It is to empiricism and that alone that we owe our first knowledge of the physiological action of Coca. There is nothing surprising in that, for empiricism is nothing more, in reality, than unconscious observation.

The Indians, who from time immemorial consumed so great a quantity of Coca leaves, did not do so merely from religious sentiment which deified the leaves of Coca, they well knew that they would derive great benefit from its use; they knew it only too well, since it is to that cause that we must attribute the legendary accounts given by the first authors who wrote on Coca.

This veneration for Coca arose, as we have seen, from its wonderful qualities. There are indeed, in this direction, some truly extraordinary accounts which should not be dismissed without notice, as they are given in good faith.

UnanuÉ, of Lima, relates that at the siege of La Paz, Bolivia, in 1781, only those inhabitants who had taken Coca were able to endure hunger and fatigue. Nearly all of the soldiers perished, deprived, as they were of food and overcome by forced marches, except those who had taken the precaution to provide themselves with Coca leaves.

It must not be believed that this prolonged fast, sustained by the use of Coca, wastes the strength and is injurious to the appetite. Indeed, according to the statement of all authors, the Indians who pass an entire day without eating, notwithstanding the hardship of forced marches, content themselves with chewing Coca leaves, and eat very heartily in the evening.

"The Indians who accompanied me on my voyage," says Weddel, "chewed Coca leaves all day, neither drinking, eating, nor showing any signs of fatigue. But at evening they replenished their stomachs like men who were completely famished, and I can assure you that I have sometimes seen them devour at one meal more aliment than I could have consumed in two days." We will see, further on, that it is in exciting the cerebro-medullary and nervous muscular functions, in part, and partly in producing a soothing effect on the mucous membrane of the stomach, that Coca produces these wonderful results in the conservation of energy without the tortures of hunger, notwithstanding the deprivation of aliment.

After this abstract of the well-known and recognized properties of Coca leaves, we will proceed to the medical study undertaken regarding this subject.

In 1850 Niemann discovered the active principle of the leaves of Coca, to which he gave the name of Cocaine, though, in fact, the discovery of this alkaloid should be attributed to Gardeke, who had separated it in 1855 under the name of Erythroxyline.

The work of Demarle appeared in that same year, on "The Coca of Peru"[4], in which he pointed out certain properties attributed by him to the alkaloid that the leaves of the plant contained, and which he studied. He remarked, among other things, the dilatation of the pupils, which he had noticed in his own case after having taken a dose of Coca; the absence of taste for a greater or less length of time after crushing some leaves with his teeth and letting them remain in the mouth.

Mantegazza has studied the effect of Coca and, according to this author, it acts as a stimulant on the nervous system, the respiration, and the circulation.

A dose of fifteen to twenty grammes of Coca produces an increase of the heart-beat, increasing pulse, and finally a rise in temperature. Mantegazza observed on himself that, under the influence of such a dose, his pulse increased from 65 to 124. Moreno, who repeated the same experiment, obtained similar results. The temperature and respiration are increased in the same proportion as the circulation.

The same dose, or even a weaker one, produces a remarkably stimulating effect on the nervous system. It is from this stimulating effect that Coca makes one more active and vigorous and enables those to accomplish more work who, without it, would soon be overcome with more or less fatigue. The use of larger doses (60 grammes for example) has caused intoxication, accompanied by sensation of happiness, which makes everything appear under a favorable aspect. Mantegazza, who experienced this intoxication, describes his sensations in an animated style, which recalls that of the Oriental legends: "Borne on the wings of two Coca leaves, I flew about in the spaces of 77,438 worlds, one more splendid than another. I prefer a life of ten years with Coca to one of a hundred thousand without it. It seemed to me that I was separated from the whole world, and I beheld the strangest images, most beautiful in color and in form that can be imagined."

In 1868, Moreno y MaÏz made some researches into the physiological action of Cocaine, and explained them in an interesting thesis which he read before the Faculty of Paris[5].

At about the same time, Lippmann, of Strasbourg, devoted his labors to the same subject, but his investigations did not yield the same results. He says that he could not establish the anÆsthetic properties of the plant.[6]

After Moreno y MaÏz, Dr. Gazeau[7], in 1870, studied the stimulating effect of Coca on nutrition, and found that it increased the pulse and respiration, assisted digestion, increased urinary excretion, and strengthened the nervous system. This author arrived at the conclusion that Coca prolongs life and promotes muscular energy. He advises its use, locally, for stomatitis, gingivitis, aphthous ulceration, and generally for painful and difficult digestion, gastric disturbance in phthisis, and also for obesity.

It was Charles Fauvel who first described the anÆsthetizing effect of Coca on the pharyngeal mucous membrane[8]. Thanks to this circumstance, he has been able to derive much benefit from the use of Coca in granular pharyngitis which is generally unaffected by any other kind of treatment.

Fauvel further showed that the stimulating effect which Coca exercises on all the muscles of the economy, appears to manifest itself specially on all the muscles of the larynx. Hence his apt qualification of the drug, "a tensor par excellence of the vocal cords."

In 1880, Von Arep published the results of his physiological researches with Cocaine. He spoke of its double effect on the nervous extremities and on the central nervous system.

We approach, on leaving this epoch, the really scientific era, that is to say, that of physiological experiments.

All the experiments having been made with Cocaine, we shall speak of it in the next chapter, which will be devoted exclusively to the study of this alkaloid.

Before closing, we will mention that it has been claimed frequently that Coca was aphrodisiac. The fact that the Peruvian Venus was represented as holding in her hand a leaf of Coca, was suggested as a proof in support of this opinion. Dr. UnanuÉ speaks of "certain coqueros, eighty years of age and over, and yet capable of such prowess as young men in the prime of life would be proud of."

Let us here add that the so-called unhappy consequences of the abuse of Coca are really much more rare than those produced even by tobacco, alcohol or opium.

The constant use of reasonable doses of Coca appears to produce a diametrically opposite effect, and the authors, who have had occasion to see a great number of Coca consumers, report cases of astonishing longevity among the Indian coqueros (Tschudy, Campbell, Mantegazza, UnanuÉ). They add that these instances are far from being exceptional.

COCAINE.

I.—A CHEMICAL STUDY.[9]

Cocaine is a crystallized alkaloid which Niemann, a pupil of Prof. Woehler, succeeded in extracting, in 1859, from some leaves of Erythroxylon Coca and to which he gave the following formula:

C³² H² O Az O²

Before it was known to him, Wackenroder, Johnston, Gardeke and Maclagan analyzed this plant without succeeding in the isolation of its active principle.

Some important works undertaken on this subject by Lassen, Humann and R. PÉrey are also quoted.

Properties.—Cocaine is colorless, odorless, and bitter to the taste. It crystallizes in the shape of oblique rhomboid prisms of from four to six facets.

It is very soluble in water, less soluble in alcohol, and absolutely insoluble in ether. It does not vaporize below 98°, but if the temperature is greatly increased it is decomposed. It possesses a strongly alkaline reaction.

United with acids it forms salts which are very difficult to crystallize.

Those which have been obtained from it are: the salicylate, oxalate, hydrobromide, sulphate, acetate, and finally the hydrochlorate, which forms an exception to the general rule, and is obtained more easily in the crystalline form than any other.

The solutions of the salts of Cocaine are precipitated by the caustic alkalies, carbonate of sodium, carbonate of ammonium, the alkaline bicarbonates, the bichloride of mercury, the protochloride of tin, bichloride of platinum, and by ammonia, which, added in excess, redissolves the precipitate formed by it. Iodine water, iodized potassium iodide, and picric acid precipitate the solutions of salts of Cocaine. When Cocaine is heated to 100° in a sealed tube with concentrated hydrochloric acid, it separates into benzoic acid and a new base, for which M. Woehler has proposed the name of Ecgonine. Lassen has discovered another nitrogenous base resulting from the separation of Cocaine—hygrine.

Preparation.—The process used by Niemann for obtaining Cocaine is as follows:

This chemist digested Coca leaves, cut into very small pieces, in alcohol (at 55°), for several days, adding sulphuric acid. The tincture which resulted from this operation was separated by expression, filtered, and treated with slaked lime. The liquid, which was primarily of a greenish-brown, was both divested of a part of its chlorophyll and also of a certain waxy substance. Niemann then neutralized this with sulphuric acid and evaporated it over a water-bath. The residue was then treated with water, which caused the separation of the rest of the chlorophyll and of the sulphate of Cocaine that it contained, and which was precipitated by means of the carbonate of sodium. He separated it finally with ether and purified it by several re-crystallizations in alcohol. This process was modified by Lassen, who precipitated the aqueous solution with the subacetate of lead.

In this way he was able to obtain about six grammes of Cocaine from a kilogramme of Coca leaves.

Moreno y MaÏz proposed a third process. He mixed intimately, slaked lime with finely-pulverized Coca leaves, letting the mixture stand for nearly twenty-four hours, in order that the lime might react suitably on the alkaloid, imitating in that, the Indian who mixes with his quid the llipta, of which we have already spoken. He afterward lixiviates it with alcohol at 40°.

II.—PHYSICAL STUDY.

We have reviewed the works of the different authors who occupied themselves with Coca; their various labors, although very interesting, did not reach the famous discovery of local anÆsthesia, and it is to KÖller, of Vienna[10], that the honor belongs of having brought to light the remarkable effect of Cocaine when applied to the conjunctival membrane.

This soon awakened general curiosity. From all quarters came works on the subject. Reuss, Koenigstein, Jellinck, Schrotter, Knapp and others hastened to give to the profession the result of their researches.

In France enthusiasm was not less strong, nor less prompt, all those whom this discovery interested undertook a series of experiments with Cocaine[11].

Among the first experimenters we must mention specially, Prof. Panas, Prof. Vulpian, Prof. Dujardin-Beaumetz, Dr. Terrier, Dr. Trousseau, Dr. Dehenne.

Prof. Panas reports in a communication made by him to the AcadÉmie de MÉdecine[12] what he has observed.

He states, besides, that in nearly all respects his personal investigations are confirmatory of those made by KÖller.

About five minutes after a few drops of a solution of hydrochloride of Cocaine composed of 0.5 gramme of that salt to a gramme of distilled water have been instilled into the eye, anÆsthesia of the conjunctival mucous membrane of the cornea begins to manifest itself and reaches the deep parts in about fifteen or twenty minutes if the instillations are repeated every five minutes.

At the same time there is a certain amount of mydriasis, but this is less pronounced than that produced by atropine. This pupillary dilatation, which is more perceptible in young subjects and not in glaucomatous states, lasts, at least, for twenty-four hours. With that occurs a slight paralysis of the ciliary muscle.

"On account of this," says Professor Panas, "Cocaine should be placed among the slightly mydriatic substances of which the passing effect might be utilized for ophthalmoscopic explorations of the fundus of the eye, under the same head as, and better than, homatropine."

According to M. Dujardin-Beaumetz, Cocaine not only deadens sensibility, but it can further be utilized with morphinomaniacs as a substitute for morphine without presenting the objections of the latter substance; and he adds that subcutaneous injections made with this alkaloid are not irritating (Bulletin de l'AcadÉmie de MÉdecine, session of the 18th of November, 1884).

Prof. Vulpian, at the outset, communicated to the AcadÉmie des Sciences the results of his interesting physiological researches with the chlorhydrate of Cocaine.

M. Vulpian, after observing similar anÆsthetic and analgesic effects on the eye in animals as already shown in man, resulting from an instillation between the eyelids of a few drops of solution of hydrochlorate of Cocaine, and also perceiving under these conditions the mydriatic action of the salt, noticed a protrusion of the ocular globe when he injected 0.10 centigramme of hydrochloride of Cocaine of a one to one hundred aqueous solution into the saphenous vein of a non-curarized dog, and that it occurred almost immediately after throwing the liquid into the vessel. Instantly the eyelids were seen to separate and the pupillary orifice to enlarge. "This," says he, "is an effect which exactly recalls the results of faradization of the upper extremity of the cervical sympathetic nerve cut transversely."

Complete anÆsthesia of the two transparent corneÆ existed in this case.

Prof. Grasset, of Montpelier, almost at the same time as Vulpian, observed the same effects of Cocaine, but a greater persistency in the phenomena of insensibility following the intravenous injection of the solution of hydrochloride of Cocaine.

At about that time, Dr. Laborde, of the AcadÉmie de MÉdecine, treated still more deeply of the action of Cocaine in three successive notes to the SociÉtÉ de Biologie (Nov. 22d and 29th and Dec. 27th, 1884). This learned physiologist studied the analgesic action generally resulting from subcutaneous injections of 0.03 of hydrochloride of Cocaine, in three doses, in the guinea-pig. He saw it at the same time produce a general hyper-excitability which irresistibly forced the animal to move, and even produced epileptic convulsions; the general analgesic state lasted for more than forty-eight hours.

M. Laborde, in attributing the secondary peripheric analgesia of intravenous or subcutaneous injections of hydrochlorate of Cocaine to the cerebral insusceptibility to pain, unconsciously made Cocaine a general anÆsthetic.

Prof. Arloing (1885, MÉmoire Soc. Biologie) has undertaken many experiments for demonstrating that Cocaine is not a general anÆsthetic.

In his experiments, the learned physiologist of Lyons confirmed the results obtained by Vulpian as to the modifications occasioned by Cocaine of the arterial pressure; he saw, like his predecessors, the excito-medullary and convulsary effect of large doses of Cocaine and the increase of the salivary secretion, and in regard to its cerebro-spinal effect, he compared it to strychnine. General analgesia did not occur except from fatal doses or when accompanied by convulsions. The hydrochlorate of Cocaine, according to M. Arloing, produces and can produce nothing but local anÆsthesia by temporarily changing the physical properties of the protoplasm of the terminal and fibrillary nervous elements easily accessible to medicinal agents in the cornea and mucous surfaces.

We will presently show that the several learned men who have been engaged in investigating the mechanism of action of the active principles of Coca were by no means in accord as regards the modus agendi of Cocaine in the production of local anÆsthesia.

While M. Dujardin-Beaumetz likens the local anÆsthetic action of Cocaine to that of cold, and while M. Laborde considers that it produces a diminished blood supply by the vaso-constrictor action of the great sympathetic nervous system, M. Arloing, on the contrary, explains it by a local action on the nervous protoplasm.

Moreover, in 1886, Schilling, a supporter of the vascular theory, advised inhalations of nine drops of nitrite of amyl, in three doses, inhalations which caused dilatation of the vessels, to revive patients poisoned with injections of Cocaine hydrochlorate.

In repeating these experiments in the laboratory, Dr. Laffont has succeeded little by little in enlarging his field of experiments, and finally has given to the AcadÉmie de MÉdecine (session of the 4th of January, 1888), a complete and definitive account of the action of the active principles of Coca on the different functions of the economy. This work of original researches and criticism of previous works will serve to explain the methodical and rational use of our preparations in the list of the different diseases where our former previsions had already led us to advise them.

In an earlier work (Comptes-rendus, SociÉtÉ de Biologie, Dec. 3, 1887), Dr. Laffont, studying the action of Cocaine on the great sympathetic nervous system, found that under the action of the active principle of Coca the functions of all the constrictor fibres of the great sympathetic nerve were increased.

The stomach contracts.

The intestines undergo an augmentation in peristalsis and borborygmi are heard.

The bladder invariably contracts, as M. Laborde has also seen.

The orbital capsule of the eye (smooth muscle) propels the eye-ball forward.

The pupil is dilated.

In a word, all the smooth-fibred muscles or muscles of organic life, subordinate to the great sympathetic nervous system constrictor, undergo an augmentation of functional activity.

In a second essay (Comptes-rendus, SociÉtÉ de Biologie, Dec. 17, 1887), the same experimenter studied more particularly the mechanism of the local or general analgesic action of Cocaine, and, like M. Arloing, as opposed to M. Laborde, he found that the cerebral perceptibility was not deadened, by a physiological dose, but on the contrary, increased.

The action of Cocaine on the nervous system is not exerted by the intervention of vascular constriction; it is a generalized exciting action, and a state of peripheric non-receptivity of external impressions[13] in the nervous extremities of the sensory nerves and the nerves of general sensation.

Cocaine, according to M. Laffont, is not the antagonist of curare, as M. Laborde describes it, but quite the contrary, a particular curare, acting like it on the periphery, and not affecting the nervous centers, the functional action of which is exaggerated thereby.

M. le docteur BeugniÈs-Corbeau describes fully in the Revue hebdomadaire de ThÉrapeutique gÉnÉrale et thermale, the internal effects of Coca, until now so obscure, and in regard to which no concrete doctrine had been formulated until M. le docteur Laffont presented to the AcadÉmie de MÉdecine his researches. He shows that Coca, from its active principles, should have these entirely distinct actions:

1^o Action on the protoplasm of the nervous extremities of the sensory nerves and on the nerves of general sensibility, producing non-transmissibility to the nerves of painful and even sensorized impressions, in a large dose;

2^o Excito-functional action on the cerebro-spinal nervous centers, producing an augmentation of intellectual and muscular activity;

3^o Excito-functional action on the great sympathetic constrictor nerve, consequently an exaltation of the functional action of all the non-striated muscles or muscles of organic life, which are subordinate to it.

Considering these distinct properties of the active principles of Coca, M. Laffont explains the long-recognized virtues of Coca, in that they conserve the natural forces, notwithstanding the withdrawal of aliments, in the following manner: "The exciting cerebro-medullary action of these principles causes an increase of the intellectual and physical activity, at the same time that the analgesic action on the extremities of the sensitive and sensory nerves, prevents the pangs of hunger, and consequently the accompanying moral and physical depression."

From another point of view, M. Laffont adds, that the dynamogenic action of the active principles of Coca on the smooth-fibered muscles "indicates its use in the list of atonic gastro-intestinal diseases, flatulent dyspepsia, dilatation of the stomach, paresis of the intestines, of the bladder, etc."

It is impossible for us to recount here all the trials which have been made with Cocaine; we will only quote the names of Dr. Deneffe, Dr. Charpentier, Dr. Morell Mackenzie, Dr. Lennox Browne, Dr. Sajous, Dr. J. Leonard Corning, Dr. Beverly Robinson, Dr. Louis Elsberg, Dr. W. Oliver Moore, Dr. Vincenzo Cozzolino, Dr. Abadie, Dr. Galezowski, Dr. Meyer, Dr. de Wecker, Dr. DolÉris, Dr. David Colombe, Dr. Rigolet, and Dr. Brasseur, the majority of whom have studied this question from an ocular, therapeutical, obstetrical, dental, and laryngological point of view.