indication that she wants the drug. The condition of this dog remains the same as it has been. B3 now is the liveliest by far of the three litter-mates, BI, Bz, and B3. When Ken-L Ration was offered to these three dogs only B3 showed any interest in it; she consumed it all. She wagged her tail when the morphine solution ran out of the needle. BI exhibited a reaction of pain to the injection of sodium rhodanate today. After the injections she curled up in her cage and was disinterested. B2 seems to be disturbed by the treatment. She was disinterested when the experimenters arrived, and remained so after the injections. She has not been so salivated as the other dogs, of late; today she began to salivate quite a little while after BI, and B3 began. The injection of sodium rhodanate did not cause this dog or HI to be in any pain. Bz vomited often yesterday; she shivered, and was not lively. When sodium rhodanate is injected the dogs do not wag their tails; whereas they do wag them when morphine is injected. This is the last day that morphine will be administered to any of the dogs. Abrupt withdrawal will begin, therefore, tomorrow.

Forty-second Day, October 27th Sodium rhodanate was administered a t 12:oo noon as follows: C I , 0.4 gram in a capsule in meat per os; H I , BI, and B2, 0 . 2 gram in water solution by subcutaneous injection. HI did not salivate when the experimenters approached. This dog is a sick dog, and has been that way for a week. The rapid loss of weight has weakened her considerably. She was not well before sodium rhodanate first was administered. During last night she stretched out on her side and was extremely disinterested. She was better this morning; she was more friendly than she has been for a couple of weeks. Her eyes were very pussy today; the condition was treated with argyrol. CI was more friendly again today. He is more quiet than he has been for some time; this does not appear to be due to depression. He is merely acting more like a normal dog. His stools are soft; but he does not have diarrhea. His appetite is good. He does not salivate so much as he did; most of the time his ears are pricked up and he is alert.


I537

Bz appeared to be subdued and disinterested; there was no change in her response to human affection, that being strong as usual. This dog did not salivate when the experimenters were around. The injection of sodium rhodanate evidently caused no pain. BI was salivated profusely when the experimenters appeared. The injection of sodium rhodanate did not hurt this dog so much today. She did not become disinterested after the injection. Cz salivated as usual when the experimenters observed her. B3 acted likewise. These two dogs showed no change in condition. Forty-third Day, October 28th Sodium rhodanate was administered as follows: C I , 0.4 gram in a capsule in meat per os; B I and B2, 0 . 2 gram in water solution by subcutaneous injection. HI was not given any sodium rhodanate on account of her poor physical condition. This dog has distemper; that is what has been ailing her. Other than to say that H I did not at any time show withdrawal symptoms, the detailed account of her behavior from this time on will be omitted. C I continues to improve; he is a sensible dog now. He has ceased gnawing at the wood in his cage. The dog was only slightly salivated today; and there are indications of diarrhea. Other observers have noticed that this animal is brighter. His appetite is better. C Z passed soft stools today. Only a very careful study revealed her true condition. The dog appears to be much brighter with not such a far-off look in her eyes. Upon the arrival of the experimenters she entirely forsook her shyness and quiet demeanor and approached them tail wagging, head up, with no hesitation, and without being called. This behavior was so foreign to her general conduct that her actions were like those of a different dog. This performance was repeated; she was then shown the hypodermic syringe which she nosed in a thoughtful manner. When the motions of injecting her were made she wagged her tail much harder. The dog quite definitely wanted the injection. Upon approaching the dog without the syringe in hand, she did not stir out of her corner. This was repeated several times with the same result. This dog either thought that the needle being thrust under the skin was an injection of morphine, or that by being friends she would not be given morphine. If the former situation is the correct one, there is in the actions of this dog a distinct parallel to the behavior of human addicts. On the other hand she may have learned quickly that she was not to have morphine today. The brightness and friendliness exhibited by this dog were probably due to nervousness. A slight horizontal head tremor was noticed. B3 exhibited the same head tremor as Cz;otherwise there was no change in her condition. Bz was more lively than she was yesterday; she did not salivate when the experimenters appeared. There was no change in the condition of BI.

I 538

WILDER D. BASCROFT,

ROBERT

s. GUTSELL, JOHN E. RUTZLER, JR.

Forty-fourth Day, October 29th H I , BI, and B3 were each given 0.2 gram of sodium rhodanate dissolved in water by subcutaneous injection a t 12:oo noon. CI was not given sodium rhodanate. All of the dogs except H I and B2 salivated when the experimenters appeared. None of the dogs salivated so profusely as they have been doing. Cz behaved in the same peculiar manner that she did yesterday. The head tremor persists. The dog passes stools frequently. She refused Ken-L Ration. B3 defecates often. She is definitely nervous; a slight head tremor is noticed now and then. Today she was not so friendly as B I and Bz were. The animal would not eat Ken-L Ration. There was a very fine general body tremor that could not be detected with B I and Bz. BI and B2 were quite friendly today; but they were not unusually so, as C2 has been. They appear to be very slightly depressed. No special change was noticed today. These dogs are not passing soft stools as B3 and C2 are. CI was no different than he was yesterday. Forty-fifth Day, October 30th Sodium rhodanate was administered only to C I today; he was given 0.6 gram in a capsule in meat per os at 5 :30 p.m. CI exhibited some important changes. He has lost all interest in human affection, is scatter-brained again, and has a maniacal look in his eye. Evidences of diarrhea were seen. The dog vomited reflexly upon seeing the experimenters; there was apparently a spastic condition of the stomach. He was hungry for he consumed the vomitus immediately. When being watched he turned his head and body toward the inside corner of the cage. This appeared to be due to negativism rather than to photophobia. The animal salivated when the experimenters appeared. He has resumed gnawing, having gnawed a hole in the wall. Shortly after being given sodium rhodanate the dog vomited again. I t is important to note that this dog has not had sodium rhodanate for almost two days, which accounts for his peculiar actions. When one attempted to pat the dog he walked off. Every once in a while he emitted a low moaning whine. C Z behaved like an entirely different dog today. When observed she was lying stretched out on her side in a disinterested fashion. Although she wagged her tail in a feeble manner, she neither moved the bulk of her body or looked up when the experimenters came. Upon entering the cage she made no movement to arise. After several repetitions of this the dog finally arose slowly. She laid down again almost immediately; and she did not move around during the brief time that she was on her feet. Although the dog was disinterested and was not lively a t all, she did not in any way resent affection. The dog salivated when the experimenters came. The head tremor was pronounced today. The dog has diarrhea. She had no appetite, as was evidenced by the fact that fresh meat remained untouched in her pan.


I539

B3 was disinterested today; she did not move when first approached in her cage. She showed little interest in leaving the cage when given an opportunity to do so. When she wandered about the cage a little her movements were slow and aimless. She showed evidences of nervousness. Normally the hungriest of the three young dogs, she refused fresh meat; whereas B I and B2 ate all that was offered them. B3 salivated when the experimenters appeared. There was a pronounced head tremor today; and the body tremor is stronger than it was yesterday. She is doing considerable gnawing at her cage. BI and B2 acted about the same as they did yesterday. The dogs seemed to be hungry for meat, particularly B2. No soft stools were noted. The dogs arose when the experimenters entered the cage, and were friendly. They seemed more interested than they did yesterday; they cared for human affection, and did not wander aimlessly about. The general health of Bz seems to be better than it has been since the start of the experiment. B I salivated when the experimenters appeared, Bz did not. None of the dogs salivate so profusely as they did when receiving morphine.

Forty-sixth Day, October 31st Sodium rhodanate was administered a t 10:30 a.m. in water solution by subcutaneous injection. H I was given 0.1 gram, and B I and Bz 0.25 gram each. C2 was inquisitive about the hypodermic syringe when it was shown to her. She wagged her tail rapidly when motions were made to inject her. She was lying on her side when first observed, and did not get up a t all. She wagged her tail feebly when she first saw the experimenters. A very fine body tremor accompanied the head tremor. Her appetite seems somewhat better. The dog continues to pass many stools. She salivated when the experimenters appeared. B3 acted about the same as she did yesterday. She was perhaps a little more quiet today. She was neither friendly nor unfriendly. The head and body tremor were still present. She salivated when the experimenters appeared. Her appetite seems to be better. CI was changed again today. He was more friendly and interested in what was going on. The maniacal look in his eye subsided; he did not face the back of his cage. So, sodium rhodanate again caused a change for the better in this dog. There were signs of diarrhea. BI and B2 were more lively today. The general health of Bz in improving rapidly. Both dogs salivated when the experimenters appeared. No soft stools were passed by these dogs. BI and B2 were extraordinarily demonstrative and friendly today. Since they were not given sodium rhodanate yesterday, this reaction may be interpreted as a desire for morphine such as was shown by C2 on the forty-third day. I n complete contrast to B3, B I and Bz were anxious to leave their cage. A test for the rhodanate ion in the saliva was positive in the case of BI and Bz.

1540

WILDER D. BANCROFT, ROBERT S. GUTSELL, JOHN E. RUTZLER, J R

Forty-seventh Day, November 1st Sodium rhodanate was administered as follows: CI, 0.6 gram in a capsule in meat per os; BI and B2,o.z gram in water solution by subcutaneous injection. All of the dogs except H I have had, in general, better appetites since the morphine was withdrawn, despite the fact that at times for periods of about 36 hours some of the animals refused food. Despite the better appetites C2 and B3 have decreased slightly in weight since withdrawal; while B I , B2, and CI have gained weight steadily. This is shown by the figures in Table I, the values being those on the last part of Fig. 2 .

TABLEI Day

38 41 44 47 49

51

Weights of Dogs in Pounds during Withdrawal W r ht Wght. Wght. Wght. Remarks W'pht. Cr 8 2 ' BI Bz B3 9.25 CI withdrawn 12.75 9.25 29.50 38.75 39.73' 30.00 13.25 9.25 10.75 C ~ , B IB2,B3 , 9.90 10.25 withdrawn 29.25 12.75 41.50 10.25 13.75 1 0 . ~ 0 29.25 41.25 11.0 10.50 14.50 30.75 42.25 11.0 I 1 .oo 14.20 30.50 43.50

The table shows that over the whole post-withdrawal period CI gained weight steadily. C2, somewhat under her original weight, did not change much. BI and Bz gained slowly; while B3 stayed about the same. The dogs that were not protected by sodium rhodanate therefore did not pick up so rapidly as those that were protected. Averaging the losses in weight of 18 dogs during the first week of withdrawal in the experiments of Plant and Pierce, we find that it was about one pound. Only one dog in 2 1 gained weight. CI showed continued improvement today. He was friendly, showed an interest in other dogs, want'ed to leave his cage, and barked continuously a t nothing in particular when chained up outside. Thus, some of his actions were much the same as before he was addicted. He salivated very little when the experimenters appeared. He does not gnaw a t his cage any more. There were only a few stools in the cage. The pupils of his eyes were normal. B3 was somewhat more lively today. The head and body tremors persist. She salivated only slightly when the experimenters appeared. Many soft stools were noted. The dog is still depressed. The pupils of her eyes were widely dilated. C2 was a little more lively and friendly. She did not arise when the experimenters appeared. When she did arise it was only for short periods of time after which she would resume her reclining position. He head tremor persists. This dog still shows a defect in interest. She exhibits a peculiar blowing movement whereby she blows air out with her mouth closed in such


1541

a manner as to make her upper lip move rapidly out and in. C I exhibited the same picture several days ago. This may be due to nervousness. The pupils of her eyes were about normal. There was not much change in the condition of BI and Bz today. They both salivated when the experimenters appeared. BI salivated more than she has for several days. Bz continues to present a more healthy general appearance; there is a noticeable daily improvement in the condition of this dog. BI and Bz apparently are passing as many stools as Cz and Bs; but the stools of the former are hard while those of the latter are soft. BI and Bz were not so demonstrative as they were yesterday; but they were neither aloof nor depressed. They were anxious to leave their cage in contrast to B3 and Cz. When sodium rhodanate is injected into these dogs they do not wag their tails as they did when morphine was injected. They learned the difference between the two very quickly. The pupils of their eyes were normal. Forty-eighth Day, November 2nd All of the dogs except H I , salivated when the experimenters appeared. Likewise, all of them were lively. The head tremor of Cz persists. C I yelped continuously and senselessly a t the sky when put outside. B3 still exhibits the body tremor; she was interested in leaving her cage today. Sodium rhodanate was not given to any of the dogs. Forty-ninth Day, November 3rd The pupils of the eyes of the several dogs make an interesting study. According to Lambert' dilation of the pupils is a common withdrawal symptom. The pupils of the eyes of B3 were widely dilated and responded only slightly and sluggishly to light. In the case of Cz the pupils were widely dilated; but they were sensitive to light. BI and Bz presented normal pupils. The pupils of the eyes of C I were somewhat larger than normal. B3 has a fine body tremor; she is not disinterested any more. Cz still exhibits a head tremor. All of the dogs began to salivate when the experimenters appeared. BI and Bz salivated more profusely than the other dogs. They were friendly and interested today. Sodium rhodanate was not administered. Fiftieth Day, November 4th BI and Bz were quiet today. The pupils of their eyes were somewhat dilated; so they were each given 0 . 2 5 gram of sodium rhodanate in water solution by subcutaneous injection. These two dogs eat anything and everything that is given to them. C2 did not salivate when the experimenters appeared. The other dogs did; it has been noticed that the induction period for salivation is becoming much longer. Cz was not active this morning. She has diarrhea. She is 1

Am. J. Psychiatry, 10, 504 (1930).

1542

WILDER D. BANCROFT, ROBERT S. GUTSELL, JOHN E. RUTZLER, JR.

not eating food well. B3 has a very poor appetite, also; a pronounced body tremor still persists. There was no change in the condition of C2 today.

Fifty-first Day, November 5th The appetites of B3 and Cz continue to be poor. All of the dogs except H I were active and practically normal today. None of the dogs exhibited dilated pupils. The dogs salivated, as usual, when the experimenters arrived. The pupils of BI and B2 were normal. This concludes the post-withdrawal study. Summary and Discussion Tables I1 and TI1 gather together in brief form some of the important data on this experiment.

TABLEI1 Dog

Daily Daily Weight Morphine Dosage Morphine Dosage* 6 days a t Start at Withdrawal after start

CI

1 . 8 mg/kg.

c2

2.1

HI BI Bz

2.8

B3

1.3 3.3 3.6

6.26 mg/kg. 7,'s 9.79 11.84 16.9 14.6

17.8 kg. 15.1 12.8 5.77

Weight 70 Increase of Morphine at withdrawal Dosage

17.55 kg. 13.6 7.9 6.0

3jo 340 750 420

4.87

4.2

510

4.5

4.87

410

*A I -+pound man addicted to 5 grains of morphine per day would be taking a daily dose of t i e drug which amounts to 4.76 mg/kg.

TABLEI11 Dog

Sex

CI

Lf

CZ

F F F F F

HI BI B2 B3

Number of days on Morphine

38 41 35 41 41 41

hmount Amount NaCNS NaCNS after before Withdrawal Withdrawal

I&%S Continued after Withdrawal

Total Amount NaCNS

0 . 8 gm.

3 . 4 gm.

0.0

0.0

I .o

0.5

5

1.5

1.1

9

2.4

.o

1.3 1.3

9

2.3

0.0

0.0

0

0.0

I

IO

0

4.2 gm. 0.0

It should be valuable at this point to compare the symptoms and behavior of these dogs during addiction and withdrawal with those found by Plant and Pierce. Symptoms during addiction will be considered first. Weight. They found a rather rapid loss in weight for the first couple of weeks, while vomiting followed the injections. Three of our dogs gained weight during the first 1 5 days. The others lost weight, but began to regain it before they stopped vomiting. The weight changes during withdrawal are discussed elsewhere.


I543

I’omitzng. The dogs of Plant and Pierce vomited for a period of from five to 1 5 days at the beginning of the addiction. Our dogs did not vomit regularly after the first sixteen days. Plant and Pierce say: “AS a rule when the vomiting had stopped, it did not return again until a very high dosage level was reached. We observed occasional vomiting at various times throughout the addiction period. This was probably reflex vomiting, and should be observed a t least occasionally if it is a conditioned reflex. Contrary to the observations of Plant and Pierce our dog HI did not vomit at all during the first four days of the addiction period. This is probably because the dose of morphine was quite small. Salzvatzon. Our experience with salivation was much the same as that of Plant and Pierce. 12’arcosis. “All of our dogs showed marked diminution in the degree of narcosis produced by the daily administration of morphine, but none of them showed complete absence of narcotic effect, even where the administration was continued for more than 300 days.” “With an initial dose of 5 to I O mgm. per kilogram the animal is deeply narcotized for three to six hours, during which it is difficult to arouse and if partially awakened, immediately sinks back into a relaxed comatose condition.” Reference to Table I1 shows that none of our dogs were given as high as five mg. per kilogram of morphine sulphate at the start of the experiment. Also, Fig. I shows that the low initial dosages were continued for a period of eight days, until some tolerance had developed, before they were raised. So, in complete contrast to the symptoms noted by Plant and Pierce our dogs were never narcotized, and the depressing effect after each injection did not manifest itself after a short time had elapsed. The condition observed by us simulates more closely the behavior of human addicts. The human addict often does not sleep well even a t night. Constipution. Both our dogs and those of Plant and Pierce showed varying degrees of constipation. Our dogs did not become so constipated as some of theirs did. We observed diarrhea on several occasions; Plant and Pierce do not mention this. General Behavior. “All of our dogs were friendly and responsive to petting and easy to handle before the administration of morphine was begun. Three of them became somewhat cross and showed tendency to snap after tolerance was developed, but in none of these was the change sufficiently marked to make handling them difficult; the attendant was never bitten and in no case was a muzzle necessary. Two became quarrelsome with other dogs and had to be watched to prevent fighting in the runway. The majority were friendly, active, and responsive in the morning before the injection, but never as much so as before addiction was begun. Two became shy and seemed to avoid all contact with the attendant and with the other dogs but were not cross and could be handled without difficulty. The tolerant dogs seldom evidence any marked interest in other animals and although they occasionally played together in the runway, they more often held aloof. We never saw any evidence of heat in the females during addiction.”

I544

WILDER D. BANCROFT, ROBERT S. GUTSELL, JOHN E. RUTZLER, JR.

Our dogs were easy to handle at all times with the exception of C I . C I was never cross or mean. With the exception of C I our dogs were friendly and responded to petting throughout the study. None of our dogs became quarrelsome with other dogs. Like two of the dogs mentioned above, C Z became shy. B3 was always interested in all of the other dogs except during the first week of withdrawal. CI showed an interest defect at all times. Appetzte. The appetites of our dogs were not so good as those of Plant and Pierce. Hypersensitioeness and skin rashes. In avoiding most of the phenomena that Plant and Pierce report under this heading we more nearly approached the conditions observed in human beings. The skin of the human addict is very often decidedly hyposensitive. H I and CI developed slight hypersensitiveness. Withdrawal symptoms will be compared now. Tremors, twitching and rigidity in voluntary muscles. “The symptoms most frequently observed during withdrawal consisted in fine, fibrillary twitching in the muscles of the legs, back and head.’’ These symptoms were not observed by us in H I , BI, B2 and CI, the dogs that were protected by sodium rhodanate. C2 and B3, not being protected by sodium rhodanate, exhibited both a gross head tremor and fibrillary twitching. Groaning, howling and whining. Except for a little whining on the part of CI these symptoms were not seen in our dogs. Restlessness. Many of the dogs that Plant and Pierce worked on exhibited restlessness of varying degrees of intensity. C2 and B3 were slightly restless and nervous at times. The restlessness was not accompanied by noisiness, but was rather intermingled with depression and disinterestedness. The dogs protected by sodium rhodanate did not appear restless or nervous. Gnawzng at objeds wzthin reach. This phenomenon probably can be classified as nervousness. C I exhibited it before and during the time that the dosage of morphine was being increased most rapidly. Several dogs showed slight tendencies to gnaw during withdrawal, especially B3, which dog was not protected by sodium rhodanate. Change in temperament and behavior. Our dogs did not become irritable and cross in contradistinction to some of those of Plant and Pierce. Cz showed a distinct desire for the drug as did one of theirs. There were marked changes in the behavior of C I ; these will be considered separately. Before abrupt withdrawal and while sodium rhodanate was being administered, BI and B2 became somewhat disinterested and quiet. Since the withdrawal symptoms are due to the slow return of the nerves to normal after stopping morphine and a consequently protracted period of irritability, we can, if necessary, describe the behavior of BI and B2 as due to withdrawal. Morphine was given in increasing dosage during this time. If the sodium rhodanate only partially overcame the effect of the morphine, partial peptization would occur with a consequent irritability of the nerves which can be manifested by depression and disinterest. I n this manner the actions of BI and B2 can be accounted for.


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Hiccough. None of our dogs showed this symptom. Photophobia. With the possible exception of C I during the time that he did not have enough sodium rhodanate, this symptom was not noticed. Salivation. Plant and Pierce noted that salivation became less marked during withdrawal. We found the same thing in the cases of B3, Cz, and CI. On the other hand Bz ,the protected dog, stopped salivating entirely for about eight ‘daysimmediately after withdrawal. BI, the other dog receiving sodium rhodanate salivated less than before wit,hdrawal. After eight days these two dogs began to salivate more profusely than any of the others. Vomiting. While Plant and Pierce observed vomiting in many of their dogs, only C I vomited during withdrawal; this was reflex in nature. Muscular weakness, respiratory distress, panting, and sleepiness were not observed in any of our dogs. Diarrhea. Plant and Pierce observed this in eight of their dogs. We observed it only in the two dogs that were not protected by sodium rhodanate. Weight changes and pupillary reactions have already been described and discussed. Plant and Pierce observed only one dog that exhibited a desire for the drug. Schiibel,’ and Tatum, Seevers, and Collins,* have not observed a desire on the part of addicted dogs for the drug. The detailed study of this group of dogs presents many instances that can be interpreted as a desire for the drug. There seems to be no question but that the dogs liked the injections that they were given. A close study of the actions, reactions and habits of this group of dogs convinces us that most of them wanted, needed, and liked the drug after they became addicted. The reactions of CI provide an exceptionally interesting behavior study. Not long before he came to us he was subjected to trauma, his right hind leg being injured. The effect of trauma is agglomeration. Before the start of the experiment he was observed to be a highly excitable, scatter-brained dog. He was hard to control, although not in any sense mean. When approached he tended t o be suspicious. He showed no desire or care for human company or affection. He barked at the sky senselessly for long spells at a time. This is akin to the hypomanic state which consists of a condition of unstable irritability, poor discrimination, in which there is a quick reaction on the part of the stimulus response mechanism. The external and internal stimuli are reacted to more promptly than normal, but less thoroughly. Eleven days on morphine quieted CI down. He was calm and less nervous; he was slightly more approachable, less wild, and ceased barking at the sky. He remained quiet for eight days. This stage is designated as “sedated hypomanic.” In the manic depressive psychoses the sympathetic nervous system and its central correlations are agglomerated. Morphine acts first on the central nervous system. It can cause agglomeration in the central nervous system that will therefore mask the hypomania. Continued administration of morphine will finally agglomerate the affected sympathetic system intensifying the psychosis. In other words, the hypomania was masked 2

Archiv exp. Path. Pharm., 88, I (1920) J. Pharm. Exp. Ther., 36,$60 (1929).

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s.


by the narcotic effect of the morphine, just as acute mania can be controlled, but not cured, by sodium amytal. The depressing effect of the morphine was noticeable during more than half of this period. At the end of nineteen days a new condition became manifest. The dog was somewhat restless, and very unapproachable. H e tended to stand faced away from human beings; sometimes with his head in the corner of his cage. There was an obvious hunted, maniacal look in the eyes of the dog during this period. I t was difficult to give him injections during this time because he was so excitable. Upon soothing him the task was sometimes easier. This stage corresponds to the chronic mania stage of the manic depressive, manic psychosis, a more agglomerated condition than hypomania. The dog stayed in this stage for 2 0 days. After withdrawing the morphine, sodium rhodanate was given for three days. This brought the dog back by peptization to a sedated hypomanic condition. The maniacal bearing disappeared and the dog quieted down. This is probably because the morphine was more rapidly eliminated from the sympathetic nervous system than from the central giving rise to a condition much the same as the original sedated hypomanic condition. Sodium rhodanate was discontinued for one and one-half days. The maniacal bearing returned, and with it the state of chronic mania. Sodium rhodanate was administered for two days, and the dog returned to the sedated hypomanic condition. Two more days brought him into the original hypomanic state. Several months later the colloids of his nervous system returned to a normal degree of dispersion, having recovered from the trauma and the drug addiction. I n this condition the dog persistently sought human affection, and cared for human company. He was easily approachable, and acted in every way like a normal dog. On the other hand the dog may have been in a schizoid state, and overdispersed, trauma not being an etiological factor. Injections of morphine for eleven days, under this interpretation, returned the dog to normal due to the agglomerating action of morphine. Eight days more brought him into a condition resembling chronic mania, a condition which is due to agglomeration of certain of the protein colloids of the brain and sympathetic nervous system. Then, three days on sodium rhodanate peptized the colloids back to normal. The chronic mania reappeared when the sodium rhodanate was discontinued for a day and a half. Upon resumption of the administration of the peptizing agent the dog again returned to normal. He was then over-dispersed by the sodium rhodanate, going into the schizoid condition. Some months after the sodium rhodanate was stopped, the over-dispersed condition disappeared, and the dog returned to normal. It does not seem necessary to insist that one or the other of these explanations is the correct one; the important thing is that there was a cycle of changes in behavior of the dog which paralleled the colloidal changes that were induced. The following diagram illustrates the cycle that this dog went through.


Sedated Hypomania Hypomania 11 days or or Schizoid on Morphine Normal

’

8 days

more

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Chronic Mania

Hypomania

A

or Normal Several Months No treatment

1

I I / z days without NaCN S

Sedated

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6. The theory requires that sodium rhodanate shall forestall or diminish greatly the withdrawal symptoms in addicted tissue because it should peptize rapidly the protein colloids that are agglomerated by morphine. 7 . Sodium rhodanate was administered to addicted dogs one week prior to the abrupt withdrawal of morphine. During this time morphine was administered in ever-increasing doses. 8. These dogs were somewhat depressed at first. This may have been due to a disturbed condition brought about by the rapid peptization of the agglomerated colloids. 9. The dogs protected by sodium rhodanate exhibited no withdrawal symptoms upon the abrupt withdrawal of morphine. They gained a little weight. IO. The dogs not protected by sodium rhodanate were nervous, listless, lost weight, exhibited head and body tremors, had diarrhea and dilated pupils. 11. Sodium rhodanate does, in fact, prevent withdrawal symptoms in dogs addicted to small amounts of morphine, thus bearing out the theory. 12. One dog exhibited definite psychic changes as his protein colloids became more or less agglomerated; these changes were reversed. The dog went from one state of dispersion to another, and back again. 13. Withdrawal symptoms appeared in the dog just mentioned when sodium rhodanate was stopped. Resumption of the administration of the drug obliterated the symptoms. 14. Gnawing is not necessarily a withdrawal symptom. 1 5 . I t is to be expected from these experiments that the effects of morphine will be counteracted at least partially in the case 'of human beings by the use of sodium rhodanate. _ I

Conell Uniuemty.

Colloid Chemistry of the Nervous Systems. IV

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