INTRODUCTION

General Remarks

From the first beginning of our knowledge of man, we find him consuming substances of no nutritive value, but taken for the sole purpose of producing for a certain time a feeling of contentment, ease, and comfort. Such a power was found in alcoholic beverages and in some vegetable substances, the same that are used for the purpose at the present day.
No chemical research has been able to produce synthetically anything in the slightest degree resembling the materials which peoples of all parts of the world have found suitable for their euphoric cravings. Their potential energy has conquered the whole earth and established communication between various races, in spite of dividing mountains and surrounding seas. These substances have formed a bond of union between men of opposite hemispheres, the uncivilized and the civilized; they have forced passages which, once open, proved of use for other purposes; they produced in ancient races characteristics which have endured to the present day, evidencing the marvelous degree of intercourse that existed between different peoples just as certainly and exactly as a chemist can judge the relation of two substances by their reactions. Hundreds or thousands of years were necessary to establish contact between whole nations by these means. Ethnology, which should endeavor to trace their routes, has never attempted to search out and investigate the elements of these questions, which are of equal importance to science and to the history of mankind. Careful inquiry, especially if combined with comparative linguistic studies, would unravel many such mysteries.
It is extremely important to note that the mere discovery of the properties and uses of narcotic and stimulating drugs implies a certain degree of scientific observation and marks the beginning of primeval culture; and if it can be taken as a symptom of civilization when men's desires, hitherto exclusively confined to the bare necessities of life, pass beyond these limits, and the individual, no longer satisfied with the crude sustenance afforded by or wrested from nature, finds and delights in stimulants which mainly affect the nervous system, then a suitable background for such physical cravings must form part of the human constitution.

Motives for the Use of Narcotic and Stimulating Drugs

The motives for the occasional or habitual use of these drugs are of greater interest than collections of facts concerning them. Here all kinds of human contrasts meet; barbarism and civilization, with all their various degrees of material possessions, social status, knowledge, belief, age, gifts of body, mind, and soul.
On this plane meet artisan and sybarite, ruler and subject; the savage from some distant island or from the Kalahari desert associates with poets, philosophers, scientists, misanthropes, and philanthropists; the man of peace rubs shoulders with the man of war; the devotee with the atheist. The physical impulses which bring under their spell such diverse classes of mankind must be extraordinary and far-reaching. Many have expressed opinions about them but few have probed and understood their intrinsic properties, and fewer still perceived the innermost significance and the motives for the use of the substances in which such energies are stored.
It has been thought that the lower the position of a race on the ladder of mental capability, the cruder would be its preferred stimulants, and the more eagerly it would seek to deceive its earthly consciousness and to obtain deliverance from the emptiness of its inner life. The Indians of South America are said to have an intuitive appreciation of their own defectiveness, and to be ever ready to rid themselves of such melancholy feelings by intense excitement, i.e. through the use of kola and similar drugs.
Such men as Tolstoy, who were unable to comprehend these problems, even went so far as to assume that the reason for smoking and drinking is to dull the conscience, and the consumption of opium in the Malay Archipelago was due to "an insufficient education on a Christian basis." Such incredible absurdities are frequently to be met with. They are calculated on the one hand to excite surprise at the limited degree of observation of man and his passions possessed by those who hold them, and on the other they evoke an earnest desire to impart more knowledge on this subject to a larger public.
The strongest inducement to a frequent or daily use of the substances in question is to be found in the properties they posses; in their capacity to excite the functions of the brain-centres which transmit agreeable sensations and to maintain for sometime the consciousness of experienced emotions. Their results differ considerably. Even within the limits of either of the two large groups of possible effects, excitation and paralysis, their intensity of action varies extremely, adapting itself more or less adequately to the temporary condition of the nervous system of the user of the drug.
The inducements which bring about a first recourse to their use, especially in the case of narcotic substances, are just as varied. It may be mere curiosity which induces people to bring ridicule and harm upon themselves, or it may arise from a recognition of the drug's beneficial effect, after it has been taken during illness as a medicine; or again, it may result from the deliberate intention to effect a pleasant though temporary change in the state of the mind and soul, to divert the susceptibilities and thoughts into new channels. For instance, an Indian of Guatemala, asked why he drank so much aguardiente, answered: "A man must sometimes zafarse de su memoria," i.e. take a rest from his memory. It is an invariable rule that the remarkable properties possessed by these substances react on the brain and through it cause a craving for their habitual use and the accompanying pathological disturbances.
I have known men who first took a narcotic remedy from pure curiosity, and later, overcome by its influence, became habitual drug-takers. The publication in a popular form of scientific articles on the properties of these drugs has produced many cases of the drug habit. At the present time, when narcomania has reached an undreamed-of extent, even people who were incredulous as to the increase of this vice are astonished.
Well-known men have applied to me for a substance which, as they had been informed, brought about mental delusions and hallucinations. They hoped to experience agreeable sensations; one of them even meant to make use of such aid for poetical production, perhaps of a supernatural kind.
Many other circumstances could be mentioned which bring about the primary or continued use of narcotic and stimulating drugs. For life itself, and the life of the individual with its innumerable functional variations and idiosyncrasies, creates these strange causes which so often determine the normality, the decrepitude, or the annihilation of the individual.

The Importance of Mental Constitution in Relation to External Stimuli

The reasons for the habitual use of drugs, and the mental and physical results arising therefrom, have been accounted for in the preceding section by the peculiar effect which these drugs exercise on the brain. A number of problems, however, remain unexplained which likewise are of the utmost importance to the life of the individual: the varying reactions of different persons, not only to narcotics in general, but also to chemical and other influences, and the fact that one man can tolerate quantities, taken apparently with impunity within a short period, which to others would spell physical ruin. Indeed, the most elementary science teaches us that most drugs contain a high degree of latent energy which acts almost exclusively on the nervous system.
From time immemorial attempts have been made to solve these problems, but without success. Biology exerts its influence, and we enter on those deepest mysteries which man has ever endeavored to fathom: personality, mental constitution, and habit. Nothing thrusts itself more forcibly on our notice, nothing harasses the investigator more, nothing more prevents all deeper insight into this chaos of propositions and problems. They will always remain hidden from our view among the many disputable problems of life and vitality. We suffer, like Faust, from our inability to discover the truth, and must sincerely regret what Moliere already satirically criticized: the fashion of clothing in meaningless Latin or Greek phrases what can never be known, or of repeating a mere surmise again and again until ignorant physicians or non-professional men venture to stamp it as a fundamental truth. Even to-day we frequently meet with interpretations of the action of medicinal and poisonous substances which are merely pseudoscientific descriptions of their effects. We are reminded of the burlesque scene in Moliere's Le malade imaginaire in which doctors of the University appear and examine a Bachelor of Medicine in a mixture of Latin and French. Asked what is the ultimate reason for the soporific action of opium-

Demandabo causam et rationem quare Opium facit dormire,

the candidate answers:

Quia est in eo Virtus dormitiva Cujus est natura Sensus assopire,

i.e. "because it is endowed with narcotic and soporific properties," and the examiners call out in chorus:

Bene, bene, bene respondere. Dignus, dignus est intrare. In nostro docto copore.

Unfortunately pharmacology and toxicology lend themselves with particular ease to metaphysical absurdities of this description. These doctrines are unable to withstand argument, and no enlightenment can be expected from them. Drugs and poisons, with their potential energies, are rooted in a material world which observes their active properties but refuses to allow us to ask the reason for them.
Man's power of resistance to potent substances or his inability in some cases to withstand them remain unexplained. The hypothesis has been put forward that a distinct kind of energy exists which envelops and governs the whole of physical life. This we may call Vital Energy. I include in this expression the sum of all the chemical, physical, and mechanical faculties which are dominated by the will but do not respond to the same extent in all individual cases.
Every part of the body—brain, nerves, muscles, glands, intestines, bones, or mucous membrane—every tissue, cellular or not, is provided with this native energy. It is not that mystic power, Spiritus rector or Archaeus, which played an important part in the theories of life of the Middle Ages, but an organization of work which is, despite individual dissimilarities, governed by manifest laws and immensely complicated as it is, varies in strength and nature according to its location, destroying, building, dissolving, or strengthening as the case may be.
The amount of work actually depends on this factor.
Its active or passive manifestations show a greater or lesser degree of working or of toleration, non-toleration or varying toleration of external or internal influences of a stimulative or other nature. The appearance of these reactions varies to a great extent, even to the point of complete dissimilarity.
The impulse and ability to compensate for the disturbances caused by foreign bodies, should be included among these differences of organic life and their responses to material and other energies. Every organism has at its disposal a certain amount of prophylactic and regulating energy which varies in quantity, just as does the energy of the normal vital functions. I look upon this adaptable activity of prophylactic and defensive support as a reaction provided for the welfare of the individual and not as an innate necessity. I corroborate the opinion expressed by Pfliiger in his Teleological Mechanics: "The cause of a desire in an organism is at the same time the source of the gratification of this desire," where by "cause of desire" is to be understood every alteration in the condition of the organism effected for the welfare of the individual. This self-defence always occurs to some extent, but ceases if, for instance, the chemically reactive power of a poison eliminates the vital energy either locally or over the whole body.
Perhaps it would be appropriate to refer to a consideration which has been for many years a subject of my lectures. It is conceivable that the impulse and the activity of regulating processes against foreign influences is enacted according to a scientific principle which has been termed by d'Alembert, Gauss, and later by Le Chatelier, the Law of Resistance to Constraint or the Law of Least Constraint, and which applies to chemical and physical processes. It may be thus stated: If to a system in equilibrium a constraint be applied, a change takes place within the system tending to nullify the effect of the constraint and to restore the equilibrium. The equilibrium is shifted in such a direction as will reduce the constraint. Systems in which the constraint applied is not reduced but magnified are not in a stable but in a labile equilibrium. In the human body both kinds exist. This is not the place to state in detail the consequences which the application of this principle to chemical reactions in the human body after the administration of a drug possess for scientific research. Enough to state that this
new point of view will tend to facilitate our conception of many of the reactive phenomena of life.
Between the two possible extremes of the regulating of powers of the organism as a whole, success and failure, there are many intermediate stages, varying with the energy of the individual life. This for the most part hereditary factor, individual life, i.e. personal disposition, which does not show any apparent physical demeanor or difference in the tissue or humours of the body must be examined for every possible reactive influence. Human nature not only exists, but thrusts itself on our notice. To deny its great importance is a sign of medical ignorance, to underestimate it may be fatal, to explain its essence is impossible to mortal man. It is and always will remain in every respect a mystery. The attempt to bring forward the ductless glands as an explanation must be rejected because of its too limited interpretation of the personality. It constitutes an equation with so many unknown factors that its solution seems impossible.
It also causes individual differences in the normal corporal functions. Hardly any functions of the organs of the body, from the activity of the brain and the spinal cord to the work of the glands, the general metabolism, the movements of the internal organs, the development of muscular power, act to the same extent in different persons. These differences in physiological attainment must be placed on the same level as the result of external influences. From the most ancient times to the present day nothing has caused such astonishment among scientists and laymen as the fact that the causes of diseases, and also medicinal substances, whether poisonous or nourishing, produce such wholly diverse results both in human beings and in animals.
In the primeval history of mankind we are told that an injury which killed one man spared another, and that some animals could consume quantities of a poisonous plant which would cause the death of others or of man. Galen, that great medical genius, who, after being regarded as an authority for more than a thousand years, was discredited by those who did not know him, held pronounced views regarding the toleration of noxious substances and their habitual and occasional use, which are of greater value than many of the statements made to-day. The latter are, for the initiated, meaningless circumscriptions of the simple though inexplicable truth that the fluctuating effective power which chemical substances have on certain individuals or races, has in like circumstances dissimilar effects on others, or is neutralized by the peculiar constitution of some given individual. This is true also of convalescence from sickness, wounds, or internal disorders. We may take it as a fact that Negroes have greater recuperation powers than white people. This is due not to climatic conditions but to certain innate qualities possessed by them.
Personal disposition affects every type of influence, mechanical, chemical, or mental, and may be of an excessive or a sub-normal sensitivity or any degree between these extremes. A physically strong man may be hypersensitive to a certain drug, a weak man hardly or not at all affected by it. Personal disposition brings about the abnormal progress of toxic diseases as well as of those caused by narcotic and stimulating drugs. None of them allow any prognosis. There is no formula or rule which affords a definite standard, for general limits are overpassed by the individual constitution.
As the astronomer has for his visual perception a "personal equation," so every man has probably what I would call a "toxic equation"—an expression first used by me and subsequently copied by dishonest plagiarists. By it I mean a greater or lesser sensibility of the body or its organs to the effects of various chemical substances. It is this toxic equation which causes a quantitative and sometimes a qualitative difference in functional reaction to one of these products. In this case the inconceivable becomes a fact: for example, of two persons who are exposed in the same room to the toxic action of carbon monoxide, one may be only slightly affected, whereas the other dies or falls victim to some form of incurable cerebral disease, inflammation of the lungs, pulmonary gangrene, or some other disturbance of the nutrition of the tissues. The transformation of the effective or injurious influences into actual harm does not take place uniformly in every human body. Until the present day no one has been able to explain the real reason for this. It is one of the profound mysteries of nature. The following words of Albrecht von Haller are and will always be applicable to these phenomena:

Ins Innere der Natur' Dringt kein erschaffener Geist, Gluckselig, wem sie nur Die aussere Schale weist.

Goethe, who lacked the authority of an expert, sought to refute his view. "For the poet," said he, "Nature has neither heart nor surface, to him she is both at once." Unfortunately, Haller's words are only too true. In biology, and in every sphere where nature affords problems of an unintelligible and inconceivable kind, there is indeed a heart and a surface; that which is visible and that which is concealed from our view. This is especially the case in biology; we recognize the dial of the clock and the movement of the hands, but we are unable to see the work and the driving power. We encounter the same unfathomable abyss as when we seek the origin of a living being, of one of its tissues or even but one of its cells, and find that we are incapable of understanding it. In this matter Kant's conviction will always remain true: "The formation of celestial bodies, the causes of their movements, and in short, the origin of the entire Cosmos, will be explained sooner than the mechanism of the creation of a plant or a caterpillar." The data which chemistry offers will likewise never lead us any further. Every man has in himself his own individual biological laws, every man bears with him his own psychological complexes. Consequently there are no psychological constants common to all individuals. The attempt to establish any such is foredoomed to failure. Thus it is impossible to foretell a priori the reaction between an organism and a given chemical body. It is significant that such a man as Kant realized the extreme importance of individual differences when writing to the physician, Marcus Herz: "Be sure to study the great diversity of human nature."

Tolerance and Habituation

The foregoing problem must be based on the same level as that of habit and custom, which has occupied philosophers since the earliest days of medicine. Habit includes somatic reactions which up to present day have not been satisfactorily explained. The point in question is that an agent capable of effecting a functional reaction in a certain portion of an animal organism under conditions constant in form and quality, has the intensity of its action reduced even to the point of inertia if its application be repeated.
This phenomena can be studied throughout organic life. If, by pressure on a part of the skin during rowing, for instance, pain and local irritation are produced, it can be ascertained that by repeating the irritating action the symptoms gradually decrease until an equal amount of mechanical influence is hardly felt. This may be, though it is not necessarily, the result of the callosities that are formed. It may be that the sensitive nerves react to a lesser degree to repeated influence of this kind even when not protected by a callosity. I have often seen gardeners in charge of cacti handle mamillaries or echinocacti without being inconvenienced by the many needles that pierced their hands, when an inexperienced person was forced to pull out even a single needle because of its irritation. There are many opportunities for studying similar functions of the sensitive nerves, especially in industry. Those whose work exposes them to the din of heavy machinery or the noise of looms experience no disagreeable sensations therefrom; similarly, soldiers in war become accustomed to the firing of guns and the detonation of exploding shells.
All sensitive organs subjected to the assault of a factor which uniformly irritates, excites, or effects a functional reaction in a certain degree, can, as is generally known, attain and manifest a dulling of susceptibility. The final result, i.e. the decrease of subjective sensitiveness, does not depend on the nature of the repeated active agent. It can be effected by any one of countless irritants. If we consider skin irritants, which apparently exercise the same influence on the same surface, we must admit that each acts differently from the other. Mechanical, luminous, thermal, and chemical action resemble each other in their final effect of establishing a habit or custom. The truth of this assertion may be ascertained by a short stay in the stokehole of a steamer. On the first occasion the heat radiated produces such a feeling of suffocation that an immediate exit is necessary, but if the experiment is repeated, the intolerable sensations disappear and even a lengthy stay imparts no ill-effects. After remaining in an accumulator-charging room for the first time it seems impossible for the mechanics to endure the foggy sulfurous vapors for any long period, because of their extremely irritating effect on the respiratory organs. Nevertheless, men who work there give no indication of inflammation of the mucous membranes produced by these fumes.
We might cite hundreds of examples of this kind, due to material influences, especially of a chemical nature. They find their analogy in other effects, verified by experience, due to psychological influences. In this field impressions differ in nature and intensity: e.g. disgust,
fear, sorrow, and perhaps even love are diminished if their duration is prolonged. Psychological impressions ranging from extreme joy to extreme sorrow, from a state of good humor to a morbid disposition, lose their influence on the individual if they are active for any length of time. A habit is established, and the subjective manifestation of the senses, the response to the influence exercised, slowly disappears: "L'habitude emouse le sentiment."
But how, by what means and to what extent a habit may be established can never be absolutely determined. It must be considered as a law that the state of custom or habit ceases to remain constant when the intensity of the instigating agent is suddenly augmented. This is what occurs if, for instance, the magnitude or the aspect of a danger to which a person has become so accustomed that he neglects his power of judgment is unexpectedly changed, or if an acute increase of pain eliminates the former habitual insensibility. Habitual toleration therefore only exists in a limited amount and for a definite quantity of a habit-producing agent. That is why a sudden increase of that last innocuous dose of morphia, cocaine, nicotine, or caffeine, poisons the habitual drug-taker as much as if his organism had not acquired a relative immunity to the effect of these noxious substances by preceding prolonged use.
The influence of habit may be traced even in unicellular organisms. A freshwater amoebae dies if 2 per cent of salt is suddenly added to the water in which it lives. But if a progressive increase of 0.1 per cent of salt is added to the daily dose, the amoeba accustoms itself to the increasing concentration, and eventually is able to live in a 2 per cent solution. If it is returned to fresh water it dies. Sea-water amoebas and rhizopods continue to live even if the water, through vaporization in an open dish, reaches a 10 per cent concentration of salt. The growth of yeast in beer is arrested by 0.17 gr. of hydrofluoric acid per litre, whereas when accustomed to this substance it can tolerate 1 gr. per litre. The bacillus of pneumonia is destroyed by a sublimate solution of 1 in 15,000, but after accommodation thereto will continue its development in a solution of 1 in 2,000.
The plasmodia of aethalium septicum can be accustomed to solutions of sugar. The fungus aspergillus niger accommodates itself to a nutrient medium with an increasing salt content, and, by slowly increasing the concentration, to a solution containing 28 per cent
sodium nitrate and even 52 per cent glycerol. After a prolonged development in contact with nickel sulfate, another fungus, penicillium glaucum, tolerates ten times the quantity which would at the beginning prevent its growth. It can likewise be accustomed to cobalt, cadmium, mercury, and thallium salts. Fungi can likewise be accustomed to concentrations of 2 to 8 per cent ethyl alcohol, or even amylic or other noxious alcohols, by suitably regulating and increasing the quantity which at the beginning is toxic. While 0.1 per cent amylic alcohol prevents all fructification, penicillium accustomed to it continues to fructify in a nutritive medium containing 0.4 per cent of this substance. In a solution of 0.005 per cent morphia, rhizopus nigricans grows well. Higher concentrations hinder its development. However, after being prepared for only five days, it will thrive in a solution containing 0.5 per cent. The plasmodia of physarum establish a habit in respect of arsenious acid, which is at first detrimental, and penicillium brevicaule and some other fungi have the property, so important in juridicial chemistry, of transforming this noxious acid into gaseous odoriferous products.
Higher organisms also manifest a certain tolerance of different poisons established through habit or custom. Rabbits can become accustomed to jerquirity seeds (abrin) to such an extent as to endure without any general disturbance of the body an infusion of four times the quantity that would normally cause death. Dogs and rabbits can even be habituated to a certain extent to curare by slowly increasing the dose. It is necessary to augment rapidly the quantity administered in order to evoke the toxic symptoms which appeared after the first doses. Horses at first strongly affected by the presence of galeopsis tetrahit in their fodder become fully accustomed to it.
A large number of similar examples might be cited; for instance, corresponding results have been observed in animals which have been treated with atropine, the active principle of atropa belladonna. If dogs are subjected for a longer period of time to the toxic action of greater or lesser quantities of this substance, it may be observed after a few days that a series of general symptoms, e.g. hyperaesthesia of the skin, trembling of the whole body, restlessness, etc., have disappeared. After 5 to 10 injections of atropine they cannot be distinguished from completely normal, unpoisoned animals. Even a substance like dimethyl sulphate, with its violently caustic action, may be given to rabbits which have been slowly inured to it, in doses of 0'15 or 0'2 gr. per day, without causing rapid intoxication, whereas 0'075 gr. is sufficient to kill others within twenty-four hours.
Animals exposed to the action of carbon monoxide gas for the first time manifested greater sensibility than those accustomed to it, e.g. as regards the temperature of the body.
In the same way, a habit can be established in respect of physical factors, such as the rarefied air on the summit of mountains. In certain places in Bolivia, Bogota, Potosi, La Paz, and others which are situated at an altitude of 2,600 to 4,000 metres, it can be ascertained that the inhabitants do not differ in physical fitness from the people of the plains. The heights in question are equal to that of Mont Blanc, where Saussure hardly had the strength to read his instruments, and his guides and experienced mountaineers fainted. Whereas the individual not inured to these heights exhibits during absolute repose, and to a greaater extent during exercise, an acceleration of the pulse accompanied by palpitation of the heart and general oppression, the accommodated pulse becomes normal after eight to ten days with only an increase of its tension. The respiration behaves in the same way: at first it is more frequent, later normal.
Such an adaptation to great altitudes took place to a most striking extent among those who tried to ascend Mount Everest in 1922. First breathing difficulties and headaches were experienced, and, at a height of 5,000 metres, Cheyne-Stokes respiration. Ten or so superficial respirations were succeeded by others which gradually became deeper and culminated in three or four deep breaths; these gradually decreased in depth until the series started again with superficial respirations. After a sojourn of some weeks all disagreeable sensations disappeared. The rate of accommodation is not interrupted by difficult or strenuous mountaineering. After a few days, adaptation takes place at a height of 6,400 metres, and the difficulties which at first seemed too great are overcome with ease; it becomes possible to reach 8,400 meters without using oxygen. Accommodation even at this altitude takes place very rapidly.
Another instance: in South Brittany the air is laden with salt to such an extent that some persons are attacked after a few days by a painful affection similar to colic. After three to eight days these symptoms vanish, never to appear again.
There is hardly a tissue in the whole body which, by suitable treatment, cannot be made to tolerate an otherwise noxious substance, and hardly an agent capable of altering the functions of an organism which cannot by habitual administration lose in whole or in part its influence on the tissues in question. According to my experience, those substances which destroy the structure of haemoglobin and phosphorous seem to be the only exceptions.
But, as I have already stated, this accommodation of the tissue takes place only to a certain degree or in the case of certain substances, whereas it may be completely absent of other substances whose action is similar. Nevertheless, this experimental law has many exceptions. Oil of croton, rubbed into the skin of the ear of a rabbit, for some weeks causes a kind of immunity which manifests itself by a lesser degree of response to the same kind of irritation after the primary inflammation has disappeared. It could be proved that a preparatory treatment with other substances producing inflammation provided a greater resistance against the action of the oil of croton, and that conversely a preliminary inflammation caused by oil of croton offered a certain degree of protection against other irritants of the skin. This habit of immunity with regard to these substances can be formed without any apparent inflammation, and continues for some weeks. It does not, however, disappear after the same length of time in respect of all agents capable of evoking a cutaneous inflammation, but endures longest for that substance to which the animal had been systematically accustomed. Analogous results were obtained by experimenting on man. If psoriasis is treated with the irritant chrysarobin in slowly increased concentrations, the portions of skin concerned become less sensitive not only to chrysarobin but also to other irritants, e.g. oil of croton and cantharides plaster. It was ascertained that the tolerance of one patient for the latter substances had disappeared, whereas it remained for weeks in the case of chrysarobin. Laboratory and clinical experiments lead to the same conclusions in this respect. They teach us that the organism in hundreds and thousands of different forms can be adapted by habit to the most diverse influences. This is true both with regard to isolated organs, e.g. the brain, and to the organism as a whole. It is known that the seeds of strychnos ignatii and strychnos nux vomica, which are rich in strychnine, have been taken regularly for years in the East as a prophylactic against snake-bite and cholera.
How can this phenomenon be explained? As a matter of course, the cause which produces the phenomenon of habit cannot at the same time be the reason of the habit itself; this must be sought for in the individual concerned. Nearly 400 years before the Christian era, we find it stated that "the effect of all medicinal and poisonous plants is diminished through habit. Sometimes they become quite ineffective. Human nature triumphs over them as if they were not poisons." The human body is here considered, by virtue of its organization, as capable of destroying the toxic powers of the drug. Some centuries later Galen expressed other views. He relates how an old woman of Athens grew used to hemlock by consuming small quantities, and later was able to take very large amounts with impunity, because "at the beginning the organism conquered the poison when taken in small doses, because of their minuteness, and habit afterwards made it a kindred, naturally assimilated substance."'
Many theories are possible with regard to the ultimate reason for the formation of a habit, for instance that of taking morphia or similar drugs. I reject those which assert the likelihood of an "anti-toxin" being formed in the blood-serum in proportion to the quantity of the drug habitually taken.
According to this hypothesis, the protecting substance is produced in such abundance that other persons can, if necessary make use of the antitoxic qualities of this serum with benefit to themselves. This supposition is all the more unreasonable because every cellular complex subjected to a chronic intoxication invariably succumbs to the poisoning in the end, in spite of an initial increase of resistance due to self-defense.
Indeed, a number of important experiments, my own among others, have proved that antitoxins are not formed against alkaloids, glycosides, substances of the aliphatic or aromatic series, or inorganic substances. Neither a cocaine- nor a morphia-antitoxin is produced in the blood, and if we are told that a so-called antitoxin serum has been prepared from animals chronically poisoned with one or other of these substances, we must suppose that scientific observation in this case was inadequate. No branch of science is more liable to insufficient experimental technique than that in question. The sad craze for conjecture is apt to spread like a contagious disease, and imitators, of whom the world is full, easily suggest themselves into finding what they want to find, because others before them believed that they had discovered the truth. If one of these antitoxic serums has really produced a temporary symptomatic success in a patient, we must attribute this to the heterogeneous albumen injected. This explanation, which I was the first to put forward,' has since been accepted by very many scientists. It also holds good in respect to "curative sera" which do not contain any specific antitoxin.
I likewise regard as unproven and fallacious the idea that the formation of a habit with regard to poisons like morphia can be attributed to the increasing ability to destroy the morphia which the organism acquires, and depends upon this ability. The following test is sufficient to refute this presumption. The brain of a rat, which had been immunized against morphia, contained, one hour after the administration of a dose which evoked no symptoms whatever, a greater quantity of the poison than that of a non-immunized animal which succumbed to the same dose.
I have repeatedly stated my opinion about the drug-habit and its nature,' and it has become public property to such an extent that many who have written on this problem at a later date, and recognized my statements as true, thought that they were expressing their own ideas. The following will illustrate my views.
If we suppose that a substance capable of provoking a reaction exercises its influence on certain cellular complexes of the organism, then an unusual functional reaction is produced which can more or less be identified. The return to the normal state takes place as soon as the tissues affected have come to rest, and as soon as the irritating influence has moreover been eliminated. But if the administration of a substance endowed with chemical energy is frequently repeated, neither of the above-indicated phenomena take place. Every new dose introduced into the organism still finds remains of the preceding doses and eventually a modified functional ability of the affected part.' Whereas a healthy cell, because of its life, i.e. through its physical or chemical elasticity, is enabled to triumph in a certain degree and for a certain time over non-assimilable foreign bodies and their effects, it becomes impossible, if the introduction of the substance is constantly repeated, for the perpetually incapacitated cell to return to a state of rest. Besides this, its normal functional ability to ward off the foreign body which exercises a hostile paralyzing or irritating influence is slowly but surely diminished. Every new dose acts on a basis whose capacity for functional reaction is reduced. In order to maintain this reaction at the required level, it is necessary to increase the dose progressively, and thus the energy of the cell is numbed over and over again until, after this process has lasted a certain time and a fixed quantity of the substance, varying with the individual, has been absorbed, the vital powers of the cell permit only of vegetation, i.e. allow it to live but do not suffice to ensure its protection against the incessant noxious influence or its normal physiological activity, which includes the necessary intimate relationship with other organs of the body.
According to my interpretation, therefore, the drug-habit, which I regard as a purely vital function, is not based upon an increase in energy of the cells, but, on the contrary, on a weakening of cellular vitality caused probably by chemical influences. Adaptation is the acquired incapacity to respond in a normal manner to a specific degree of excitation.
This weakness of the disarmed cell, the result of progressive adaptation, produces a certain degree of immunity from the toxic action of the irritating agent. lf, by excessive administration of the poison, the limit of tolerance is surpassed, the toxic effects appear as with non-adapted persons.
The vegetative functions of the defective group of cells are threatened in their existence, and disturbances of the functions of other cells, which are subject to their regulating influence, can be ascertained. There exists in a healthy state, on the other hand, harmonious co-operation between the functions of the organs of the body.
This organic relationship may be compared with a limited company, in which the single shareholders have a greater or lesser influence, but nevertheless all work together with one object in view: the conversation of the normal vital functions of the body. If one of the partners comes to grief, the others are also involved, and do their utmost to compensate for the initial damage up to the limit of their capability. Eventually they are exhausted, and each one takes the luckless path which destiny has assigned him. The bond which connected them is severed, and it will be difficult if not impossible to unite the company again. These diseases, due to the interdependence of the tissues, may result from any morbid disorder, and become worse than the primary affection.

If the functions of the brain, for example, have been brought through habit to a modified state, then every decrease in the quantity of the drug to which the habit has accustomed it disturbs the artificially established equilibrium with regard to the toleration of the foreign influence. The life of the cell has adapted itself to or was dominated by the drug, and if it is lacking a craving appears.
This reminds us of the hunger for salt which may be observed when a person has been deprived of this substance for some time. Just as the body needs to be supplied with this substance, which is an indispensable component of it, so certain narcotic or other substances become through their habitual employment integral substances of the brain, and the lack of them is felt in the same way as that of a necessary ingredient of the body. Thus we may say that morphia becomes a "hormone" for a morphinist. It enters into the community of the body, and is, as Galen said, 615/./OvTov. For instance, a certain person was able during a period of three years to pour 0.1 to 0.2 gr. of quinine four to six times a day on his tongue and swallow it without water. When asked the reason of this strange habit, he replied that he liked the effect of the substance. If he ceased to take it he became flurried and could not fulfill his professional duties. The same was probably the case with that old woman of whom Galen states that she gradually habituated herself to "cicuta" (i.e. presumably spotted cowbane and not water hemlock). In the same manner the people whom the Spaniards encountered on the coast of Peru made use of caustic lime in order to stimulate the organs of taste. The Goaj iros at the mouth of the Rio la Hacha, and others, do the same at the present day. A deprivation of this irritant causes internal disorders of a general nature.
We can but put forward bare hypotheses as to whether the action of these substances depends upon their absorption in the cells' or whether any alternative explanation may be supposed. I do not see the necessity for such a supposition, especially since signs of the chemical affinity of the substances in question, morphia, cocaine, etc., to cellular bodies have been sought for in vain. But even if this were otherwise, it would in no respect alter my analytical interpretation of the process, for it is really immaterial to the final result whether there takes place a combination with the cell or simply an exertion of energy by contact. It is essential only that the cell be brought under the influence of one of these substances.

The influence is removed by suppressing the drug in question. Then in the most favorable case the cell, thanks to the energies with which it is still provided or which it receives anew from life, can recover its former functional integrity, in the same way as a person, after being anaesthetized with ether or chloroform, comes back to a normal state when the anesthetic has been eliminated, although the functional activity of the ganglion-cells of his brain was temporarily diminished or suspended. Nevertheless, a certain modification of the functional constitution of the cell may have been established which does not disappear, and which may, when occasion arises, reveal itself by an easy relapse into the former state of dependence on the toxic agent. The reason for the relapse in such individuals is generally the remembrance of the agreeable sensations experienced when making use of the substance. The will-power, in the cellular life similar to that which so vividly preserves the agreeable impressions, cannot resist the attraction of a fresh dose of the drug, and a relapse occurs.
These material influences resemble in large measure those which we find in the spiritual life. Love of a woman, for instance, may degenerate into a passion for which there is no justification and which changes the life of the lover in regard of his judgment, will-power, and activity to such an extent that even the restraints of nature are thrust aside. Adaptation to this altered emotional life, even if it is inconvenient for the individual, is certain to take place with greater rapidity the more frequently the personal impression of the beloved object makes itself felt. If the woman who occasioned this state can be completely removed from the lover's horizon, an irritable weakness remains which prevents the rapid recovery of his normal faculties. He lives in the remembrance of the past, and though this may fade, the old passion with all its consequences is re-kindled as soon as the woman he loves appears again before his eyes.
The narcotic substances differ greatly among themselves with regard to the agreeable sensations they produce as inducements for their habitual use. These differences account for the degree of craving which they excite, but it has been found impossible to give an explanation of this. Such an explanation can probably be found in very delicate dissimilarities in the exciting qualities. So far we have discovered as the cause of the action of these substances and the resulting habitual adaptation, only functional reactions of the cell, which we must interpret in the last resort as chemical reactions. Morphological changes in the cell have so far not been demonstrated. All these cases in which so-called modifications in the microscopical structure of the cerebral or spinal tissues have been shown to occur are in my opinion based on errors in scientific judgment. Even in cases, for example, of adaptation to skin irritants, where the histology of the affected parts has been experimentally studied, no pathological modifications could be found. The narcotics do not leave any observable traces of their action in the nervous system. Nevertheless it is possible that modifications take place.

Immunity against Poisons

To the rich and varied field of personality in its widest sense appertain manifestations of immunity which, being innate, sometimes provide an apparently absolute protection against toxic or other factors. This immunity can, as described in the preceding pages, be realized, up to a certain limit if at all, through the formation of a habit by slowly increased dosage. It would even seem that this immunity is not merely peculiar to certain animal species, but that an analogous state can be produced in mankind. For instance, during long and dangerous epidemics it has been noticed that persons remain uninfected who must necessarily have absorbed some of the contagious matter. So far I am not certain of the existence of an immunity which a priori protects man against known noxious substances of a chemical nature. In all cases where an immunity of this kind has been thought to have been found, against the action of a toxic vapor, for example, there were probably certain external influences which prevented apparent toxic effects; or, on the other hand, the individuals concerned were hyposensitive and the quantity of the toxic agent insufficient. The very marked hyposensibility which can be ascertained towards, e.g. ethyl bromide, ethyl chloride, or chloroform should not be placed on the same level with the immunity we observe among certain animals to poisons which are capable of acting under all circumstances on man. In this respect the animal organism must be provided with certain peculiar quantities which allow for the absorption of proved poisons without apparent harm.
The hedgehog has long been considered as an animal extremely resistant to poisons. In fact, I have been able to prove' that although it can endure large quantities of cantharides or the venom of the common viper, this resistance is only relative. The viper itself seemed to be, during my experiments, not absolutely immune from its own venom; it could tolerate only certain quantities, and under these circumstances a retardation of the effect took place.
Nevertheless, there exist a considerable number of other observations which tend to confirm an absolute immunity towards certain poisons in the case of certain animals. If these are accurate, we cannot but suppose that the parts wherein the toxic action should be effective are differently conditioned from those of man or of other animals in which toxic reactions appear. The fungus mucor rhizopodiformis , for instance, poisons rabbits but has no effect on dogs. Tylenchus tritici thrives in glycerol, and belladonna, morphia, atropine, and strychnine do it no harm; on the other hand the salts of metals, acids, and alkalis have a detrimental effect. Ducks, hens, and doves are not poisoned by the internal application of opium. The rhinoceros-bird consumes the seeds of stychnos nux vomica, mice those of the bearded darnel, the blackbird belladonna, titmice the seeds of stramony, starlings those of spotted cowbane, rabbits and guinea-pigs the leaves and the fruit of belladonna.' Cows, sheep, and pigs, it is said, eat hembane, and snails the leaves of belladonna. The larva of defopeia pulchella derives its nourishment from the highly poisonous calabar bean. The caterpillars of ornithoptera darsius consume a poisonous aristolochia from which the poison is supposed to be transformed to the butterfly. The oleandor caterpillar eats the poisonous leaves of the plant from which it is named, and cimex hyoscyami the leaves of henbane. It is said that wild boars devour fern-roots, that rabbits are refractory to hashish, and that in Guadeloupe horses ravenously consume the leaves of rhus toxicodendron, which cause severe inflammation in man. In the Caucasus goats and sheep eat veratrum or hellebore, which intoxicates cows and horses.
The reaction of certain animals to low temperatures must also be placed among these enigmas. The "glacier flea," desoria glacialis, can not only jump about on the snowfields but remains in a frozen state for weeks and months at a temperature of —11°C without losing any of its vital energy. The snow flea of the plains, degeeria, can do the same. And they are composed of albumen! On the other hand, the common flea is unable to endure the climate of Tierra del Fuego, and perishes on being imported—a pleasant reflection for the ladies of the island!
Everywhere in this sphere of the difference in or absence of reaction of living matter to foreign or indigenous influences we are confronted with insoluble riddles. It is impossible to find the answer to them but it is necessary to become acquainted with the infinitely diverse forms in which they present themselves. Those which are connected with the narcotic and stimulating drugs should be of interest to everyone, even to those who exhibit selfish indifference. They constitute one of the world's problems, and those who are concerned in its solution—as who is not ?—must of necessity co-operate, consciously or otherwise.