chapter XVII

that there is no definite compound "caffetannic acid," and that the heterogeneous material designated by this name does not possess the properties of tanning. Further substantiation of this contention, and more evidence of the innocuous character of the tannin-like compounds in coffee, are contained in the testimony of Sollmann.[247] "Tannins precipitate proteins, gelatine, and connective tissue, and thus act as astringents, styptics, and antiseptics. The different tannins are not equivalent in these respects. Some (which are perhaps misnamed) such as those of coffee and ipecac, are practically non-precipitant.... On the whole, one may say that the small quantities of tannin ordinarily taken with the food and drink are not injurious, but that large quantities (excessive tea drinking) are certainly deleterious. The tannin of coffee is scarcely astringent, and, therefore, lacks this action," which is proven by the fact that it does not precipitate proteins.

"It has been claimed that 'caffetannic acid' injures the stomach walls, but there is no evidence that this is so."[248] Wiley,[249] in reporting some of his experiments, says: "Apparently the efforts to saddle the injurious effects of coffee-drinking upon caffetannic acid in any form in which it may exist in the coffee-extract are not supported by these recent data." The fact that tannins retard intestinal peristalsis, whereas coffee promotes this digestive action, lends further proof to the non-existence of tannin in coffee. These statements by eminent authorities may be consolidated into the verity that there is no tannin, in the true sense of the term, in coffee; and that the constituents of the coffee brew which have been so designated are physiologically harmless.

_Physiological Action of Caffeol_

The evidence regarding the physiological action of caffeol is contradictory in many cases. J. Lehmann found in 1853, that the "empyreumatic oil of coffee, _caffeone_," is active; but more recent investigations have yielded results at variance with this. Hare and Marshall[250] believe that they proved it to be active. E.T. Reichert,[251] however, found it inactive in dogs, excepting in so far that, when given intravenously, it mechanically interfered with the circulation. With it Binz[252] was able to produce in man only feeble nervous excitement, with restlessness and increase in the rate and depth of respirations.

The general effects, as summated by Sollmann[253] are, for _small doses_, pleasant stimulation; increased respiration; increased heart rate, but fall of blood pressure; muscular restlessness; insomnia; perspiration; congestion; for _large doses_, increased peristalsis and defecation; depression of respiration and heart; fall of blood pressure and temperature; paralytic phenomena. It is doubtful whether the quantities taken in the beverage cause any direct central stimulation.

Investigations have also been conducted with the various known constituents of this "coffee oil." Erdmann[254] found that in doses of between 0.5 and 0.6 gram per kilo of body weight, furane-alcohol kills a rabbit by respiratory paralysis; and that the symptoms of poisoning are a short primary excitement, salivation, diarrhea, respiratory depression, continuous fall of the body temperature, and death from collapse with respiratory failure. In man, doses of from 0.6 to 1 gram of furane-alcohol increased respiratory activity without producing other symptoms.

However, man is not as susceptible to these compounds as are the smaller animals. But even if their relative susceptibility be assumed to be the same, the lethal dose given the rabbit is equivalent to giving a 140-pound man one dose containing the furane-alcohol content of over 5,000 cups of coffee. Thus, in view of the very apparent minuteness of the quantity of this compound present in one cup of coffee, together with the fact that it is not cumulative in its physiological action, the importance of its toxic properties becomes very inconsequential to even the most profuse and inveterate coffee drinkers.

Burmann[255] reported the volatile principle to have a reducing action on the hemoglobin; a depressing effect on the blood pressure; a depressant action on the central nervous system, disturbing the cardiac rhythm; and an action on the respiratory centers, causing dyspnea. The report of Sayre[256] regarding the minimum lethal dose of the concentrated combined active principles of coffee obtained from dry distillation is, for frogs, administered intraperitoneally and subcutaneously, 0.03 cubic centimeters per gram of body weight; for guinea pigs per stomach, 7.0 cc. per kilogram of body weight, and administered intravenously and intraperitoneally, about 1.0 cc. per kilogram.

This evidence regarding the physiological action of caffeol can not in any wise be construed to indicate a harmfulness of coffee. The percentage of these volatile substances in a cup of coffee infusion is so low as to be relatively negligible in its action. And, again, the caffein content of the brew, as will be seen, tends to counteract any possible desultory effects of the caffeol.

_General Physiological Action of Caffein_

More attention has been given to the study of the physiological action of caffein than to that of the other individual constituents of coffee. Since certain of the effects of coffee drinking have been attributed to this alkaloid, a brief presentment of the pharmacology of caffein will be given as an exposition of the many statements made regarding it. According to the _British Pharmaceutical Codex_[257]:

Caffein exerts three important actions: (1) on the central nervous system: (2) on muscles, including cardiac: and (3) on the kidney. The action on the central nervous system is mainly on that part of the brain connected with psychical functions. It produces a condition of wakefulness and increased mental activity. The interpretation of sensory impressions is more perfect and correct, and thought becomes clearer and quicker. With larger doses of caffein the action extends from the psychical areas to the motor area and to the cord, and the patient becomes at first restless and noisy, and later may show convulsive movements.

Caffein facilitates the performance of all forms of physical work, and actually increases the total work which can be obtained from muscle. On the normal man, however, it is impossible to say how much of the action on the muscle is central and how much peripheral, but, as fatigue shows itself first by an action on the center, it is probable that the action of caffein in diminishing fatigue is mainly central. Caffein accelerates the pulse and slightly raises blood pressure. It has no action in any way resembling digitalis; by increasing the irritability of the cardiac muscle, its prolonged use rather tends to fatigue than to rest the heart.

Caffein and its allies form a very important group of diuretics. The urine is generally of a lower specific gravity than normal, since it contains a lesser proportion of salt and urea; but the total excretion of solids, both as regards urea, uric acid, and salts, is increased. Caffein, by exciting the medulla, produces an initial vaso-constriction of the kidneys, which tends at first to retard the flow of urine. So in recent years, other drugs have been introduced, allies of caffein, which act like it on the kidneys, but are without the stimulant action on the brain. Theobromine is such a drug.

Another authority states that[258]:

One of the most constant symptoms produced in man by over-doses of caffein is excessive diuresis, and experiments made upon the lower animals show that caffein acts as a diuretic not only by influencing the circulation, but also by directly affecting the secreting cells, the probabilities being in favor of the first of these theories of action. According to Schroeder, not only the water but also the solids of the urine are increased.

The question whether caffein has an influence upon tissue changes and the consequent nitrogenous elimination can not be considered as distinctly answered, though the most probable conclusion is that the action of caffein upon urea elimination and upon general nutrition is not direct or pronounced. While the therapeutic dose of caffein is broken up in the body with the formation of methylxanthin, which escapes with the urine, the toxic dose is at least in part eliminated by the kidney unchanged.

The metabolism of the methyl purins, of which group caffein is a member, appears to vary with the quantity ingested. The manner in which the methyl group is liberated by the cell protoplasm is said[259] to determine the amount of stimulus which the tissues receive from these substances. The xanthin group is almost without any excitatory action, and its metabolic end products are constant. Perhaps the variation in the excretions of unchanged methylpurins is dependent upon the amount of total reactive energy they invoke.

Baldi[260] found that caffein in small doses increases muscular excitability in dogs and frogs. The spinal and muscular hyperic excitability produced by caffein is, in his opinion, due to the methyl groups attached to the xanthin nucleus. Fredericq[261] states that caffein increases the irritability of the cardiac vagus and accelerates the appearance of pseudofatigue of the vagus which is produced by prolonged stimulation of the nerve. The action of caffein on the mammalian heart has also been investigated by Pilcher,[262] who found that, following the rapid intravenous injection of caffein, there is an acute fall of blood pressure; and with a maximal quantity of caffein, 10 milligrams per kilogram, the cardiac volume and the amplitude of the excursions are usually unchanged. With larger quantities, the volume progressively increases and the amplitude of the excursion decreases.

Salant[263] found that the intravenous injection of 15 to 25 milligrams of caffein per kilogram in animals was followed by a fall of blood pressure amounting to 7 to 35 percent in most cases, which was transitory, although in some animals it remained unchanged. A moderate rise was rarely observed. Caffein aids the action of nitrates, acetanilid, ethyl alcohol and amyl alcohol, and increases the toxicity of barium chloride. In a very thorough study of the toxicity of caffein which he made with Reiger,[264] a greater toxicity of about 15 to 20 percent by subcutaneous injection than by mouth, and but about one-half this when injected peritoneally, was found. Intramuscularly the toxicity is 30 percent greater than subcutaneously. In making the tests on animals, they found that individuality, season, age, species, and certain pathological conditions caused variation in the toxic effect of the administered caffein. Low protein diet tends to decrease resistance to caffein in dogs, and a milk or meat diet does the same for growing dogs. Caffein is not cumulative for the rabbit or dog.

As a result of experiments on the action of caffein on the bronchiospasm caused by peptone (Witte), silk peptone, B-imidoazolyl-ethylamin, curare, vasodilation, and mucarin, Pal[265] concluded that caffein stimulates certain branches of the peripheral sympathetic and is thus enabled to widen the bronchi or remove bronchiospasm.

According to Lapicque[266], caffein produces a change in the excitability of the medulla of the frog similar to that produced by raising the temperature of the nerve centers. Schürhoff[267] has pointed out that the continued use of large quantities of caffein will produce cardiac irregularity and sleeplessness.

Cochrane[268] cited three cases where caffein was hypodermically administered in cases of acute indigestion, etc., and concluded that the cases prove that caffein, or a compound containing it as a synergist, does indirectly make the injection of morphia a safe proceeding, and directly increases the force of the heart and arterial tension. However, Wood[269] found that medium doses of caffein do not produce any marked rise in blood pressure, and cause a reduction in pulse rate. He attributes the contradictory results which prior investigations gave, to employment of unusually large doses and to inaccurate experimental methods.

Caffein was found by Nonnenbruch and Szyszka[270] to have a slight

## action toward accelerating the coagulation time of the blood, being

## active over several hours. It inhibits coagulation _in vitrio_. Its

## action in the body apparently rests on an increase of the fibrin

ferment. There is no reason to believe that the behavior is dependent on a toxic action, but there is probably an action on the spleen; for in several rabbits from which the spleen was removed, no action was observed.

Experiments conducted by Levinthal[271] gave no positive information as to the formation of uric acid from caffein in the human organism. The elimination of caffein has also been studied by Salant and Reiger[272], who found that larger amounts of caffein are demethylated in carnivora than in herbivora, and resistance to caffein is inversely as demethylation, caffein being much more toxic in the former class. In a similar investigation, Zenetz[273] observed that caffein is very slightly eliminated from the system by the kidneys, and that its action on the heart is cumulative; therefore he concludes that it is contra-indicated in all renal diseases, in arterio-sclerosis, and in cardiac affections secondary to them. The inaccuracy of these conclusions regarding the non-elimination of caffein and those of Albanese,[274] Bondzynski and Gottlieb[275], Leven[276], Schurtzkwer[277], and Minkowski[278], has been shown by Mendel and Wardell[279], who point out that many of these experimenters worked with dogs, in which the chief end-product of purin metabolism is not uric acid, but allantoin. They observe that the increase in excretion of uric acid after the addition of caffein to the diet seems to be proportional to the quantity of caffein taken, and equivalent to from 10 to 15 percent of the ingested caffein. The remainder of the caffein is probably eliminated as mono-methylpurins.

Regarding the alleged cumulative action of caffein, Pletzer[280], Liebreich,[281] Szekacs[282], Pawinski,[283] and Seifert[284] all concluded from their investigations that the action of caffein is usually of brief duration, and does not have a cumulative effect, because of its rapid elimination; so that there is no danger of intoxication.

Dr. Oswald Schmiedeberg says:

Caffein is a means of refreshing bodily and mental activity, so that this may be prolonged when the condition of fatigue has already begun to produce restraint, and to call for more severe exertion of the will, a state which, as is well known, is painful or disagreeable.

This advantageous effect, in conditions of fatigue, of small quantities of caffein, as it is commonly taken in coffee or tea, might, however, by continued use become injurious, if it were in all cases necessarily exerted; that is to say, if by caffein the muscles and nerves were directly spurred on to increased activity. This is not the case, however, and just in this lies the peculiarity of the effect in question. The muscles and the simultaneously-acting nerves only under the influence of caffein respond more easily to the impulse of the will, but do not develop spontaneous activity; that is, without the co-operation of the will.

The character of caffein action makes plain that these food materials do not injure the organism by their caffein content, and do not by continued use cause any chronic form of illness.

According to Dr. Hollingworth's[285] deductions, caffein is the only known stimulant that quickens the functions of the human body without a subsequent period of depression. His explanation for this behavior is that "caffein acts as a lubricator for the nervous system, having an actual physical action whereby the nerves are enabled to do their work more easily. Other stimulants act on the nerves themselves, causing a waste of energy, and consequently, according to nature's law, a period of depression follows, and the whole process tends to injure the human machine." In not a single instance during his experiments at Columbia University did depression follow the use of caffein.

Of course, caffein, like any other alkaloid, if used to excess will prove harmful, due to the over-stimulation induced by it. However, taken in moderate quantities, as in coffee and tea by normal persons, the conclusions of Hirsch[286] may be taken as correct, namely: caffein is a mild stimulant, without direct effect on the muscles, the effect resulting from its own destruction and being temporary and transitory; it is not a depressant either initially or eventually; and is not habit-forming but a true stimulant, as distinguished from sedatives and habit-forming drugs.

_Caffein and Mental and Motor Efficiency_

The literature on the influence of caffein on fatigue has been summarized, and the older experiments clearly pointed out, by Rivers[287]. A summary of the most important researches which have had as their object the determination of the influence of caffein on mental and motor processes has been made by Hollingworth[288], from whose monograph much of the following material has been taken.

Increase in the force of muscular contractions was demonstrated in 1892 by De Sarlo and Barnardini[289] for caffein and by Kraepelin for tea. These investigators used the dynamometer as a measure of the force of contraction; however, most of the subsequent work on motor processes has been by the ergographic method. Ugolino Mosso[290], Koch[291]. Rossi[292], Sobieranski[293], Hoch and Kraepelin,[294] Destrée,[295] Benedicenti,[296] Schumberg,[297] Hellsten,[298] and Joteyko,[299] have all observed a stimulating effect of caffein on ergographic performance. Only one investigation of those reported by Rivers failed to find an appreciable effect, that of Oseretzkowsky and Kraepelin,[300] while Feré[301] affirms that the effect is only an acceleration of fatigue.

In spite of the general agreement as to the presence of stimulation there is some dissension regarding whether only the height of the contractions or their number or both are affected. As might be expected from the great diversity of methods employed, the quantitative results also have varied considerably. Carefully controlled experiments by Rivers and Webber[302] "confirm in general the conclusion reached by all previous workers that caffein stimulates the capacity for muscular work; and it is clear that this increase is not due to the various psychical factors of interest, sensory stimulation, and suggestion, which the experiments were especially designed to exclude. The greatest increase ... falls, however, far short of that described by some previous workers, such as Mosso; and it is probable that part of the effect described by these workers was due to the factors in question."

Investigations of mental processes under the influence of caffein have been much less frequent, most notable among which are those of Dietl and Vintschgau,[303] Dehio,[304] Kraepelin and Hoch,[305] Ach,[306] Langfeld,[307] and Rivers.[308] Kraepelin[309] observes: "We know that tea and coffee increase our mental efficiency in a definite way, and we use these as a means of overcoming mental fatigue ... In the morning these drinks remove the last traces of sleepiness and in the evening when we still have intellectual tasks to dispose of they aid in keeping us awake." Their use induces a greater briskness and clearness of thought, after which secondary fatigue is either entirely absent or is very slight.

Tendency toward habituation of the pyschic functions to caffein has been studied by Wedemeyer[310], who found that in the regular administration of it in the course of four to five weeks there is a measurable weakening of its action on psychic processes.

Rivers[311], who seems to have been the first to appreciate fully the genuine and practical importance of thoroughly controlling the psychological factors that are likely to play a rôle in such experiments, concludes that "caffein increases the capacity for both muscular and mental work, this stimulating action persisting for a considerable time after the substance has been taken without there being any evidence, with moderate doses, of reaction leading to diminished capacity for work, the substance thus really diminishing and not merely obscuring the effects of fatigue."

EFFECT OF CAFFEIN ON MENTAL AND MOTOR PROCESSES

Schematic Summary of All Results

St.=Stimulation. 0=No effect. Ret.=Retardation.

PRIMARY EFFECT Small Doses | Medium Doses | | Large Doses | | | Secondary Reaction | | | | Action Time Hrs. | | | | | Duration | | | | | in Hrs. Process Tests | | | | | | Motor speed 1. Tapping St. St. St. None .75-1.5 2-4 Coordination 2. Three-hole St. 0 Ret. None 1-1.5 3-4 3. Typewriting (a) Speed St. 0 Ret. None Results show (b) Errors Fewer for all None only in total doses days' work Association 4. Color-naming St. St. St. None 2-2.5 3-4 5. Opposites St. St. St. None 2.5-3 Next day 6. Calculation St. St. St. None 2.5 Next day Choice 7. Discrimination reaction time Ret. 0 St. None 2-4 Next day 8. Cancellation Ret. ? St. None 3-5 No data 9. S-W illusion 0 0 0 General 10. Steadiness ? Unsteadiness None 1-3 3-4 11. Sleep quality Individual differences 12. Sleep quantity depending on body weight 2 ? 13. General health and conditions of administration

Subsequent to these investigations was that of Hollingworth[312] which is at once the most comprehensive, carefully conducted, and scientifically accurate one yet performed. He employed an ample number of subjects in his experimentation; and both his subjects, and the assistants who recorded the observations, were in no wise cognizant of the character or quantity of the dose of caffein administered, the other experimental conditions being similarly rigorous and extensive.

The purpose of his study was to determine both qualitatively and quantitatively the effect of caffein on a wide range of mental and motor processes, by studying the performance of a considerable number of individuals for a long period of time, under controlled conditions; to study the way in which this influence is modified by such factors as the age, sex, weight, idiosyncrasy, and previous caffein habits of the subjects, and the degree to which it depends on the amount of the dose and the time and conditions of its administration; and to investigate the influence of caffein on the general health, quality and amount of sleep, and food habits of the individual tested.

To obtain this information the chief tests employed were the steadiness, tapping, coordination, typewriting, color-naming, calculations, opposites, cancellation, and discrimination tests, the familiar size-weight illusion, quality and amount of sleep, and general health and feeling of well-being. A brief review of the results of these tests is given in the tabular summary.

From these Hollingworth concluded that caffein influenced all the tests in a given group in much the same way. The effect on motor processes comes quickly and is transient, while the effect on higher mental processes comes more slowly and is more persistent. Whether this result is due to quicker reaction on the part of motor-nerve centers, or whether it is due to a direct peripheral effect on the muscle tissue is uncertain, but the indications are that caffein has a direct action on the muscle tissue, and that this effect is fairly rapid in appearance. The two principal factors which seem to modify the degree of caffein influence are _body weight_ and _presence of food_ in the stomach at the time of ingestion of the caffein. In practically all of the tests the magnitude of the caffein influence varied inversely with the body weight, and was most marked when taken on an empty stomach or without food substance. This variance in action was also true for both the quality and amount of sleep, and seemed to be accentuated when taken on successive days; but it did not appear to depend on the age, sex, or previous caffein habits of the individual. Those who had given up the use of caffein-containing beverages during the experiment did not report any craving for the drinks as such, but several expressed a feeling of annoyance at not having some sort of a warm drink for breakfast.

It is interesting to note that he also found a complete absence of any trace of secondary depression or of any sort of secondary reaction consequent upon the stimulation which was so strikingly present in many of the tests. The production of an increased capacity for work was clearly demonstrated, the same being a genuine drug effect, and not merely the effect of excitement, interest, sensory stimulation, expectation, or suggestion. However, this study does not show whether this increased capacity comes from a new supply of energy introduced or rendered available by the drug action, or whether energy already available comes to be employed more effectively, or whether fatigue sensations are weakened and the individual's standard of performance thereby raised. But they do show that from a standpoint of mental and productive physical efficiency "the widespread consumption of caffeinic beverages, even under circumstances in which and by individuals for whom the use of other drugs is stringently prohibited or decried, is justified."

_Conclusion_

Brief summarization of the information available on the pharmacology of coffee indicates that it should be used in moderation, particularly by children, the permissible quantity varying with the individual and ascertainable only through personal observation. Used in moderation, it will prove a valuable stimulant increasing personal efficiency in mental and physical labor. Its action in the alimentary régime is that of an adjuvant food, aiding digestion, favoring increased flow of the digestive juices, promoting intestinal peristalsis, and not tanning any portion of the digestive organs. It reacts on the kidneys as a diuretic, and increases the excretion of uric acid, which, however, is not to be taken as evidence that it is harmful in gout. Coffee has been indicated as a specific for various diseases, its functions therein being the raising and sustaining of low vitalities. Its effect upon longevity is virtually _nil_. A small proportion of humans who are very nervous may find coffee undesirable; but sensible consumption of coffee by the average, normal, non-neurasthenic person will not prove harmful but beneficial.

[Illustration]

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