Morphine addiction in chimpanzees
By the mid-1930s, tolerance to morphine and other opiates had been demonstrated in some animals, but no one had produced convincing data that any species other than man would work to produce a dose of a drug. The experimental evidence on this point was gathered by S. D. S. Spragg, who started his work in the fall of 1935 (Spragg, 1940). Spragg worked at the Yale Laboratories of Primate Biology, Orange Park, Florida, having just received his Ph.D. from Yale. Spragg set up a procedure showing that a chimpanzee would actually do something to get a shot of morphine. R. M. Yerkes, Director at Orange Park, suggested that Spragg study chronic morphinism in chimpanzees in order to resolve the controversy concerning whether addiction was a peculiarly human phenomenon (Spragg, 1940, p. 2). The prevailing viewpoint was that typified by the words of a sociologist, A. R. Lindesmith (see Spragg, 1940), who argued that "only those to whom the drug's effects can be explained can become addicts," and "Certainly from the point of view of social science it would be ridiculous to include animals and humans together in the concept of addiction" (Lindesmith quoted by Spragg, 1940, pp. 121-122). Spragg defined addiction to mean that "an actual desire or striving for the drug is clearly demonstrated in addition to the induced physiological dependence" (pp. 10-11). He took as his problem the measurement of "desire or striving." Note that the emphasis was not upon the morphine as a reinforcer; this language was not yet used routinely. Repeated injections of drug were supposed to increase "desire," which then led to some behavior. Spragg dosed chimpanzees regularly with morphine (usually twice daily) until physiological dependence developed (evidenced by the appearance of abstinence symptoms when the drug was withheld) and then tested his subjects in various ways.
Some of the most compelling evidence was captured in a short movie made of two subjects during the regimen on morphine. For instance, a chimp can be seen pulling Spragg toward the injection room, something he did if deprived of morphine for a time.
Figure 1. A morphine-dependent chimpanzee pulling the experimenter, S. D. S. Spragg, toward the room in which morphine was to be administered. The photograph is from a movie made by Spragg and J. D. Bruhn. Reprinted with the permission of Dr. Spragg.
Most important, morphine-deprived chimps would work to get their shots, having first learned what behavior produced the drug. This was the main measure of "desire" and demonstrated the similarity of addiction in chimp and man. Spragg set up a preference test, giving the animal access to two sticks, one black and one white, that would open different boxes (Fig. 2).
Figure 2. The apparatus used by Spragg to determine whether a chimpanzee ''desired" an injection of morphine or a banana. The choice boxes and associated keys (a white triangular stick that could open the white box, which contained a morphine-filled syringe and a black round stick that could open the black box, which contained a banana). Note the syringe and banana on top of the boxes in this illustrative photograph.
The following three stills are from the film. The first two are from the viewpoint of the chimpanzee. The first photograph is the arrangement of the two boxes in the preference-testing chamber. The animal was presented with a choice of two keys on a sliding platform that was presented to the animal behind a grillwork; the animal would reach in and take one of the two keys, turn around and walk to the appropriate box containing either the syringe or a banana.
Figure 3. The choice procedure.
When food deprived but not morphine deprived, the chimp would choose the black stick and open the black box, take out a banana and eat it. When deprived of morphine, he would pick up the white stick, put it in the slot of the white box to open it, take out a loaded syringe, and occasionally even hand it to Spragg, who would then make the injection. The animal is running off a perfectly fine chain of behavior that eventuates in a shot; all the elements of self-administration are there but are not all under the full control of the animal.
The obvious conclusion from this work was that the chimpanzee resembled man in its reaction to morphine and could serve as a model for man. But the flavor of the times is given by the way Spragg (1940) himself commented upon the possibility of the rat showing true evidence of addictive behavior. He did not believe that the rat would show morphine addiction, writing as follows:
"...Since morphine addiction seems to depend essentially upon forming an association between the administration of the drug and the alleviation of withdrawal symptoms, and since this sequence involves a time lag of 10-15 minutes or more, the value of using subjects high enough in the phyletic scale to be able to make a delayed association of this nature is obvious. By this token, animals such as the rat, for example, could probably never become addicted to morphine, simply because they are not capable of forming associations of this order..." (p 126)
Reference
Spragg, S.D.S. Morphine Addiction in Chimpanzees. Comparative Psychology Monographs. 15:1-132, 1940.
Adapted from: Victor G. Laties: Lessons from the History of Behavioral Pharmacology. In: Advances in Behavioral Pharmacology, Vol. 5: Developmental Behavioral Pharmacology. 1986. ( N.A. Krasnegor, D.B. Gray, T. Thompson, Eds.) Hillsdale, NJ, Lawrence Erlbaum Associates. pp. 21-39.
The experimental and other observational data which have been presented in this report serve to sketch in a picture of chronic morphinism as it is seen in the chimpanzee. The effects of small single doses, of chronic administration of the drug, and of with drawal have been shown to resemble closely many of the effects reported for human morphine addicts. A comparison with re sults reported in the experimental literature shows that chimpanzee morphinism as reported here is definitely more human-like than is that of any other animal form that has been studied.
A question that may well concern us at this point is the problem of whether or not the condition which we have described for chimpanzees really deserves to be called addiction, in the sense in which the term is used to describe human morphinists, even granting the experimental results described above. This ques tion is raised in view of the findings of the present investigation, and in connection with statements as to the nature of addiction which have appeared from time to time in the literature.
A point of view which has been fairly persistent is one which was early expressed by Biberfeld (1916) with regard to morphinism experiments with animals. He stated that such experi ments could have no relevance for problems of addiction, but bear only on matters of the physiological action of the drug, induced tolerance, etc., etc.
This view has recently been quoted with approval and ex tended, by Lindesmith (1937), in a sociology doctoral disserta tion. Lindesmith's position seems worthy of quotation here because of the point of view taken regarding animal experi mentation in this field, and because of the "pre-judgment" of investigations such as the present one. Quotation is made from several passages in which the position seems most definitely stated. Italics are those of the present writer.
Pp. 84-85...we may define the object of our study as consisting in that behavior in regard to opiate drugs which is distinguished pri marily by an intense self-conscious desire for the drug and by a tend ency to relapse, evidently caused by the persistence, in some form, of this desire after the drug is removed. Other or correlated aspects of this behavior are the sense of dependence upon the drug as a twenty four hour a day necessity, the impulse to increase the dosage far beyond the point of bodily necessity, and the definition of self as an addict...We presume that it will be evident from the above definition that an animal could not be called an "addict" in the sense of the word as it has been defined, regardless of how much of an opiate drug it were to be given. It seems to us that Johannes Biberfeld has correctly expressed the relationship and bearing of animal experimentation to the problem of drug addiction when he asserted that addiction involved two types of phenomena tolerance for morphine, and craving for morphine and that it was only the former which has any connection whatever with animal experimentation. The craving, he felt, was a phenomenon of an entirely different character and, so to speak, on a different level, so that animal phenomena could not shed any illumination upon it. Certainly from the point of view of social science it would be ridiculous to include animals and humans together in the concept of addiction. For precisely the same reasons it seems evident that infants cannot be included in the concept of addiction, regardless of how long they may be given opiates.
P. 204. The belief that withdrawal symptoms are caused by the absence of the drug is a social belief which has been built up and elabo rated gradually in the history of the race. Each individual addict does not rediscover this knowledge for himself but rather has it thrust upon him by his social environment, for it is present in many parts of our culture...(Footnote) We have never encountered an addict who did not have some knowledge of beliefs concerning addiction prior to becoming an addict, although the hypothetical possibility of redis covering the belief that withdrawal distress is due to the withdrawal of opiates, etc., by trial and error must be admitted, since that was no doubt the manner in which the interpretation was first built up. It must be emphasized, however, that this interpretation as a result of trial and error processes, or any interpretation, presupposes the existence of a culture which supplies the categories and the language in terms of which the interpretation is made. Neither a feral man nor a chimpanzeecould be expected to achieve this interpretation of withdrawal distress, regardless of any experiences they might have with the drug.
P. 208. We may thus say that, taking into account the fact that animals, infants, idiots and the insane, as well as normal people, may have the drug administered to them regularly without their knowledge, only those to whom the drug's epects can be explained can become addicts...The immunity of the insane, of animals, of idiots and of young children is based upon the feature common to all that the withdrawal symptoms cannot be satisfactorily explained to them.
P. 220. The social factors are therefore not incidental to addiction but central. The phenomenon of opiate addiction is neither physi ological nor psychological in essence -- it is social through and through. If there were no organized social life there would be no addiction, and addiction itself does not and cannot exist outside of human society.
If the conclusion that has been made from the data of the present investigation is valid, namely that a genuine addiction to morphine has been unambiguously demonstrated in chimpanzee subjects, then such factual material necessarily forces at least a mod)fication of the theoretical position and the predictions therefrom as set forth by Lindesmith. The subjects of the present investigation did not have the nature of morphine addiction "explained" to them; nor did it appear in them as a "social phenomenon" in the sense in which Lindesmith has used the term.
The appearance of addiction in these animals involved essentially the formation of an association between the hypodermic injection and the alleviation of withdrawal symptoms. That the association was actually learned has been, in the writer's opinion, amply demonstrated; it is his contention that this association, and not anything "social" (in the sense of societal) is the essence of morphine addiction. Theories of the nature of drug addic tion based upon the belief that a chimpanzee or other infra human organism could not independently discover (i.e., by "trial and error") the association between injection and relief of with drawal symptoms must be revised in the light of the present data. The demonstration of chimpanzee addiction is crucial for Lindesmith's central thesis as to the essentially societal nature of addiction.
It should readily be granted, as Lindesmith maintains, that the "social phenomenon" factors are important in the etiology of human drug addiction. But the fact that chimpanzees become addicted to morphine indicates that these factors are not indis pensable. Morphine addiction seems to be fundamentally a phenomenon of learning or perception, which may or may not be socially facilitated.
It should be pointed out, however, that there is at least one sense in which the subjects of the present study were not shown to be addicted in the full sense of the definition ordinarily used, and as formulated by Lindesmith (1937, p. 84). This concerns the tendency to relapse into use of the drug following a complete withdrawal or "cure," which is so characteristic of human addicts.
In the present study the one ease of complete withdrawal of morphine from an addicted animal (Kambi) showed no evidence of interest in, or desire for, the injection two weeks after cessation of the drug and after the withdrawal symptoms had disappeared. It is obvious, however, that our evidence is far too limited to justify any assertion that addicted and "cured" chimpanzees would not exhibit any tendency to seek readdiction. This one case was relatively lightly and briefly addicted and opportunity for readdiction was merely an informal presentation of the injection situation. It might well be that conditions could have been established (perhaps involving frustrations or other psychic stresses) which would have led the animal to evince a desire for the reestablishment of morphine administration, as an "escape" from an unpleasant environment.
A valuable extension of the present study would be the induction of morphine addiction in one or more chimpanzees and then a sequence of complete withdrawals from the drug, followed in each case, after an appropriate interval, by readdiction. Such a program, especially if the animals were subjected systematically to various traumatic experiences and frustrations following each withdrawal, might produce a "tendency lo relapse" into mor phine addiction when the opportunity to do so was made avail able. If such results were secured they would have considerable sign)ficance for drug addiction theory in general.
The data of this study indicate that a possible euphoria produced by the drug played little, if any, part in the induction of these addictions. The initial doses were so small and the in creases in dose size so gradual that tolerance to addicting doses was acquired without the subject's experiencing any definite sedation (with which the euphoria is associated in man) from them. We obviously did not possess any technique for detecting or measuring euphoria in chimpanzees, but the conditions of the experiment, in the light of human addictions, seem to justify the assumption that it was probably not a factor in the present cases.
The addiction of chimpanzees to morphine thus appears not to be an attempt to recapture pleasurable states which were previously induced by injections, but rather an attempt to alleviate the symptoms produced by the delay or omission of the regular injection. Clinical evidence indicates that this condition is usually the case in human addictions. The period of euphoria from the drug is relatively short, but the drug must be continued to keep the individual feeling "normal," i.e., to keep warding off the distressing withdrawal effects. Any "pleasure" in morphine addiction then is at best a negative sort of thing the prevention of, or escape from, the pangs created by absence of the drug.
This study also contains implications for those theories of drug addiction which have maintained that the genesis of human morphine addiction is to be sought primarily in predisposing personality factors emotional instability, conflicts, depressions, etc. -- and that morphine use and subsequent addiction are essen tially an "escape" from the harsh realities of life. Such a view is often used to explain the fact that therapeutic administration of morphine induces addiction in some persons and not in others.
To show that chimpanzees can become addicted to morphine is to provide additional evidence that this view is not adequate as an exclusive explanation of addiction. These animals were presumably not neurotic or unstable, and did not take the drug in order to escape from reality; yet they became addicted. It is not intended by this argument to minimize the importance of predisposing personality factors in the etiology of many human addictions, but rather to urge that this cause appears in the light of the present evidence not to be an absolutely essential one. Kolb (1925) and others have shown that personality defects are frequently, although not invariably, predisposing factors in addiction; the present study presents further evidence that addiction can be induced in the absence of such predisposing (human social) factors.
Morphine addiction then is not necessarily dependent on personality defect nor on social knowledge of the drug and its effects. It is not simply a neurosis. This study has added further corroboration, if such were needed, to the view that addiction has a firm organic basis (whatever future research may reveal its exact nature to be) and that the withdrawal symptoms are essentially physiological symptoms. The older view that withdrawal symptoms were a "play for sympathy" on the part of the addict in order to win him another dose, has been pretty well abandoned in present day thinking, although it is beyond question that the human addict can control the severity of the symptoms to a considerable extent, if it seems advantageous to do so. The similarity of the withdrawal syndrome in chimpanzee and man strengthens the view that the symptoms are predominantly physiological and involuntarily produced.
Drug addiction, whether in the human or the chimpanzee subject, can be considered as a state of equilibrium, the departure from which creates a condition that generates powerful motivations to restore that equilibrium -- motivations that pervade the behavior of the organism and predominate over other, normally primary, desires.
Reference
The above text is from SDS Spragg's Morphine Addiction in Chimpanzees, which appeared in Comparative Psychology Monographs, 15 (7):120-127, 1940.
The employment of chimpanzee subjects in this investigation has made it possible to narrow considerably the gap which hitherto existed between the nature of chronic morphinism in human and in infrahuman forms. Prior to this investigation morphine addiction had not been established for any infrahuman organism, and the statements of Biberfeld (1916), Plant and Pierce (1928), Lindesmith (1937), and others regarding the essential differences between morphinism in man and all other animals seemed to be valid. Even studies using the rhesus monkey as subject had not succeeded in narrowing this gap significantly.
The use of chimpanzees in a morphinism investigation has provided an experimental organism whose behavioral capacities have been shown to resemble those of humans more closely than any other laboratory animal. Also, and this is a highly important factor, it is an organism which can be trained to a high degree of intelligent cooperation in many experimental procedures, and also to the use of symbolic rewards of various sorts.
Since morphine addiction seems to depend essentially upon forming an association between the administration of the drug and the alleviation of withdrawal symptoms, and since this sequence involves a time lag of 10-15 minutes or more, the value of using subjects high enough in the phyletic scale to be able to make a delayed association of this nature is obvious. By this token, animals such as the rat, for example, could probably never become addicted to morphine, simply because they are not capable of forming associations of this order.
There still remains the question of why monkeys have not become genuinely addicted to morphine in studies in which they have served as subjects. Many lines of evidence indicate that their behavioral capacities are sufficiently complex to enable them to form associations of the order of complexity needed here. The answer seems to lie partly in the lack of crucial tests for the presence of addiction and, more importantly, in the fact that they have ordinarily been caught and injected by force in such experiments. Careful pre-morphinism training of the animals in cooperation and voluntary submission to injection procedures might have resulted in a much different picture.
Although the chimpanzee is thus seen to be at present the most valuable animal available for experimental studies of morphine administration, it must be admitted that there are certain factors contraindicating its extensive use in problems of this sort. Chief among these are expensiveness and relative non-availability of subjects, as well as the expense of equipment needed for their caging and use. For these reasons chimpanzee studies in this field must necessarily be studies with small numbers of subjects. It seems clear, therefore, that the chimpanzee, although clearly the most valuable and promising animal available for addiction studies, will never be widely used in such investigations.
However, the use of chimpanzees in the present experiments seems to indicate rather clearly ways in which various types of monkey might be used in research in this field with considerably more behavioral success than has been the case so far. It is the writer's belief that if a relatively tractable monkey, such as the mangabey (Cercocebus) for example, be given the training and experimental procedures which were used in the present investigation, the chances of developing a genuine addiction to morphine would be very good.
If such should prove to be the case, it would be of considerable practical importance for research in fundamental problems in drug addiction. It would mean that investigations in this field could be carried out in a great many laboratories (instead of a very few, as with chimpanzees), and that relatively large numbers of animals could be employed as subjects. This would make feasible various statistical comparisons, as well as the investigation of problems requiring the experimental sacrifice of several subjects, without excessive expense.
Reference
The above text is from SDS Spragg's Morphine Addiction in Chimpanzees, which appeared in Comparative Psychology Monographs, 15 (7):120-127, 1940.