Alexander Wynter Blyth

PART VI.--ALKALOIDS AND POISONOUS VEGETABLE PRINCIPLES SEPARATED FOR THE MOST PART BY ALCOHOLIC SOLVENTS. DIVISION I.--VEGETABLE ALKALOIDS. I.--General Methods of Testing and Extracting Alkaloids.

§ 301. General Tests for Alkaloids.—In order to ascertain whether an alkaloid is present or not, a method of extraction must be pursued which, while disposing of fatty matters, salts, &c., shall dissolve as little as possible of foreign substances—such a method, e.g., as the original process of Stas, or one of its modern modifications.

If to the acid aqueous solution finally obtained by this method a dilute solution of soda be added, drop by drop, until it is rendered feebly alkaline, and no precipitate appear, whatever other poisonous plant-constituents may be present, all ordinary alkaloids[324] are absent.

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[324] In the case of morphine tartrate, this test will not answer. See the article on Morphine.

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In addition to this negative test, there are also a number of substances which give well-marked crystalline or amorphous precipitates with alkaloids.§ 302. These may be called “group reagents.” The chief members of the group-reagents are—Iodine dissolved in hydriodic acid, iodine dissolved in potassic iodide solution, bromine dissolved in potassic bromide solution, hydrargo-potassic iodide, bismuth-potassic iodide, cadmic potassic iodide; the chlorides of gold, of platinum, and mercury; picric acid, gallic acid, tannin, chromate of potash, bichromate of potash, phospho-molybdic acid, phospho-tungstic acid, silico-tungstic acid, and FrÖhde’s reagent. It will be useful to make a few general remarks on some of these reagents.

Iodine in hydriodic acid gives either crystalline or amorphous precipitates with nearly all alkaloids; the compound with morphine, for example, is in very definite needles; with dilute solutions of atropine, the precipitate is in the form of minute dots, but the majority of the precipitates are amorphous, and all are more or less coloured.

Iodine dissolved in a solution of potassic iodide gives with alkaloids a reddish or red-brown precipitate, and this in perhaps a greater dilution than almost any reagent. When added to an aqueous solution, the precipitates are amorphous, but if added to an alcoholic solution, certain alkaloids then form crystalline precipitates; this, for example, is the case with berberine and narceine. By treating the precipitate with aqueous sulphurous acid, a sulphate of the alkaloid is formed and hydriodic acid, so that by suitable operations the alkaloid may readily be recovered from this compound. A solution of bromine in potassic bromide solution also gives similar precipitates to the above, but it forms insoluble compounds with phenol, orcin, and other substances.

Mercuric potassic iodide is prepared by decomposing mercuric chloride with potassic iodide in excess. The proportions are 13·546 grms. of mercuric chloride and 49·8 of potassic iodide, and water sufficient to measure, when dissolved, 1 litre. The precipitates from this reagent are white and flocculent; many of them become, on standing, crystalline.

Bismuthic potassic iodide in solution precipitates alkaloids, and the compounds formed are of great insolubility, but it also forms compounds with the various albuminoid bodies.

Chloride of gold forms with the alkaloids compounds, many of which are crystalline, and most admit of utilisation for quantitative determinations. Chloride of gold does not precipitate amides or ammonium compounds, and on this account its value is great. The precipitates are yellow, and after a while are partly decomposed, when the colour is of a reddish-brown.

Platinic chloride also forms precipitates with most of the alkaloids, but since it also precipitates ammonia and potassic salts, it is inferior to gold chloride in utility.§ 303. (1.) Phosphomolybdic Acid as a Reagent for Alkaloids.—Preparation; Molybdate of ammonia is precipitated by phosphate of soda; and the well-washed yellow precipitate is suspended in water and warmed with carbonate of soda, until it is entirely dissolved. This solution is evaporated to dryness, and the ammonia fully expelled by heating. If the molybdic acid is fairly reduced by this means, it is to be moistened by nitric acid, and the heating repeated. The now dry residue is warmed with water, nitric acid added to strong acid reaction, and the mixture diluted with water, so that 10 parts of the solution contain 1 of the dry salt. The precipitates of the alkaloids are as follows:—

Aniline,	Bright-yellow, flocculent.
Morphine,	Bright„yellow, floc „
Narcotine,	Brownish-yellow, c„
Quinine,	Whitish-yellow, oc„
Cinchonine,	Whitis„yellow, floc„
Codeine,	Brownish-yellow, voluminous.
Strychnine,	White-yellow, w, volum„
Brucine,	Yelk-yellow, flocculent.
Veratrine,	Bright-yellow, oc„
Jervine,	Bright„ yellow, fl„
Aconitine,	Bright„ yellow, fl„
Emetine,	Bright„ yellow, fl„
Theine,	Bright-yellow, voluminous.
Theobromine,	Bright„yellow, volu„
Solanine,	Citron-yellow, pulverulent.
Atropine,	Bright-yellow, flocculent.
Hyoscyamine,	Bright„yellow, floc„
Colchicine,	Orange-yellow,loc „
Delphinine,	Grey-yellow, voluminous.
Berberine,	Dirty-yellow, flocculent.
Coniine,	Bright-yellow, voluminous.
Nicotine,	Bright„yellow, volu„
Piperine,	Brownish-yellow, flocculent.

(2.) Silico-Tungstic Acid as a Reagent for Alkaloids.—Sodium tungstate is boiled with freshly precipitated gelatinous silica. To the solution is added mercurous nitrate, which precipitates the yellow mercurous silico-tungstate. This is filtered, well-washed, and decomposed by an equivalent quantity of hydrochloric acid; silico-tungstic acid then goes into solution, and mercurous chloride (calomel) remains behind. The clear filtrate is evaporated to drive off the excess of hydrochloric acid, and furnishes, on spontaneous evaporation, large, shining, colourless octahedra of silico-tungstic acid, which effloresce in the air, melt at 36°, and are easily soluble in water or alcohol.

This agent produces no insoluble precipitate with any metallic salt. CÆsium and rubidium salts, even in dilute solutions, are precipitated by it; neutral solutions of ammonium chloride give with it a white precipitate, soluble with difficulty in large quantities of water. It precipitates solutions of the salts of quinine, cinchonine, morphine, atropine, &c.; if in extremely dilute solution, an opalescence only is produced: for instance, it has been observed that cinchonine hydrochlorate in ¹/₂₀₀₀₀₀, quinia hydrochlorate in ¹/₂₀₀₀₀, morphia hydrochlorate in ¹/₁₅₂₈₅ dilution, all gave a distinct opalescence.—Archiv der Pharm., Nov., Dr. Richard Godeffroy.

(3.) Scheibler’s Method for Alkaloids: Phospho-Tungstic Acid.—Ordinary commercial sodium tungstate is digested with half its weight of phosphoric acid, specific gravity 1·13, and the whole allowed to stand for some days, when the acid separates in crystals. A solution of these crystals will give a distinct precipitate with the most minute quantities of alkaloids, ¹/₂₀₀₀₀₀ of strychnine, and ¹/₁₀₀₀₀₀ of quinine. The alkaloid is liberated by digestion with barium hydrate (or calcium hydrate); and if volatile, may be distilled off, if fixed, dissolved out by chloroform. In complex mixtures, colouring-matter may be removed by plumbic acetate, the lead thrown out by SH₂, and concentrated, so as to remove the excess of SH₂.§ 304. Schulze’s reagent is phospho-antimonic acid. It is prepared by dropping a strong solution of antimony trichloride into a saturated solution of sodic phosphate. The precipitation of the alkaloids is effected by this reagent in a sulphuric acid solution.§ 305. Dragendorff’s reagent is a solution of potass-bismuth iodide; it is prepared by dissolving bismuth iodide in a hot solution of potassium iodide, and then diluting with an equal volume of iodide of potassium solution. On the addition of an acid solution of an alkaloid, a kermes-red precipitate falls down, which is in many cases crystalline.

Marm’s reagent is a solution of potass-cadmium iodide. It is made on similar principles.

Potass-zinc iodide in solution is also made similarly. The precipitates produced in solutions of narceine and codeine are crystalline and very characteristic.§ 306. Colour Tests.—FrÖhde’s reagent is made by dissolving 1 part of sodic molybdate in 10 parts of strong sulphuric acid; it strikes distinctive colours with many alkaloids.

Mandelin’s reagent is a solution of meta-vanadate of ammonia in mono- or dihydrated sulphuric acid. The strength should be 1 part of the salt to 200 of the acid. This reagent strikes a colour with many alkaloids, and aids to their identification. It is specially useful to supplement and correct other tests. The following table gives the chief colour reactions, with the alkaloids. (See also p. 55 for the spectroscopic appearances of certain of the colour tests.)

METHODS OF SEPARATION.

§ 307. Stas’s Process.—The original method of Stas[325] (afterwards modified by Otto)[326] consisted in extraction of the organic matters by strong alcohol, with the addition of tartaric acid; the filtered solution was then carefully neutralised with soda, and shaken up with ether, the ethereal solution being separated by a pipette. Subsequent chemists proposed chloroform instead of ether,[327] the additional use of amyl-alcohol,[328] and the substitution of acetic, hydrochloric, and sulphuric for tartaric acid.

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[325] Annal d. Chem. u. Pharm., 84, 379.[326] Ib., 100, 44. Anleitung zur Ausmittel. d. Gifte.[327] Rodgers and Girwood, Pharm. Journ. and Trans., xvi. 497; Prollin’s Chem. Centralb., 1857, 231; Thomas, Zeitschr. fÜr analyt. Chem., i. 517, &c.[328] Erdmann and v. Ushlar, Ann. Chem. Pharm., cxx. pp. 121-360.

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COLOUR REACTIONS[329] OF CERTAIN ALKALOIDS.

Name of Substance.	Strong Sulphuric Acid.	FrÖhde’s Reagent.	Mandelin’s Reagent.
Strychnine.	...	...	Violet-blue, then lastly cinnabar-red.
Brucine.	Pale red.	Red, then yellow.	Yellow-red to orange, afterwards blood-red.
Curarine.	Fine red.	...	...
Quinine.	...	Greenish.	Weak orange, then blue-green, lastly green-brown.
Atropine.	...	...	Red, then yellow-red, and lastly yellow.
Aconitine.	...	...	...
Veratrine.	Yellow, then orange, blood-red, lastly carmine-red.	Gamboge-yellow, then cherry-red.	Yellow, orange, blood-red, lastly carmine-red.
Morphine.	...	Violet, green, blue-green, and yellow.	Reddish, then blue-violet.
Narcotine.	Yellow, then raspberry colour.	Green, then brown-green, yellow, lastly red.	Cinnabar-red, then carmine-red.
Codeine.	...	Dirty green, then blue, lastly yellow.	Green-blue to blue.
Papaverine.	...	Green, then blue-violet, lastly cherry-red.	Blue-green to blue.
Thebaine.	Blood-red, then yellow-red.	Orange, then colourless.	Red to orange.
Narceine.	Grey-brown, then blood-red.	Brown, green, red, lastly blue.	Violet, then orange.
Nicotine.	...	Yellowish, then red.	Transitory dark colour.
Coniine.	...	Yellow.	...
Colchicine.	Intense yellow.	Yellow to green-yellow.	Blue-green, then brown.
Delphinidine.	Red.	Red-brown.	Red-brown to brown.
Solanine.	Red-yellow, then brown.	Cherry-red, red-brown, yellow, yellow-green.	Yellow-orange, cherry-red, and lastly violet.

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[329] Caustic potash also gives characteristic colours with certain alkaloids. Out of seventy-two alkaloids (using 0·5 mgrm.), the following alone gave characteristic colours when fused with KHO:—Quinine, grass-green, and peculiar odour; quinidine, becoming yellower and finally brown; cinchonine, at first brownish-red to violet, with green edges, later, bluish-green; cinchonidine, blue passing into grey; cocaine, greenish-yellow, turning to blue, and then dirty red on strong heating.—W. Lenz, Zeit. f. anal. Chem., 25, 29-32.

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§ 308. Selmi’s Process for Separating Alkaloids.—A method of separating alkaloids from an ethereal solution has been proposed by Selmi.[330] The alcoholic extract of the viscera, acidified and filtered, is evaporated at 65°; the residue taken up with water, filtered, and decolorised by basic acetate of lead. The lead is thrown out by sulphuretted hydrogen; the solution, after concentration, repeatedly extracted with ether; and the ethereal solution saturated with dry CO₂, which generally precipitates some of the alkaloids. The ethereal solution is then poured into clean vessels, and mixed with about half its volume of water, through which a current of CO₂ is passed for twenty minutes; this may cause the precipitation of other alkaloids not thrown down by dry CO₂. If the whole of the alkaloids are not obtained by these means, the solution is dehydrated by agitation with barium oxide, and a solution of tartaric acid in ether is added (care being taken to avoid excess); this throws down any alkaloid still present. The detection of any yet remaining in the viscera is effected by mixing with barium hydrate and a little water, and agitating with purified amylic alcohol; from the alcohol the alkaloids may be subsequently extracted by agitation with very dilute sulphuric acid.

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[330] F. Selmi, Gazett. Chim. Ital., vj. 153-166, and Journ. Chem. Soc., i., 1877, 93.

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Another ingenious method (also the suggestion of Selmi) is to treat the organic substance with alcohol, to which a little sulphuric acid has been added, to filter, digest with alcohol, and refilter. The filtrates are united, evaporated down to a smaller bulk, filtered, concentrated to a syrup, alkalised by barium hydrate, and, after the addition of freshly ignited barium oxide and some powdered glass, exhausted with dry ether; the ether filtered, the filtrate digested with lead hydrate; the ethereal solution filtered, evaporated to dryness, and finally again taken up with ether, which, this time, should leave on evaporation the alkaloid almost pure.§ 309. Dragendorff’s Process.—To Dragendorff we owe an elaborate general method of separation, since it is applicable not only to alkaloids, but to glucosides, and other active principles derived from plants. His process is essentially a combination of those already known, and its distinctive features are the shaking up—(1) of the acid fluid with the solvent, thus removing colouring matters and certain non-alkaloidal principles; and (2) of the same fluid made alkaline. The following is his method in full. It may be advantageously used when the analyst has to search generally for vegetable poison, although it is, of course, far too elaborate for every case; and where, from any circumstance, there is good ground for suspecting the presence of one or two particular alkaloids or poisons, the process may be much shortened and modified.[331]

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[331] Dragendorff’s Gerichtlich-chemische Ermittelung von Giften, St. Petersburg, 1876, p. 141.

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I. The substance, in as finely-divided form as possible, is digested for a few hours in water acidified with sulphuric acid, at a temperature of 40° to 50°, and this operation is repeated two or three times, with filtering and pressing of the substances; later, the extracts are united. This treatment (if the temperature mentioned is not exceeded) does not decompose the majority of alkaloids or other active substances; but there are a few (e.g., solanine and colchicine) which would be altered by it; and, if such are suspected, maceration at the common temperature is necessary, with substitution of acetic for sulphuric acid.[332]

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[332] When blood is to be examined, it is better to dry it, and then powder and extract with water acidified with dilute sulphuric acid. However, if the so-called volatile alkaloids are suspected, this modification is to be omitted.

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II. The extract is next evaporated until it begins to be of a syrupy consistence; the residue mixed with three to four times its volume of alcohol, macerated for twenty-four hours at about 34°, allowed to become quite cool, and filtered from the foreign matters which have separated. The residue is washed with alcohol of 70 per cent.

III. The filtrate is freed from alcohol by distillation, the watery residue poured into a capacious flask, diluted (if necessary) with water, and filtered. Acid as it is, it is extracted at the common temperature, with frequent shaking, by freshly-rectified petroleum ether; and, after the fluids have again separated, the petroleum ether is removed, carrying with it certain impurities (colouring matter, &c.), which are in this way advantageously displaced. By this operation ethereal oils, carbolic acid, picric acid, &c., which have not been distilled, besides piperin, may also be separated. The shaking up with petroleum ether is repeated several times (as long as anything remains to be dissolved), and the products are evaporated on several watch-glasses.

RESIDUE OF PETROLEUM ETHER FROM THE ACID SOLUTION.

1. It is Crystalline.	2. It is Amorphous.	3. It is Volatile, with a powerful odour;
		ethereal oil, carbolic acid, &c.
A. It is yellowish, and with difficulty volatilised.	A. It is fixed.
a. The crystals are dissolved by concentrated sulphuric acid, with the production of a clear yellow colour, passing into brown and greenish-brown.	a. Concentrated sulphuric acid dissolves it immediately—violet, and later greenish-blue.
Piperin.	Constituents of the black hellebore.
. The solution in sulphuric acid remains yellow; potassic cyanide and caustic potash colour it, on warming, blood-red.	. It dissolves with a yellow colour, changing into fallow-brown.
Picric acid.	Constituents of aconite plant and products of the decomposition of Aconitine.
B. It Is Colourless, Liquefies easily, and Smells Strongly.	B. It Is White, Sharp-Tasting, and Reddens the Skin.
Camphor and similar matters.	Capsicin.

It may be expected that the substances mentioned under the heads 1, 2, and 3 will be, in general, fully obtained by degrees. This is not the case, however, as regards piperin and picric acid.IV. The watery fluid is now similarly shaken up with benzene, and the benzene removed and evaporated. Should the evaporated residue show signs of an alkaloid (and especially of theine), the watery fluid is treated several times with a fresh mixture of benzene, till a little of the last-obtained benzene extraction leaves on evaporation no residue. The benzene extracts are now united, and washed by shaking with distilled water; again separated and filtered, the greater part of the benzene distilled from the filtrate, and the remainder of the fluid divided and evaporated on several watch-glasses.

The evaporated residue may contain theine, colchicine, cubebin, digitalin, cantharidin, colocynthin, elaterin, caryophylline, absinthin, cascarillin, populin, santonin, &c., and traces of veratrine, delphinine, physostigmine, and berberine.

A remnant of piperin and picric acid may remain from the previous treatment with petroleum ether.

THE BENZENE RESIDUE FROM THE ACID SOLUTION.

1. It is Crystalline.	2. It is Amorphous.
A. Well-formed, Colourless Crystals.	A. Colourless or Pale Yellow Residue.
a. Sulphuric acid dissolves the hair-like crystals without change of colour; evaporation with chlorine water, and subsequent treatment with ammonia, gives a murexide reaction.	a. Sulphuric acid dissolves it at first yellow; the solution becoming later red. FrÖhde’s reagent does not colour it violet.
Theine.	Elaterin.
. Sulphuric acid leaves the rhombic crystals uncoloured. The substance, taken up by oil, and applied to the skin, produces a blister.	. Sulphuric acid dissolves red; FrÖhde’s reagent violet-red;[333] tannic acid does not precipitate.
Cantharidin.	Populin.
?. Sulphuric acid leaves the scaly crystals at first uncoloured, then slowly develops a reddening. It does not blister. Warm alcoholic potash-lye colours it a transitory red.	?. Sulphuric acid dissolves it with a red colour; FrÖhde’s reagent[334] a beautiful cherry-red; tannic acid precipitates a yellowish-white.
Santonin.	Colocynthin.
d. Sulphuric acid colours the crystals almost black, whilst it takes itself a beautiful red colour.	d. Sulphuric acid colours it gradually a beautiful red, whilst tannin does not precipitate.
Cubebin.	Constituents of the Pimento.
B. Crystals Pale to Clear Yellow.	B. Pure Yellow Residue.
a. Piperin.	a. Sulphuric acid dissolves it yellow; on the addition of nitric acid, this solution is green, quickly changing to blue and violet.
	Colchicine.
. Picric Acid.	. Sulphuric acid dissolves with separation of a violet powder; caustic potash colours it red; sulphide of ammonia violet, and, by heating, indigo-blue.
	Chrysammic acid.
?. Caustic potash dissolves it purple.
Aloetin.
C. Mostly Undefined Colourless Crystals.	C. A Greenish Bitter Residue, which dissolves brown in concentrated sulphuric acid; in FrÖhde’s reagent, likewise, at first brown, then at the edge green, changing into blue-violet, and lastly violet.
	Constituents of wormwood, with absynthin, besides quassiin, menyanthin, ericolin, daphnin, cnicin, and others.
a. Sulphuric acid dissolves it green-brown; bromine colours this solution red; dilution with water again green. The substance renders the heart-action of a frog slower.
Digitalin.
. Sulphuric acid dissolves it orange, then brown, lastly red-violet. Nitric acid dissolves it yellow, and water separates as a jelly out of the latter solution. Sulphuric acid and bromine do not colour it red.
Gratiolin.
?. Sulphuric acid dissolves it red-brown. Bromine produces in this solution red-violet stripes. It does not act on frogs.
Cascarillin.
D. Generally Undefined Yellow Crystallisation.—Sulphuric acid dissolves it olive-green. The alcoholic solution gives with potassic iodide a colourless and green crystalline precipitate.
Berberin.

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[333, 334] FrÖhde’s reagent is described at page 239.

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V. As a complete exhaustion of the watery solution is not yet attained by the benzene agency, another solvent is tried.

THE WATERY SOLUTION IS NOW EXTRACTED IN THE SAME WAY BY CHLOROFORM.

In chloroform the following substances are especially taken up:—Theobromine, narceine, papaverine, cinchonine, jervine, besides picrotoxin, syringin, digitalin, helleborin, convallamarin, saponin, senegin, smilacin. Lastly, portions of the bodies named in Process IV., which benzene failed to extract entirely, enter into solution, as well as traces of brucine, narcotine, physostigmine, veratrine, delphinine. The evaporation of the chloroform is conducted at the ordinary temperature in four or five watch-glasses.

THE CHLOROFORM RESIDUE FROM THE ACID SOLUTION.[335]

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[335] Chloroform removes small portions of acetate of aconitine from acid solution, Dunstan and Umney, J. C. S., 1892, p. 338.

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1. The Residue is more or less markedly Crystalline.	2. The Residue is Amorphous.
A. It gives in the sulphuric acid solution evidence of an alkaloid by its action towards iodine and iodide of potassium.	A. In acetic acid solution it renders the action of the frog’s heart slower, or produces local anÆsthesia.
	aa. It does not produce local anÆsthesia.
a. Sulphuric acid dissolves it without the production of colour, and chlorine and ammonia give no murexide reaction.	a. Sulphuric acid dissolves it red-brown, bromine produces a beautiful purple colour, water changes it into green, hydrochloric acid dissolves it greenish-brown.
Cinchonine.	Digitalin.
. Sulphuric acid dissolves it without colour, chlorine and ammonia give, as with theine, a murexide reaction.	. Sulphuric acid dissolves it yellow, then brown-red; on addition of water this solution becomes violet. Hydrochloric acid, on warming, dissolves it red.
Theobromine.	Convallamarin.
	bb. It produces local anÆsthesia.
	a. Sulphuric acid dissolves it brown. The solution becomes, by extracting with water, violet, and can even be diluted with two volumes of water without losing its colour.
	Saponin.
	. Sulphuric acid dissolves it yellow. On diluting with water the same reaction occurs as in the previous case, but more feebly.
	Senegin.
?. Sulphuric acid does not colour in the cold; on warming, the solution becomes a blue violet.	?. Sulphuric acid dissolves brown, and the solution becomes red by the addition of a little water. The action is very weak.
Papaverine.	Smilacin.
	cc. Sulphuric acid dissolves it with the production of a dirty red, hydrochloric acid, in the cold, with that of a reddish-brown colour, and the last solution becomes brown on boiling.
	Constituents of the hellebore, particularly Jervine.
d. Sulphuric acid dissolves it in the cold with the production of a blue colour.
Unknown impurities, many commercial samples of Papaverine.
e. Sulphuric acid dissolves it at first grey-brown; the solution becomes in about twenty-four hours blood-red. Iodine water colours it blue.
Narceine.
B. It gives no Alkaloid Reaction.	B. Is inactive, and becomes blue by sulphuric acid; by FrÖhde’s reagent[336] dark cherry-red. Hydrochloric acid dissolves it red. The solution becomes, by boiling, colourless.
	Syringin.
a. Sulphuric acid dissolves it with a beautiful yellow colour; mixed with nitre, then moistened with sulphuric acid, and lastly treated with concentrated soda-lye, it is coloured a brick-red.
Picrotoxin.
. Sulphuric acid dissolves it with the production of a splendid red colour. The substance renders the heart-action of a frog slower.
Helleborin.

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[336] Described at p. 239.

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VI. THE WATERY FLUID IS NOW AGAIN SHAKEN UP WITH PETROLEUM ETHER,

in order to take up the rest of the chloroform, and the watery fluid is saturated with ammonia. The watery solution of aconitine and emetine is liable to undergo, through free ammonia, a partial decomposition; but, on the other hand, it is quite possible to obtain, with very small mixtures of the substances, satisfactory reactions, even out of ammoniacal solutions.

VII. THE AMMONIACAL WATERY FLUID WITH PETROLEUM ETHER.

In the earlier stages Dragendorff advises the shaking up with petroleum ether at about 40°, and the removal of the ether as quickly as possible whilst warm. This is with the intention of separating by this fluid strychnine, brucine, emetine, quinine, veratrine, &c. Finding, however, that a full extraction by petroleum ether is either difficult or not practicable, he prefers, as we have seen, to conclude the operation by other agents, coming back again upon the ether for certain special cases. Such are the volatile alkaloids; and here he recommends treatment of the fluid by cold petroleum ether, taking care not to hasten the removal of the latter. Strychnine and other fixed alkaloids are then only taken up in small quantities, and the greater portion remains for the later treatment of the watery fluid by benzene.

A portion of the petroleum ether, supposed to contain in solution volatile alkaloids, is evaporated in two watch-glasses; to the one, strong hydrochloric acid is added, the other being evaporated without this agent. On the evaporation of the petroleum ether, it is seen whether the first portion is crystalline or amorphous, or whether the second leaves behind a strongly-smelling fluid mass, which denotes a volatile alkaloid. If the residue in both glasses is without odour and fixed, the absence of volatile acids and the presence of fixed alkaloids, strychnine, emetine, veratrine, &c., are indicated.

THE PETROLEUM ETHER RESIDUE FROM AMMONIACAL SOLUTION.

1. It is fixed and Crystalline.	2. It is fixed and Amorphous.	3. It is fixed and Odorous.
A. The crystals are volatilised with difficulty.		A. On adding to the watch-glass a little hydrochloric acid, crystals are left behind.
aa. Sulphuric acid dissolves it without colour.		aa. Its solution is not precipitated by platin chloride.
a. Potassic chromate colours this solution a transitory blue, then red.	a. The purest sulphuric acid dissolves it almost without colour; sulphuric acid containing nitric acid, red quickly becoming orange.	a. The crystals of the hydrochloric compound act on polarised light; and are mostly needle-shaped and columnar.
Strychnine.	Brucine.	Coniine and Methyl-Coniine.
. Potassic chromate does not colour it blue; with chlorine water and ammonia it gives a green colour.	. Sulphuric acid dissolves it yellow, becoming deep red.	. The crystals are cubical or tetrahedral.
Quinine.	Veratrine.	Alkaloid from Capsicum.
	?. Sulphuric acid dissolves it brown-green; FrÖhde’s reagent red, changing into green.
	Emetine.
		bb. The solution of the hydrochlorate of the alkaloid is precipitated by platin chloride.
		Sarracinin.
?. Sulphuric acid dissolves it yellow, and the solution becomes gradually a beautiful deep red.		B. The residue of the hydrochlorate of the alkaloid is amorphous, or, by further additions of HCl, becomes crystalline.
Sabadilline.
d. The crystals are easily volatilised.
Coniine.
		aa. Its diluted aqueous solution is precipitated by platin chloride.
		a. The hydrochlorate salt, being quickly treated with FrÖhde’s reagent, gives after about two minutes a violet solution which gradually fades.
		Lobeliin.
		. The hydrochlorate smells like nicotine, and becomes by FrÖhde’s reagent yellow, and after twenty-four hours pale red.
		Nicotine.
		?. The hydrochlorate is without odour, the free base smells faintly like aniline.
		Sparteine.
		bb. The substance is not precipitated from a diluted solution by platin chloride.
		a. Its petroleum ether solution produces no turbidity with a solution of picric acid in petroleum ether; but it leaves behind, when mixed with the above, crystals mostly of three-sided plates.
		Trimethylamine.
		. The petroleum ether solution gives, on evaporation, when treated similarly, moss-like crystals. The substance is made blue by chloride of lime, as well as by diluted sulphuric acid and bichromate of potash.
		Aniline.
		?. The alkaloid does not smell like methylamine, and is not coloured by chloride of lime, sulphuric acid, or chromate of potash.
		Volatile alkaloid of the Pimento.

VIII. THE AMMONIACAL SOLUTION IS SHAKEN UP WITH BENZENE.

In most cases petroleum ether, benzene, and chloroform are more easily separated from acid watery fluids than from ammoniacal, benzene and chloroform causing here a difficulty which has perhaps deterred many from using this method. Dragendorff, however, maintains that he has never examined a fluid in which he could not obtain a complete separation of the benzene and water. If the upper benzene layer is fully gelatinous and emulsive, the under layer of water is to be removed with a pipette as far as possible, and the benzene with a few drops of absolute alcohol and filtration. As a rule, the water goes through first alone, and by the time the greater part has run through, the jelly in the filter, by dint of stirring, has become separated from the benzene, and, finally, the jelly shrinks up to a minimum, and the clear benzene filters off. Dragendorff filters mostly into a burette, from which ultimately the benzene and the water are separated.

The principal alkaloids which are dissolved in benzene are—strychnine, methyl and ethyl strychnine, brucine, emetine, quinine, cinchonine, atropine, hyoscyamine, physostigmine, aconitine, nepalin, the alkaloid of the Aconitum lycoctonum, aconellin, napellin, delphinine, veratrine, sabatrin, sabadilline, codeine, thebaine, and narcotine.

THE BENZENE RESIDUE DERIVED FROM THE AMMONIACAL SOLUTION.

1. It is for the most part Crystalline.	2. It is for the most part Amorphous.
a. Sulphuric acid dissolves it without colour, the solution being coloured neither on standing nor on the addition of nitric acid.	a. Pure sulphuric acid dissolves it either whitish-red or yellowish.
aa. It dilates the pupil of a cat.
a. Platin chloride does not precipitate the aqueous solution. The sulphuric acid solution gives, on warming, a peculiar smell.	a. The solution becomes by nitric acid immediately red, then quickly orange.
Atropine.	Brucine.
. Platin chloride applied to the solution precipitates.	. The solution becomes by little and little brownish-red. The substance is coloured red by chloride of lime solution, and it contracts the pupil.
Hyoscyamine.	Physostigmine.
bb. It does not dilate the pupil.
a. The sulphuric acid solution becomes blue by chromate of potash.
aa. The substance applied to a frog produces tetanus.
Strychnine.
. It lowers the number of respirations in a frog.
Ethyl and Methyl Strychnine.
. Sulphuric acid and bichromate of potash do not colour it blue.
aa. The sulphuric acid watery solution is fluorescent, and becomes green on the addition of chlorine water and ammonia.
Quinine and Cinchonine.
(The last is more difficult to dissolve in petroleum ether than quinine.)
. The solution is not fluorescent.
Cinchonine.
b. Sulphuric acid dissolves it at first colourless; the solution takes on standing a rose or violet-blue; on addition of nitric acid, a blood-red or brown coloration.	b. Pure sulphuric acid dissolves it yellow, and the solution becomes later beautiful red (with delphinine, more quickly a darker cherry-red.)
a. A solution in diluted sulphuric acid becomes, on heating, gradually deep blood-red, and, when cooled, violet, with nitric acid. The aqueous solution is precipitated by ammonia.	a. The hydrochloric acid solution becomes red on heating.
Narcotine.
	aa. The substance acts on a frog, causing, in large doses, tetanus.
	Veratrine.
	. It is almost without action on frogs.
	Sabatrin.
. The solution in diluted sulphuric acid becomes, on heating, a beautiful blue. Excess of ammonia does not precipitate in a diluted watery solution.	. The hydrochloric acid solution does not, on heating, become red.
Codeine.	Delphinine.
c. Sulphuric acid dissolves it with the production of a yellow colour.	c. Pure sulphuric acid dissolves it yellow, and the solution becomes later red-brown, and gradually violet-red.
a. The solution remains yellow on standing.	a. The substance even in small doses paralyses frogs, and dilates the pupil of a cat’s eye. Ether dissolves it with difficulty.
Acolyctin.	Nepalin.
. It becomes beautifully red.	. It is easily soluble in ether, its effects are not so marked, and it does not dilate the pupil.
Sabadilline.	Aconitine.
	?. Its effects are still feeble; it does not dilate the pupil, and is with difficulty dissolved by ether.
	Napellin.
d. Sulphuric acid dissolves it with an immediate deep red-brown colour.	d. Sulphuric acid dissolves it with a dark green colour, and the solution becomes, even after a few seconds, a beautiful blood-red.
Thebaine.	Alkaloidal substances out of the Aconitum lycoctonum.
e. Sulphuric acid dissolves it immediately blue.	e. Sulphuric acid dissolves it brown-green, and FrÖhde’s reagent red, becoming beautifully green.
Substances accompanying the Papaverins.	Emetine.

IX. SHAKING OF THE AMMONIACAL WATERY SOLUTION WITH CHLOROFORM.

This extracts the remainder of the cinchonine and papaverine, narceine, and a small portion of morphine, as well as an alkaloid from the celandine.

The Residue from the Chloroform.

aa. The solution, on warming, is only slightly coloured.

a. But, after it is again cooled, it strikes with nitric acid a violet-blue; chloride of iron mixed with the substance gives a blue colour; FrÖhde’s reagent also dissolves it violet.

Morphine.

. It is not coloured by nitric acid; it is also indifferent to chloride of iron.

Cinchonine.

bb. The solution becomes by warming violet-blue.

Papaverine.

?. Sulphuric acid dissolves it greenish-brown, and the solution becomes, on standing, blood-red.

Narceine.

d. Sulphuric acid dissolves it a violet-blue.

Alkaloidal constituent of the Celandine.

X. SHAKING UP OF THE WATERY FLUID WITH AMYL ALCOHOL.

From this process, besides morphine and solanine, as well as salicin, the remnants of the convallamarin, saponin, senegin, and narceine are also to be expected.

The Amyl Alcohol Residue.

a. Sulphuric acid dissolves it without colour in the cold.

Morphine (see above).

b. Sulphuric acid dissolves it with the production of a clear yellow-red and the solution becomes brownish. Iodine water colours it a deep brown. The alcoholic solution gelatinises.

Solanine.

c. Sulphuric acid dissolves it green-brown, becoming red.

Narceine (see above).

d. Sulphuric acid dissolves it yellow, then brown-red, becoming violet on dilution with water. Hydrochloric acid dissolves it, and it becomes red on warming. It stops the heart-action in the systole.

Convallamarin.

e. Hydrochloric acid dissolves it for the most part without colour.

Saponin.

f. As the foregoing, but acting more feebly.

Senegin.

g. Sulphuric acid dissolves it immediately a pure red. On warming with sulphuric acid and bichromate of potash, a smell of salicylic acid is developed.

Salicin.

XI. DRYING THE WATERY FLUID WITH THE ADDITION OF POWDERED GLASS, AND EXTRACTION OF THE FINELY-DIVIDED RESIDUE BY CHLOROFORM.

The residue of the first chloroform extract lessens the number of respirations of a frog; the residue of the second and third chloroform extract becomes, by sulphuric acid and bichromate of potash, blue, passing into a permanent red.

Another portion of this residue becomes red on warming with diluted sulphuric acid.

Curarine.

Shorter Process for Separating some of the Alkaloids.

§ 310. A shorter process, recommended conditionally by Dragendorff, for brucine, strychnine, quinine, cinchonine, and emetine, is as follows:—

The substance, if necessary, is finely divided, and treated with sulphuric acid (dilute) until it has a marked acid reaction. To every 100 c.c. of the pulp (which has been diluted with distilled water to admit of its being filtered later), at least 5 to 10 c.c. of diluted sulphuric acid (1: 5) are added. It is digested at 50° for a few hours, filtered, and the residue treated again with 100 c.c. of water at 50°. This extract is, after a few hours, again filtered; both the filtrates are mixed and evaporated in the water-bath to almost the consistency of a thin syrup. The fluid, however, must not be concentrated too much, or fully evaporated to dryness. The residue is now placed in a flask, and treated with three to four times its volume of alcohol of 90 to 95 per cent.; the mixture is macerated for twenty-four hours, and then filtered. The filtrate is distilled alcohol-free, or nearly so, but a small amount of alcohol remaining is not objectionable. The watery fluid is diluted to about 50 c.c., and treated with pure benzene; the mixture is shaken, and after a little time the benzene removed—an operation which is repeated. After the removal the second time of the benzene, the watery fluid is made alkaline with ammonia, warmed to 40° or 50°, and the free alkaloid extracted by twice shaking it up with two different applications of benzene. On evaporation of the latter, if the alkaloid is not left pure, it can be dissolved in acid, precipitated by ammonia, and again extracted by benzene.

§ 311. Scheibler’s Process.—A method very different from those just described is one practised by Scheibler. This is to precipitate the phosphotungstate of the alkaloid, and then to liberate the latter by digesting the precipitate with either hydrate of barium or hydrate of calcium, dissolving it out by chloroform, or, if volatile, by simple distillation. The convenience of Scheibler’s process is great, and it admits of very general application. In complex mixtures, it will usually be found best to precede the addition of phosphotungstic acid[337] by that of acetate of lead, in order to remove colouring matter, &c.; the excess of lead must in its turn be thrown out by SH₂, and the excess of SH₂ be got rid of by evaporation. Phosphotungstic acid is a very delicate test for the alkaloids, giving a distinct precipitate with the most minute quantities (¹/₂₀₀₀₀₀ of strychnine and ¹/₁₀₀₀₀₀ of quinine). A very similar method is practised by Sonnenschein and others with the aid of phospho-molybdic acid. The details of Scheibler’s process are as follows:—

---

[337] The method of preparing this reagent is as follows:—Ordinary commercial sodium tungstate is treated with half its weight of phosphoric acid, specific gravity, 1·13, and then allowed to stand for some days. Phosphotungstic acid separates in crystals.

---

The organic mixture is repeatedly extracted by water strongly acidified with sulphuric acid; the extract is evaporated at 30° to the consistence of a thin syrup; then diluted with water, and, after several hours’ standing, filtered in a cool place. To the filtered fluid phosphotungstic acid is added in excess, the precipitate filtered, washed with water to which some phosphotungstic acid solution has been added, and, whilst still moist, rinsed into a flask. Caustic baryta or carbonate of potash is added to alkaline reaction, and after the flask has been connected with bulbs containing HCl, it is heated at first slowly, then more strongly. Ammonia and any volatile alkaloids are driven over into the acid, and are there fixed, and can be examined later by suitable methods. The residue in the flask is carefully evaporated to dryness (the excess of baryta having been precipitated by CO₂), and then extracted by strong alcohol. On evaporation of the alcohol, the alkaloid is generally sufficiently pure to be examined, or, if not so, it may be obtained pure by re-solution, &c.

The author has had considerable experience of Scheibler’s process, and has used it in precipitating various animal fluids, but has generally found the precipitate bulky and difficult to manage.

§ 312. Grandval and Lajoux’s Method.[338]—The alkaloids are precipitated from a solution slightly acidified by hydrochloric or sulphuric acid by a solution of hydrarg-potassium iodide. The precipitate is collected on a filter, washed and then transferred to a flask; drop by drop, a solution of sodium sulphide is added; after each addition the suspended precipitate is shaken and allowed to stand for a few minutes, and a drop of the liquid taken out and tested with lead acetate; directly a slight brown colour appears, sufficient sodic sulphide has been added. The liquid is now left for half-an-hour, with occasional shaking. Then sulphuric acid is added until it is just acid, and the liquid is filtered and the mercury sulphide well washed. In the filtrate will be the sulphate of any alkaloid in solution; this liquid is now made alkaline with soda carbonate and shaken up, as in Dragendorff’s process, with appropriate solvents; such, for example, as ether, or chloroform, or acetone, or amylic alcohol, according to the particular alkaloid the analyst is searching for, and the solvent finally separated and allowed to evaporate, when the alkaloid is found in the residue.

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[338] “Dosage des alcaloides À l’aide de l’iodure double de mercure et de potassium,” par MM. A. Grandval et Henri Lajoux, Journ. de Pharmacie, 5 sÉr. t. xxviii. 152-156.

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§ 313. Identification of the Alkaloids.—Having obtained, in one way or other, a crystalline or amorphous substance, supposed to be an alkaloid, or, at all events, an active vegetable principle, the next step is to identify it. If the tests given in Dragendorff’s process have been applied, the observer will have already gone a good way towards the identification of the substance; but it is, of course, dangerous to trust to one reaction.

In medico-legal researches there is seldom any considerable quantity of the material to work upon. Hence the greatest care must be taken from the commencement not to waste the substance in useless tests, but to study well at the outset what—by the method of extraction used, the microscopic appearance, the reaction to litmus paper, and the solubility in different menstrua—it is likely to be. However minute the quantity may be, it is essential to divide it into different parts, in order to apply a variety of tests; but as any attempt to do this on the solid substance will probably entail loss, the best way is to dissolve it in a watch-glass in half a c.c. of alcohol, ether, or other suitable solvent. Droplets of this solution are then placed on watch-glasses or slips of microscopic glass, and to these drops, by the aid of a glass rod, different reagents can be applied, and the changes watched under the microscope as the drops slowly evaporate.

§ 314. Sublimation of the Alkaloids.—A very beautiful and elegant aid to the identification of alkaloids, and vegetable principles generally, is their behaviour towards heat.

Alkaloids, glucosides, the organic acids, &c., when carefully heated, either—(1) sublime wholly without decomposition (like theine, cytisin, and others); or (2) partially sublime with decomposition; or (3) are changed into new bodies (as, for example, gallic acid); or (4) melt and then char; or (5) simply char and burn away.

Many of these phenomena are striking and characteristic, taking place at different temperatures, subliming in characteristic forms, or leaving characteristic residues.

One of the first to employ sublimation systematically, as a means of recognition of the alkaloids, &c., was Helwig.[339] His method was to place a small quantity (from ¹/₂ to ¹/₄₀₀₀ of a mgrm.) in a depression on platinum foil, cover it with a slip of glass, and then carefully heat by a small flame. After Helwig, Dr. Guy[340] greatly improved the process by using porcelain discs, and more especially by the adoption of a convenient apparatus, which may be termed “the subliming cell.” It is essentially composed of a ring of glass from ¹/₈ to ²/₃ of an inch in thickness, such as may be obtained by sections of tubing, the cut surfaces being ground perfectly smooth. This circle is converted into a closed cell by resting it on one of the ordinary thin discs of glass used as a covering for microscopic purposes, and supporting a similar disc. The cell was placed on a brass plate, provided with a nipple, which carried a thermometer, and was heated by a small flame applied midway between the thermometer and the cell; the heat was raised very gradually, and the temperature at which any change took place was noted. In this way Dr. Guy made determinations of the subliming points of a large number of substances, and the microscopic appearances of the sublimates were described with the greatest fidelity and accuracy. On repeating with care Dr. Guy’s determinations, however, I could in no single instance agree with his subliming points, nor with the apparatus he figures and describes could two consecutive observations exactly coincide. Further, on examining the various subliming temperatures of substances, as stated by different authors, the widest discrepancies were found—differences of 2 or even 3 degrees might be referred to errors of observation, a want of exact coincidence in the thermometers employed, and the like; but to what, for example, can we ascribe the irreconcilable statements which have been made with regard to theine? According to Strauch, this substance sublimes at 177°; according to Mulder, at 184·7°. But that both of these observations deviate more than 70° from the truth may be proved by any one who cares to place a few mgrms. of theine, enclosed between two watch-glasses, over the water-bath; in a few minutes a distinct sublimate will condense on the upper glass, and, in point of fact, theine will be found to sublime several degrees below 100°.

---

[339] Das Mikroskop in der Toxicologie.[340] Pharm. Journ. Trans. (2), viij. 719; ix. 10, 58. Forensic Medicine, London, 1875.

---

Since this great divergency of opinion is not found either in the specific gravity, or the boiling-points, or any of the like determinations of the physical properties of a substance, it is self-evident that the processes hitherto used for the determination of subliming points are faulty. The sources of error are chiefly—

(1.) Defects in the apparatus employed—the temperature read being rather that of the metallic surface in the immediate vicinity of the thermometer than of the substance itself.

(2.) The want of agreement among observers as to what should be called a sublimate—one considering a sublimate only that which is evident to the naked eye, another taking cognisance of the earliest microscopic film.

(3.) No two persons employing the same process.

With regard to the apparatus employed, I adopt Dr. Guy’s subliming cell; but the cell, instead of resting on a metallic solid, floats on a metallic fluid. For any temperature a little above 100° this fluid is mercury, but for higher temperatures fusible metal is preferable.

Subliming Cell.

The exact procedure is as follows:—A porcelain crucible (a in fig.), about 3 inches in diameter, is nearly filled with mercury or fusible metal, as the case may be; a minute speck (or two or three crystals of the substance to be examined) is placed on a thin disc of microscopic covering glass, floated on the liquid, and the cell is completed by the glass ring and upper disc. The porcelain crucible is supported on a brass plate (b), fixed to a retort-stand in the usual way, and protected from the unequal cooling effects of currents of air by being covered by a flask (c), from which the bottom has been removed. The neck of the flask conveniently supports a thermometer, which passes through a cork, and the bulb of the thermometer is immersed in the bath of liquid metal. In the first examination of a substance the temperature is raised somewhat rapidly, taking off the upper disc with a forceps at every 10° and exchanging it for a fresh disc, until the substance is destroyed. The second examination is conducted much more slowly, and the discs exchanged at every 4° or 5°, whilst the final determination is effected by raising the temperature with great caution, and exchanging the discs at about the points of change (already partially determined) at every half degree. All the discs are examined microscopically. The most convenient definition of a sublimate is this—the most minute films, dots, or crystals, which can be observed by ¹/₄-inch power, and which are obtained by keeping the subliming cell at a definite temperature for 60 seconds. The commencement of many sublimates assumes the shape of dots of extraordinary minuteness, quite invisible to the unaided eye; and, on the other hand, since the practical value of sublimation is mainly as an aid to other methods for the recognition of substances, if we go beyond short intervals of time, the operation, otherwise simple and speedy, becomes cumbersome, and loses its general applicability.

There is also considerable discrepancy of statement with regard to the melting-point of alkaloidal bodies; in many instances a viscous state intervenes before the final complete resolution into fluid, and one observer will consider the viscous state, the other complete fluidity, as the melting-point.

In the melting-points given below, the same apparatus was used, but the substance was simply placed on a thin disc of glass floating on the metallic bath before described (the cell not being completed), and examined from time to time microscopically, for by this means alone can the first drops formed by the most minute and closely-adherent crystals to the glass be discovered.

Cocaine melts at 93°, and gives a faint sublimate at 98°; if put between two watch-glasses on the water-bath, in fifteen minutes there is a good cloud on the upper glass.

Aconitine turns brown, and melts at 179° C.; it gives no characteristic sublimate up to 190°.

Morphine, at 150°, clouds the upper disc with nebulÆ; the nebulÆ are resolved by high magnifying powers into minute dots; these dots gradually become coarser, and are generally converted into crystals at 188°; the alkaloid browns at or about 200°.

Thebaine sublimes in theine-like crystals at 135°; at higher temperatures (160° to 200°), needles, cubes, and prisms are observed. The residue on the lower disc, if examined before carbonisation, is fawn-coloured with non-characteristic spots.

Narcotine gives no sublimate; it melts at 155° into a yellow liquid, which, on raising the temperature, ever becomes browner to final blackness. On examining the residue before carbonisation, it is a rich brown amorphous substance; but if narcotine be heated two or three degrees above its melting-point, and then cooled slowly, the residue is crystalline—long, fine needles radiating from centres being common.

Narceine gives no sublimate; it melts at 134° into a colourless liquid, which undergoes at higher temperatures the usual transition of brown colours. The substance, heated a few degrees above its melting-point, and then allowed to cool slowly, shows a straw-coloured residue, divided into lobes or drops containing feathery crystals.

Papaverine gives no sublimate; it melts at 130°. The residue, heated a little above its melting-point, and then slowly cooled, is amorphous, of a light-brown colour, and in no way characteristic.

Hyoscyamine gives no crystalline sublimate; it melts at 89°, and appears to volatilise in great part without decomposition. It melts into an almost colourless fluid, which, when solid, may exhibit a network not unlike vegetable parenchyma; on moistening the network with water, interlacing crystals immediately appear. If, however, hyoscyamine be kept at 94° to 95° for a few minutes, and then slowly cooled, the edges of the spots are arborescent, and the spots themselves crystalline.

Atropine (daturine) melts at 97°; at 123° a faint mist appears on the upper disc. Crystals cannot be obtained; the residue is not characteristic.

Solanine.—The upper disc is dimmed with nebulÆ at 190°, which are coarser and more distinct at higher temperatures; at 200° it begins to brown, and then melts; the residue consists of amber-brown, non-characteristic drops.

Strychnine gives a minute sublimate of fine needles, often disposed in lines, at 169°; about 221° it melts, the residue (at that temperature) is resinous.

Brucine melts at 151° into a pale yellow liquid, at higher temperatures becoming deep-brown. If the lower disc, after melting, be examined, no crystals are observed, the residue being quite transparent, with branching lines like the twigs of a leafless tree; light mists, produced rather by decomposition than by true sublimation, condense on the upper disc at 185°, and above.

Saponin neither melts nor sublimes; it begins to brown about 145°, is almost black at 185°, and quite so at 190°.

Delphinine begins to brown about 102°; it becomes amber at 119°, and melts, and bubbles appear. There is no crystalline sublimate; residue not characteristic.

Pilocarpine gives a distinct crystalline sublimate at 153°; but thin mists, consisting of fine dots, may be observed as low as 140°. Pilocarpine melts at 159°; the sublimates at 160° to 170° are in light yellow drops. If these drops are treated with water, and the water evaporated, feathery crystals are obtained; the residue is resinous.

Theine wholly sublimes; the first sublimate is minute dots, at 79°; at half a degree above that very small crystals may be obtained; and at such a temperature as 120°, the crystals are often long and silky.

Theobromine likewise wholly sublimes; nebulÆ at 134°, crystals at 170°, and above.

Salicin melts at 170°; it gives no crystalline sublimate. The melted mass remains up to 180° almost perfectly colourless; above that temperature browning is evident. The residue is not characteristic.

Picrotoxin gives no crystalline sublimate. The lowest temperature at which it sublimes is 128°; the usual nebulÆ then make their appearance; between 165° and 170° there is slight browning; at 170° it melts. The residue, slowly cooled, is not characteristic.

Cantharidin sublimes very scantily between 82° and 83°; at 85° the sublimate is copious.

The active principles of plants may, in regard to their behaviour to heat, be classed for practical purposes into—

• 1. Those which give a decided crystalline sublimate:
• • (a.) Below 100°, e.g., cocaine, theine, thebaine, cantharidin.
  • (b.) Between 100° and 150°, e.g., quinetum.
  • (c.) Between 150° and 200°, e.g., strychnine, morphine, pilocarpine.
• 2. Those which melt, but give no crystalline sublimate:
• • (a.) Below 100°, e.g., hyoscyamine, atropine.
  • (b.) Between 100° and 150°, e.g., papaverine.
  • (c.) Between 150° and 200°, e.g., salicin.
  • (d.) Above 200°, e.g., solanine.
• 3. Those which neither melt nor give a crystalline sublimate, e.g., saponin.

§ 315. Melting-point.—The method of sublimation just given also determines the melting-point; such a determination will, however, seldom compare with the melting-points of the various alkaloids as given in text-books, because the latter melting-points are not determined in the same way. The usual method of determining melting-points is to place a very small quantity in a glass tube closed at one end; the tube should be almost capillary. The tube is fastened to a thermometer by means of platinum wire, and then the bulb of the thermometer, with its attached tube, is immersed in strong sulphuric acid or paraffin, contained in a flask. The thermometer should be suspended midway in the liquid and heat carefully applied, so as to raise the temperature gradually and equably. It will be found that rapidly raising the heat gives a different melting-point to that which is obtained by slowly raising the heat. During the process careful watching is necessary: most substances change in hue before they actually melt. A constant melting-point, however often a substance is purified by recrystallisation, is a sign of purity.§ 316. Identification by Organic Analysis.—In a few cases (and in a few only) the analyst may have sufficient material at hand to make an organic analysis, either as a means of identification or to confirm other tests. By the vacuum process described in “Foods,” in which carbon and nitrogen are determined by measuring the gases evolved by burning the organic substance in as complete a vacuum as can be obtained, very minute quantities of a substance can be dealt with, and the carbon and nitrogen determined with fair accuracy. It is found in practice that the carbon determinations appear more reliable than those of the nitrogen, and there are obvious reasons why this should be so.

Theoretically, with the improved gas-measuring appliances, it is possible to measure a c.c. of gas; but few chemists would care to create a formula on less than 10 c.c. of CO₂. Now, since 10 c.c. of CO₂ is equal to 6·33 mgrms. of carbon, and alkaloids average at least half their weight of carbon, it follows that 12 mgrms. of alkaloid represent about the smallest quantity with which a reliable single combustion can be made.

The following table gives a considerable number of the alkaloids and alkaloidal bodies, arranged according to their content in carbon:—

TABLE SHOWING THE CONTENT OF CARBON AND NITROGEN IN VARIOUS ALKALOIDAL BODIES.

	Carbon.		Nitrogen.
Asparagin,	36	·36	21	·21
Methylamine,	38	·71	45	·17
Betaine,	44	·44	10	·37
Theobromine,	46	·67	31	·11
Theine,	49	·48	28	·86
Indican,	49	·60	2	·22
Muscarine,	50	·42	11	·77
Lauro-cerasin,	52	·47	1	·53
Amanitine,	57	·69	13	·46
Narceine,	59	·63	3	·02
Colchicine,	60	·53	4	·15
Oxyacanthine,	60	·57	4	·42
Solanine,	60	·66	1	·68
Trimethylamine,	61	·02	23	·73
Jervine,	61	·03	5	·14
Sabadilline,	61	·29	3	·46
Aconitine,	61	·21	2	·16
Nepaline,	63	·09	2	·12
Colchicein,	63	·44	4	·38
Veratroidine,	63	·8	3	·1
Narcotine,	63	·92	3	·39
Veratrine,	64	·42	2	·91
Delphinine,	64	·55	3	·42
Physostigmine,	65	·49	15	·27
Rhoeadine,	65	·79	3	·65
Cocaine,	66	·44	4	·84
Gelsemine,	67	·00	7	·10
Conhydrine,	67	·12	9	·79
Staphisagrine,	67	·5	3	·6
Chelidonine,	68	·06	12	·34
Atropine, Hyoscyamine,	70	·58	4	·84
Sanguinarine,	70	·59	4	·33
Papaverine,	70	·79	4	·13
Delphinoidine,	70	·9	3	·9
Morphine and Piperine,	71	·58	4	·91
Berberine,	71	·64	4	·18
Codeine,	72	·24	4	·68
Thebaine,	73	·31	4	·50
Cytisine,	73	·85	12	·92
Nicotine,	74	·08	17	·28
Quinine,	75	·02	8	·64
Coniine,	76	·81	11	·20
Strychnine,	77	·24	8	·92
Curarine,	81	·51	5	·28

§ 317. Quantitative Estimation of the Alkaloids.—For medico-legal purposes the alkaloid obtained is usually weighed directly, but for technical purposes other processes are used. One of the most convenient of these is titration with normal or decinormal sulphuric acid, a method applicable to a few alkaloids of marked basic powers—e.g., quinine is readily and with accuracy estimated in this way, the alkaloid being dissolved in a known volume of the acid, and then titrated back with soda. If a large number of observations are to be made, an acid may be prepared so that each c.c. equals 1 mgrm. of quinine. A reagent of general application is found in the so-called Mayer’s reagent, which consists of 13·546 grms. of mercuric chloride, and 49·8 grms. of iodide of potassium in a litre of water. Each c.c. of such solution precipitates—

Of	Strychnine,	·0167	grm.
„	Brucine,	·0233	„
„	Quinine,	·0108	„
„	Cinchonine,	·0102	„
„	Quinidine,	·0120	„
„	Atropine,	·0145	„
„	Aconitine,	·0268	„
„	Veratrine,	·0269	„
„	Morphine,	·0200	„
„	Narcotine,	·0213	„
„	Nicotine,	·00405	„
„	Coniine,	·00416	„

The final reaction is found by filtering, from time to time, a drop on to a glass plate, resting on a blackened surface, and adding the test until no precipitate appears. The results are only accurate when the strength of the solution of the alkaloid is about 1: 200; so that it is absolutely necessary first to ascertain approximatively the amount present, and then to dilute or concentrate, as the case may be, until the proportion mentioned is obtained.

A convenient method of obtaining the sulphate of an alkaloid for quantitative purposes, and especially from organic fluids, is that recommended by Wagner. The fluid is acidulated with sulphuric acid, and the alkaloid precipitated by a solution of iodine in iodide of potassium. The precipitate is collected and dissolved in an aqueous solution of hyposulphite of soda. The filtered solution is again precipitated with the iodine reagent, and the precipitate dissolved in sulphurous acid, which, on evaporation, leaves behind the pure sulphate of the base.

It is also very useful for quantitative purposes to combine an alkaloid with gold or platinum, by treating the solution with the chlorides of either of those metals—the rule as to selection being to give that metal the preference which yields the most insoluble and the most crystallisable compound.

The following table gives the percentage of gold or platinum left on ignition of the double salt:—

	Gold.		Platinum.
Atropine,	31	·57	...
Aconitine	20	·0	...
Amanitine,	44	·23	...
Berberine,	29	·16	18	·11
Brucine,	...		16	·52
Cinchonine,	...		27	·36
Cinchonidine,	...		27	·87
Codeine,	...		19	·11
Coniine,	...		29	·38
Curarine,	...		32	·65
Delphinine,	26	·7	...
Delphinoidine,	29	·0	15	·8
Emetine,	...		29	·7
Hyoscyamine,	34	·6	...
Morphine,	...		19	·52
Muscarine,	43	·01	...
Narcotine,	15	·7	15	·9
Narceine,	...		14	·52
Nicotine,	...		34	·25
Papaverine,	...		17	·82
Pilocarpine,	35	·5	23	·6 to 25·2.
Piperine,	...		12	·7
Quinine,	40	·0	26	·26
Strychnine,	29	·15	18	·16
Thebaine,	...		18	·71
Theine,	37	·02	24	·58
Theobromine,	...		25	·55
Veratrine,	21	·01	...

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II.—Liquid Volatile Alkaloids.

THE ALKALOIDS OF HEMLOCK—NICOTINE—PITURIE—SPARTEINE.

1. THE ALKALOIDS OF HEMLOCK (CONIUM).

§ 318. The Conium maculatum, or spotted hemlock, is a rather common umbelliferous plant, growing in waste places, and flowering from about the beginning of June to August. The stem is from three to five feet high, smooth, branched, and spotted with purple; the leaflets of the partial involucres are unilateral, ovate, lanceolate, with an attenuate point shorter than the umbels; the seeds are destitute of vittÆ, and have five prominent crenate wavy ridges. The whole plant is foetid and poisonous. Conium owes its active properties to a volatile liquid alkaloid, Coniine, united with a crystalline alkaloid, Conhydrine.§ 319. Coniine (conia, conicine), (C₈H₁₇N)—specific gravity 0·862 at 0°; melting-point, -2·5°; boiling-point, 166·6°. Pure coniine has been prepared synthetically by Ladenburg, and found to be propyl-piperidine C₅H₁₀NC₃H₇, but the synthetically-prepared piperidine has no action on polarised light. By uniting it with dextro-tartaric acid, and evaporating, it is possible to separate the substance into dextro-propyl-piperidine and lÆvo-propyl-piperidine. The former is in every respect identical with coniine from hemlock; it is a clear, oily fluid, possessing a peculiarly unpleasant, mousey odour. One part is soluble in 150 parts of water,[341] in 6 parts of ether, and in almost all proportions of amyl alcohol, chloroform, and benzene. It readily volatilises, and, provided air is excluded, may be distilled unchanged. It ignites easily, and burns with a smoky flame. It acts as a strong base, precipitating the oxides of metals and alkaline earths from their solutions, and it coagulates albumen. Coniine forms salts with hydrochloric acid (C₈H₁₅N.HCl), phosphoric acid, iodic acid, and oxalic acid, which are in well-marked crystals. The sulphate, nitrate, acetate, and tartrate are, on the other hand, non-crystalline.

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[341] The saturated watery solution of coniine at 15°, becomes cloudy if gently warmed, and clears again on cooling.

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If coniine is oxidised with nitric acid, or bichromate of potash, and diluted sulphuric acid, butyric acid is formed; and since the latter has an unmistakable odour, and other characteristic properties, it has been proposed as a test for coniine. This may be conveniently performed thus:—A crystal of potassic bichromate is put at the bottom of a test-tube, and some diluted sulphuric acid with a drop of the supposed coniine added. On heating, the butyric acid reveals itself by its odour, and can be distilled into baryta water, the butyrate of baryta being subsequently separated in the usual way, and decomposed by sulphuric acid, &c.

Another test for coniine is the following:—If dropped into a solution of alloxan, the latter is coloured after a few minutes an intense purple-red, and white needle-shaped crystals are separated, which dissolve in cold potash-lye into a beautiful purple-blue, and emit an odour of the base.[342] Dry hydrochloric acid gives a purple-red, then an indigo-blue colour, with coniine; but if the acid is not dry, there is formed a bluish-green crystalline mass. This test, however, is of little value to the toxicologist, the pure substance alone responding with any definite result.

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[342] Schwarzenbach, Vierteljahrsschr. f. prakt. Pharm., viij. 170.

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The ordinary precipitating agents, according to Dragendorff, act as follows:—

Potass bismuth iodide.

• 1:2000, a strong orange precipitate.
• 1:3000. The drop of the reagent is surrounded with a muddy border.
• 1:4000. The drop of the reagent is surrounded with a muddy border.
• 1:5000, still perceptible.
• 1:6000. The last limit of the reaction.

Phosphomolybdic acid gives a strong yellow precipitate; limit, 1: 5000.

Potass. mercuric iodide gives a cheesy precipitate; limit, 1: 1000 in neutral, 1: 800 in acid, solutions.

Potass. cadmic iodide gives an amorphous precipitate, 1: 300. The precipitate is soluble in excess of the precipitant. (Nicotine, under similar circumstances, gives a crystalline precipitate.)

FlÜckiger recommends the following reaction:[343]—“Add to 10 drops of ether in a shallow glass crystallising dish 2 drops of coniine, and cover with filter paper. Set upon the paper a common-sized watch-glass containing bromine water, and invert a beaker over the whole arrangement. Needle-shaped crystals of coniine hydro-bromine soon form in the dish as well as in the watch-glass.” Hydrochloric acid, used in the same way, instead of bromine water, forms with coniine microscopic needles of coniine hydrochlorate; both the hydro-bromide and the hydrochlorate doubly refract light. Nicotine does not respond to this reaction.

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[343] Reactions, by F. A. FlÜckiger, Detroit, 1893.

Coniine forms with carbon disulphide a thiosulphate and a sulphite. If carbon disulphide, therefore, be shaken with an aqueous solution of coniine, the watery solution gives a brown precipitate with copper sulphate, colours ferric chloride solution dark brown red, and gives a milky opalescence with dilute acids. If coniine itself is added to carbon disulphide, there is evolution of heat, separation of sulphur, and formation of thiosulphate. Nicotine does not respond to this reaction.§ 320. Other Coniine Bases.—Methyl- and ethyl-coniine have been prepared synthetically, and are both similar in action to coniine, but somewhat more like curarine. By the reduction of coniine with zinc dust conyrine (C₈H₁₁N) is formed; between coniine and conyrine stands coniceine (C₈H₁₅NO). De Coninck has made synthetically by the addition of 6 atoms of hydrogen to collidine, a new fluid alkaloid (C₈H₁₁N + 6H = C₈H₁₇N), which he has called isocicutine: it has the same formula as coniine. Paraconiine Schiff prepared synthetically from ammonia and normal butyl aldehyde; it has the formula C₈H₁₅N, and therefore differs from coniine in containing two atoms less of hydrogen. All the above have a similar physiological action to coniine. a-stillbazoline (C₁₁H₁₉N), prepared by Baurath from benzaldehyde and picoline, is analogous to coniine, and according to Falck has similar action, but is more powerful.§ 321. Pharmaceutical Preparations.—The percentage of coniine in the plant itself, and in pharmaceutical preparations, can be approximately determined by distilling the coniine over, in a partial vacuum,[344] and titrating the distillate with Mayer’s reagent, each c.c. = about ·00416 grm. of coniine. It appears to be necessary to add powdered potassic chloride and a small quantity of diluted sulphuric acid before titrating, or the precipitate does not separate. In any case, the end of the reaction is difficult to observe.[345]

The fresh plant is said to contain from about ·04 to ·09 per cent., and the fruit about 0·7 per cent. of coniine.

The officinal preparations are—the leaves, the fruit, a tincture of the fruit, an extract of the leaves, the juice of the leaves (Succus conii), a compound hemlock pill (composed of extract of hemlock, ipecacuanha, and treacle), an inhalation of coniine (Vapor conii), and a poultice (Cataplasma conii) made with the leaves.§ 322. Statistics of Coniine Poisoning.—F. A. Falck[346] has been able to collect 17 cases of death recorded in medical literature, up to the year 1880, from either coniine or hemlock. Two of these cases were criminal (murders), 1 suicidal, 2 cases in which coniine had been used medicinally (in one instance the extract had been applied to a cancerous breast; in the other, death was produced from the injection of an infusion of hemlock leaves). The remaining 12 were cases in which the root, leaves, or other portions of the plant had been ignorantly or accidentally eaten.

§ 323. Effects on Animals.—It destroys all forms of animal life. The author made some years ago an investigation as to its action on the common blow-fly. Droplets of coniine were applied to various parts of blow-flies, which were then placed under glass shades. The symptoms began within a minute by signs of external irritation, there were rapid motions of the wings, and quick and aimless movements of the legs. Torpor set in speedily, the buzz soon ceased, and the insects lay on their sides, motionless, but for occasional twitching of the legs. The wings, as a rule, became completely paralysed before the legs, and death occurred at a rather variable time, from ten minutes to two hours. If placed in a current of air in the sun, a fly completely under the influence of coniine may recover. Coniine causes in frogs, similar to curarine, peripheral paralysis of the motor nerves, combined with a transitory stimulation, and afterwards a paralysis of the motor centres; in frogs the paralysis is not preceded by convulsions. Dragendorff experimented on the action of coniine when given to five cats, the quantities used being ·05 to ·5 grm. The symptoms came on almost immediately, but with the smaller dose given to a large cat, no effect was witnessed until twenty-five minutes afterwards; this was the longest interval. One of the earliest phenomena was dilatation of the pupil, followed by weakness of the limbs passing into paralysis, the hinder legs being affected prior to the fore. The respiration became troubled, and the frequency of the breathing diminished; the heart in each case acted irregularly, and the sensation generally was blunted; death was preceded by convulsions. In the cases in which the larger dose of ·4 to ·5 grm. was administered, death took place within the hour, one animal dying in eight minutes, a second in eighteen minutes, a third in twenty minutes, and a fourth in fifty-eight minutes. With the smaller dose of ·051 grm. given to a large cat, death did not take place until eight hours and forty-seven minutes after administration.§ 324. Effects on Man.—In a case recorded by Bennet,[347] and quoted in most works on forensic medicine, the symptoms were those of general muscular weakness deepening into paralysis. The patient had eaten hemlock in mistake for parsley; in about twenty minutes he experienced weakness in the lower extremities, and staggered in walking like a drunken man; within two hours there was perfect paralysis of both upper and lower extremities, and he died in three and a quarter hours. In another case, related by Taylor, the symptoms were also mainly those of paralysis, and in other instances stupor, coma, and slight convulsions have been noted.

§ 325. Physiological Action.—It is generally agreed that coniine paralyses, first the ends of the motor nerves, afterwards their trunks, and lastly, the motor centre itself. At a later period the sensory nerves participate. In the earlier stage the respiration is quickened, the pupils contracted, and the blood-pressure increased; but on the development of paralysis the breathing becomes slowed, the capillaries relaxed, and the blood-pressure sinks. Death takes place from cessation of the respiration, and not primarily from the heart, the heart beating after the breathing has stopped. Coniine is eliminated by the urine, and is also in part separated by the lungs, while a portion is, perhaps, decomposed in the body.§ 326. Post-mortem Appearances.—There is nothing characteristic in the appearances after death.

Fatal Dose.—The fatal dose of coniine is not accurately known; it is about 150 mgrms. (2·3 grains). In the case of Louise Berger, 10 to 15 drops appear to have caused death in a few minutes. The auto-experiments of Dworzak, Heinrich, and Dillaberger would indicate that one drop may cause unpleasant symptoms. Albers, in the treatment of a woman suffering from cancer of the breast, witnessed convulsions and loss of consciousness from a third dose of 4 mgrms. (·06 grain); and Eulenberg, its full narcotic effects on a child after subcutaneous injection of 1 mgrm. (·015 grain).§ 327. Separation of Coniine from Organic Matters or Tissues.—The substances are digested with water, acidulated with H₂SO₄, at a temperature not exceeding 40°, and then filtered. If the filtrate should be excessive, it must be concentrated; alcohol is then added, the liquid refiltered, and from the filtrate the alcohol separated by distillation.

On cooling, the acid fluid is agitated with benzene, and the latter separated in the usual way. The fluid is now alkalised with ammonia, and shaken up once or twice with its own volume of petroleum ether; the latter is separated and washed with distilled water, and the alkaloid is obtained almost pure. If the petroleum ether leaves no residue, it is certain that the alkaloid was not present in the contents of the stomach or intestine.

The affinity of coniine with ether or chloroform is such, that its solution in either of these fluids, passed through a dry filter, scarcely retains a drop of water. In this way it may be conveniently purified, the impurities dissolved by water remaining behind.

In searching for coniine, the stomach, intestines, blood, urine, liver, and lungs are the parts which should be examined. According to Dragendorff, it has been discovered in the body of a cat six weeks after death.

Great care must be exercised in identifying any volatile alkaloid as coniine, for the sources of error seem to be numerous. In one case[348] a volatile coniine-like ptomaine, was separated from a corpse, and thought to be coniine; but Otto found that in its behaviour to platinic chloride, it differed from coniine; it was very poisonous—·07 was fatal to a frog, ·44 to a pigeon, in a few minutes. In the seeds of Lupinus luteus there is a series of coniine-like substances,[349] but they do not give the characteristic crystals with hydrochloric acid.

2. TOBACCO—NICOTINE.

§ 328. The different forms of tobacco are furnished by three species of the tobacco plant, viz., Nicotianum tabacum, N. rustica, and N. persica.

Havanna, French, Dutch, and the American tobaccos are in the main derived from N. tabacum; Turkish, Syrian, and the Latakia tobaccos are the produce of N. rustica. There seems at present to be little of N. persica in commerce.

All the species of tobacco contain a liquid, volatile, poisonous alkaloid (Nicotine), probably united in the plant with citric and malic acids. There is also present in tobacco an unimportant camphor (nicotianin). The general composition of the plant may be gathered from the following table:—

TABLE SHOWING THE COMPOSITION OF FRESH LEAVES OF TOBACCO
(POSSELT AND RIENMANN).

§ 329. Quantitative Estimation of Nicotine in Tobacco.—The best process (although not a perfectly accurate one) is the following:—25 grms. of the tobacco are mixed with milk of lime, and allowed to stand until there is no odour of ammonia; the mixture is then exhausted by petroleum ether, the ether shaken up with a slight excess of normal sulphuric acid, and titrated back by baryta water; the sulphate of baryta may be collected and weighed, so as to control the results. With regard to the percentage of nicotine in commercial tobacco, Kosutany found from 1·686 to 3·738 per cent. in dry tobacco; Letheby, in six samples, from 1·5 to 3·2 per cent.; whilst SchlÖssing gives for Havanna 2 per cent., Maryland 2·29 per cent., Kentucky 6·09 per cent., Virginian 6·87 per cent., and for French tobacco, quantities varying from 3·22 to 7·96 per cent. Again, Lenoble found in Paraguay tobacco from 1·8 to 6 per cent.; and Wittstein, in six sorts of tobacco in Germany, 1·54 to 2·72 per cent.

Mr. Cox[350] has recently determined the amount of nicotine in a number of tobaccos. The results are tabulated in the following table as follows:—

TABLE OF RESULTS, ARRANGED ACCORDING TO PER CENT. OF NICOTINE.

It is therefore obvious that the strength of tobacco in nicotine varies between wide limits.

Twenty-five grammes (or more or less, according to the amount of the sample at disposal) of the dried and powdered tobacco were intimately mixed with slaked lime, and distilled in a current of steam until the condensed steam was no longer alkaline; the distillate was slightly acidulated with dilute H₂SO₄, and evaporated to a conveniently small bulk. This was made alkaline with soda, and agitated repeatedly with successive portions of ether. The separated batches of ethereal solution of nicotine were then mixed and exposed to the air in a cool place. This exposure to the air carries away ammonia, if any be present, as well as ether.

Water was added to the ethereal residue, and the amount of nicotine present determined by decinormal H₂SO₄, using methyl-orange as an indicator. One c.c. of decinormal H₂SO₄ represents 0·0162 gramme of nicotine (C₁₀H₁₄N₂).§ 330. Nicotine (C₁₀H₁₄N₂).—Hexahydro dipyridyl (C₅H₄N)₂H₆, when pure, is an oily, colourless fluid, of 1·0111, specific gravity at 15°.[351] It evaporates under 100° in white clouds, and boils at about 240°, at which temperature it partly distils over unchanged, and is partly decomposed—a brown resinous product remaining. It volatilises with aqueous and amyl alcohol vapour notably, and is not even fixed at -10°. It has a strong alkaline reaction, and rotates a ray of polarised light to the right. Its odour, especially on warming, is strong and unpleasantly like tobacco, and it has a sharp caustic taste. It absorbs water exposed to the air, and dissolves in water in all proportions, partly separating from such solution on the addition of a caustic alkali. The aqueous solution acts in many respects like ammonia, saturating acids fully, and may therefore be in certain cases estimated with accuracy by titration, 49 parts of H₂SO₄ corresponding to 162 of nicotine. It gives on oxidation nicotinic acid = m() pyridincarbo acid C₅H₄N(COOH), and by oxidation with elimination of water dipyridyl (C₅H₄N)₂, and through reduction dipiperydil (C₅H₁₀N)₂.

Alcohol and ether dissolve nicotine in every proportion; if such solutions are distilled, nicotine goes over first. The salts which it forms with hydrochloric, nitric, and phosphoric acids crystallise with difficulty; tartaric and oxalic acid form white crystalline salts, and the latter, oxalate of nicotine, is soluble in alcohol, a property which distinguishes it from the oxalate of ammonia. The best salts are the oxalate and the acid tartrate of nicotine, from which to regenerate nicotine in a pure state.

Hydrochloride of nicotine is more easily volatilised than the pure base. Nicotine is precipitated by alkalies, &c., also by many oxyhydrates, lead, copper, &c. By the action of light, it is soon coloured yellow and brown, and becomes thick, in which state it leaves, on evaporation, a brown resinous substance, only partly soluble in petroleum ether.

A very excellent test for nicotine, as confirmatory of others, is the beautiful, long, needle-like crystals obtained by adding to an ethereal solution of nicotine a solution of iodine in ether. The crystals require a few hours to form.

Chlorine gas colours nicotine blood-red or brown; the product is soluble in alcohol, and separates on evaporation in crystals.

Cyanogen also colours nicotine brown; the product out of alcohol is not crystalline. Platin chloride throws down a reddish crystalline precipitate, soluble on warming; and gallic acid gives a flocculent precipitate. A drop of nicotine poured on dry chromic acid blazes up, and gives out an odour of tobacco camphor; if the ignition does not occur in the cold, it is produced by a gentle heat. It is scarcely possible to confound nicotine with ammonia, by reason of its odour; and, moreover, ammonia may always be excluded by converting the base into the oxalate, and dissolving in absolute alcohol.

On the other hand, a confusion between coniine and nicotine is apt to occur when small quantities only are dealt with. It may, however, be guarded against by the following tests:—

(1.) If coniine be converted into oxalate, the oxalate dissolved in alcohol, and coniine regenerated by distillation (best in vacuo) with caustic lye, and then hydrochloric acid added, a crystalline hydrochlorate of coniine is formed, which doubly refracts light, and is in needle-shaped or columnar crystals, or dendritic, moss-like forms. The columns afterwards become torn, and little rows of cubical, octahedral, and tetrahedral crystals (often cross or dagger-shaped) grow out of yellow amorphous masses. Crystalline forms of this kind are rare, save in the case of dilute solutions of chloride of ammonium (the presence of the latter is, of course, rendered by the treatment impossible); and nicotine does not give anything similar to this reaction.

(2.) Coniine coagulates albumen; nicotine does not.

(3.) Nicotine yields a characteristic crystalline precipitate with an aqueous solution of mercuric chloride; the similar precipitate of coniine is amorphous.

(4.) Nicotine does not react with CS₂ to form thiosulphate (see p. 266).§ 331. Effects on Animals.—Nicotine is rapidly fatal to all animal life—from the lowest to the highest forms. That tobacco-smoke is inimical to insect-life is known to everybody; very minute quantities in water kill infusoria. Fish of 30 grms. weight die in a few minutes from a milligram of nicotine; the symptoms observed are rapid movements, then shivering and speedy paralysis, with decreased motion of the gills, and death. With frogs, if doses not too large are employed, there is first great restlessness, then strong tetanic convulsions, and a very peculiar position of the limbs; the respiration after fatal doses soon ceases, but the heart beats even after death. Birds also show tetanic convulsions followed by paralysis and speedy death. The symptoms witnessed in mammals poisoned by nicotine are not essentially dissimilar. With large doses the effect is similar to that of prussic acid—viz., a cry, one or two shuddering convulsions, and death. If the dose is not too large, there is trembling of the limbs, excretion of fÆces and urine, a peculiar condition of stupor, a staggering gait, and then the animal falls on its side. The respiration, at first quickened, is afterwards slowed, and becomes deeper than natural; the pulse, also, with moderate doses, is first slowed, then rises in frequency, and finally, again falls. Tetanic convulsions soon develop, during the tetanus the pupils have been noticed to be contracted, but afterwards dilated, the tongue and mouth are livid, and the vessels of the ear dilated. Very characteristic of nicotine poisoning as witnessed in the cat, the rabbit, and the dog, is its peculiarly violent action, for after the administration of from one to two drops, the whole course from the commencement of symptoms to the death may take place in five minutes. F. Vas has drawn the smoke of tobacco from an immense pipe, and condensed the products; he finds the well-washed tarry products without physiological action, but the soluble liquid affected the health of rabbits,—they lost weight, the number of the blood corpuscles was decreased, and the hÆmoglobin of the blood diminished.[352]

The larger animals, such as the horse, are affected similarly to the smaller domestic animals. A veterinary surgeon, Mr. John Howard, of Woolwich,[353] has recorded a case in which a horse suffered from the most violent symptoms of nicotine-poisoning, after an application to his skin of a strong decoction of tobacco. The symptoms were trembling, particularly at the posterior part of the shoulders, as well as at the flanks, and both fore and hind extremities; the superficial muscles were generally relaxed and felt flabby; and the pupils were widely dilated. There was also violent dyspnoea, the respirations being quick and short, pulse 32 per minute, and extremely feeble, fluttering, and indistinct. When made to walk, the animal appeared to have partly lost the use of his hind limbs, the posterior quarter rolling from side to side in an unsteady manner, the legs crossing each other, knuckling over, and appearing to be seriously threatened with paralysis. The anus was very prominent, the bowels extremely irritable, and tenesmus was present. He passed much flatus, and at intervals of three or four minutes, small quantities of fÆces in balls, partly in the liquid state, and coated with slimy mucus. There was a staring, giddy, intoxicated appearance about the head and eyes, the visible mucous membrane being of a dark-red colour. A great tendency to collapse was evident, but by treatment with cold douches and exposure to the open air, the horse recovered.

In a case occurring in 1863, in which six horses ate oats which had been kept in a granary with tobacco, the symptoms were mainly those of narcosis, and the animals died.[354]

§ 332. Effects on Man.—Poisoning by the pure alkaloid nicotine is so rare that, up to the present, only three cases are on record. The first of these is ever memorable in the history of toxicology, being the first instance in which a pure alkaloid had been criminally used. The detection of the poison exercised the attention of the celebrated chemist Stas. I allude, of course, to the poisoning of M. Fougnies by Count BocarmÉ and his wife. For the unabridged narrative of this interesting case the reader may consult Tardieu’s Étude MÉdico-LÉgale sur L’Empoisonnement.

BocarmÉ actually studied chemistry in order to prepare the alkaloid himself, and, after having succeeded in enticing his victim to the chateau of Bitremont, administered the poison forcibly. It acted immediately, and death took place in five minutes. BocarmÉ now attempted to hide all traces of the nicotine by pouring strong acetic acid into the mouth and over the body of the deceased. The wickedness and cruelty of the crime were only equalled by the clumsy and unskilful manner of its perpetration. The quantity of nicotine actually used in this case must have been enormous, for Stas separated no less than ·4 grm. from the stomach of the victim.

The second known case of nicotine-poisoning was that of a man who took it for the purpose of suicide. The case is related by Taylor. It occurred in June 1863. The gentleman drank an unknown quantity from a bottle; he stared wildly, fell to the floor, heaving a deep sigh, and died quietly without convulsion. The third case happened at Cherbourg,[355] where an officer committed suicide by taking nicotine, but how much had been swallowed, and what were the symptoms, are equally unknown, for no one saw him during life.

Poisoning by nicotine, pure and simple, then is rare. Tobacco-poisoning is very common, and has probably been experienced in a mild degree by every smoker in first acquiring the habit. Nearly all the fatal cases are to be ascribed to accident; but criminal cases are not unknown. Christison relates an instance in which tobacco in the form of snuff was put into whisky for the purpose of robbery. In 1854, a man was accused of attempting to poison his wife by putting snuff into her ale, but acquitted. In another case, the father of a child, ten weeks old, killed the infant by putting tobacco into its mouth. He defended himself by saying that it was applied to make the child sleep.

In October 1855,[356] a drunken sailor swallowed (perhaps for the purpose of suicide) his quid of tobacco, containing from about half an ounce to an ounce. He had it some time in his mouth, and in half an hour suffered from frightful tetanic convulsions. There was also diarrhoea; the pupils were dilated widely; the heart’s action became irregular; and towards the end the pupils again contracted. He died in a sort of syncope, seven hours after swallowing the tobacco.

§ 333. In 1829 a curious instance of poisoning occurred in the case of two girls, eighteen years of age, who suffered from severe symptoms of tobacco-poisoning after drinking some coffee. They recovered; and it was found that tobacco had been mixed with the coffee-berries, and both ground up together.[357]

Accidents have occurred from children playing with old pipes. In 1877[358] a child, aged three, used for an hour an old tobacco-pipe, and blew soap bubbles with it. Symptoms of poisoning soon showed themselves, and the child died in three days.

Tobacco-juice, as expressed or distilled by the heat developed in the usual method of smoking, is very poisonous. Sonnenschein relates the case of a drunken student, who was given a dram to drink, into which his fellows had poured the juice from their pipes. The result was fatal. Death from smoking is not unknown.[359] Helwig saw death follow in the case of two brothers, who smoked seventeen and eighteen German pipefuls of tobacco. Marshall Hall[360] records the case of a young man, nineteen years of age, who, after learning to smoke for two days, attempted two consecutive pipes. He suffered from very serious symptoms, and did not completely recover for several days. Gordon has also recorded severe poisoning from the consecutive smoking of nine cigars. The external application of the leaf may, as already shown in the case of the horse, produce all the effects of the internal administration of nicotine. The old instance, related by Hildebrand, of the illness of a whole squadron of hussars who attempted to smuggle tobacco by concealing the leaf next to their skin, is well known, and is supported by several recent and similar cases. The common practice of the peasantry, in many parts of England, of applying tobacco to stop the bleeding of wounds, and also as a sort of poultice to local swellings, has certainly its dangers. The symptoms—whether nicotine has been taken by absorption through the broken or unbroken skin, by the bowel, by absorption through smoking, or by the expressed juice, or the consumption of the leaf itself—show no very great difference, save in the question of time. Pure nicotine acts with as great a rapidity as prussic acid; while if, so to speak, it is entangled in tobacco, it takes more time to be separated and absorbed; besides which, nicotine, taken in the concentrated condition, is a strong enough base to have slight caustic effects, and thus leaves some local evidences of its presence. In order to investigate the effects of pure nicotine, Dworzak and Heinrich made auto-experiments, beginning with 1 mgrm. This small dose produced unpleasant sensations in the mouth and throat, salivation, and a peculiar feeling spreading from the region of the stomach to the fingers and toes. With 2 mgrms. there was headache, giddiness, numbness, disturbances of vision, torpor, dulness of hearing, and quickened respirations. With 3 to 4 mgrms., in about forty minutes there was a great feeling of faintness, intense depression, weakness, with pallid face and cold extremities, sickness, and purging. One experimenter had shivering of the extremities and cramps of the muscles of the back, with difficult breathing. The second suffered from muscular weakness, fainting, fits of shivering, and creeping sensations about the arms. In two or three hours the severer effects passed away, but recovery was not complete for two or three days. It is therefore evident, from these experiments and from other cases, that excessive muscular prostration, difficult breathing, tetanic cramps, diarrhoea, and vomiting, with irregular pulse, represent both tobacco and nicotine poisoning. The rapidly-fatal result of pure nicotine has been already mentioned; but with tobacco-poisoning the case may terminate lethally in eighteen minutes. This rapid termination is unusual, with children it is commonly about an hour and a half, although in the case previously mentioned, death did not take place for two days.

§ 334. Physiological Action.—Nicotine is absorbed into the blood and excreted unchanged, in part by the kidneys and in part by the saliva (Dragendorff). According to the researches of Rosenthal and Krocker,[361] nicotine acts energetically on the brain, at first exciting it, and then lessening its activity; the spinal marrow is similarly affected. The convulsions appear to have a cerebral origin; paralysis of the peripheral nerves follows later than that of the nerve centres, whilst muscular irritability is unaffected. The convulsions are not influenced by artificial respiration, and are therefore to be considered as due to the direct influence of the alkaloid on the nervous system. Nicotine has a striking influence on the respiration, first quickening, then slowing, and lastly arresting the respiratory movements: section of the vagus is without influence on this action. The cause of death is evidently due to the rapid benumbing and paralysis of the respiratory centre. Death never follows from heart-paralysis, although nicotine powerfully influences the heart’s action, small doses exciting the terminations of the vagus in the heart, and causing a slowing of the beats. Large doses paralyse both the controlling and exciting nerve-centres of the heart; the heart then beats fast, irregularly, and weakly. The blood-vessels are first narrowed, then dilated, and, as a consequence, the blood-pressure first rises, then falls. Nicotine has a special action on the intestines. As O. Nasse[362] has shown, there is a strong contraction of the whole tract, especially of the small intestine, the lumen of which may be, through a continuous tetanus, rendered very small. This is ascribed to the peripheral excitation of the intestinal nerves and the ganglia. The uterus is also excited to strong contraction by nicotine; the secretions of the bile and saliva are increased.

[361] Ueber die Wirkung des Nicotines auf den thierischen Organismus, Berlin, 1868.[362] BeitrÄge zur Physiologie der Darmbewegung, Leipsic, 1866.

§ 335. Fatal Dose.—The fatal dose for dogs is from ¹/₂ to 2 drops; for rabbits, a quarter of a drop; for an adult not accustomed to tobacco the lethal dose is probably 6 mgrms.§ 336. Post-mortem Appearances.—There seem to be no appearances so distinctive as to be justly ascribed to nicotine or tobacco-poisoning and no other.

A more or less fluid condition of the blood, and, generally, the signs of death by the lungs, are those most frequently found. In tobacco-poisoning, when the leaves themselves have been swallowed, there may be some inflammatory redness of the stomach and intestine.§ 337. Separation of Nicotine from Organic Matters, &c.—The process for the isolation of nicotine is precisely that used for coniine (see p. 269). It appears that it is unaltered by putrefaction, and may be separated and recognised by appropriate means a long time after death. Orfila detected it in an animal two or three months after death; Melsens discovered the alkaloid unmistakably in the tongues of two dogs, which had been buried in a vessel filled with earth for seven years; and it has been found, by several experiments, in animals buried for shorter periods. Nicotine should always be looked for in the tongue and mucous membrane of the mouth, as well as in the usual viscera. The case may be much complicated if the person supposed to be poisoned should have been a smoker; for the defence would naturally be that there had been either excessive smoking or chewing, or even swallowing accidentally a quid of tobacco.[363] A ptomaine has been discovered similar to nicotine. Wolckenhaar separated also an alkaloid not unlike nicotine from the corpse of a woman addicted to intemperate habits; but this base was not poisonous, nor did it give any crystals when an ethereal solution was added to an ether solution of iodine. It will be well always to support the chemical evidence by tests on animal life, since the intensely poisonous action of nicotine seems not to be shared by the nicotine-like ptomaines.

3. PITURIE.[364]

4. SPARTEINE.

5. ANILINE.

III.—The Opium Group of Alkaloids.

§ 344. General Composition.—Opium contains a larger number of basic substances than any plant known. The list reaches at present to 18 or 19 nitrogenised bases, and almost each year there have been additions. Some of these alkaloids exist in very small proportion, and have been little studied. Morphine and narcotine are those which, alone, are toxicologically important. Opium is a gummy mass, consisting of the juice of the incised unripe fruit of the Papaver somniferum hardened in the air. The following is a nearly complete list of the constituents which have been found in opium:—

The various opiums differ, the one from the other, in the percentages of alkaloids, so that only a very general statement of the mean composition of opium can be made. The following statement may, however, be accepted as fairly representative of these differences:—

The general results of the analysis of 12 samples of Turkey opium, purchased by Mr. Bott,[369] from leading druggists in London, Dublin, and Edinburgh, are as follows:—

Water.—Highest, 31·2; lowest, 18·4; mean, 22·4 per cent.

Insoluble Residue.—Highest, 47·9; lowest, 25·45; mean, 32·48 per cent.

Aqueous Extract.—Highest, 56·15; lowest, 20·90; mean, 45·90 per cent.

Crude Morphine (containing about ⁷/₁₀ of pure morphine).—Highest, 12·30; lowest, 6·76; mean, 9·92 per cent., which equals 12·3 per cent. of the dried drug.

Persian Opium, examined in the same way, varied in crude morphine from 2·1 to 8·5 per cent.; Malwa, from 5·88 to 7·30. In 18 samples of different kinds of opium, the mean percentage of crude morphine was 8·88 per cent. (11 per cent. of the dried opium). According to Guibourt, Smyrna opium, dried at 100°, yields 11·7 to 21·46 per cent., the mean being 12 to 14 per cent.; Egyptian, from 5·8 to 12 per cent.; Persian, 11·37 per cent. In East Indian Patna opium, for medical use, he found 7·72; in a sample used for smoking, 5·27 per cent.; in Algerian opium, 12·1 per cent.; in French opium, 14·8 to 22·9 per cent.§ 345. Action of Solvents on Opium.—The action of various solvents on opium has been more especially studied by several scientists who are engaged in the extraction of the alkaloids.

Water dissolves nearly everything except resin, caoutchouc, and woody fibre. Free morphine would be left insoluble; but it seems always to be combined with meconic and acetic acids. The solubility of free narcotine in water is extremely small.

Alcohol dissolves resin and caoutchouc, and all the alkaloids and their combinations, with meconic acid, &c.

Amylic Alcohol dissolves all the alkaloids, if they are in a free state, and it also takes up a little of the resin.

Ether, Benzene, and Carbon Sulphide do not dissolve the resin, and only slightly morphine, if free; but they dissolve the other free alkaloids as well as caoutchouc.

Acids dissolve all the alkaloids and the resin.

Fixed Alkalies, in excess, dissolve in part resin; they also dissolve morphine freely; narcotine remains insoluble.

Lime Water dissolves morphine, but is a solvent for narcotine only in presence of morphine.

Ammonia dissolves only traces of morphine; but narceine and codeine readily. It does not dissolve the other alkaloids, nor does it dissolve the resin.§ 346. Assay of Opium.—The following processes may be described:—

Process of Teschemacher and Smith.—This process, with a few modifications, is as follows:—10 grms. of opium are as completely exhausted with proof spirit at a boiling temperature as possible. The resulting alcoholic extract is treated with a few drops of ammonium oxalate solution, and the solution is almost neutralised with ammonia. The solution is concentrated to one-third, cooled, and filtered. The filtrate is farther concentrated to 5 c.c., and transferred to a small flask, it is washed into this flask by 4 c.c. of water, and 3 c.c. of 90 per cent. alcohol; next 2 c.c. solution of ammonia (sp. gr. 0·960) and 25 c.c. of dry ether are added. The flask is corked, shaken, and then allowed to rest over-night.

The ether is decanted as completely as possible. Two filter papers are taken and counterpoised—that is to say, they are made precisely the same weight. The filters are placed one inside the other, and the precipitate collected on the inner one; the precipitate is washed with morphinated water—that is to say, water in which morphine has been digested for some days. The filter papers with their contents are washed with benzene and dried, the outer paper put on the pan of the balance carrying the weights, and the inner filter with the precipitate weighed. The precipitate is now digested with a known volume of decinormal acid, and then the excess of acid ascertained by titration with decinormal alkali, using either litmus or methyl orange; each c.c. of decinormal acid is equal to 30·3 mgrms. of morphine.[370]

Dott’s Process.—Dott has recently proposed a new process, which he states has given good results. The process is as follows:—10 grammes of powdered opium are digested with 25 c.c. water; 1·8 gramme barium chloride dissolved in about 12 c.c. water is then added, the solution made up to 50 c.c., well mixed, and after a short time filtered. 22 c.c. (representing 5 grammes opium) are mixed with dilute sulphuric acid in quantity just sufficient to precipitate the barium. About 1 c.c. is required, and the solution should be warmed to cause the precipitate to subside, and the solution to filter clear. To this filtered solution a little dilute ammonia, about 0·5 c.c. is added to neutralise the free acid, and the solution concentrated to 6 or 7 c.c., and allowed to cool. 1 c.c. spirit and 1 c.c. ether are then added, and next ammonia in slight excess. The ammonia should be added gradually until there is no further precipitation, and a perceptible odour of ammonia remains after well stirring and breaking down any lumps with the stirring rod. After three hours the precipitate is collected on counterpoised filters and washed. Before filtering, it should be noted that the solution has a faint odour of ammonia: if not, one or two drops of ammonia solution should be added. The dried precipitate is washed with benzene or chloroform, dried, and weighed. It is then titrated with ⁿ/₁₀ acid, until the morphine is neutralised, as indicated by the solution reddening litmus paper.[371]

§ 347. Medicinal and other Preparations of Opium.—The chief mixtures, pills, and other forms, officinal and non-officinal, in which opium may be met with, are as follows:—

(1.) Officinal.

Compound Tincture of Camphor, P. B. (Paregoric).—Opium, camphor, benzoic acid, oil of anise, and proof spirit: the opium is in the proportion of about 0·4 per cent., or 1 grain of opium in 240 minims.

Ammoniated Tincture of Opium (Scotch paregoric).—Strong solution of ammonia, rectified spirit, opium, oil of anise, saffron, and benzoic acid. Nearly 1 per cent. or 1 grain of opium in every 96 minims.

Tincture of Opium (Laudanum).—Opium and proof spirit. One grain of opium in 14·8 min.—that is, about 6·7 parts by weight in 100 by measure.

The amount of opium actually contained in laudanum has been investigated by Mr. Woodland,[372] from fourteen samples purchased from London and provincial chemists. The highest percentage of extract was 5·01, the lowest 3·21, the mean being 4·24; the highest percentage of morphine was ·70 per cent., the lowest ·32, the mean being ·51 per cent. It is, therefore, clear that laudanum is a liquid of very uncertain strength.

Aromatic Powder of Chalk and Opium.—Opium 2·5 per cent., the rest of the constituents being cinnamon, nutmeg, saffron, cloves, cardamoms, and sugar.

Compound Powder of Ipecacuanha (Dover’s Powder).

Confection of Opium (Confectio opii) is composed of syrup and compound powder of opium; according to its formula, it contains 2·4 per cent. of opium by weight.

Extract of Opium contains the solid constituents capable of extraction by water; it should contain 20 per cent. of morphine, and is therefore about double the strength of dry powdered opium.

Liquid Extract of Opium has been also examined by Mr. Woodland:[373] ten samples yielded as a mean 3·95 per cent. of dry extract, the highest number being 4·92 per cent., the lowest 3·02. The mean percentage of morphine was ·28 per cent., the highest amount being ·37, and the lowest ·19 per cent.

Liniment of Opium is composed of equal parts of laudanum and soap liniment; it should contain about 0·0375 per cent. morphine.

The Compound Soap-pill is made of soap and opium, one part of opium in every 5·5 of the mass—i.e., about 18 per cent.

Ipecacuanha and Morphine Lozenges, as the last, with the addition of ipecacuanha; each lozenge contains ¹/₃₆ grain (1·8 mgrms.) morphine hydrochlorate, ¹/₁₂ grain (5·4 mgrms.) ipecacuanha.

Morphia Suppositories are made with hydrochlorate of morphine, benzoated lard, white wax, and oil of theobroma; each suppository contains ¹/₂ grain (32·4 mgrms.) of morphine salt.

Opium Lozenges are composed of opium extract, tincture of tolu, sugar, gum, extract of liquorice, and water. Each lozenge contains ¹/₁₀ grain (6·4 mgrms.) of extract of opium, or about ¹/₅₀ grain (1·3 mgrm.) morphine.

The Ointment of Galls and Opium contains one part of opium in 14·75 parts of the ointment—i.e., opium 6·7 per cent.

Opium Wine, P. B.—Sherry, opium extract, cinnamon, and cloves. About 5 of opium extract by weight in 100 parts by measure (22 grains to the ounce).

Solutions of Morphine, both of the acetate and hydrochlorate, P. B., are made with a little free acid, and with rectified spirit. The strength of each is half a grain in each fluid drachm (·0324 grm. in 3·549), or ·91 part by weight in 100 by measure.

Solution of Bimeconate of Morphine.—One fluid oz. contains 5¹/₂ grains of bimeconate of morphine.

Morphia Lozenges are made with the same accessories as opium lozenges, substituting morphine for opium; each lozenge contains ¹/₃₆ grain of hydrochlorate of morphia (1·8 mgrm.).

Syrup of Poppies.—The ordinary syrup of poppies is sweetened laudanum. It should, however, be what it is described—viz., a syrup of poppy-heads. As such, it is said to contain one grain of extract of opium to the ounce.

(2.) Patent and other Non-Officinal Preparations of Opium.

§ 348. Statistics.—During the ten years 1883-1892 no less than 1424 deaths in England and Wales were attributed to some form or other of opium or its active constituents; 45 of these deaths were ascribed to various forms of soothing syrup or to patent medicines containing opium or morphine; 876 were due to accident or negligence; 497 were suicidal and 6 were homicidal deaths. The age and sex distribution of the deaths ascribed to accident and those ascribed to suicide are detailed in the following tabular statement:—

DEATHS IN ENGLAND AND WALES DURING THE TEN YEARS 1883-1892 FROM OPIUM, LAUDANUM, MORPHINE, &c.

Of European countries, England has the greatest proportional number of opium poisonings. In France, opium or morphine poisoning accounts for about 1 per cent. of the whole; and Denmark, Sweden, Switzerland, Germany, all give very small proportional numbers; arsenic, phosphorus, and the acids taking the place of opiates. The more considerable mortality arises, in great measure, from the pernicious practice—both of the hard-working English mother and of the baby-farmer—of giving infants various forms of opium sold under the name of “soothing syrups,” “infants’ friends,” “infants’ preservatives,” “nurses’ drops” and the like, to allay restlessness, and to keep them during the greater part of their existence asleep. Another fertile cause of accidental poisoning is mistakes in dispensing; but these mistakes seem to happen more frequently on the Continent than in England. This is in some degree due to the decimal system, which has its dangers as well as its advantages, e.g.:—A physician ordered ·5 decigrm. of morphine acetate in a mixture for a child, but omitted the decimal point, and the apothecary, therefore, gave ten times the dose desired, with fatal effect. Again, morphine hydrochlorate, acetate, and similar soluble salts are liable to be mistaken for other white powders, and in this way unfortunate accidents have occurred—accidents that, with proper dispensing arrangements, should be impossible.§ 349. Poisoning of Children by Opium.—The drugging of children by opium—sometimes with a view to destroy life, sometimes merely for the sake of the continual narcotism of the infant—is especially rife in India.[377] A little solid opium is applied to the roof of the mouth, or smeared on the tongue, and some Indian mothers have been known to plaster the nipples with opium, so that the child imbibes it with the milk. Europeans, again and again, have discovered the native nurses administering opiates to the infants under their care, and it is feared that in many cases detection is avoided.

[377] See Dr. Chevers’s Jurisprudence, 3rd ed., 232 et seq.

The ignorant use of poppy-tea has frequently caused the death of young children; thus in 1875 an inquest was held at Chelsea on the body of a little boy two years and a half old. He had been suffering from whooping-cough and enlargement of the bowels, and poppy-tea was by the advice of a neighbour given to him. Two poppy-heads were used in making a quart of tea, and the boy, after drinking a great portion of it, fell into a deep sleep, and died with all the symptoms of narcotic poisoning.§ 350. Doses of Opium and Morphia.—Opium in the solid state is prescribed for adults in quantities not exceeding 3 grains, the usual dose being from 16·2 mgrms. to 64·8 mgrms. (¹/₄ to 1 grain). The extract of opium is given in exactly the same proportions (special circumstances, such as the habitual use of opium, excepted); the dose of all the compounds of opium is mainly regulated by the proportion of opium contained in them.

The dose for children (who bear opium ill) is usually very small; single drops of laudanum are given to infants at the breast, and the dose cautiously increased according to age. Most practitioners would consider half a grain a very full dose, and, in cases requiring it, would seldom prescribe at first more than ¹/₁₆ to ¹/₄ grain.

The dose of solid opium for a horse is from 1·77 grm. to 7·08 grms. (¹/₂ drachm to 2 drachms); in extreme cases, however, 4 drachms (14·16 grms.) have been given.

The dose for large cattle is from ·648 grm. to 3·88 grms. (10 to 60 grains); for calves, ·648 grm. (10 grains); for dogs it is greatly regulated by the size of the animal, 16·2 to 129·6 mgrms. (¹/₄ grain to 2 grains).

Fatal Dose.—Cases are recorded of infants dying from extremely small doses of opium, e.g., ·7, 4·3, and 8·1 mgrms. (¹/₉₀, ¹/₁₅, and ¹/₈ of a grain); but in such instances one cannot help suspecting some mistake. It may, however, be freely conceded that a very small quantity might be fatal to infants, and that 3 mgrms. given to a child under one year would probably develop serious symptoms.

The smallest dose of solid opium known to have proved fatal to adults was equal to 259 mgrms. (4 grains) of crude opium (Taylor), and the smallest dose of the tincture (laudanum), 7·0 c.c. (2 drachms), (Taylor); the latter is, however, as already shown, uncertain in its composition.

A dangerous dose (save under special circumstances) is:—For a horse, 14·17 grms. (4 drachms); for cattle, 7·04 grms. (2 drachms); for a dog of the size and strength of a foxhound, 204 mgrms. (3 grains).

Enormous and otherwise fatal doses may be taken under certain conditions by persons who are not opium-eaters. I have seen 13 cgrms. (2 grains) of morphine acetate injected hypodermically in a strong man suffering from rabies with but little effect. Tetanus, strychnine, convulsions, and excessive pain all decrease the sensibility of the nervous system to opium.§ 351. General Method for the Detection of Opium.—It is usually laid down in forensic works that, where poisoning by opium is suspected, it is sufficient to detect the presence of meconic acid in order to establish that of opium. In a case of adult poisoning there is generally substance enough available to obtain one or more alkaloids, and the presence of opium may, without a reasonable doubt, be proved, if meconic acid (as well as either morphine, narcotine, thebaine, or other opium alkaloid) has been detected. Pills containing either solid opium or the tincture usually betray the presence of the drug by the odour, and in such a case there can be no possible difficulty in isolating morphine and meconic acid, with probably one or two other alkaloids. The method of extraction from organic fluids is the same as before described, but it may, of course, be modified for any special purpose. If opium, or a preparation of opium, be submitted to Dragendorff’s process (see p. 242), the following is a sketch of the chief points to be noticed.

If the solution is acid—

(1.) Benzene mainly extracts meconin, which dissolves in sulphuric acid very gradually (in twenty-four to forty-eight hours), with a green colour passing into red. Meconin has no alkaloidal reaction.

(2.) Amyl alcohol dissolves small quantities of meconic acid, identified by striking a blood-red colour with ferric chloride.

If now the amyl alcohol is removed with the aid of petroleum ether, and the fluid made alkaline by ammonia—

(1.) Benzene extracts narcotine, codeine, and thebaine. On evaporation of the benzene the alkaloidal residue may be dissolved in water, acidified with sulphuric acid, and after filtration, on adding ammonia in excess, thebaine and narcotine are precipitated, codeine remaining in solution. The dried precipitate, if it contain thebaine, becomes blood-red when treated with cold concentrated sulphuric acid, while narcotine is shown by a violet colour developing gradually when the substance is dissolved in dilute sulphuric acid 1: 5, and gently warmed. The codeine in the ammoniacal solution can be recovered by shaking up with benzene, and recognised by the red colour which the solid substance gives when treated with a little sugar and sulphuric acid.

(2.) Chloroform especially dissolves the narceine, which, on evaporation of the chloroform, may be identified by its general characters, and by its solution in FrÖhde’s reagent becoming a beautiful blue colour. Small quantities of morphine may be extracted with codeine.

(3.) Amyl alcohol extracts from the alkaline solution morphine, identified by its physical characters, by its forming a crystalline precipitate with iodine and hydriodic acid, and the reaction with iodic acid to be described.§ 352. Morphine (C₁₇H₁₇NO(OH)₂ + H₂O).—Morphine occurs in commerce as a white powder, sp. gr. 1·205, usually in the form of more or less perfect six-sided prisms, but sometimes in that of white silky needles. When heated in the subliming cell (described at pp. 257-8), faint nebulÆ, resolved by high microscopic powers into minute dots, appear on the upper disc at 150°. As the temperature is raised the spots become coarser, and at 188° distinct crystals may be obtained, the best being formed at nearly 200°, at which temperature morphine begins distinctly to brown, melt, and carbonise. At temperatures below 188°, instead of minute dots, the sublimate may consist of white circular spots or foliated patterns. One part of morphine, according to P. Chastaing, is soluble at a temperature of 3° in 33,333 parts of water; at 22°, in 4545 parts; at 42°, 4280; and at 100°, 4562. It is scarcely soluble in ether or benzene. Absolute alcohol, according to Pettenkofer, dissolves in the cold one-fortieth of its weight; boiling, one-thirtieth. Amyl alcohol, in the cold, dissolves one-fourth per cent., and still more if the alkaloid be thrown out of an aqueous acid solution by ammonia in the presence of amyl alcohol; for under such circumstances the morphine has no time to become crystalline. According to Schlimpert, 1 part of morphine requires 60 of chloroform for solution; according to Pettenkofer, 175.

Morphine is easily soluble in dilute acids, as well as in solutions of the caustic alkalies and alkaline earths; carbonated alkalies and chloride of ammonium also dissolve small quantities. The acid watery, and the alcoholic solutions, turn the plane of polarisation to the left; for sulphuric, nitric, and hydrochloric acids [a]r = 89·8°; in alkaline solution the polarisation is less, [a]r = 45·22°. It is alkaline in reaction, neutralising acids fully; and, in fact, a convenient method of titrating morphine is by the use of a centinormal sulphuric acid—each c.c. equals 2·85 mgrms. of anhydrous morphine.§ 353. The salts of morphine are for the most part crystalline, and are all bitter, neutral, and poisonous. They are insoluble in amylic alcohol, ether, chloroform, benzene, or petroleum ether.

Morphine meconate is one of the most soluble of the morphine salts; it is freely soluble in water. Of all salts this is most suitable for subcutaneous injection; it is the form in which the alkaloid exists in opium.

Morphine hydrochlorate (C₁₇H₁₉NO₃HCl) crystallises in silky fibres; it is readily soluble in alcohol, and is soluble in cold, more freely in boiling water. The purest morphine hydrochlorate is colourless, but that which is most frequently met with in commerce is fawn or buff-coloured.

Morphine acetate is a crystallisable salt, soluble in water or alcohol; it is in part decomposed by boiling the aqueous solution, some of the acetic acid escaping.

Morphine Tartrates.—These are readily soluble salts, and it is important to note that the morphine might escape detection, if the expert trusted alone to the usual test of an alkaloidal salt giving a precipitate when the solution is alkalised by the fixed or volatile alkalies; for the tartrates of morphine do not give this reaction, nor do they give any precipitate with calcic chloride. By adding a solution of potassium acetate in spirit, and also alcohol and a little acetic acid to the concentrated solution, the tartrate is decomposed, and acid tartrate of potassium is precipitated in the insoluble form; the morphine in the form of acetate remains in solution, and then gives the usual reactions.

The solubility of morphine salts in water and alcohol has been investigated by Mr. J. U. Lloyd. His results are as follows:—

§ 354. Constitution of Morphine.—The chief facts bearing on the constitution of morphine are as follows:—

It certainly contains two hydroxyl groups, because by the action of acetic anhydride, acetyl morphine and diacetyl morphine, C₁₇H₁₈(CH₃CO)NO₃ and C₁₇H₁₇(CH₃CO)₂NO₃ are produced. The formation of the monomethyl ether of morphine (codeine), C₁₇H₁₇(OH)(OCH₃)NO, is also a testimony to the existence of hydroxyl groups. One of the hydroxyl groups has phenolic functions, the other alcoholic functions. By suitable oxidation morphine yields trinitrophenol (picric acid), and by fusion with an alkali, protocatechuic acid; both of these reactions suggest a benzene ring. On distilling with zinc dust phenanthrene, pyridine, pyrrol, trimethylamine, and ammonia are formed; evidence of a pyridine nucleus. If morphine is mixed with 10 to 15 times its weight of a 20 per cent. solution of potash, and heated at 180° for from four to six hours, air being excluded, a phenol-like compound is formed, and a volatile amine, ethylmethylamine (the amine boils at 34° to 35°, and its hydrochloride melts at 133°). This reaction is interpreted by Z. H. Skrauk[378] and L. Wiegmann to indicate that the nitrogen is directly connected with two alkyl groups—that is, ethyl and methyl.

G. N. Vis,[379] after a careful review of the whole of the reactions of morphine, has proposed the following constitutional formula as the one that agrees best with the facts:—

§ 355. Tests for Morphine.—(1.) One hundredth of a milligrm. of pure morphine gives a blue colour to a paste of ammonium molybdate in sulphuric acid; 20 mgrms. of ammonium molybdate are rubbed with a glass rod in a porcelain dish, and well mixed with 5 drops of pure strong sulphuric acid and the morphine in a solid form applied; titanic acid and tungstates give similar reactions.

(2.) Morphine possesses strong reducing properties; a little solid morphine dissolved in a solution of ferric chloride gives a Prussian blue precipitate when ferridcyanide solution is added. A number of ptomaines and other substances also respond to this test, so that in itself it is not conclusive.

(3.) Iodic Acid Test.—The substance supposed to be morphine is converted into a soluble salt by adding to acid reaction a few drops of hydrochloric acid, and then evaporating to dryness. The salt thus obtained is dissolved in as little water as possible—this, as in toxicological researches only small quantities are recovered, will probably be but a few drops. A little of the solution is now mixed with a very small quantity of starch paste, and evaporated to dryness at a gentle heat in a porcelain dish. After cooling, a drop of a solution of 1 part of iodic acid in 15 of water is added to the dry residue; and if even the ¹/₂₀₀₀₀ of a grain of morphine be present, a blue colour will be developed.

Another way of working the iodic acid test is to add the iodic acid solution to the liquid in which morphine is supposed to be dissolved, and then shake the liquid up with a few drops of carbon disulphide. If morphine be present, the carbon disulphide floats to the top distinctly coloured pink. Other substances, however, also set free iodine from iodic acid, and it has, therefore, been proposed to distinguish morphine from these by the after addition of ammonia. If ammonia is added to the solution, which has been shaken up with carbon disulphide, the pink or red colour of the carbon disulphide is deepened, if morphine was present; on the contrary, if morphine was not present, it is either discharged or much weakened.

Other Reactions.—There are some very interesting reactions besides the two characteristic tests just mentioned. If a saturated solution of chloride of zinc be added to a little solid morphine, and heated over the water-bath for from fifteen minutes to half-an-hour, the liquid develops a beautiful and persistent green colour. This would be an excellent test for morphine were it not for the fact that the colour is produced with only pure morphine. For example, I was unable to get the reaction from morphine in very well-formed crystals precipitated from ordinary laudanum by ammonia, the least trace of resinous or colouring-matter seriously interfering. By the action of nitric acid on morphine, the liquid becomes orange-red, and an acid product of the formula C₁₀H₉NO₉ is produced, which, when heated in a closed tube with water at 100°, yields trinitrophenol or picric acid. This interesting reaction points very decidedly to the phenolic character of morphine. On adding a drop of sulphuric acid to solid morphine in the cold, the morphine solution becomes of a faint pink; on gently warming and continuing the heat until the acid begins to volatilise, the colour changes through a series of brownish and indefinite hues up to black. On cooling and treating the black spot with water, a green solution is obtained, agreeing in hue with the same green produced by chloride of zinc. Vidali[380] has proposed the following test:—Morphine is dissolved in strong sulphuric acid, and a little arsenate of sodium is added; on gently warming, a passing blue colour develops; on raising the temperature higher, the liquid changes into green, then into blue, and finally again into green. Codeine acts very similarly. The following test originated with Siebold (American Journal of Pharmacy, 1873, p. 544):—The supposed morphine is heated gently with a few drops of concentrated sulphuric acid and a little pure potassic perchlorate. If morphine be present the liquid immediately takes a pronounced brown colour—a reaction said to be peculiar to morphine, and to succeed with ¹/₁₀ of a mgrm. In order to obtain absolutely pure perchlorate, potassic perchlorate is heated with hydrochloric acid so long as it disengages chlorine; it is then washed with distilled water, dried, and preserved for use. There is also a test known as “Pellagri’s”; it depends on the production of apomorphine. The suspected alkaloid is dissolved in a little strong hydrochloric acid, and then a drop of concentrated sulphuric acid is added, and the mixture heated for a little time from 100° to 120°, until it assumes a purple-black colour. It is now cooled, some hydrochloric acid again added, and the mixture neutralised with sodic carbonate. If morphine be present, on the addition of iodine in hydriodic acid, a cherry-red colour is produced, passing into green. Morphine and codeine are believed alone to give this reaction.

The acetate of morphine, and morphine itself, when added to ferric chloride solution, develop a blue colour. When 1 molecule of morphine is dissolved in alcohol, containing 1 molecule of sodium hydroxide, and 2 vols. of methyl iodide are added, and the mixture gently heated, a violent reaction sets in and the main product is codeine methiodide (C₁₇H₁₈NO₂OCH,MeI). If only half the quantity of methyl iodide is added, then free codeine is in small quantity produced; if ethyl iodide be substituted for methyl, a new base is formed homologous with codeine—codeine is therefore the methyl ether of morphine. If morphine is heated with iodide of methyl and absolute alcohol in a closed tube for half an hour at 100°, methyl iodide of morphine is obtained in colourless, glittering, quadratic crystals, easily soluble in water (C₁₇H₁₉NO₃MeI + H₂O); similarly the ethyl iodide compound can be produced.

If morphine is heated for from two to three hours in a closed tube with dilute hydrochloric acid, water is eliminated—

(C₁₇H₁₉NO₃ = C₁₇H₁₇NO₂ + H₂O),

and the hydrochlorate of apomorphine is produced. This succeeds when even ¹/₂ mgrm. is heated with ¹/₁₀ c.c. of strong HCl, and the tests for apomorphine applied.

If concentrated sulphuric acid be digested on morphine for twelve to fifteen hours (or heated for half an hour at 100°), on adding to the cooled violet-coloured solution either a crystal of nitrate of potash or of chlorate of potash, or a drop of dilute nitric acid, a beautiful violet-blue colour is produced, which passes gradually into a dark blood-red. ¹/₁₀₀ of a mgrm. will respond distinctly to this test. FrÖhde’s reagent strikes with morphine a beautiful violet colour, passing from blue into dirty green, and finally almost vanishing. ¹/₂₀₀ of a mgrm. will respond to the test, but it is not itself conclusive, since papaverine and certain glucosides give an identical reaction.§ 356. Symptoms of Opium and Morphine Poisoning.—The symptoms of opium and morphine poisoning are so much alike, that clinically it is impossible to distinguish them; therefore they may be considered together.

Action on Animals—Frogs.—The action of morphine or opium on frogs is peculiar: the animal at first springs restlessly about, and then falls into a condition extremely analogous to that seen in strychnine poisoning, every motion or external irritation producing a tetanic convulsion. This condition is, however, sometimes not observed. The tetanic stage is followed by paralysis of reflex movements and cessation of breathing, the heart continuing to beat.

Dogs.—0·2 to 0·5 grm. of morphine meconate, or acetate, injected directly into the circulation of a dog, shows its effects almost immediately. The dog becomes uneasy, and moves its jaws and tongue as if some peculiar taste were experienced; it may bark or utter a whine, and then in a minute or two falls into a profound sleep, which is often so deep that while it lasts—usually several hours—an operation may be performed. In whatever attitude the limbs are placed, they remain. The respiration is rapid and stertorous, and most reflex actions are extinguished. Towards the end of the sleep, any sudden noise may startle the animal, and when he wakes his faculties are evidently confused. A partial paralysis of the hind legs has often been noticed, and then the dog, with his tail and pelvis low, has something the attitude of the hyena. Hence this condition (first, I believe, noticed by Bernard) has been called the “hyenoid” state. If the dose is larger than 2 to 3 grms. (31 to 46 grains), the symptoms are not dissimilar, save that they terminate in death, which is generally preceded by convulsions.[381]

Goats.—According to Guinard, goats are proof against the narcotic influence of morphine. Large doses kill goats, but death is caused by interference with the respiratory function. A young goat weighing 30 kilos, showed little effect beyond a slightly increased cerebral excitability after two doses of 8 and 8·5 grms. respectively of morphine hydrochlorate had been administered by intravenous injection, the second being given an hour and a half after the first. To the same animal two days afterwards 195 grms. were administered in the same way, yet the goat recovered. The lethal dose for a goat seems to be no less than 1000 times that which will produce narcotism in man, and lies somewhere between 0·25 to 0·30 per kilo. of the body weight.[382]

Cats and the FelidÆ.—According to Guinard,[383] morphine injected subcutaneously or intravenously into cats, in doses varying from 0·4 mgrm. to 90 mgrms. per kilo., never produces sleep or narcotic prostration. On the contrary, it causes a remarkable degree of excitement, increasing in intensity with the dose given. This excitement is evidently accompanied by disorder in the functions of the brain, and if the dose is large convulsions set in, ending in death. According to Milne-Edwards, the same symptoms are produced in lions and tigers.

Birds, especially pigeons, are able to eat almost incredible quantities of opium. A pigeon is said[384] to have consumed 801 grains of opium, mixed with its food, in fourteen days. The explanation of this is that the poison is not absorbed; for subcutaneous injections of salts of morphine act rapidly on all birds hitherto experimented upon.

§ 357. Physiological Action.—From experiments on animals, the essential action of morphine on the nervous and arterial systems has in some measure been examined. There is no very considerable action on the heart. The beats are first accelerated, then diminished in frequency; but very large doses introduced directly into the circulation at once diminish the pulsations, and no acceleration is noticed. The slowing may go on to heart-paralysis. The slowing is central in its origin, for on the vagi being cut, morphine always quickens. With regard to the peripheric ends of the vagi, small doses excite, large paralyse. If all the nerves going to the heart are divided, there is first a considerable acceleration, and then a slowing and weakening of the pulsations. The arterial blood-pressure, at first increased, is afterwards diminished. This increase of blood-pressure is noticed during the acceleration of the pulse, and also during some portion of the time during which the pulse is slowed. Stockman and D. B. Dott,[385] experimenting on rabbits and frogs, consider that a medium dose of morphine first of all depresses the spinal cord and then excites it, for tetanus follows. If morphine is in sufficient quantity thrown into the circulation then tetanus at once occurs. It would thus appear that depression and stimulation is entirely a matter of dosage. Gescheidlen, in his researches on the frog, found the motor nerves at first excited, and then depressed. When the doses were large, there was scarcely any excitement, but the reverse effect, in the neighbourhood of the place of application. According to other observers, the function of the motor nerves may be annihilated.[386] According to Meihuizen, reflex action, at first much diminished, is later, after several hours, normal, and later still again increased. The intestinal movements are transitorily increased. In the dog there has been noticed a greater flow of saliva than usual, and the flow of bile from the gall-bladder is diminished. The pupils in animals are mostly contracted, but, if convulsions occur towards death, they are dilated.

§ 358. Physiological Effect of Morphine Derivatives.—By introducing methyl, or amyl, or ethyl, into the morphine molecule, the narcotic action is diminished, while the tetanic effects are increased. Acetyl, diacetyl, benzoyl, and dibenzoyl morphine, morphine sulphuric ether, and nitrosomorphine are all weaker narcotics than morphine, but, on the other hand, they depress the functions of the spinal cord and bring on, in large doses, tetanus.

The introduction of two methyl groups into morphine, as in metho-codeine, C₁₇H₁₇MeNO(OH)-Me, entirely alters the physiological effect. This compound has an action on voluntary muscle causing gradual paralysis.

The chlorine derivatives, trichlormorphine and chlorcodeine, have the characteristic action of the morphine group on the central nervous system and, in addition, act energetically as muscle poisons, soon destroying the contractile power of the voluntary muscles with which they first come into contact at the place of injection, and more gradually affecting the other muscles of the body.[387]

§ 359. Action on Man.—There are at least three forms of opium poisoning:—(1) The common form, as seen in about 99 per cent. of cases; (2) A very sudden form, in which death takes place with fearful rapidity (the foudroyante variety of the French);[388] and (3) a very rare entirely abnormal form, in which there is no coma, but convulsions.

In the common form there are three stages, viz.:—(1) Excitement; (2) Narcosis; (3) Coma. In from half an hour to an hour[389] the first symptoms commence, the pulse is quickened, the pupils are contracted, the face flushes, and the hands and feet reddened,—in other words, the capillary circulation is active. This stage has some analogy to the action of alcohol; the ideas mostly flow with great rapidity, and instead of a feeling of sleepiness, the reverse is the case. It, however, insensibly, and more or less rapidly, passes into the next stage of heaviness and stupor. There is an irresistible tendency to sleep; the pulse and the respiration become slower; the conjunctivÆ are reddened; the face and head often flushed. In some cases there is great irritability of the skin, and an eruption of nettle-rash. If the poison has been taken by the mouth, vomiting may be present. The bowels are usually—in fact almost invariably—constipated. There is also some loss of power over the bladder.

In the next stage, the narcosis deepens into dangerous coma; the patient can no longer be roused by noises, shaking, or external stimuli; the breathing is loud and stertorous; the face often pale; the body covered with a clammy sweat. The pupils are still contracted, but they may in the last hours of life dilate: and it is generally agreed that, if a corpse is found with the pupils dilated, this circumstance, taken in itself, does not contra-indicate opium or morphine poisoning. Death occasionally terminates by convulsion.

The sudden form is that in which the individual sinks into a deep sleep almost immediately—that is, within five or ten minutes—and dies in a few hours. In these rapid cases the pupils are said to be constantly dilated.

Examples of the convulsive form are to be sought among opium-eaters, or persons under otherwise abnormal conditions.

A man, forty years old, who had taken opiates daily since his twenty-second year—his dose being 6 grms. (92·4 grains) of solid opium—when out hunting, of which sport he was passionately fond, took cold, and, as a remedy, administered to himself three times his accustomed dose. Very shortly there was contraction of the left arm, disturbance of vision, pain in the stomach, faintness, inability to speak, and unconsciousness which lasted half an hour. Intermittent convulsions now set in, and pains in the limbs. There was neither somnolence nor delirium, but great agitation; repeated vomiting and diarrhoea followed. After five hours these symptoms ceased; but he was excessively prostrate.[390] There was complete recovery.

One may hazard a surmise that, in such a case, tolerance has been established for morphine, but not for other morphine alkaloids in the same degree, and that the marked nervous symptoms were in no small degree the effect of some of the homologous alkaloids, which, in such an enormous dose, would be taken in sufficient quantity to have a physiological action.

There are several instances of a relapsing or remittent form of poisoning—a form in which the patient more or less completely recovers consciousness, and then sinks back into a fatal slumber. One of the best known is the case of the Hon. Mrs Anson (January 1859), who swallowed an ounce and a half of laudanum by mistake. After remaining in a comatose condition for more than nine hours, she revived. The face became natural, the pulse steady. She was able to recognise her daughter, and in a thick voice to give an account of the mistake. But this lasted only ten minutes, when she again became comatose, and died in fourteen hours.[391]

In a Swedish case quoted by Maschka,[392] a girl, nine years old, in weak health and suffering from slight bronchitis, had been given a non-officinal acetate of morphia lozenge, which was supposed to contain 5 mgrms. (·075 grain) of morphine acetate. She took the lozenge at eight in the evening; soon slept, woke at ten, got out of bed, laughed, talked, and joked with the nurse, again got into bed, and very quickly fell asleep. At four A.M. the nurse came and found her breathing with a rattling sound, and the physician, who arrived an hour later, found the girl in a state of coma, with contracted pupils, breathing stertorously, and the pulse scarcely to be felt. Despite all attempts to rouse the patient, she died at eight in the morning, twelve hours after taking the lozenge.

The post-mortem examination showed some hyperÆmia of the brain and serous effusion in the ventricles, and there was also tubercle in the pleura. Three lozenges similar to the one taken by the patient were chemically investigated by Hamberg, who found that the amount of acetate was very small, and that the lozenges, instead of morphine acetate, might be considered as prepared with almost pure morphine; the content in the three of morphine being respectively 35, 37, and 42 mgrms. (that is, from half a grain to three-fifths of a grain). There was a difference of opinion among the experts as to whether in this case the child died from morphine poisoning or not—a difference solely to be attributed to the waking up of the child two hours after taking the poison. Now, considering the great probability that a large dose for a weakly child of that age had been taken, and that this is not the only case in which a relapse has occurred, it seems just to infer that it was really a case of poisoning.

As unusual symptoms (or rather sequelÆ) may be noted in a few cases, hemiplegia, which soon passes off; a weakness of the lower extremities may also be left, and inability to empty the bladder thoroughly; but usually on recovery from a large dose of opium, there is simply heaviness of the head, a dry tongue, constipation, and loss of appetite. All these symptoms in healthy people vanish in a day or two. There have also been noticed slight albuminuria, eruptions on the skin, loss of taste, and numbness of parts of the body.

Opium, whether taken in substance, or still more by subcutaneous injection, in some individuals constantly causes faintness. In my own case, I have several times taken a single grain of opium to relieve either pain or a catarrh; almost invariably within an hour afterwards there has been great coldness of the hands and feet, lividity of the face, a feeling of deadly faintness followed by vomiting; this stage (which has seldom lasted more than half an hour) passed, the usual narcotic effects have been produced.

Some years ago I injected one-sixth of a grain of morphine hydrochlorate subcutaneously into an old gentleman, who was suffering from acute lumbago, but was otherwise healthy, and had no heart disease which could be detected; the malady was instantly relieved, and he called out, “I am well; it is most extraordinary.” He went out of the front door, and walked some fifty yards, and then was observed to reel about like a drunken man. He was supported back and laid in the horizontal posture; the face was livid, the pulse could scarcely be felt, and there was complete loss of consciousness. This state lasted about an hour, and without a doubt the man nearly died. Medical men in practice, who have been in the habit of using hypodermic injections of morphine, have had experiences very similar to this and other cases, and although I know of no actual death, yet it is evident that morphine, when injected hypodermically even in a moderate dose, may kill by syncope, and within a few minutes.[393] Absorption by hypodermic administration is so rapid that by the time, or even before the needle of the syringe is withdrawn, a contraction of the pupil may be observed.

[393] See a case of morphia poisoning by hypodermic injection, and recovery, by Philip E. Hill, M.R.C.S., Lancet, Sept. 30, 1882. In this instance a third of a grain introduced subcutaneously caused most dangerous symptoms in a gardener, aged 48.

Opium or morphine is poisonous by whatever channel it gains access to the system, the intestinal mucous membrane absorbs it readily, and narcotic effects may be produced by external applications, whether a wound is present or not. A case of absorption of opium by a wound is related in Chevers’s Jurisprudence.[394] A Burman boy, about nine or ten years of age, was struck on the forehead by a brick-bat, causing a gaping wound about an inch long; his parents stuffed the wound with opium. On the third day after the accident, and the opium still remaining in the wound, he became semi-comatose, and, in short, had all the symptoms of opium narcosis; with treatment he recovered. The unbroken skin also readily absorbs the drug. Tardieu states that he had seen 30 grms. of laudanum, applied on a poultice to the abdomen, produce death. Christison has also cited a case in which a soldier suffered from erysipelas, and died in a narcotic state, apparently produced from the too free application of laudanum to the inflamed part.

To these cases may be added the one cited by Taylor, in which a druggist applied 30 grains of morphine to the surface of an ulcerated breast, and the woman died with all the symptoms of narcotic poisoning ten hours after the application—an event scarcely surprising. It is a curious question whether sufficient of the poison enters into the secretions—e.g., the milk—to render it poisonous. An inquest was held in Manchester, Nov. 1875, on the body of a male child two days old, in which it seemed probable that death had occurred through the mother’s milk. She was a confirmed opium-eater, taking a solid ounce per week.§ 360. Diagnosis of Opium Poisoning.—The diagnosis is at times between poisoning by opium or other narcotic substances, at others, between opium and disease. Insensibility from chloral, from alcohol, from belladonna or atropine, and from carbon oxide gas, are all more or less like opium poisoning. With regard to chloral, it may be that only chemical analysis and surrounding circumstances can clear up the matter. In alcohol poisoning, the breath commonly smells very strongly of alcohol, and there is no difficulty in separating it from the contents of the stomach, &c., besides which the stomach is usually red and inflamed. Atropine and belladonna invariably dilate the pupil, and although just before death opium has the same effect, yet we must hold that mostly opium contracts, and that a widely-dilated pupil during life would, per se, lead us to suspect that opium had not been used, although, as before mentioned, too much stress must not be laid upon the state of the pupils. In carbon oxide, the peculiar rose-red condition of the body affords a striking contrast to the pallor which, for the most part, accompanies opium poisoning. In the rare cases in which convulsions are a prominent symptom, it may be doubtful whether opium or strychnine has been taken, but the convulsions hitherto noticed in opium poisoning seem to me to have been rather of an epileptiform character, and very different from the effects of strychnine. No rules can be laid down for cases which do not run a normal course; in medicine such are being constantly met with, and require all the care and acumen of the trained observer. Cases of disease render a diagnosis often extremely difficult, and the more so in those instances in which a dose of laudanum or other opiate has been administered. In a case under my own observation, a woman, suffering from emphysema and bronchitis, sent to a chemist for a sleeping draught, which she took directly it arrived. A short time afterwards she fell into a profound slumber, and died within six hours. The draught had been contained in an ounce-and-a-half bottle; the bottle was empty, and the druggist stated in evidence that it only contained 20 minims of laudanum, 10 grains of potassic bromide, and water. On, however, diluting the single drop remaining in the bottle, and imitating its colour with several samples of laudanum diluted in the same way, I came to the conclusion that the quantity of laudanum which the bottle originally contained was far in excess of that which had been stated, and that it was over 1 drachm and under 2 drachms. The body was pallid, the pupils strongly contracted, the vessels of the brain membranes were filled with fluid blood, and there was about an ounce of serous fluid in each ventricle. The lungs were excessively emphysematous, and there was much secretion in the bronchi; the liver was slightly cirrhotic. The blood, the liver, and the contents of the stomach were exhaustively analysed with the greatest care, but no trace of morphine, narcotine, or meconic acid could be separated, although the woman did not live more than six hours after taking the draught. I gave the opinion that it was, in the woman’s state, improper to prescribe a sedative of that kind, and that probably death had been accelerated, if not directly caused, by opium.

Deaths by apoplexy will only simulate opium-poisoning during life; a post-mortem examination will at once reveal the true nature of the malady. In epilepsy, however, it is different, and more than once an epileptic fit has occurred and been followed by coma—a coma which certainly cannot be distinguished from that produced by a narcotic poison. Death in this stage may follow, and on examining the body no lesion may be found.§ 361. Opium-eating.—The consumption of opium is a very ancient practice among Eastern nations, and the picture, drawn by novelist and traveller, of poor, dried-up, yellow mortals addicted to this vice, with their faculties torpid, their skin hanging in wrinkles on their wasted bodies, the conjunctivÆ tinged with bile, the bowels so inactive that there is scarcely an excretion in the course of a week, the mental faculties verging on idiocy and imbecility, is only true of a percentage of those who are addicted to the habit. In the British Medical Journal for 1894, Jan. 13 and 20, will be found a careful digest of the evidence collated from 100 Indian medical officers, from which it appears that opium is taken habitually by a very large number of the population throughout India, those who are accustomed to the drug taking it in quantities of from 10 to 20 grains in the twenty-four hours; so long as this amount is not exceeded they do not appear to suffer ill-health or any injurious effect. The native wrestlers even use it whilst training. The habitual consumption of opium by individuals has a direct medico-legal bearing. Thus in India, among the Rajpoots, from time immemorial, infused opium has been the drink both of reconciliation and of ordinary greeting, and it is no evidence of death by poison if even a considerable quantity of opium be found in the stomach after death, for this circumstance taken alone would, unless the history of the case was further known, be considered insufficient proof. So, again, in all climates, and among all races, it is entirely unknown what quantity of an opiate should be considered a poisonous dose for an opium-eater. Almost incredible quantities have, indeed, been consumed by such persons, and the commonly-received explanation, that the drug, in these cases, passes out unabsorbed, can scarcely be correct, for Hermann mentions the case of a lady of Zurich who daily injected subcutaneously 1 to 2 grms. (15-31 grains) of a morphine salt. In a case of uterine cancer, recorded by Dr. W. C. Cass,[395] 20 grains of morphine in the twelve hours were frequently used subcutaneously; during thirteen months the hypodermic syringe was used 1350 times, the dose each time being 5 grains. It is not credible that an alkaloid introduced into the body hypodermically should not be absorbed.

Opium-smoking is another form in which the drug is used, but it is an open question as to what poisonous alkaloids are in opium smoke. It is scarcely probable that morphine should be a constituent, for its subliming point is high, and it will rather be deposited in the cooler portion of the pipe. Opium, specially prepared for smoking, is called “Chandoo”; it is dried at a temperature not exceeding 240°. H. Moissan[396] has investigated the products of smoking chandoo, but only found a small quantity of morphine. N. GrÉhant and E. Martin[397] have also experimented with opium smoke; they found it to have no appreciable effect on a dog; one of the writers smoked twenty pipes in succession, containing altogether 4 grms. of chandoo. After the fourth pipe there was some headache, at the tenth pipe and onwards giddiness. Half an hour after the last pipe the giddiness and headache rapidly went off. In any case, opium-smoking seems to injure the health of Asiatics but little. Mr. Vice-Consul King, of Kew-Kiang, in a tour through Upper Yangtse and Stechnan, was thrown much into the company of junk sailors and others, “almost every adult of whom smoked more or less.” He says:—“Their work was of the hardest and rudest, rising at four and working with hardly any intermission till dark, having constantly to strip and plunge into the stream in all seasons, and this often in the most dangerous parts. The quantity of food they eat was simply prodigious, and from this and their work it seems fairly to be inferred that their constitution was robust. The two most addicted to the habit were the pilot and the ship’s cook. On the incessant watchfulness and steady nerve of the former the safety of the junk and all on board depended, while the second worked so hard from 3 A.M. to 10 P.M., and often longer, and seemed so independent of sleep or rest, that to catch him seated or idle was sufficient cause for good-humoured banter. This latter had a conserve of opium and sugar which he chewed during the day, as he was only able to smoke at night.”

§ 362. Treatment of Opium or Morphine Poisoning.—The first thing to be done is doubtless to empty the stomach by means of the flexible stomach tube; the end of a sufficiently long piece of indiarubber tubing is passed down into the pharynx and allowed to be carried into the stomach by means of the natural involuntary movements of the muscles of the pharynx and gullet; suction is then applied to the free end and the contents syphoned out; the stomach is, by means of a funnel attached to the tube, washed out with warm water, and then some coffee administered in the same way.

Should morphine have been taken, and permanganate of potash be at hand, it has been shown that under such circumstances potassic permanganate is a perfect antidote, decomposing at once any morphine remaining in the stomach, but it, of course, will have no effect upon any morphine which has already been absorbed. In a case of opium poisoning, reported in the Lancet of June 2, 1894, by W. J. C. Merry, M.B., inhalations of oxygen, preceded by emptying the stomach and other means, appeared to save a man, who, three hours before the treatment, had drank 2 ozs. of chlorodyne. It is also the received treatment to ward off the fatal sleep by stimulation; the patient is walked about, flicked with a towel, made to smell strong ammonia, and so forth. This stimulation must, however, be an addition, but must never replace the measures first detailed.§ 363. Post-mortem Appearances.—There are no characteristic appearances after death save hyperÆmia of the brain and blood-vessels of the membranes, with generally serous effusion into the ventricles. The pupils are sometimes contracted, sometimes dilated, the dilatation occurring, as before mentioned, in the act of dying. The external surface of the body is either livid or pale. The lungs are commonly hyperÆmic, the bladder full of urine; still, in not a few cases, there is nothing abnormal, and in no single case could a pathologist, from the appearance of the organs only, declare the cause of death with confidence.§ 364. Separation of Morphine from Animal Tissues and Fluids.—Formerly a large proportion of the opium and morphine cases submitted to chemical experts led to no results; but owing to the improved processes now adopted, failure, though still common, is less frequent. The constituents of opium taken into the blood undergo partial destruction in the animal body, but a portion may be found in the secretions, more especially in the urine and fÆces. First Bouchardat[398] and then Lefort[399] ascertained the excretion of morphine by the urine after medicinal doses; Dragendorff and Kauzmann showed that the appearance of morphine in the urine was constant, and that it could be easily ascertained and separated from the urine of men and animals; and Levinstein[400] has also shown that the elimination from a single dose may extend over five or six days. The method used by Dragendorff to extract morphine from either urine or blood is to shake the liquid (acidified with a mineral acid) several times with amyl alcohol, which, on removal, separates urea and any bile acids. The liquid thus purified is then alkalised, and shaken up with amyl alcohol, and this amyl alcohol should contain any morphine that was present. On evaporation it may be pure enough to admit of identification, but if not, it may be redissolved and purified on the usual principles. Considerable variety of results seems to be obtained by different experimenters. Landsberg[401] injected hypodermically doses of ·2 to ·4 grm. of morphine hydrochlorate into dogs, making four experiments in all, but failed to detect morphine in the urine. A large dose with 2·4 mgrms. of the salt gave the same result. On the other hand, ·8 grm. of morphine hydrochlorate injected direct into the jugular vein, was partly excreted by the kidneys, for 90 c.c. of the urine yielded a small quantity of morphine. Voit, again, examined the urine and fÆces of a man who had taken morphine for years; he could detect none in the urine, but separated morphine from the fÆces.[402] Morphine may occasionally be recognised in the blood. Dragendorff[403] found it in the blood of a cat twenty-five minutes after a subcutaneous dose, and he also separated it from the blood of a man who died of morphine poisoning in six hours. Haidlen[404] recognised morphine in the blood of a suicide who had taken opium extract.

On the other hand, in a case recorded at p. 304, where a woman died in six hours from a moderate dose, probably of laudanum, although the quantity of blood operated upon was over a pound in weight, and every care was taken, the results were entirely negative. In poisoning by laudanum there may be some remaining in the stomach, and also if large doses of morphine have been taken by the mouth; but when morphine has been administered hypodermically, and in all cases in which several hours have elapsed, one may almost say that the organ in which there is the least probability of finding the poison is the stomach. It may, in some cases, be necessary to operate on a very large scale;—to examine the fÆces, mince up the whole liver, the kidney, spleen, and lungs, and treat them with acid alcohol. The urine will also have to be examined, and as much blood as can be obtained. In cases where all the evidence points to a minute quantity (under a grain) of morphine, it is decidedly best to add these various extracts together, to distil off the alcohol at a very gentle heat, to dry the residue in a vacuum, to dissolve again in absolute alcohol, filter, evaporate again to dryness, dissolve in water, and then use the following process:—§ 365. Extraction of Morphine.—To specially search for morphine in such a fluid as the urine, it is, according to the author’s experience, best to proceed strictly as follows:—The urine is precipitated with acetate of lead, the powdered lead salt being added to the warm urine contained in a beaker on the water-bath, until a further addition no longer produces a precipitate; the urine is then filtered, the lead precipitate washed, and the excess of lead thrown down by SH₂; the lead having been filtered off, and the precipitate washed, the urine is concentrated down to a syrup in a vacuum. The syrup is now placed in a separating tube (if not acid, it is acidified with hydrochloric acid), and shaken up successively with petroleum ether, chloroform, ether, and, lastly, with amylic alcohol (the latter should be warm); finally, the small amount of amylic alcohol left dissolved in the liquid is got rid of by shaking it up with petroleum ether. To get rid of the last traces of petroleum ether, it may be necessary to turn the liquid into an evaporating dish, and gently heat for a little time over the water-bath. The acid liquid is now again transferred to the separating tube, and shaken up with ether, after being made alkaline with ammonia; this will remove nearly all alkaloids save morphine,—under the circumstances, a very small quantity of morphine may indeed be taken up by the ether, but not the main bulk. After separating the ether, the liquid is again made slightly acid, so as to be able to precipitate morphine in the presence of the solvent; the tube is warmed on the water-bath, at least its own bulk of hot amylic alcohol added and the liquid made alkaline, and the whole well shaken. The amylic alcohol is removed in the usual way, and shaken with a small quantity of decinormal sulphuric acid; this washes out the alkaloid from the amyl alcohol, and the same amyl alcohol can be used again and again. It is best to extract the liquid for morphine at least thrice, and to operate with both the solution and the amyl hot. The decinormal acid liquid is made slightly alkaline with ammonia, and allowed to stand for at least twelve hours; any precipitate is collected and washed with ether, and then with water; the alkaline liquid from which the morphine has been separated is concentrated to the bulk of 5 c.c. on the water bath, and again allowed to stand for twelve hours; a little more morphine may often in this way be obtained.

The author in some test experiments, in which weighed small quantities of morphine (60-80 mgrms.) were dissolved in a little decinormal sulphuric acid, and added to large quantities of urine, found the process given to yield from 80 to 85 per cent. of the alkaloid added, and it was always recovered in fine crystals of a slight brown tint, which responded well to tests.

Various other methods were tried, but the best was the one given; the method not only separates the alkaloid with but little loss, but also in a sufficiently pure state to admit of identification.

From the tissues the alkaloid may be dissolved out by the general method given at p. 239, and the ultimate aqueous solution, reduced to a bulk of not more than 25 c.c., treated by the ethereal solvents in the way just described.§ 366. Narcotine (C₂₂H₂₃NO₇) crystallises out of alcohol or ether in colourless, transparent, glittering needles, or groups of needles, belonging to the orthorhombic system.

It is only slightly soluble in boiling, and almost insoluble in cold water. One part requires 100 parts of cold, and 20 of boiling 84 per cent. alcohol; 126 parts of cold, 48 of boiling ether (specific gravity 0·735); 2·69 parts of chloroform; 400 of olive oil; 60 of acetic ether; 300 of amyl alcohol; and 22 parts of benzene, for solution. The neutral solution of narcotine turns the plane of polarisation to the left [a]r = 130·6; the acid solution to the right. Narcotine has no effect on red litmus paper.

Narcotine gives no crystalline sublimate; its behaviour in the subliming cell is described at p. 259. Its melting-point, taken in a tube, is about 176°.

Behaviour of Narcotine with Reagents.—Narcotine, dissolved in dilute hydrochloric acid, and then treated with a little bromine, gives a yellow precipitate, which on boiling is dissolved; by gradually adding solution of bromine and boiling, a fine rose colour is produced, readily destroyed by excess of bromine. This is perhaps the best test for the presence of narcotine. Concentrated sulphuric acid dissolves narcotine; the solution in the cold is at first colourless, after a few minutes yellow, and in the course of a day or longer the tints gradually deepen. If the solution is warmed, it first becomes orange-red, then at the margin violet-blue; and if heated until hydric sulphate begins to volatilise, the colour is an intense red-violet. If the heating is not carried so far, but the solution allowed to cool, a delicate cherry-red hue slowly develops. If the sulphuric acid solution contains 1: 2000 of the alkaloid, this test is very evident; with 1: 40,000, the colour is only a faint carmine.—A. Husemann.

A solution of narcotine in pure sulphuric acid, to which a drop of nitric acid has been added, becomes of a red colour; if the solution is warmed to 150°, hypochlorite of soda develops a carmine-red; and chloride of iron, first a violet, then a cherry-red. The precipitants of narcotine are—phosphomolybdic acid, picric acid, sulphocyanide of potash, potassio cadmic iodide, mercuric chloride, platinic chloride, auric chloride, and several other reagents.

From the brown mass left after heating narcotine above 200°, hydrochloric acid extracts a small portion of a base but little studied. The residue consists of humopic acid (C₄₀H₁₉O₁₄), which can be obtained by dissolving in caustic potash, precipitating with HCl, dissolving the precipitate in boiling alcohol, and finally throwing it down by water.§ 367. Effects.—Narcotine in itself has toxic action only in rather large doses; from 1 to 2 grms. have been given to man, and slight hypnotic effects have followed. It is poisonous in very large doses; an ordinary-sized cat is killed by 3 grms. The symptoms are mainly convulsions.§ 368. Codeine (Codomethylene), C₁₇H₁₇OCH₃(OH)NO + H₂O, is the methyl of morphine; it is an alkaloid contained in opium in small quantity only. Mulder, indeed, quotes ·66 to ·77 per cent. as present in Smyrna opium, but Merck and Schindler give ·25 per cent. Schindler found in Constantinople, ·5 per cent.; and Merck, in Bengal, ·5 per cent. also.

Codeine crystallises out of dry ether in small, colourless, anhydrous, crystals; but crystallised slowly from an aqueous solution, the crystals are either in well-defined octahedra, or in prisms, containing one atom of water, and melting in boiling-water to an oily fluid. The anhydrous crystals have a melting-point of 150°, and solidify again on cooling. Its watery solution is alkaline to litmus paper.

It requires 80 parts of cold, 17 of boiling water, 10 parts of benzole, and 7 parts of amyl alcohol respectively, for solution. Alcohol, benzene, ether, carbon disulphide, and chloroform freely dissolve it, but in petroleum ether it is almost insoluble. Further, it is also soluble in aqueous ammonia, and in dilute acids, but insoluble in excess of caustic potash or soda, and may thus be thrown out of an aqueous solution. A solution of codeine turns the plane of polarisation to the left, [a]r = 118·2°.

Concentrated sulphuric acid dissolves codeine without colour, but after eight days the solution becomes blue; this reaction is quicker if the acid contains a trace of nitric acid. If the sulphuric acid solution be warmed to 150°, and a drop of nitric acid be added after cooling, a blood-red colour is produced. FrÖhde’s reagent produces a dirty green colour, soon becoming Prussian blue, and terminating after twenty-four hours in a pale yellow.

Cyanogen gas, led into an alcoholic solution of codeine, gives first a yellow and then a brown colour; lastly, a crystalline precipitate falls. On warming with a little sulphuric acid and ferric chloride, a blue colour is produced. This blue colour is apparently common to all ethers of the codeine class.

Of the group reagents, the following precipitate solutions of codeine:—Mercuric potassium iodide, mercuric chloride, mercuric bromide, picric acid, and tannin solutions. The following do not precipitate:—Mercuric cyanide and potassium ferrocyanide solutions. Potassium dichromate gives no immediate precipitate, but crystals form on long standing. It does not give the reaction with iodic acid like morphine; it is distinguished from narceine by dropping a small particle of iodine into the aqueous solution, the iodine particle does not become surrounded with fine crystals.§ 369. Effects.—The physiological action of codeine on animals has been investigated by Claude Bernard, Magendie, Crum Brown and Fraser, Falck, and a large number of others.[405] It has also been administered to man, and has taken in some degree the place of morphine. Claude Bernard showed that, when given to dogs in sufficient quantity to produce sleep, the sleep was different in some respects to that of morphine sleep, especially in its after-effects. Thus, in his usual graphic way, he describes the following experiment:—“Two young dogs, accustomed to play together, and both a little beyond the average size, received in the cellular tissue of the axillÆ, by the aid of a subcutaneous syringe, the one 5 centigrammes of morphine hydrochloride, the other 5 centigrammes of codeine hydrochloride. At the end of a quarter of an hour both dogs showed signs of narcosis. They were placed on their backs in the experimental trough, and slept tranquilly for three or four hours. When the animals woke, they presented the most striking contrast. The morphine dog ran with a hyena-like gait (dÉmarche hyÉnoid), the eye wild, recognising no one, not even his codeine comrade, who vainly bit him playfully, and jumped sportively on his back. It was not until the next day that the morphine dog regained his spirits and usual humour. A couple of days after, the two dogs being in good health, I repeated the same experiment, but in an inverse order—that is to say, I gave the codeine to that which previously had the morphine, and vice versÂ. Both dogs slept about as long as the first time; but on waking the attitudes were completely reversed, just as the administration of the two substances had been. The dog which, two days before, after having been codeinised, woke lively and gay, was now bewildered and half paralysed at the end of his morphine sleep; whilst the other was wide awake and in the best spirits.”

Subsequent experimenters found what Bernard does not mention—viz., that codeine produced epileptiform convulsions. Falck made some very careful experiments on pigeons, frogs, and rabbits. To all these in high enough doses it was fatal. Falk puts the minimum lethal dose for a rabbit at 51·2 mgrms. per kilo. Given to man, it produces a sleep very similar to that described by Claude Bernard—that is, a sleep which is very natural, and does not leave any after-effect. Therefore it is declared to be the best alkaloid of a narcotic nature to give when lengthened slumber is desired, more especially since it does not confine the bowels, nor has it been found to produce any eruption on the skin. Before it has a full narcotic effect, vomiting has often been excited, and in a few cases purging. The maximum dose for an adult is about ·1 grm. (1·5 grain); three times this quantity, ·3 grms. (4-5 grains), would probably produce unpleasant, if not dangerous, symptoms.[406]

[412] Sitzungsber. d. Wien. Akadem., lvi. pp. 2, 89, 1867; Arch. f. Anat. u. Physiol., Hft. 1, p. 112, 1869.[413] F. W. MÜller, Das Thebaine, eine Monographie, Diss., Marburg 1868.

TABLE SHOWING SOME OF THE REACTIONS OF THE RARER ALKALOIDS OF OPIUM.

The most generally accepted view at the present time is that the physiological action of meconic acid is similar to that of lactic acid—viz., large doses cause some depression and feeble narcosis.

In a special research amongst organic fluids for meconic acid, the substances are extracted by alcohol feebly acidulated with nitric acid; on filtration the alcohol, after the addition of a little water, is distilled off, and to the remaining fluid a solution of acetate of lead is added, and the whole filtered. The filtrate will contain any alkaloids, whilst meconic acid, if present, is bound up with the lead on the filter. The meconate of lead may be either washed or digested in strong acetic acid to purify it, suspended in water, and freed from lead by SH₂; the filtrate from the lead sulphide may be tested by ferric chloride, or preferably, at once evaporated to dryness, and weighed. After this operation it is identified. If the quantity is so small that it cannot be conveniently weighed, it may be estimated colorimetrically, by having a standard solution of meconic acid, containing 1 mgrm. in every c.c. A few drops of neutral ferric chloride are added in a Nessler cylinder to the liquid under examination; and the tint thus obtained is imitated in the usual way, in another cylinder, by means of ferric chloride, the standard solution, and water. It is also obvious that the weight of the meconic acid may be increased by converting it into the barium salt—100 parts of anhydrous baric meconate, (Ba₂C₇H₂O₇), being equivalent to 42·3 of meconic acid (C₇H₄O₇).

IV.—The Strychnine or Tetanus-Producing[422] Group of Alkaloids.

1. NUX VOMICA GROUP—STRYCHNINE—BRUCINE—IGASURINE.

§ 385. Nux vomica is found in commerce both in the entire state and as a powder. It is the seed of the Strychnos nux vomica, or Koochla tree. The seed is about the size of a shilling, round, flattened, concavo-convex, of a yellowish-grey or light-brown colour, covered with a velvety down of fine, radiating, silky hairs, which are coloured by a solution of iodine beautiful gold-yellow; the texture is tough, leathery, and not easily pulverised; the taste is intensely bitter. The powder is not unlike that of liquorice, and, if met with in the pure state, gives a dark orange-red colour with nitric acid, which is destroyed by chloride of tin; the aqueous infusion gives a precipitate with tincture of galls, is reddened by nitric acid, and gives an olive-green tint with persulphate of iron. The best method, however, of recognising quickly and with certainty that the substance under examination is nux vomica powder, is to extract strychnine from it by the following simple process:—The powder is completely exhausted by boiling alcohol (90 per cent.), the alcoholic extract evaporated to dryness, and then treated with water; the aqueous solution is passed through a wet filter, and concentrated by evaporation to a small bulk. To this liquid a drop or so of a concentrated solution of picric acid is added, and the yellow precipitate of picrates thus obtained is separated, treated with nitric acid, the picric acid removed by ether, and the pure alkaloid precipitated by soda, and shaken out by chloroform.§ 386. Chemical Composition.—Nux vomica contains at least four distinct principles:—

• (1.) Strychnine.
• (2.) Brucine.
• (3.) Igasurine.
• (4.) Strychnic or igasuric acid.

§ 387. Strychnine (C₂₁H₂₂N₂O₂) is contained in the bean of S. ignatius, in the bark (false angustura bark) and seeds of the Strychnos nux vomica, in the Strychnos colubrina, L., in the Strychnos tieutÉ, Lesch, and probably in various other plants of the same genus.

Commercial strychnine is met with either in colourless crystals or as a white powder, the most usual form being that of the alkaloid itself; but the nitrate, sulphate, and acetate are also sold to a small extent.

The microscopical appearance of strychnine, as thrown down by the solution of vapour of ammonia, may be referred to three leading forms—the long rectangular prism, the short hexagonal prism, or the regular octahedron. If obtained from the slow evaporation of an alcoholic solution, it is usually in the form of four-sided pyramids or long prisms; but if obtained by speedy evaporation or rapid cooling, it appears as a white granular powder. If obtained from a benzene solution, the deposit is usually crystalline, but without a constant form, though at times the crystals are extremely distinct, the short six-sided prism prevailing; but triangular plates, dodecahedral, rhomboidal, and pentagonal, may also be met with. An ethereal solution on evaporation assumes dendritic forms, but may contain octahedra and four-sided prisms. A chloroform solution deposits rosettes, veined leaves, stellate dotted needles, circles with broken radii, and branched and reticulated forms of great delicacy and beauty.—Guy.

Strychnine is very insoluble in water, although readily dissolved by acidulated water. According to Wormley’s repeated experiments, one part of strychnine dissolves in 8333 parts of cold water; and, according to Pelletier and Cahours, it dissolves in 6667 parts of cold, and 2500 parts of boiling water. It may be convenient, then, to remember that a gallon of cold water would hardly dissolve more than 10 grains (·142 grm. per litre); the same amount, if boiling, about 30 grains (·426 grm. per litre) of strychnine. The solubility of one part of strychnine in other menstrua is as follows:—Cold alcohol, 0·833 specific gravity, 120, boiling, 10 parts (Wittstein); cold alcohol, 0·936 specific gravity, 240 parts (Merck); cold alcohol, 0·815 specific gravity, 107 parts (Dragendorff); amyl alcohol, 181 parts; benzene, 164; chloroform, 6·9 (Schlimpert), 5 (Pettenkofer); ether, 1250 parts; carbon disulphide, 485 parts; glycerin, 300 parts. Creosote and essential and fixed oils also dissolve strychnine.

Of all the above solvents, it is evident that chloroform is the best for purposes of separation, and next to chloroform, benzene.

If a speck of strychnine be placed in the subliming cell, it will be found to sublime usually in a crystalline form at 169°. A common form at this temperature, according to the writer’s own observations, is minute needles, disposed in lines; but, as Dr. Guy has remarked, the sublimate may consist of drops, of waving patterns, and various other forms; and, further, while the sublimates of morphia are made up of curved lines, those of strychnine consist of lines either straight or slightly curved, with parallel feathery lines at right angles. On continuing the heat, strychnine melts at about 221°, and the lower disc, if removed and examined, is found to have a resinous residue; but it still continues to yield sublimates until reduced to a spot of carbon. The melting-point taken in a tube is 268°.

Strychnine is so powerfully bitter, that one part dissolved in 70,000 of water is distinctly perceptible; it is a strong base, with a marked alkaline reaction, neutralising the strongest acids fully, and precipitating many metallic oxides from their combinations, often with the formation of double salts. Most of the salts of strychnine are crystalline, and all extremely bitter. Strychnine, in the presence of oxygen, combines with SH₂ to form a beautiful crystalline compound:—

2C₂₁H₂₂N₂O₂ + 6H₂S + O₃ = 2C₂₁H₂₂N₂O₂3H₂S₂ + 3H₂O.

On treatment with an acid this compound yields H₂S₂.—Schmidt, Ber. Deutsch. Chem. Ges., 8, 1267.

An alcoholic solution of strychnine turns the plane of polarisation to the left, [a]r = -132·08° to 136·78° (Bouchardat); but acid solutions show a much smaller rotatory power.

The salts used in medicine are—the sulphate, officinal only in the French pharmacopoeia; the nitrate, officinal in the German, Austrian, Swiss, Norse, and Dutch pharmacopoeias; and the acetate, well known in commerce, but not officinal.

The commercial Sulphate (C₂₁H₂₂N₂O₂H₂SO₄ + 2H₂O) is an acid salt crystallising in needles which lose water at 150°, the neutral sulphate (2C₂₁H₂₂N₂O₂,H₂SO₄ + 7H₂O) crystallises in four-sided, orthorhombic prisms, and is soluble in about 50 parts of cold water.

The Nitrate (C₂₁H₂₂N₂O₂,HNO₃) crystallises on evaporation from a warm solution of the alkaloid in dilute nitric acid, in silky needles, mostly collected in groups. The solubility of this salt is considerable, one part dissolving in 50 of cold, in 2 of boiling water; its solubility in boiling and cold alcohol is almost the same, taking 60 of the former and 2 of the latter.

The Acetate crystallises in tufts of needles; as stated, it is not officinal in any of the European pharmacopoeias.

The chief precipitates or sparingly soluble crystalline compounds of strychnine are—

(1.) The Chromate of Strychnine (C₂₁H₂₂N₂O₂CrHO₂), formed by adding a neutral solution of chromate of potash to a solution of a strychnine salt, crystallises out of hot water in beautiful, very insoluble, orange-yellow needles, mixed with plates of various size and thickness. The salt is of great practical use to the analyst; for by its aid strychnine may be separated from a variety of substances, and in part from brucine—the colour tests being either applied direct to the strychnine chromate, or the chromate decomposed by ammonia, and the strychnine recovered from the alkaline liquid by chloroform.

(2.) Sulphocyanide of Strychnine (C₂₁H₂₂N₂O₂CNHS) is a thick, white precipitate, produced by the addition of a solution of potassic sulphocyanide to that of a strychnine salt; on warming it dissolves, but on cooling reappears in the form of long silky needles.

(3.) Double Salts.—The platinum compound obtained by adding a solution of platinic chloride to one of strychnine chloride has the composition C₂₁H₂₂N₂O₂HClPtCl₂, and crystallises out of weak boiling alcohol (in which it is somewhat soluble) in gold-like scales. The similar palladium compound (C₂₁H₂₂N₂O₂HCl,PdCl) is in dark brown needles, and the gold compound (C₂₁H₂₂N₂O₂HClAuCl₃) in orange-coloured needles.

(4.) Strychnine Trichloride.—The action of chlorine on strychnine—by which chlorine is substituted for a portion of the hydrogen—has been proposed as a test. The alkaloid is dissolved in very dilute HCl, so as to be only just acid; on now passing through chlorine gas, a white insoluble precipitate is formed, which may be recrystallised from ether; it has probably the composition C₂₁H₁₉Cl₃N₂O₂, and is extremely insoluble in water.

(5.) The Iodide of Strychnine (C₂₁H₂₂N₂O₂HI₃) is obtained by the action of iodine solution on strychnine sulphate; on solution of the precipitate in alcohol, and evaporation, it forms violet-coloured crystals, very similar to those of potassic permanganate.§ 388. Pharmaceutical and other Preparations of Nux Vomica and Strychnine, with Suggestions for their Valuation.

An aqueous extract of nux vomica, officinal in the German pharmacopoeia, appears to contain principally brucine, with a small percentage of strychnine; the proportion of brucine to strychnine being about four-fifths to one-fifth. Blossfield found in a sample 4·3 per cent. of total alkaloid, and two samples examined by Grundmann consisted (No. 1) of strychnine, 0·6 per cent.; brucine, 2·58 per cent.—total, 3·18 per cent.; (No. 2) strychnine, 0·68 per cent.; brucine, 2·62 per cent.—total, 3·3 per cent. A sample examined by Dragendorff yielded—strychnine, 0·8 per cent.; brucine, 3·2 per cent.—total, 4 per cent. The maximum medicinal dose is put at ·6 grm. (9¹/₁₄ grains).

The spirituous extract of nux vomica, officinal in the British and all the Continental pharmacopoeias, differs from the aqueous in containing a much larger proportion of alkaloids, viz., about 15 per cent., and about half the total quantity being strychnine. The medicinal dose is 21·6-64·8 mgrms. (¹/₃ grain to a grain).

There is also an extract of St. Ignatius bean which is used in the United States; nearly the whole of its alkaloid may be referred to strychnine.

The tincture of nux vomica, made according to the British Pharmacopoeia, contains in 1 fl. oz. 1 grain of alkaloids, or 0·21 part by weight in 100 by volume, but the strength of commercial samples often varies. Lieth found in one sample 0·122 per cent. of strychnine and 0·09 per cent. brucine; and two samples examined by Wissel consisted respectively of 0·353 per cent. and 0·346 per cent. of total alkaloids. Dragendorff found in two samples ·2624 per cent. and ·244 per cent. of total alkaloids, about half of which was strychnine.

Analysis.—Either of the extracts may be treated for a few hours on the water-bath, with water acidulated by sulphuric acid, filtered, the residue well washed, the acid liquid shaken up with benzene to separate impurities, and, on removal of the benzene, alkalised with ammonia, and shaken up two or three times with chloroform; the chloroform is then evaporated in a tared vessel, and the total alkaloids weighed. The alkaloids can then be either (a) treated with 11 per cent. of nitric acid on the water-bath until all the brucine is destroyed, and then (the liquid being neutralised) precipitated by potassic chromate; or (b) the alkaloids may be converted into picrates. Picrate of strychnine is very insoluble in water, 1 part requiring no less than 10,000 of water.[423] The tincture is analysed on precisely similar principles, the spirit being got rid of by distillation, and the residue treated by acidified water, &c.

The nux vomica powder itself may be valued as follows:—15 to 20 grms., pulverised as finely as possible, are treated three times with 150 to 300 c.c. of water, acidified with sulphuric acid, well boiled, and, after each boiling, filtered and thoroughly pressed. The last exhaustion must be destitute of all bitter taste. The united filtrates are then evaporated to the consistence of a thick syrup, which is treated with sufficient burnt magnesia to neutralise the acid. The extract is now thoroughly exhausted with boiling alcohol of 90 per cent.; the alcoholic extract, in its turn, is evaporated nearly to dryness, and treated with acidulated water; this acid solution is freed from impurities by shaking up with benzene, and lastly alkalised with ammonia, and the alkaloids extracted by shaking up with successive portions of chloroform. The chloroformic extract equals the total alkaloids, which may be separated in the usual way.

In four samples of nux vomica examined by Dragendorff, the total alkaloids ranged from 2·33 to 2·42 per cent. Grate found in two samples 2·88 per cent. and 2·86 per cent. respectively; while Karing from one sample separated only 1·65 per cent. The strychnine and brucine are in about equal proportions, Dragendorff[424] finding 1·187 per cent. strychnine and 1·145 per cent. brucine.[425]

The vermin-killers in use in this country are those of Miller, Battle, Butler, Clift, Craven, Floyd, Gibson, Hunter, Stenier, and Thurston. Ten samples from these various makers were examined recently by Mr. Allen (Pharm. Journal, vol. xii., 1889), and the results of the analyses are embodied in the following table:—

§ 389. Statistics.—In England, during the ten years 1883-92, out of 6666 total deaths from poison, strychnine, nux vomica, and vermin-killer account for 325. Out of these deaths, 118 were ascribed to “vermin-killer.” “Vermin-killer” may be presumed to include not only strychnine mixtures, but also phosphorus and arsenic pastes and powders, so that there are no means of ascertaining the number of strychnine cases comprised under this heading. Taking the deaths actually registered as due to strychnine or nux vomica, they are about 4·7 per cent. of the deaths from all sorts of poison. Of these deaths, 268, or 82·4 per cent., were suicidal, 8 were homicidal, and 49 only were accidental.

Schauenstein has collected from literature 130 cases of poisoning by strychnine, but most of these occurred during the last twenty-five years; 62 of the 130, or about one-half, were fatal, and 15 were homicidal. It has been stated that strychnine is so very unsuitable for the purpose of criminal poisoning as to render it unlikely to be often used. Facts, however, do not bear out this view; for, allowing its intensely bitter taste, yet it must be remembered that bitter liquids, such as bitter ale, are in daily use, and a person accustomed to drink any liquid rapidly might readily imbibe sufficient of a toxic liquid to produce death before he was warned by its bitterness. It is, indeed, capable of demonstration, that taste is more vivid after a substance has been taken than just in the act of swallowing, for the function of taste is not a rapid process, and requires a very appreciable interval of time.

The series of murders by Thomas Neill, or, more correctly, Thomas Neill Cream, is an example of the use of strychnine for the purposes of murder. Thomas Neill Cream was convicted, October 21, 1892, for the murder of Matilda Clover on October 20, 1891; there was also good evidence that the same criminal had murdered Ellen Dunworth, October 13, 1891; Alice Marsh, April 12, 1892; Emma Shrivell, April 12, 1892, and had attempted the life of Louie Harvey. The agent in all these cases was strychnine. There was no evidence as to what form of the poison was administered in the case of Clover, but Ellen Dunworth, who was found dying in the streets at 7.45 P.M., and died less than two hours afterwards, stated that a gentleman gave her “two drops” of white stuff to drink.

In the cases of Marsh and Shrivell, Neill Cream had tea with them on the night of April 11, and gave them both “three long pills;” half an hour after Neill Cream left them they were found to be dying, and died within six hours. From Marsh 7 grains, from Shrivell nearly 2 grains of strychnine were separated; the probability is that each pill contained at least 3 grains of strychnine. The criminal met Louie Harvey on the Embankment, and gave her “some pills” to take; she pretended to do so, but threw them away. Hence it seems probable that Neill Cream took advantage of the weakness that a large number of the population have for taking pills, and mostly poisoned his victims in this manner. Clover’s case was not diagnosed during life, but strychnine was found six or seven months after burial in the body. It may be mentioned incidentally that the accused himself furnished the clue which led to his arrest, by writing letters charging certain members of the medical profession with poisoning these poor young prostitutes with strychnine.§ 390. Fatal Dose.—In a research, which may, from its painstaking accuracy, be called classical, F. A. Falck has thrown much light upon the minimum lethal dose of strychnine for various animals. It would seem that, in relation to its size, the frog is by no means so sensible to strychnine as was believed, and that animals such as cats and rabbits take a smaller dose in proportion to their body-weight. The method used by Falck was to inject subcutaneously a solution of known strength of strychnine nitrate, and, beginning at first with a known lethal dose, a second experiment was then made with a smaller dose, and if that proved fatal, with a still smaller, and so on, until such a quantity was arrived at, that the chances as determined by direct observation were as great of recovery as of death. Operating in this way, and making no less than 20 experiments on the rabbit, he found that the least fatal dose for that animal was ·6 mgrm. of strychnine nitrate per kilogramme. Cats were a little less susceptible, taking ·75 mgrm. Operating on fowls, he found that strychnine taken into the crop in the usual way was very uncertain; 50 mgrms. per kilo, taken with the food had no effect, but results always followed if the poison was introduced into the circulation by the subcutaneous needle—the lethal dose for fowls being, under those circumstances, 1 to 2 mgrms. per kilo. He made 35 experiments on frogs, and found that to kill a frog by strychnine nitrate, at least 2 mgrms. per kilo, must be injected. Mice take a little more, from 2·3 to 2·4 mgrms. per kilo. In 2 experiments on the ring adder, in one 62·5 mgrms. per kilo. of strychnine nitrate, injected subcutaneously, caused death in seven hours; in the second, 23·1 mgrms. per kilo. caused death in five days; hence the last quantity is probably about the least fatal dose for this particular snake.

These observations may be conveniently thrown into the following table (see next page), placing the animals in order according to their relative sensitiveness.[426]

[426] According to Christison’s researches, 0·2 grm. (about ¹/₃ grain) is fatal to swine; ·03 grm. (¹/₂ grain) to bears, if injected into the pleura. 1 to 3 grains (·0648 to ·1944 grm.) is given to horses in cases of paralysis, although 3 grains cannot but be considered a dangerous dose, unless smaller doses have been previously administered without effect; 10 grains would probably kill a horse, and 15 grains (·972 grm.) have certainly done so.

Now, the important question arises, as to the place in this series occupied by man—a question difficult to solve, because so few cases are recorded in which strychnine has been administered by subcutaneous injection with fatal result. Eulenberg has observed poisonous symptoms, but not death, produced by 6 mgrms. (¹/₁₁ grain) and by 10 mgrms. (about ¹/₆ grain). Bois observed poisonous symptoms from the similar subcutaneous administrations of 8 mgrms. to a child six years old, and 4 mgrms. to another child four years old—the latter dose, in a case recorded by Christison, actually killing a child of three years of age. On the other hand, the smallest lethal dose taken by an adult was swallowed in solution. Dr. Warner took 32 mgrms. (¹/₂ grain) of strychnine sulphate, mistaking it for morphine sulphate, and died in twenty minutes. In other cases 48 mgrms. (⁷/₁₀ grain) have been fatal. It will be safe to conclude that these doses by the stomach would have acted still more surely and energetically if injected subcutaneously. The case of Warner is exceptional, for he was in weak health; and, if calculated out according to body-weight, presuming that Dr. Warner weighed 68 kilos., the relative dose as strychnine nitrate would be ·24 per kilo.—a smaller dose than for any animal hitherto experimented upon. There is, however, far more reason for believing that the degree of sensitiveness in man is about the same as that of cats or dogs, and that the least fatal dose for man is ·70 per kilo., the facts on record fairly bearing out this view. It is, therefore, probable that death would follow if 38 mgrms. (⁷/₁₀ grain) were injected subcutaneously into a man of the average weight of 68 kilos. (150 lbs.). Taylor estimates the fatal dose of strychnine for adults as from 32·4 to 129·6 mgrms. (·5 to 2 grains); Guy puts the minimum at 16·2 mgrms. (·25 grain).

TABLE SHOWING THE ACTION OF STRYCHNINE ON ANIMALS.

Large doses of strychnine may be recovered from if correct medical treatment is sufficiently prompt. Witness the remarkable instances on record of duplex poisonings, in which the would-be-suicide has unwittingly defeated his object by taking strychnine simultaneously with some narcotic, such as opium or chloral. In a case related by Schauenstein,[427] a suicidal pharmacist took ·48 grm. or ·6 grm. (7·4 to 9·25 grains) of strychnine nitrate dissolved in about 30 c.c. of bitter-almond water, and then, after half an hour, since no symptoms were experienced, ·6 grm. (9·25 grains) of morphine acetate, which he likewise dissolved in bitter-almond water and swallowed. After about ten minutes, he still could walk with uncertain steps, and poured some chloroform on the pillow-case of his bed, and lay on his face in order to breathe it. In a short time he lost consciousness, but again awoke, and lay in a half-dreamy state, incapable of motion, until some one entered the room, and hearing him murmur, came to his bedside. At that moment—two and a quarter hours after first taking the strychnine—the pharmacist had a fearful convulsion, the breathing was suspended, and he lost consciousness. Again coming to himself, he had several convulsions, and a physician who was summoned found him in general tetanus. There were first clonic, then tonic convulsions, and finally opisthotonus was fully developed. The treatment consisted of emetics, and afterwards tannin and codeine were given separately. The patient slept at short intervals; in ten hours after the taking of the poison the seizures were fewer in number and weaker in character, and by the third day recovery was complete. Dr. Macredy[428] has also placed on record an interesting case, in which the symptoms, from a not very large dose of strychnine, were delayed by laudanum for eight hours. A young woman, twenty-three years of age, pregnant, took at 10 A.M. a quantity of strychnine estimated at 1·5 grain, in the form of Battle’s vermin-killer, and immediately afterwards 2 ounces of laudanum. She was seen by Dr. Macredy in four hours, and was then suffering from pronounced narcotic symptoms. A sulphate of zinc emetic was administered. In eight hours after taking the strychnine, there were first observed some clonic convulsive movements of the hands, and, in a less degree, the legs. These convulsions continued, at times severe, for several hours, and were treated with chloral. Recovery was speedy and complete.

In a similar case related by Dr. Harrison,[429] a man, aged 54, took a packet of Battle’s vermin-killer, mixed with about a drachm and a half of laudanum and some rum. At the time he had eaten no food for days, and had been drinking freely; yet fifty minutes elapsed before the usual symptoms set in, and no medical treatment was obtained until four hours after taking the dose. He was then given chloral and other remedies, and made a rapid recovery.

§ 391. Action on Animals.—The action of strychnine has been experimentally studied on all classes of animals, from the infusoria upwards. The effects produced on animal forms which possess a nervous system are strikingly alike, and even in the cephalopoda, tetanic muscular spasm may be readily observed. Of all animals the frog shows the action of strychnine in its purest form, especially if a dose be given of just sufficient magnitude to produce toxic effects. The frog sits perfectly still and quiet, unless acted upon by some external stimuli, such as a breath of air, a loud noise, or the shaking of the vessel which contains it, then an immediate tetanic convulsion of all the muscles is witnessed, lasting a few seconds only, when the animal again resumes its former posture. This heightened state of reflex action has its analogue in hydrophobia as well as in idiopathic tetanus. If the frog thus poisoned by a weak dose is put under a glass shade, kept moist, and sheltered from sound, or from other sources of irritation, no convulsions occur, and after some days it is in its usual health. If, on the other hand, by frequent stimuli, convulsions are excited, the animal dies. M. Richet[430] has contributed a valuable memoir to the Academy of Sciences on the toxic action of strychnine. He has confirmed the statement of previous observers that, with artificial respiration, much larger doses of strychnine may be taken without fatal result than under normal conditions, and has also recorded some peculiar phenomena. Operating on dogs and rabbits, after first securing a canula in the trachea, and then injecting beneath the skin or into the saphena vein 10 mgrms. of strychnine hydrochlorate, the animal is immediately, or within a few seconds, seized with tetanic convulsions, and this attack would be mortal, were it not for artificial respiration. Directly this is practised the attack ceases, and the heart, after a period of hurried and spasmodic beats, takes again its regular rhythm. Stronger and stronger doses may then be injected without causing death. As the dose is thus augmented, the symptoms differ. M. Richet distinguishes the following periods:—(1.) A period of tetanus. (2.) A period of convulsion, characterised by spasmodic and incessant contraction of all the muscles. (3.) A little later, when the quantity exceeds 10 mgrms. per kilo., a choreic period, which is characterised by violent rhythmic shocks, very sudden and short, repeated at intervals of about three to four seconds; during these intervals there is almost complete relaxation. (4.) A period of relaxation; this period is attained when the dose exceeds 40 mgrms. per kilo. Reflex action is annihilated, the spontaneous respiratory movements cease, the heart beats tumultuously and regularly in the severe tetanic convulsions at first, and then contracts with frequency but with regularity. The pupils, widely dilated at first, become much contracted. The arterial pressure, enormously raised at the commencement, diminishes gradually, in one case from 0·34 mm. to 0·05 mm. The temperature undergoes analogous changes, and during the convulsions is extraordinarily elevated; it may even attain 41° or 42°, to sink in the period of relaxation to 36°. Dogs and rabbits which have thus received enormous quantities of strychnine (e.g., 50 mgrms. per kilo.), may, in this way, live for several hours, but the slightest interruption to the artificial respiration, in the relaxed state, is followed by syncope and death.

§ 392. Effects on Man: Symptoms.—The commencement of symptoms may be extremely rapid, the rapidity being mainly dependent on the form of the poison and the manner of application. A soluble salt of strychnine injected subcutaneously will act within a few seconds;[431] in a case of amaurosis, related by Schuler,[432] 5·4 mgrms. of a soluble strychnine salt were introduced into the punctum lachrymale;—in less than four minutes there were violent tetanic convulsions. In a case related by Barker, the symptoms commenced in three minutes from a dose of ·37 grm. (5·71 grains).[433] Here the poison was not administered subcutaneously. Such short periods, to a witness whose mind was occupied during the time, might seem immediate. On the other hand, when nux vomica powder has been taken, and when strychnine has been given in the form of pill, no such rapid course has been observed, or is likely to occur, the usual course being for the symptoms to commence within half an hour. It is, however, also possible for them to be delayed from one to two hours, and under certain circumstances (as in the case related by Macredy) for eight hours. In a few cases, there is first a feeling of uneasiness and heightened sensibility to external stimuli, a strange feeling in the muscles of the jaw, and a catching of the respiration; but generally the onset of the symptoms is as sudden as epilepsy, and previous to their appearance the person may be pursuing his ordinary vocation, when, without preliminary warning, there is a shuddering of the whole frame, and a convulsive seizure. The convulsions take the form of violent general tetanus; the limbs are stretched out involuntarily, the hands are clenched, the soles of the feet incurved, and, in the height of the paroxysm, the back may be arched and rigid as a board, the sufferer resting on head and heels, and the abdomen tense. In the grasp of the thoracic muscles the walls of the chest are set immovable, and from the impending suffocation the face becomes congested, the eyes prominent and staring. The muscles of the lower jaw—in “disease tetanus” the first to be affected—are in “strychnos tetanus,” as a rule, the last; a distinction, if it were more constant, of great clinical value. The convulsions and remissions recur until death or recovery, and, as a rule, within two hours from the commencement of the symptoms the case in some way or other terminates. The number of the tetanic seizures noted has varied—in a few cases the third spasm has passed into death, in others there have been a great number. The duration of the spasm is also very different, and varies from thirty seconds to five or even eight minutes, the interval between lasting from forty-five seconds[434] to one or even one and a half hours.[435]

§ 393. Diagnosis of Strychnine Poisoning.—However striking and well defined the picture of strychnine tetanus may be, mistakes in diagnosis are rather frequent, especially when a medical man is hastily summoned, has never seen a case of similar poisoning, and has no suspicion of the possible nature of the seizure. If a young woman, for instance, is the subject, he may put it down to hysteria, and certainly hysteria not unfrequently affects somewhat similar convulsions. In a painful case in which the author was engaged, a young woman either took or was given (for the mystery was never cleared up fully) a fatal dose of strychnine, and though the symptoms were well marked, the medical attendant was so possessed with the view that the case was due to hysteria, that, even after making the post-mortem examination, and finding no adequate lesion, he theorised as to the possibility of some fatal hysteric spasm of the glottis, while there was ample chemical evidence of strychnine, and a weighable quantity of the alkaloid was actually separated from the contents of the stomach. The medical attendant of Matilda Clover, one of Neill’s victims, certified that the girl died from delirium tremens and syncope, although the symptoms were typically those produced by strychnine. Such cases are particularly sad, for we now know that, with judicious treatment, a rather large dose may be recovered from.

If the case is a male, a confusion with epilepsy is possible, though hardly to be explained or excused; while in both sexes idiopathic tetanus is so extremely similar as to give rise to the idea that all cases of idiopathic tetanus are produced by poison, perhaps secreted by the body itself. As for the distinction between idiopathic and strychnic tetanus, it is usually laid down (1) that the intervals in the former are characterised by no relaxation of the muscles, but that they continue contracted and hard; and (2) that there is a notable rise of temperature in disease tetanus proper, and not in strychnine tetanus. Both statements are misleading, and the latter is not true, for in strychnic poisoning the relaxation is not constant, and very high temperatures in animals have been observed.§ 394. Physiological Action.—The tetanic convulsions are essentially reflex, and to be ascribed to a central origin; the normal reflex sensibility is exaggerated and unnaturally extended. If the ischiatic plexus supplying the one leg of an animal is cut through, that leg takes no part in the general convulsions, but if the artery of the leg alone is tied, then the leg suffers from the muscular spasm, as well as the limbs in which the circulation is unrestrained. In an experiment by Sir B. W. Richardson, a healthy dog was killed, and, as soon as practicable, a solution of strychnine was injected through the systemic vessels by the aorta—the whole body became at once stiff and rigid as a board. These facts point unmistakably to the spinal marrow as the seat of the toxic influence. Strychnine is, par excellence, a spinal poison. On physiological grounds the grey substance of the cord is considered to have an inhibitory action upon reflex sensibility, and this inhibitory power is paralysed by strychnine. The spinal cord, it would appear, has the power of collecting strychnine from the circulation and storing it up in its structure.[436]

Much light has been thrown upon the cause of death by Richet’s experiments.[437] It would seem that, in some cases, death takes place by a suffocation as complete as in drowning, the chest and diaphragm being immovable, and the nervous respiratory centres exhausted. In such a case, immediate death would be averted by a tracheal tube, by the aid of which artificial respiration might be carried on; but there is another asphyxia due to the enormous interstitial combustion carried on by muscles violently tetanised. “If,” says Richet, “after having injected into a dog a mortal dose of strychnine, and employed artificial respiration according to the classic method twenty or thirty times a minute, the animal dies (sometimes at the end of ten minutes, and in every case at the end of an hour or two), and during life the arterial blood is examined, it will be ascertained that it is black, absolutely like venous blood.”

This view is also supported by the considerable rise of temperature noticed: the blood is excessively poor in oxygen, and loaded with carbon dioxide. That this state of the blood is produced by tetanus, is proved by the fact that an animal poisoned by strychnine, and then injected subcutaneously with curare in quantity just sufficient to paralyse the muscular system, does not exhibit these phenomena. By the aid of artificial respiration, together with the administration of curare, an animal may live after a prodigious dose of strychnine.

Meyer[438] has investigated carefully the action of strychnine on the blood-pressure—through a strong excitement of the vaso-motor centre, the arteries are narrowed in calibre, and the blood-pressure much increased; the action of the heart in frogs is slowed, but in the warm-blooded animals quickened.

§ 395. Post-mortem Appearances.—There is but little characteristic in the post-mortem appearances from strychnine poisoning. The body becomes very stiff a short time after death, and this rigidity remains generally a long time. In the notorious Palmer case, the body was rigid two months after death, but, on the other hand, the rigor mortis has been known to disappear within twenty-four hours. If the convulsions have been violent, there may be minute hÆmorrhages in the brain and other parts. I have seen considerable hÆmorrhage in the trachea from this cause. When death occurs from asphyxia, the ordinary signs of asphyxia will be found in the lungs, &c. The heart mostly has its right side gorged with blood, but in a few cases it is empty and contracted.

In a case which Schauenstein has recorded[439] he found strychnine still undissolved, coating the stomach as a white powder; but this is very unusual, and I believe unique. The bladder often contains urine, which, it need scarcely be said, should be preserved for chemical investigation.

§ 396. Treatment.—From the cases detailed, and from the experiments on animals, the direction which treatment should take is very clear. As a matter of course, if there is the slightest probability of any of the poison remaining in the stomach, it should be removed. It is doubtful whether the stomach pump can be ever applied with benefit in strychnine poisoning, the introduction of the tube is likely to aggravate the tetanus, but apomorphine can be injected subcutaneously. Large and frequent doses of chloral should be administered in order to lessen the frequency of convulsions, or prevent their occurrence, and it may be necessary in a few cases, where death threatens by suffocation, to perform tracheotomy, and to use artificial respiration. Where chloral or chloroform is not at hand, and in cases of emergency, where this may easily happen, the medical man must administer in full doses the nearest narcotic at hand.[440]

§ 397. Separation of Strychnine from Organic Matters.—The separation of strychnine from organic matters, &c., is undertaken strictly on the general principles already detailed. It may happen, however, that in cases of poisoning there is the strongest evidence from symptoms in the person or animal that strychnine alone is to be sought for. In an instance of the kind, if a complex organic liquid (such as the contents of the stomach) is under examination, it is best to remove the solid substances by filtration through glass, wool, or linen, and evaporate nearly to dryness over the water-bath, acidifying with acetic acid, and then exhausting the residue repeatedly with boiling alcohol of 80 per cent. The alcoholic extract is in its turn evaporated to dryness, and taken up with water; the aqueous solution is passed through a wet filter, and then shaken up with the usual succession of fluids, viz., petroleum ether, benzene, chloroform, and amyl alcohol, which will remove a great number of impurities, but will not dissolve the strychnine from the acid solution. The amyl alcohol may lastly be removed by petroleum ether; and on removal of the final extractive (which should be done as thoroughly as possible) chloroform is added, and the fluid is alkalised by ammonia, which precipitates the alkaloid in the presence of the solvent. Should the reverse process be employed—that is, ammonia added first, and then chloroform—the strychnine is not so perfectly dissolved, since it has time to assume a crystalline condition. On separation and evaporation of the chloroform, the residue (if much discoloured, or evidently impure) may be dissolved in alcohol or benzene, and recrystallised several times. Cushman has published an improved method of separating strychnine, which, according to test experiments, appears to give good results. He describes the method as follows:[441]—

Should search be made for minute portions of strychnine in the tissues, considering the small amount of the poison which may produce death, it is absolutely necessary to operate on a very large quantity of material. It would be advisable to take the whole of the liver, the brain, spinal cord, spleen, stomach, duodenum, kidneys, all the blood that can be obtained, and a considerable quantity of muscular tissue, so as to make in all about one-eighth to one-tenth of the whole body; this may be cut up into small pieces, and boiled in capacious flasks with alcohol, acidified with acetic acid. Evaporation must be controlled by adapting to the cork an upright condenser.

Should the analyst not have apparatus of a size to undertake this at one operation, it may be done in separate portions—the filtrate from any single operation being collected in a flask, and the spirit distilled off in order to be used for the next. In this way, a large quantity of the organs and tissues can be exhausted by half a gallon of alcohol. Finally, most of the alcohol is distilled off, and the remainder evaporated at a gentle heat in a capacious dish, the final extract being treated, evaporating to a syrup, and using Cushman’s process (ante, p. 334) as just described. It is only by working on this large scale that there is any probability of detecting absorbed strychnine in those cases where only one or two grains have destroyed life, and even then it is possible to miss the poison.

Strychnine is separated by the kidneys rapidly. In a suicidal case recorded by Schauenstein,[442] death took place in an hour and a half after taking strychnine, yet from 200 c.c. of the urine, Schauenstein was able to separate nitrate of strychnine in well-formed crystals. Dr. Kratter[443] has made some special researches on the times within which strychnine is excreted by the kidneys. In two patients, who were being treated by subcutaneous injection, half an hour after the injection of 7·5 mgrms. of strychnine nitrate the alkaloid was recognised in the urine. The strychnine treatment was continued for eight to ten days, and then stopped; two days after the cessation, strychnine was found in the urine, but none on the third day, and the inference drawn is that the elimination was complete within forty-eight hours.

Strychnine has been detected in the blood of dogs and cats in researches specially undertaken for that purpose, but sometimes a negative result has been obtained, without apparent cause. Dragendorff[444] gave dogs the largest possible dose of strychnine daily. On the first few days no strychnine was found in the urine, but later it was detected, especially if food was withheld. M’Adam was the first who detected the absorbed poison, recognising it in the muscles and urine of a poisoned horse, and also in the urine of a hound. Dragendorff has found it in traces in the kidneys, spleen, and pancreas; Gay, in different parts of the central nervous system, and in the saliva. So far as the evidence goes, the liver is the best organ to examine for strychnine; but all parts supplied with blood, and most secretions, may contain small quantities of the alkaloid. At one time it was believed that strychnine might be destroyed by putrefaction, but the question of the decomposition of the poison in putrid bodies may be said to be settled. So far as all evidence goes, strychnine is an extremely stable substance, and no amount of putrescence will destroy it. M’Adam found it in a horse a month after death, and in a duck eight weeks after; Nunneley in 15 animals forty-three days after death, when the bodies were much decomposed; Roger in a body after five weeks’ interment; Richter in putrid tissues exposed for eleven years to decomposition in open vessels; and, lastly, W. A. Noyes[445] in an exhumed body after it had been buried 308 days.

It would appear from Ibsen’s[446] experiments that strychnine gets dissolved in the fluids of the dead body—so that whether strychnine remains or not, greatly depends as to whether the fluids are retained or are allowed to soak away; it is, therefore, most important in exhumations to save as much of the fluid as possible.

§ 398. Identification of the Alkaloid.—A residue containing strychnine, or strychnine mixed with brucine, is identified—

(1.) By its alkaline reaction and its bitter taste. No substance can possibly be strychnine unless it tastes remarkably bitter.

(2.) By the extremely insoluble chromate of strychnine, already described.[447] A fluid containing 1: 1000 of strychnine gives with chromate of potash (if allowed to stand over-night) a marked precipitate, dissimilar to all others, except those of lead and baryta chromates, neither of which can possibly occur if any of the processes described are followed.

(3.) If the chromate just described is treated on a porcelain plate with a drop of pure strong sulphuric acid, a deep rich blue colour, passing through purple into red, rapidly makes its appearance. This colour possesses an absorption spectrum (figured at p. 55). Dr. Guy, neglecting intermediate colours, aptly compares the succession—(1) to the rich blue of the Orleans plum; (2) to the darker purple of the mulberry; and (3) to the bright clear red of the sweet orange. These characters—viz., alkalinity, bitterness, and the property of precipitation by potassic chromate in a definite crystalline form, the crystals giving the colours detailed—belong to no other substance known save strychnine, and for all purposes sufficiently identify the alkaloid. The same colour is obtained by mixing a drop of sulphuric acid with strychnine and a crystal, or speck, of any one of the following substances:—Ferridcyanide of potash, permanganate of potash, peroxide of lead, peroxide of manganese, and cerous hydroxide.

Potassic permanganate and sulphuric acid is the most delicate, and will detect 0·001 mgrm. of strychnine; cerous hydroxide is, on the other hand, most convenient, for cerous hydroxide is white; all the others have colours of their own. Cerous hydroxide is prepared strychnine; 3 gave 3·811 of the chromate, = 78·77 per cent. of strychnine.—Mohr. by dissolving cerium oxalate in dilute sulphuric acid and precipitating with ammonia, filtering and well washing the precipitate; and the latter may be used while moist, and responds well to ¹/₁₀₀ mgrm. of strychnine.

The influence of mixtures on the colour reactions of strychnine have been studied by FlÜckiger, who states:—

“No strychnine reaction appears with sulphuric acid containing chromic acid (made by dissolving 0·02 grm. of pot. bichromate in 10 c.c. of water, and then adding 30 grms. strong sulphuric acid) when brucine and strychnine mixed in equal parts are submitted to the test; it succeeds, however, in this proportion with sulphuric acid containing potassium permanganate (·02 grm. pot. permanganate in 10 c.c. of water, and 30 grms. of strong sulphuric acid).

“If the brucine is only one-tenth of the mixture, the blue-violet colour is obtained. A large excess of atropine does not prevent or obscure the strychnine reaction. A solution of 1 milligrm. atropine sulphate evaporated to dryness, together with 5 c.c. of a solution of strychnine (1: 100,000) has no influence on the reaction, neither in the proportion of 1 mgrm. to 1 c.c. of the same solution; neither has cinchonine nor quinine any effect.

“Morphine obscures the reaction in the following proportions:—

“A solution of 0·01 mgrm. strychnine evaporated with a solution of 1 mgrm. of morphine sulphate on a water-bath, yields a blurred strychnine reaction when the residue is dissolved in sulphuric acid, and a crystal of potassic permanganate added. But still there is evidence whereby to suspect the presence of strychnine.

“A solution of 2 mgrms. of morphine sulphate treated in like manner with 0·01 mgrm. of strychnine yields like results.

“A solution of 3 mgrms. of morphine sulphate evaporated to dryness, with a solution of 0·01 mgrm. strychnine yielded results with the potassic permanganate test the same as if no strychnine was present.

“A solution of 1 mgrm. of morphine sulphate, treated as above, with a solution of 0·1 mgrm. strychnine, offered positive proof of the presence of the latter.”[448]

[448] FlÜckiger’s Reactions, translated by Nagelvoort, Detroit, 1893.

Dragendorff was able to render evident ·025 mgrm. mixed with twenty times its weight of quin. sulphate; the same observer likewise recognised ·04 mgrm. of strychnine in thirty-three times its weight of caffeine. Veratrine is likewise not injurious.

The physiological test consists in administering the substance to some small animal (preferably to a frog), and inducing the ordinary tetanic symptoms. It may be at once observed that if definite chemical evidence of strychnine has been obtained, the physiological test is quite unnecessary; and, on the other hand, should the application of a liquid or substance to a frog induce tetanus, while chemical evidence of the presence of strychnine was wanting, it would be hazardous to assert that strychnine was present, seeing that caffeine, carbolic acid, picrotoxin, certain of the opium alkaloids, hypaphorine, some of the ptomaines, and many other substances induce similar symptoms. The best method (if the test is used at all) is to take two frogs,[449] and insert under the skin of the one the needle of a subcutaneous syringe, previously charged with a solution of the substance, injecting a moderate quantity. The other frog is treated similarly with a very dilute solution of strychnine, and the two are then placed under small glass shades, and the symptoms observed and compared. It is not absolutely necessary to inject the solution under the skin, for if applied to the surface the same effects are produced; but, if accustomed to manipulation, the operator will find the subcutaneous application more certain, especially in dealing with minute quantities of the alkaloid.[450]

§ 401. Brucine (C₂₃H₂₆N₂O₄ + 4H₂O)[453] occurs associated with strychnine in the plants already mentioned; its best source is the so-called false angustura bark, which contains but little strychnine. Its action is similar to that of strychnine. If crystallised out of dilute alcohol it contains 4 atoms of water, easily expelled either in a vacuum over sulphuric acid or by heat. Crystallised thus, it forms transparent four-sided prisms, or arborescent forms, like boric acid. If thrown down by ammonia from a solution of the acetate, it presents itself in needles or in tufts.

The recently-crystallised alkaloid has a solubility different from that which has effloresced, the former dissolving in 320 parts of cold, and 150 parts of boiling water; whilst the latter (according to Pelletier and Caventou) requires 500 of boiling, and 850 parts of cold water for solution. Brucine is easily soluble in absolute, as well as in ordinary alcohol; 1 part dissolves in 1·7 of chloroform, in 60·2 of benzene. Petroleum ether, the volatile and fatty oils and glycerine, dissolve the alkaloid slightly, amyl alcohol freely; it is insoluble in anhydrous ether. The behaviour of brucine in the subliming cell is described at p. 260. Anhydrous brucine melts in a tube at 178°. The alcoholic solution of brucine turns the plane of polarisation to the left [a]r = -11·27°. The taste is bitter and acrid. Soubeiran maintains that it can be recognised if 1 part is dissolved in 500,000 parts of water. If nitric trioxide be passed into an alcoholic solution of brucine, first brucine nitrate is formed; but this passes again into solution, from which, after a time, a heavy, granular, blood-red precipitate separates: it consists of dinitro-brucine (C₂₃H₂₄(NO₂)₂N₂O₄). Brucine fully neutralises acids, and forms salts, which are for the most part crystalline. The neutral sulphate (C₂₃H₂₅N₂O₄SH₂O₄ + 3¹/₂H₂O) is in long needles, easily soluble in water. The acetate is not crystalline, that of strychnine is so (p. 321).

Brucine is precipitated by ammonia, by the caustic and carbonated alkalies, and by most of the group reagents. Ammonia does not precipitate brucine, if in excess; on the other hand, strychnine comes down if excess of ammonia is added immediately. This has been proposed as a method of separation; if the two alkaloids are present in acid solution, ammonia in excess is added, and the solution is immediately filtered; the quantitative results are, however, not good, the strychnine precipitate being invariably contaminated by brucine.

Chromate and dichromate of potassium give no precipitate with neutral salts of brucine; on the other hand, strychnine chromate is at once formed if present. It might, therefore, be used to separate strychnine from brucine. The author has attempted this method, but the results were not satisfactory.§ 402. Physiological Action.—The difference between the action of strychnine and that of brucine on man or animals is not great. Mays states that strychnine affects more the anterior, brucine the posterior extremities. In strychnine poisoning, convulsions occur early, and invariably take place before death; but death may occur from brucine without any convulsions, and in any case they develop late. Brucine diminishes local sensibility when applied to the skin; strychnine does not.[454] In a physiological sense, brucine may be considered a diluted strychnine. The lethality of brucine, especially as compared with strychnine, has been investigated by F. A. Falck.[455] He experimented on 11 rabbits, injecting subcutaneously brucine nitrate, in doses of varying magnitude, from 100 mgrms. down to 20 mgrms. per kilogram of body-weight. He found that brucine presented three stages of symptoms. In the first, the respiration is quickened; in 3 of the 11 cases a strange injection of the ear was noticed; during this period the pupils may be dilated. In the second stage, there are tetanic convulsions, trismus, opisthotonus, oppressed respiration, and dilated pupils. In the third stage, the animal is moribund. Falck puts the minimum lethal dose for rabbits at 23 mgrms. per kilo. Strychnine kills 3·06 times more quickly than brucine, the intensity of the action of strychnine relative to that of brucine being as 1: 117·4. Falck has also compared the minimum lethal dose of strychnine and brucine with the tetanising opium alkaloids, as shown in the following table:—

TABLE SHOWING THE LETHAL DOSES OF VARIOUS TETANISING POISONS.

If these views are correct, it follows that the least fatal dose for an adult man would be 1·64 grm. (about 24·6 grains) of brucine nitrate.

§ 403. Tests.—If to a solution of brucine in strong alcohol a little methyl iodide is added, at the end of a few minutes circular rosettes of crystal groups appear (see fig.): they are composed of methyl brucine iodide (C₂₃H₂₅(CH₃)N₂O₄HI). Crystals identical in shape are also obtained if an alcoholic solution of iodine, or hydriodic acid with iodine, is added to an alcoholic solution of brucine. A solution of strychnine gives with methyl iodide no similar reaction. Strychnine in alcoholic solution, mixed with, brucine in no way interferes with the test. The methyl iodide test may be confirmed by the action of nitric acid. With that reagent it produces a scarlet colour, passing into blood-red, into yellow-red, and finally ending in yellow. This can be made something more than a mere colour test, for it is possible to obtain a crystalline body from the action of nitric acid on brucine. If a little of the latter be put in a test-tube, and treated with nitric acid of 1·4 specific gravity (immersing the test-tube in cold water to moderate the action), the red colour is produced. On spectroscopic examination of the blood-red liquid a broad, well-marked absorption band is seen, the centre of which (see page 55) is between E. & F. [W. L. about 500]. There is also a development of nitric oxide and carbon dioxide, and the formation of methyl nitrite, oxalic acid, and kakotelin (C₂₃H₂₆N₂O₄ + 5NHO₃ = C₂₀H₂₂N₄O₉ + N(CH₃)O₂ + C₂H₂O₄ + 2NO + 2H₂O). On diluting abundantly with water, the kakotelin separates in yellow flocks, and may be crystallised out of dilute hydrochloric or dilute nitric acid in the form of yellow or orange-red crystals, very insoluble in water, but dissolving readily in dilute acid. On removal by dilution of the product just named, neutralisation with ammonia, and addition of a solution of chloride of calcium, the oxalate of lime is thrown down. The nitric acid test is, therefore, a combined test, consisting of—the production by the action of nitric acid (1) of a red colour; (2) of yellow scales or crystals insoluble in water; (3) of oxalic acid. No alkaloid save brucine is known to give this reaction.

There are other methods of producing the colour test. If a few drops of nitric acid are mixed with the substance in a test-tube, and then sulphuric acid cautiously added, so as to form a layer at the bottom, at the junction of the liquids a red zone, passing into yellow, is seen.

A solution of brucine is also coloured red by chlorine gas, ammonia changing the colour into yellow.

FlÜckiger[456] has proposed as a test mercurous nitrate, in aqueous solution with a little free nitric acid. On adding this reagent to a solution of brucine salt, and gently warming, a fine carmine colour is developed.

In regard to the separation of brucine from organic fluids or tissues, the process already detailed for strychnine suffices. It is of very great importance to ascertain whether both strychnine and brucine are present or not—the presence of both pointing to nux vomica or one of its preparations. The presence of brucine may, of course, be owing to impure strychnine; but if found in the tissues, that solution of the question is improbable, the commercial strychnine of the present day being usually pure, or at the most containing so small a quantity of brucine as would hardly be separated from the tissues.

2. THE QUEBRACHO GROUP OF ALKALOIDS.

3. PEREIRINE.

4. GELSEMINE.

5. COCAINE.

§ 414. Cocaine Hydrochlorate (C₁₇H₂₁NO₄HCl).—Crystallised from alcohol, cocaine hydrochlorate appears in prismatic crystals; these crystals, according to Hesse,[463] when perfectly pure, should melt at 186°, although the melting-point is generally given as 200° or even 202°. Cocaine hydrochlorate is soluble in half its weight of water, insoluble in dry ether, but readily soluble in alcohol, amyl alcohol, or chloroform.

§ 415. Pharmaceutical Preparations.—Cocaine hydrochlorate is officinal. Gelatine discs, weighing 1·31 mgrms. (¹/₅₀ grain), and each containing 0·33 mgrm. (¹/₂₀₀ grain) of the salt are officinal, and used by ophthalmic surgeons. A solution of the hydrochlorate, containing 10 per cent. of cocaine hydrochlorate and (for the purposes of preserving the solution) 0·15 per cent. of salicylic acid is also officinal. Stronger solutions may also be met with; for instance, a 20 per cent. solution in oil of cloves for external application in cases of neuralgia.§ 416. Separation of Cocaine and Tests.—Cocaine may be shaken out of solutions made slightly alkaline by ammonia by treatment with benzene; it also passes into petroleum ether under the same circumstances. The best method is to extract a solution, made feebly alkaline, thoroughly by ether, and then shake it out by benzene and evaporate the separated benzene at the ordinary air temperature. The property of the alkaloid to melt at or below the temperature of boiling water, and the ready decomposition into benzoic acid and other products, render cocaine easy of identification. If, for instance, a small particle of cocaine is put in a tube, a drop of strong sulphuric acid added and warmed by the water-bath, colourless crystals of benzoic acid sublime along the tube, and an aromatic odour is produced.

FlÜckiger has recommended the production of benzoate of iron as a useful test both for cocaine and for cocaine hydrochlorate.

One drop of a dilute solution of ferric chloride added to a solution of 20 mgrms. of cocaine hydrochlorate in 2 c.c. of water, gives a yellow fluid, which becomes red on boiling from the production of iron benzoate. This reaction is of little use unless a solution of the same strength of ferric chloride, but to which the substance to be tested has not been added, is boiled at the same time for comparison, because all solutions of ferric chloride deepen in colour on heating.

A solution of the alkaloid evaporated to dryness on the water-bath, after being acidulated with nitric acid, and then a few drops of alcoholic solution of potash or soda added, develops an odour of benzoic ethyl-ester. Cocaine hydrochlorate, when triturated with calomel, blackens by the slightest humidity or by moistening it with alcohol. Cocaine in solution is precipitated by most of the group reagents, but is not affected by mercuric chloride, picric acid, nor potassic bichromate.

Added to the tests above mentioned, there is the physiological action; cocaine dilates the pupil, tastes bitter, and, for the time, arrests sensation; hence the after-effect on the tongue is a sensation of numbness.§ 417. Symptoms.—A large number of accidents occur each year from the external application of cocaine; few, however, end fatally. Cocaine has thus produced poisonous symptoms when applied to the eye, to the rectum, to the gums, to the urethra, and to various other parts. There have been a few fatal cases, both from its external and internal administration; Mannheim, for example, has collected eleven of such instances.

The action of cocaine is twofold; there is an action on the central and the peripheral nervous system. In small doses cocaine excites the spinal cord and the brain; in large it may produce convulsions and then paralysis. The peripheral action is seen in the numbing of sensation. There is always interference with the accommodation of vision, and dilatation of the pupil. The eyelids are wider apart than normal, and there may be some protrusion of the eyeball.

The usual course of an acute case of poisoning is a feeling of dryness in the nose and throat, difficulty of swallowing, faintness, and there is often vomiting; the pulse is quickened; there is first cerebral excitement, followed usually by great mental depression. Occasionally there is an eruption on the skin. HyperÆsthesia of the skin is followed by great diminution of sensation, the pupils, as before stated, are dilated, the eyes protruding, the eyelids wide open, the face is pale, and the perspiration profuse. Convulsions and paralysis may terminate the scene. Death takes place from paralysis of the breathing centre; therefore the heart beats after the cessation of respiration. As an antidote, nitrite of amyl has apparently been used with success.

There is a form of chronic poisoning produced from the taking of small doses of cocaine daily. The symptoms are very various, and are referable to disturbance of the digestive organs, and to the effect on the nervous system. The patients become extremely emaciated, and it seems to produce a special form of mania.§ 418. Post-mortem Appearances.—The appearances found in acute cases of poisoning have been hyperÆmia of the liver, spleen, and kidneys, as well as of the brain and spinal cord.

In the experimental poisoning of mice with cocaine Ehrlich[464] found a considerable enlargement of the liver.

[464] Deutsche med. Wochens., 1890, No. 32.

§ 419. Fatal Dose.—The fatal dose, according to Mannheim,[465] must be considered as about 1 grm. (15·4 grains); the smallest dose known to have been fatal is 0·08 grm. (1·2 grain) for an adult, and 0·05 grm. (0·7 grain) for a child.

6. CORYDALINE.

V.—The Aconite Group of Alkaloids.

§ 421. The officinal aconite is the Aconitum napellus—monkshood or wolfsbane—a very common garden plant in this country, and one cultivated for medicinal purposes. Many varieties of aconite exist in other regions, which either are, or could be, imported. Of these the most important is the Aconitum ferox, a native of the Himalayan mountains, imported from India.

All the aconites, so far as known, are extremely poisonous, and it appears probable that different species contain different alkaloids. The root of A. napellus is from 2 to 4 inches long, conical in shape, brown externally, and white internally. The leaves are completely divided at the base into five wedge-shaped lobes, each of the five lobes being again divided into three linear segments. The numerous seeds are three-sided, irregularly twisted, wrinkled, of a dark-brown colour, in length one-sixth of an inch, and weighing 25 to the grain (Guy). The whole plant is one of great beauty, from 2 to 6 feet high, and having a terminal spike of conspicuous blue flowers. The root has been fatally mistaken for horse-radish, an error not easily accounted for, since no similarity exists between them.§ 422. Pharmaceutical Preparations of Aconite.—The preparations of aconite used in medicine are—

Aconitine, officinal in all the pharmacopoeias.

Aconite liniment (linimentum aconiti), made from the root with spirit, and flavoured with camphor; officinal in the British Pharmacopoeia. It may contain about 2·0 per cent. of aconitine.

Aconite tincture, officinal in all the pharmacopoeias.

Aconite ointment, 8 grains of aconitine to the oz. (i.e., 1·66 per cent.); officinal in the British Pharmacopoeia.

Aconite extract, the juice of the leaves evaporated; officinal in most of the pharmacopoeias. The strength in alkaloid of the extract varies; in six samples examined by F. Casson, the least quantity was 0·16 per cent., the maximum 0·28 per cent.[466]

Fleming’s tincture of aconite is not officinal, but is sold largely in commerce. It is from three to four times stronger than the B.P. tincture.§ 423. The Alkaloids of Aconite.—The researches of Dr. Alder Wright and Luff, and especially those of Professor Dunstan,[467] have established that in the root of the true aconite there exist four alkaloids, one only of which has been as yet crystallised.

Three of the alkaloids have been fairly well worked out; the fourth homo-napelline has not yet been satisfactorily investigated.

The three alkaloids are aconitine, aconine and benzoyl-aconine; besides which pyraconitine and pyraconine can be obtained by suitable treatment from aconitine and aconine.

The formulÆ of the alkaloids and their derivatives are as follows:—

§ 424. Aconitine, C₃₃H₄₅NO₁₂.—This base has been shown by Dunstan to be acetyl-benzoyl-aconine; one molecule of the base breaking up, on complete hydrolysis, into one molecule of aconine, one of acetic acid, and one of benzoic acid—

That is to say that 100 parts of aconitine, according to theory, should yield:—

Acetic acid, 9·37 per cent.; benzoic acid, 18·85 per cent.; and aconine, 77·52 per cent.

Pure aconitine has a tube melting-point of 188·6°. The behaviour of a sample of Merck’s aconitine in the subliming cell, which had a melting-point of 184°, was as described at page 259.

Aconitine dissolves in water at 22° in the proportion of 1 in 4431 (Dunstan); it is soluble in 37 of absolute alcohol, 64 of anhydrous ether, 5·5 parts of chloroform and benzene (A. Jurgens); it has basic properties, and a cold watery solution has an alkaline reaction to cochineal, but not to litmus nor to phenol-phthalein. Aconitine is not precipitated by mercuric potassium iodide, but gives a voluminous precipitate with an aqueous solution of iodine in potassium iodide.

It gives a crystalline yellow gold compound with gold chloride, which has a melting-point of 135·5°, and according to its composition, C₃₃H₄₅NO₁₂HAuCl₄, should give 19·9 per cent. of gold.

Aconitine is best extracted from the plant, or from organic matters generally, by a 1 per cent. sulphuric acid; this strength is stated not to hydrolyse aconitine if acting in the cold; after purifying the acid liquid by shaking it with amyl alcohol, and then with chloroform, always operating in the cold, the liquid is precipitated by ammonia in very slight excess, and the liquid shaken with ether; the ether is removed, dehydrated by standing over calcium chloride, and then evaporated spontaneously; should the aconitine be mixed with the other alkaloids, advantage can be taken of the method of separating aconitine by converting it into hydrobromide, as described under “Benzoyl-aconine.”§ 425. Tests for Aconitine.—The most satisfactory and the most delicate is the physiological test; the minutest trace of an aconite-holding liquid, applied to the tongue or lips, causes a peculiar numbing, tingling sensation which, once felt, can readily be remembered.

An alkaloidal substance which, heated in a tube, melts approximately near the melting-point of aconitine, and gives off an acid vapour, would render one suspicious of aconitine, for most alkaloids give off alkaline vapours. Aconitine also may, by heating with dilute acids, be made to readily yield benzoic acid, an acid easy of identification. Aconitine dissolved in nitric acid, evaporated to dryness, and then treated with alcoholic potash, gives off an unmistakable odour of benzoic ester.

Should there be sufficient aconitine recovered to convert it into the gold salt, the properties of the gold salt (that is, its melting-point, and the percentage of gold left after burning) assist materially in the identification.

A minute quantity of aconitine dissolved in water, acidified with acetic acid, and a particle of KI added and the solution allowed to evaporate, gives crystals of aconitine hydriodide, from which water will dissolve out the KI. Iodine water gives a precipitate of a reddish-brown colour in a solution of 1: 2000.[468]

The chemical tests are supplementary to the physiological; if the alkaloidal extract does not give the tingling, numbing sensation, aconitine cannot be present.§ 426. Benzoyl-aconine (“isaconitine”), C₃₁H₄₃NO₁₁, is obtained from aconitine by heating an aqueous solution of the sulphate or hydrochloride in a closed tube at 120°-130° for two or three hours, a molecule of acetic acid (9·27 per cent.) being split off, and benzoyl-aconine left.

It may be separated from the mixed alkaloids of the Aconitum napellus by dissolving in a 5 per cent. solution of hydrobromic acid (excess of acid being avoided), precipitating with a slight excess of ammonia, and shaking out with ether. The residue left after the ether is evaporated chiefly consists of aconitine; it is dissolved in just sufficient hydrobromic acid and the exactly neutral hydrobromate solution allowed to evaporate spontaneously in a desiccator; crystals of aconitine hydrobromide separate out, the mother liquor containing some benzoyl-aconine and “homonapelline.” The aqueous solution which has been exhausted with ether is now shaken out with chloroform. This chloroform solution contains most of the benzoyl-aconine, and on separation the residue is dissolved in just sufficient hydrochloric acid to form a neutral solution; this solution is concentrated on the water-bath with constant stirring, crystals of the hydrochloride form, and are filtered off from time to time and washed with a little cold water, the washings being added to the original liquid; the different fractions are mixed together, and the process repeated until they have a melting-point of 268°. Benzoyl-aconine is obtained from the hydrochloride by precipitating the aqueous solution by the addition of dilute ammonia, and extracting the solution with ether; the solution in ether is washed with water, dried by means of calcium chloride, and then distilled off. Benzoyl-aconine is left as a transparent colourless non-crystalline varnish of a melting-point near 125°.

The solution in water is alkaline to litmus. The base is readily soluble in alcohol, in chloroform, and in ether. The alcoholic solution is dextrorotatory. The solutions are bitter, but do not give the tingling sensation characteristic of aconitine. The hydrochloride, the hydrobromide, the hydriodide, and the nitrate have been obtained in a crystalline state. The most characteristic salt is, however, the aurochlor derivative. When aqueous solutions of benzoyl-aconine chloride and auric chloride are mixed, a yellow precipitate is thrown down, which (dissolved in alcohol, after being dried over calcium chloride, and slowly evaporated in a desiccator) deposits colourless crystals entirely different from the yellow crystals of aconitine gold chloride. These crystals have the composition C₃₁H₄₂(AuCl₂)NO₁₁, and therefore, by theory, should yield 22·6 per cent. of gold, and 8·2 per cent. of chlorine.

By hydrolysis benzoyl-aconine yields benzoic acid, which can be shaken out of an acid solution by ether and identified; one molecule of benzoic acid is formed from one molecule of benzoyl-aconine. Twenty per cent. of benzoic acid should, according to the formula, be obtained; Professor Dunstan found only 18·85 per cent.[469]

Benzoic acid in the subliming cell begins to give a cloud at about 77°-80°, and at or near 100° sublimes most rapidly.

Benzoic acid, recovered from an acid solution by shaking out with ether, may be recognised as follows:—To the film left on evaporating off the ether add a drop of H₂SO₄, and a few crystals of sodic nitrate, and heat gently for a short time; pour the clear liquid into ammonia water, and add a drop of ammonium sulphide. A red-brown colour indicates benzoic acid. The rationale of the test is as follows:—Dinitro-benzoic acid is first formed, and next, by the action of ammonium sulphide, this is converted into the red-brown ammonium diamidobenzoate.—E. Mohler, Bull. Soc. Chem. (3), iii. 414-416.§ 427. Pyraconitine, C₃₁H₄₁NO₁₀, is anhydro-benzoyl-aconine; it differs from benzoyl-aconine by a molecule of water; picraconitine is obtained by keeping aconitine at its melting-point (188°-190°) for some time, when acetic acid distils over and pyraconitine is left. Pyraconitine is an amorphous varnish, sparingly soluble in water, but readily dissolving in alcohol, chloroform, and ether; it gives a pale yellow precipitate with gold chloride, and forms crystalline salts with hydriodic, hydrobromic, and hydrochloric acids. Pyraconitine readily undergoes hydrolysis by the action of dilute acids, or by potash or soda, or with water in a closed tube; the products are benzoic acid and an alkaloid, to which the name of pyraconine has been given.§ 428. Pyraconine, C₂₄H₃₇NO₉.—This base is anhydro-aconine, the formula differing from aconine by one atom of water. It is amorphous, closely resembling aconine; it is soluble in water and ether; the aqueous solution has a somewhat sweet taste, and is lÆvorotatory; it combines with acids to form crystalline salts, which are very soluble in water.§ 429. Aconine, C₂₄H₃₉NO₁₀, m.p. 132°.—Aconine does not crystallise. Its aqueous solution is decidedly alkaline, and, like aconitine, it is lÆvorotatory, although to a less degree. Its taste is bitter, but causes no tingling sensation. Aconine is very soluble in water or alcohol, and slightly in chloroform, but insoluble in ether or in petroleum ether. It does, however, dissolve, in the presence of aconitine, slightly in ether. The aqueous solutions reduce the salts of gold and silver, and also Fehling’s solution. A solution of aconine gives precipitates with the general alkaloidal reagents; with mercuric chloride it gives a copious yellow precipitate, which darkens on standing.

Aconine hydrochloride, the hydriodide, the hydrobromide, and the sulphate, have all been crystallised; solutions of these salts are lÆvorotatory.§ 430. Commercial Aconitine and the Lethal Dose of Aconitine.—Commercial aconitine has in the past varied in appearance from that of a gummy amorphous mass up to a purer kind in white crystals.

Professor Dunstan[470] has recently examined fourteen samples, some of them of considerable age, and only found two samples (one of English, another of German make) which approached in melting-point and crystalline appearance pure aconitine; the one, the English, melted at 186°-187°, and contained about 3 per cent. of benzoyl-aconine; the other, a German specimen, was almost pure; the melting-point was 187·5°. At the present time it is, however, not difficult to obtain fairly pure crystalline aconitine, and to assay it accurately by determining the proportion of acetic and benzoic acids. The physiological action of commercial aconitine is, however, in all cases the same, the difference being in quantitative not qualitative action; in the small doses usually administered, the physiological action depends wholly upon the true aconitine present, the other bases being practically without toxic action. Professor Plugge[471] has made some researches on the fatal dose (for the lower animals) of Petit’s, Merck’s, and FriedlÄnder’s aconitine nitrate, which in 1882 were the purest in commerce. He administered the following doses to the animals mentioned:—

TABLE SHOWING FATAL DOSES (FOR ANIMALS) OF ACONITINE.

The conclusions Plugge draws from his researches are that Petit’s aconitine was at least eight times stronger than that of Merck, and seventy times more toxic than that of FriedlÄnder, while Merck’s “aconitine again was twenty to thirty times stronger than FriedlÄnder’s.” He was inclined to put seven commercial samples which he has examined in the following diminishing order of toxicity:—(1) Petit’s crystalline aconitine nitrate; (2) Morson’s aconitine nitrate; (3) Hottot’s aconitine nitrate; (4) Hopkins & Williams’ pseudaconitine; (5) Merck’s aconitine nitrate; (6) Schuchart’s aconitine sulphate; and (7) FriedlÄnder’s aconitine nitrate.

From a study of Dr. Harley’s experiments,[472] however, made a few years ago, there would appear to have been but little difference between the activity of Petit’s and Morson’s aconitine. Dr. Harley experimented on a young cat, 3 lbs. in weight, and nearly killed it with a ¹/₁₀₀₀ of a grain of Morson’s aconitine; two other cats, also weighing 3 lbs. each, died in seven and a half hours and three-quarters of an hour respectively, killed from a subcutaneous dose of of a grain. Reducing these values to the ordinary equivalents, the dose, after which the cat recovered with difficulty, is equal to about ·048 mgrm. per kilo., while a certainly fatal dose is ·092 mgrm. per kilo.; therefore, it seems likely that the least fatal dose for Morson’s, as for Petit’s, is some number between ·075 and ·09 mgrm. per kilo.

Man is evidently more sensitive to aconitine than any of the dogs or cats experimented upon, since, in the German cases to be recorded, 1·6 mgrm. of Petit’s aconitine nitrate, taken by the mouth, gave rise to symptoms so violent that it was evidently a dangerous dose, while 4 mgrms. were rapidly fatal; but if man took the same amount per kilo. as dogs or cats, he would require a little over 6 mgrms. to be certainly fatal. It seems, then, from the evidence obtainable, that ·03 grain (2 mgrms.) is about the least fatal dose for an adult man of standard weight. This dose is equal to ·028 mgrm. per kilo., and, of course, refers either to Morson’s aconitine or French aconitine, the alkaloid being taken by the mouth. If given by subcutaneous injection, probably 1·5 mgrm. would kill, for the whole of the poison is then thrown on the circulation at one time, and there is no chance of its elimination by vomiting.

The lethal dose of the pure alkaloid being even approximately settled, it is possible to get a more exact idea as to the suitable medicinal dose of the tincture and extract, and also to study more profitably the “quantitative toxicity.” The English officinal tincture, although variable in strength, may for our purposes be regarded as averaging 1 per cent. of alkaloid—that is, in every 100 parts by volume there will be 1 part of the alkaloid by weight, and Fleming’s tincture may be considered as one-third stronger, containing in every 100 parts 1·3 part of alkaloid. The medicinal dose of the P.B. tincture is laid down as from 5 to 15 min.—equal to from ·005 to ·015 grain of aconitine. The German pharmacopoeia gives the maximum single dose as 1 c.c. (say 15 mins.), and the maximum quantity to be taken in the twenty-four hours as four times that quantity. As before stated, 2 mgrms. (·030 grain) of aconitine being considered a fatal dose, this is equivalent to about 2 c.c. (30 mins.) of the P.B. tincture, or to 1·2 c.c. (20 mins.) of Fleming’s tincture in a single dose; and on these theoretical grounds I should consider this dose dangerous, and in the absence of prompt treatment likely to be fatal to an adult man. The usual least fatal dose laid down in medical toxicological works, however, is greater than this—viz., 3·75 c.c. (a drachm).

In 1863 a woman took 70 minims of Fleming’s tincture, and a grain of acetate of morphine, and died in about four hours; but as this was a complex case of poisoning, it is not of much value. Fifteen minims of the tincture caused very serious symptoms in the case of a woman under the care of Dr. Topham,[473] the effects lasting many hours. Probably the smallest quantity of the tincture recorded as having destroyed life is in the case of Dr. Male, of Birmingham.[474] He died from the effects of 80 drops taken in ten doses, extending over a period of four days—the largest dose at any one time being 10 drops, the total quantity would perhaps equal ·08 grain of aconitine.

The P.B. extract is not a very satisfactory preparation, varying much in strength. It may be taken to average about ·6 per cent., and if so, applying the same reasoning as before, from ·26 to ·32 grm. (4 to 5 grains) would be a fatal dose.[475] On the other hand, there is an alcoholic extract which is very powerful, and averages 5 per cent. of aconitine: 40 mgrms. (·6 grain) of this extract would be likely to be fatal. With regard to the root itself, 3·8 grms. (60 grains) have been known to produce death, and from the average alkaloidal contents it is probable that ·648 grm. (10 grains) would be a highly dangerous dose. Dunstan’s researches will now alter probably the whole of the pharmacy of aconite, and the tendency will be to make the preparations of greater activity, and, consequently, to make the dangerous doses smaller than formerly.

§ 431. Effects of Aconitine on Animal Life.—There are few substances which have been experimented upon in such a variety of ways and upon so many classes of animals as aconitine in different forms; but there does not seem to be any essential difference in the symptoms produced in different animals save that which is explained by the organisation of the life-form under experiment.

Insects.—The author has made experiments with the active principles of aconite upon blow-flies. An extract was made by allowing the ordinary tincture to evaporate spontaneously at the temperature of the atmosphere. If a minute dot of this is placed upon the head of a blow-fly, absorption of the active principle takes place in from fifteen to thirty minutes, and marked symptoms result. The symptoms consist essentially of muscular weakness, inability to fly, and to walk up perpendicular surfaces; there is also, in all cases, a curious entanglement of the legs, and very often extrusion of the proboscis; trembling of the legs and muscular twitchings are frequent. A progressive paralysis terminates in from four to five hours in death; the death is generally so gradual that it is difficult to know when the event occurs, but in one case there were violent movements of the body, and sudden death.[476]

Fish.—The action on fish has been studied by Schulz and Praag. There is rapid loss of power and diminished breathing; the respiration seems difficult, and the fish rapidly die.

Reptiles—Frogs.—The most recent experiments on frogs are those of Plugge, and although his interpretation of the phenomena in some points is different from that of previous observers, the symptoms themselves are, as might have been expected, not different from those described by Achscharumow, L. v. Praag, and others. Plugge found no qualitative difference in the action of any of the commercial samples of aconitine. This fact gives the necessary value to all the old experiments, for we now know that, although they were performed with impure or weak preparations, yet there is no reason to believe that the symptoms described were due to any other but the alkaloid aconitine in varying degrees of purity or dilution. Frogs show very quickly signs of weakness in the muscular power; the respiration invariably becomes laboured, and ceases after a few minutes; the heart’s action becomes slowed, irregular, and then stops in diastole. The poisoned heart, while still pulsating, cannot be arrested either by electrical stimulation of the vagus or by irritation of the sinus, nor when once arrested can any further contraction be excited in it. Opening of the mouth and apparent efforts to vomit, Plugge observed both with Rana esculenta and Rana temporaria. He considers them almost invariable signs of aconitine poisoning. A separation of mucus from the surface of the body of the frog is also very constantly observed. Dilatation of the pupils is frequent, but not constant; there may be convulsions, both of a clonic and tonic character, before death, but fibrillar twitchings are seldom. (With regard to the dose required to affect frogs, see ante, pp. 355 and 356.)

Birds.—There is a discrepancy in the descriptions of the action of aconitine on birds. L. v. Praag thought the respiration and circulation but little affected at first; while Achscharumow witnessed in pigeons dyspnoea, dilatation of the pupils, vomiting, shivering, and paresis. It may be taken that the usual symptoms observed are some difficulty in breathing, a diminution of temperature, a loss of muscular power generally (but not constantly), dilatation of the pupils, and convulsions before death.

Mammals.—The effects vary somewhat, according to the dose. Very large doses kill rabbits rapidly. They fall on their sides, are violently convulsed, and die in an asphyxiated condition; but with smaller doses the phenomena first observed are generally to be referred to the respiration. Thus, in an experiment on the horse, Dr. Harley found that the subcutaneous administration of ·6 mgrm. (·01 grain) caused in a weakly colt some acceleration of the pulse and a partial paralysis of the dilator narium. Double the quantity given to the same animal some time after, caused, in six hours and a half, some muscular weakness, and an evident respiratory trouble. The horse recovered in eighteen hours. 2·7 mgrms. (¹/₂₄ grain) given in the same way, after a long interval of time, caused, at the end of an hour, more pronounced symptoms; the pulse, at the commencement 50, rose in an hour and a half to 68, then the respiration became audible and difficult. In an hour and three-quarters there were great restlessness and diminution of muscular power. Two hours after the injection the muscular weakness increased so much that the horse fell down; he was also convulsed. After eight hours he began to improve. In another experiment, 32·4 mgrms. (¹/₂ grain) killed a sturdy entire horse in two hours and twenty minutes, the symptoms commencing within the hour, and consisting of difficulty of breathing, irregularity of the heart’s action, and convulsions.

The general picture of the effects of fatal, but not excessive, doses given to dogs, cats, rabbits, &c., resembles closely that already described. The heart’s action is at first slowed, then becomes quick and irregular, there is dyspnoea, progressive paralysis of the muscular power, convulsions, and death in asphyxia. Vomiting is frequently observed, sometimes salivation, and very often dilatation of the pupil. Sometimes the latter is abnormally active, dilating and contracting alternately. Diarrhoea also occurs in a few cases. Vomiting is more frequent when the poison is taken by the mouth than when administered subcutaneously.[477]

§ 432. Statistics.—During the ten years, 1883-92, there were recorded in England and Wales, 40 accidental deaths from the various forms of aconite (19 males, 21 females); and 19 suicidal deaths (9 males, 10 females) from the same cause, which makes a total of 59.§ 433. Effects on Man.—I have collected from European medical literature, 87 cases of poisoning by aconite in some form or other. These comprise only 2 cases of murder, 7 of suicide, and 77 which were more or less accidental. Six of the cases were from the use of the alkaloid itself; 10 were from the root; in two cases children eat the flowers; in 1, the leaves of the plant were cooked and eaten by mistake; in 7, the tincture was mistaken for brandy, sherry, or liqueur; the remainder were caused by the tincture, the liniment, or the extract.§ 434. Poisoning by the Root.—A case of murder which occurred some years ago in America, and also the Irish case which took place in 1841 (Reg. v. M’Conkey), were, until the recent trial of Lamson, the only instances among English-speaking people of the use of aconite for criminal purposes; but if we turn to the Indian records, we find that it has been largely used from the earliest times as a destroyer of human life. In 1842 a tank of water destined for the use of the British army in pursuit of the retreating Burmese, was poisoned by intentional contamination with the bruised root of Aconitum ferox; it was fortunately discovered before any harm resulted. A preparation of the root is used in all the hill districts of India to poison arrows for the destruction of wild beasts. A Lepcha described the root to a British officer as being “useful to sportsmen for destroying elephants and tigers, useful to the rich for putting troublesome relations out of the way, and useful to jealous husbands for the purpose of destroying faithless wives.” From the recorded cases, the powdered root, mixed with food, or the same substance steeped in spirituous liquor, is usually the part chosen for administration. In M’Conkey’s case, the man’s wife purchased powdered aconite root, mixed it with pepper, and strewed it over some greens, which she cooked and gave to him. The man complained of the sharp taste of the greens, and soon after the meal vomited, and suffered from purging, became delirious with lock-jaw, and clenching of the hands; he died in about three hours. The chief noticeable post-mortem appearance was a bright red colour of the mucous membrane of the stomach.

The symptoms in this case were, in some respects, different from those met with in other cases of poisoning by the root. A typical case is given by Dr. Chevers (op. cit.), in which a man had taken by mistake a small portion of aconite root. Immediately after chewing it he felt a sweetish taste, followed immediately by tingling of the lips and tongue, numbness of the face, and severe vomiting. On admission to hospital he was extremely restless, tossing his limbs about in all directions and constantly changing his position. He complained of a burning sensation in the stomach, and a tingling and numbness in every part of the body, excepting his legs. The tingling was specially marked in the face and tongue—so much so that he was constantly moving the latter to and fro in order to scratch it against the teeth. Retching and vomiting occurred almost incessantly, and he constantly placed his hand over the cardiac region. His face was anxious, the eyes suffused, the lips pale and exsanguine, the eyelids swollen, moderately dilated, and insensible to the stimulus of light; the respiration was laboured, 64 in a minute; the pulse 66, small and feeble. There was inability to walk from loss of muscular power, but the man was perfectly conscious. The stomach-pump was used, and albumen and milk administered. Three and three-quarter hours after taking the root the symptoms were increased in severity. The tongue was red and swollen, the pulse intermittent, feeble, and slower. The tingling and numbness had extended to the legs. On examining the condition of the external sensibility with a pair of scissors, it was found that, on fully separating the blades and bringing the points in contact with the skin over the arms and forearms, he felt them as one, although they were 4 inches apart. But the sensibility of the thighs and legs was less obtuse, for he could feel the two points distinctly when they were 4 inches apart, and continued to do so until the distance between the points fell short of 2³/₄ inches. He began to improve about the ninth hour, and gradually recovered, although he suffered for one or two days from a slight diarrhoea. As in the case detailed (p. 363), no water was passed for a long time, as if the bladder early lost its power.§ 435. Poisoning by the Alkaloid Aconitine.—Probably the earliest instance on record is the case related by Dr. Golding Bird in 1848.[478] What kind of aconitine was then in commerce I know not, and since apparently a person of considerable social rank was the subject of the poisoning, the case has been imperfectly reported. It seems, however, that, whether for purposes of suicide, or experiment, or as a medicine, two grains and a half of aconitine were swallowed. The symptoms were very violent, consisting of vomiting, collapse, and attacks of muscular spasm; the narrator describes the vomiting as peculiar. “It, perhaps, hardly deserved that title; the patient was seized with a kind of general spasm, during which he convulsively turned upon his abdomen, and with an intense contraction of the abdominal muscles, he jerked out, as it were, with a loud shout the contents of his stomach, dependent apparently on the sudden contraction of the diaphragm.” On attempting to make him swallow any fluid, a fearful spasm of the throat was produced; it reminded his medical attendants of hydrophobia. The patient recovered completely within twenty-four hours.

[478] Lancet, vol. i. p. 14.

One of three cases reported by Dr. Albert Busscher,[479] of poisoning by aconitine nitrate, possesses all the exact details of an intentional experiment, and is of permanent value to toxicological literature.

A labourer of Beerta, sixty-one years of age, thin, and of somewhat weak constitution, suffered from neuralgia and a slight intermittent fever; Dr. Carl Meyer prescribed for his ailment:—

Twenty drops to be taken four times daily. The patient was instructed verbally by Dr. Meyer to increase the dose until he attained a maximum of sixty drops per day.

The doses which the man actually took, and the time of taking them, are conveniently thrown into a tabular form as follows:—

In the whole seven doses, which were distributed over forty-eight hours, he took 9·2 mgrms. (·14 grain) of aconitine nitrate.

On taking dose No. 1, he experienced a feeling of constriction (Zusammenziehung), and burning spreading from the mouth to the stomach, but this after a little while subsided. Two hours afterwards he took No. 2, four times the quantity of No. 1. This produced the same immediate symptoms, but soon he became cold, and felt very ill. He had an anxious oppressive feeling about the chest, with a burning feeling about the throat; the whole body was covered with a cold sweat, his sight failed, he became giddy, there was excessive muscular weakness, he felt as if he had lost power over his limbs, he had great difficulty in breathing. During the night he passed no water, nor felt a desire to do so. About half an hour after he had taken the medicine, he began to vomit violently, which relieved him much; he then fell asleep.

Dose No. 3, equal as before to 1·6 mgrm., he took in the morning. He experienced almost exactly the same symptoms as before, but convulsions were added, especially of the face; the eyes were also prominent; twenty minutes after he had taken the dose, vomiting came on, after which he again felt better.

He took dose No. 4, and had the same repetition of symptoms, but in the interval between the doses he felt weaker and weaker; he had no energy, and felt as if paralysed. No. 5 was taken, and produced, like the others, vomiting, after which he felt relieved. Neither he nor his wife seemed all this time to have had any suspicion that the medicine was really doing harm, but thought that the effects were due to its constant rejection by vomiting, so, in order to prevent vomiting with No. 6, he drank much cold water. After thus taking the medicine, the patient seemed to fall into a kind of slumber, with great restlessness; about an hour and a half afterwards he cried, “I am chilled; my heart, my heart is terribly cold. I am dying; I am poisoned.” His whole body was covered with perspiration; he was now convulsed, and lost sight and hearing; his eyes were shut, his lips cracked and dry, he could scarcely open his mouth, and he was extremely cold, and thought he was dying. The breathing was difficult and rattling; from time to time the muscular spasms came on. His wife now made a large quantity of hot strong black tea, which she got him to drink with great difficulty; although it was hot, he did not know whether it was hot or cold. About five minutes afterwards he vomited, and did so several times; this apparently relieved him, and he sank into a quiet sleep; during the night he did not urinate. In the morning the wife went to Dr. Carl Meyer, described the symptoms, and accused the medicine. So convinced was Dr. Meyer that the medicine did not cause the symptoms, that he poured out a quantity of the same, equal to 4 mgrms. of aconitine nitrate, and took it himself in some wine, to show that it was harmless, and ordered them to go on with it. The unhappy physician died of aconitine poisoning five hours after taking the medicine.[480] In the meantime, the woman went home, and her husband actually took a seventh, but smaller dose, which produced similar symptoms to the former, but of little severity; no more was taken.

The absence of diarrhoea, and of the pricking sensations so often described, is in this case noteworthy. Both diarrhoea and formication were also absent in a third case reported by Dr. Busscher in the same paper.§ 436. The most important criminal case is undoubtedly that of Lamson:—At the Central Criminal Court, in March, 1882, George Henry Lamson, surgeon, was convicted of the murder of his brother-in-law, Percy Malcolm John. The victim was a weakly youth of eighteen years of age, paralysed in his lower limbs from old standing spinal disease. The motive for perpetrating the crime was that Lamson, through his wife (Malcolm John’s sister), would receive, on the death of his brother-in-law, a sum of £1500, and, according to the evidence, it is probable that there had been one or more previous attempts by Lamson on the life of the youth with aconitine given in pills and in powders. However this may be, on November 24, 1880, Lamson purchased 2 grains of aconitine, came down on Dec. 3 to the school where the lad was placed, had an interview with his brother-in-law, and, in the presence of the head-master, gave Malcolm John a capsule, which he filled then and there with some white powder, presumed at the time to be sugar. Lamson only stayed altogether twenty minutes in the house, and directly after he saw his brother-in-law swallow the capsule, he left. Within fifteen minutes Malcolm John became unwell, saying that he felt as if he had an attack of heart-burn, and then that he felt the same as when his brother-in-law had on a former occasion given him a quinine pill. Violent vomiting soon set in, and he complained of pains in his stomach, a sense of constriction in his throat, and of being unable to swallow. He was very restless—so much so that he had to be restrained by force from injuring himself. There was delirium a few minutes before death, which took place about three hours and three-quarters after swallowing the fatal dose. The post-mortem appearances essentially consisted of redness of the greater curvature of the stomach, and the posterior portion of the same organ. In one part there was a little pit, as if a blister had broken; the rest of the viscera were congested, and the brain also slightly congested.[481]

§ 437. The symptoms of poisoning by the tincture, extract, or other preparation, do not differ from those detailed. As unusual effects, occasionally seen, may be noted profound unconsciousness lasting for two hours (Topham’s case), violent twitching of the muscles of the face, opisthotonos, and violent convulsions. It is important to distinguish the symptoms which are not constant from those which are constant, or nearly so. The tingling and creeping sensations about the tongue, throat, lips, &c., are not constant; they certainly were not present in the remarkable German case cited at p. 363. Speaking generally, they seem more likely to occur after taking the root or the ordinary medicinal preparations. A dilated state of the pupil is by no means constant, and not to be relied upon. Diarrhoea is seen after taking the root or tincture by the stomach, but is often absent. In short, the only constant symptoms are difficulty of breathing, progressive muscular weakness, generally vomiting, and a weak intermittent pulse.§ 438. Physiological Action.—Aconitine, according to Dr. S. Ringer, is a protoplasmic poison, destroying the functions of all nitrogenous tissue—first of the central nervous system, next of the nerves, and last of the muscles. Aconitine without doubt acts powerfully on the heart, ultimately paralysing it; there is first a slowing of the pulse, ascribed to a central excitation of the vagus; then a quickening, due to paralysis of the peripheral termination of the vagus in the heart; lastly, the heart’s action becomes slow, irregular, and weak, and the blood-pressure sinks. The dyspnoea and convulsions are the usual result, seen among all warm-blooded animals, of the heart affection. Plugge found that the motor nerves, and more especially their intra-muscular terminations, were always paralysed; but if the dose was small the paralysis might be incomplete. Boehm and Wartmann, on the other hand, considered that the motor paralysis had a central origin, a view not supported by recent research. The action of aconitine in this way resembles curare. The muscles themselves preserve their irritability, even after doses of aconitine which are five to ten times larger than those by which the nerve terminations are paralysed.§ 439. Post-mortem Appearances.—Among animals (mammals) the appearances most constantly observed have been hyperÆmia of the cerebral membranes and brain, a fulness of the large veins, the blood generally fluid—sometimes hyperÆmia of the liver, sometimes not. When aconitine has been administered subcutaneously, there have been no inflammatory appearances in the stomach and bowels.

In the case of Dr. Carl Meyer, who died in five hours from swallowing 4 mgrms. of aconitine nitrate, the corpse was of a marble paleness, the pupils moderately dilated. The colour of the large intestine was pale; the duodenum was much congested, the congestion being most intense the nearer to the stomach; the mucous membrane of the stomach itself was strongly hyperÆmic, being of an intense red colour; the spleen was enlarged, filled with much dark blood. The liver and kidneys were deeply congested, the lungs also congested; the right ventricle of the heart was distended with blood; in the pericardium there was a quantity of bloody serum. The brain was generally blood-red; in the cerebral hemispheres there were several large circumscribed subarachnoid extravasations. The substance of the brain on section showed many red bloody points.

In a case recorded by Taylor, in which a man died in three hours from eating a small quantity of aconitine root, the only morbid appearance found was a slight reddish-brown patch on the cardiac end of the stomach, of the size of half a crown; all the other organs being healthy.§ 440. Separation of Aconitine from the Contents of the Stomach or the Organs.—It would appear certain that in all operations for the separation of aconite alkaloids (whether from the organic matters which make up the plant, or from those constituting animal tissues), mineral acids and a high heat should be avoided. A 1 per cent. sulphuric acid does not, however, hydrolyse, if acting in the cold, so that the process already given, p. 352, may be followed.

The chemical examination in the Lamson case was entrusted to Dr. Stevenson, assisted by Dr. DuprÉ, and was conducted on the principles detailed. The contents of the stomach were treated with alcohol, and digested at the ordinary temperature of the atmosphere; the contents were already acid, so no acid in this first operation was added. The mixture stood for two days and was then filtered. The insoluble portion was now exhausted by alcohol, faintly acidulated by tartaric acid, and warmed to 60°; cooled and filtered, the insoluble part being washed again with alcohol. The two portions—that is, the spirituous extract acid from acids pre-existing in the contents of the stomach, and the alcohol acidified by tartaric acid—were evaporated down separately, exhausted by absolute alcohol, the solutions filtered, evaporated, and the residue dissolved in water. The two aqueous solutions were now mixed, and shaken up with ether, which, as the solution was acid, would not remove any alkaloid, but might remove various impurities; the residue, after being thus partially purified by ether, was alkalised by sodic carbonate, and the alkaloid extracted by a mixture of chloroform and ether. On evaporation of the chloroform and ether, the resulting extract was tested physiologically by tasting, and also by injections into mice. By means analogous to those detailed, the experts isolated aconitine from the vomit, the stomach, liver, spleen, and urine, and also a minute quantity of morphine, which had been administered to the patient to subdue the pain during his fatal attack. When tasted, the peculiar numbing, tingling sensation lasted many hours. These extracts were relied upon as evidence, for their physiological effect was identical with that produced by aconitine. For example, the extract obtained from the urine caused symptoms to commence in a mouse in two minutes, and death in thirty minutes, and the symptoms observed by injecting a mouse with known aconitine coincided in every particular with the symptoms produced by the extraction from the urine.

With regard to the manner of using “life tests,” since in most cases extremely small quantities of the active principle will have to be identified, the choice is limited to small animals, and it is better to use mice or birds, rather than reptiles. In the Lamson case, subcutaneous injections were employed, but it is a question whether there is not less error in administering it by the mouth. If two healthy mice are taken, and the one fed with a little meal, to which a weighed quantity of the extract under experiment has been added, while to the other some meal mixed with a supposed equal dose of aconitine is given, then the symptoms may be compared; and several objections to any operative proceeding on such small animals are obviated. It is certain that any extract which causes distinct numbness of the lips will contain enough of the poison to kill a small bird or a mouse, if administered in the ordinary way.[482]

VI.—The Mydriatic Group of Alkaloids—Atropine—Hyoscyamine—Solanine—Cytisine.

1. ATROPINE.

§ 441. Atropine (Daturine), C₁₇H₂₃NO₃.—This important alkaloid has been found in all parts of the Atropa belladonna, or deadly nightshade, and in all the species of Datura.

The Atropa belladonna is indigenous, and may be found in some parts of England, although it cannot be said to be very common. It belongs to the SolanaceÆ, and is a herbaceous plant with broadly ovate entire leaves, and lurid-purple axillary flowers on short stalks; the berries are violet-black, and the whole of the plant is highly poisonous. The juice of the leaves stains paper a purple colour. The seeds are very small, kidney-shaped, weighing about 90 to the grain; they are covered closely with small, round projections, and are easily identified by an expert, who may be supposed to have at hand (as is most essential) samples of different poisonous seeds for comparison. The nightshade owes its poisonous properties to atropine.

The yield of the different parts of belladonna, according to Gunther,[483] is as follows:—

TABLE SHOWING THE ALKALOIDAL CONTENT OF VARIOUS PARTS OF THE BELLADONNA PLANT.

Atropine appears to exist in the plant in combination with malic acid. According to a research by Ladenburg, hyoscyamine is associated with atropine, both in the Belladonna and Datura plants.[484]

From a research by W. SchÜtte,[485] it appears that the younger roots of wild belladonna contain hyoscyamine only, whilst the older roots contain atropine as well as hyoscyamine, but only in small proportion; the same was observed to be the case in the older cultivated roots.

The ripe berries of cultivated Atropa belladonna nigra contain atropine and hyoscyamine; those of the wild plant contain atropine only; the ripe fruit of Atropa belladonna lutea contains only atropine and another base, perhaps identical with atropamine; the unripe fruit of wild Atropa belladonna nigra contains hyoscyamine, with only a small quantity of atropine.

The leaves of the yellow and black-fruited wild Atropa belladonna contain hyoscyamine and atropine, the latter being in small quantity only.

Fresh and old seeds of Datura Stramonium contain chiefly hyoscyamine; small quantities of atropine and scopolamine are also present.§ 442. The Datura Stramonium or Thorn-apple is also indigenous in the British Islands, but, like belladonna, it cannot be considered a common plant. Datura belongs to the SolanaceÆ; it grows from 1 to 2 feet in height, and is found in waste places. The leaves are smooth, the flowers white; the fruit is densely spinous (hence the name thorn-apple), and is divided into four dissepiments below, two at the top, and containing many seeds.

The Datura, or the Dhatura-plants, of India have in that country a great toxicological significance, the white-flowered datura, or Datura alba, growing plentifully in waste places, especially about Madras. The purple-coloured variety, or Datura fastuosa, is also common in certain parts. There is a third variety, the Datura atrox, found about the coast of Malabar. The seeds of the white datura have been mistaken in India for those of capsicum. The following are some of the most marked differences:—

The identity of the active principle in both the datura and belladonna tribes is now completely established.[486]

§ 443. Pharmaceutical Preparations.—(a.) Of the leaves. Extract of Belladonna.—This contains, according to Squire,[487a] from 0·73 to 1·7 per cent. of total alkaloids. Belladonna Juice (succus belladonnÆ).—Strength in alkaloid about 0·05 per cent. Tincture of Belladonna.—Half the strength of the juice, and therefore yielding about 0·025 per cent. of alkaloid.

(b.) Belladonna Root.—Belladonna plaster contains 20 per cent. of alcoholic extract of belladonna. Alcoholic Extract of Belladonna.—This extract, according to Squire,[487b] contains from 1·6 to 4·45 per cent. of alkaloid. Belladonna liniment is an alcoholic extract with the addition of camphor; its strength is about equal to 0·2 per cent. of alkaloid. Belladonna ointment contains about 10 per cent. of the alcoholic extract.

(c.) The Alkaloid.—Atropine Discs (lamellÆ atropinÆ).—These are discs of gelatin, each weighing about ¹/₅₀ grain, and containing for ophthalmic use ¹/₅₀₀₀ grain of atropine sulphate. Similar discs are made for hypodermic use, but stronger; each containing ¹/₁₂₀ grain. Solution of Atropine Sulphate.—Strength about 1 per cent. Atropine Ointment.—Strength about 1 in 60, or 1·60 per cent. of atropine.

(d.) Stramonium.—An extract of the seeds is officinal in Britain; the alkaloidal content is from 1·6 to 1·8 per cent. There is also a tincture which contains about 0·06 per cent. of alkaloid.§ 444. Properties of Atropine, C₁₇H₂₃NO₃.—Atropine, hyoscyamine, and hyoscine have all the same formula, but differ in their molecular constitution. Atropine by hydrolysis, either by heating it with hydrochloric acid or baryta water, is decomposed into tropine and tropic acid:—

On the other hand, by heating tropic acid and tropine together, atropine is regenerated. Hence it is proved by analysis and synthesis, that atropine is tropic acid-tropine, just as aconitine is benzoyl-aconine. Tropic acid has been produced synthetically by boiling -chlorphenyl-propionic acid with potash, which at once shows its constitutional formula, viz.:—

Tropic acid has a melting-point of 117° to 118°. Tropine is a four-fold hydrated oxethyl-methyl-pyridine, and has the constitutional formula of C₅H₃(H₄)(C₂H₄OH)N(CH₃); hence the constitutional formula of atropine is—

Tropine is a white, crystalline, strongly alkaline mass, melting at 60°, and volatilising at 230° undecomposed. It is soluble in water, alcohol, and ether, and gives precipitates with tannic acid, iodised hydriodic acid, Mayer’s reagent, gold chloride, and mercuric chloride. Tropine gold chloride melts at 210° to 212°. Atropic acid (C₉H₈O₂), melting-point 198° to 200°, and isatropic acid (C₉H₈O₂), may also be obtained by the action of hydrochloric acid—the first, in radiating crystals, melting at 106°, and capable of distillation; the second, in thin rhombic plates, melting about 200°, and not volatile. Picric acid also gives a precipitate of beautiful plates. To obtain this the carbazotic acid must be in excess, and time must be given for the precipitate to form.

Atropine forms colourless crystals (mostly in groups or tufts of needles and prisms), which are heavier than water, and possess no smell, but an unpleasant, long-enduring, bitter taste. The experiments of E. Schmidt place the melting-point between 115° and 115·5°. It is said to sublime scantily in a crystalline form, but the writer has been unable to obtain any crystals by sublimation; faint mists collect on the upper disc, at about 123°, but they are perfectly amorphous.

Its reaction is alkaline; one part requires, of cold water, 300; of boiling, 58; of ether, 30; of benzene, 40; and of chloroform, 3 parts for solution. In alcohol and amyl alcohol it dissolves in almost every proportion. It turns the plane of polarisation weakly to the left.§ 445. Tests.—Atropine mixed with nitric acid exhibits no change of colour. The same is the case with concentrated sulphuric acid in the cold; but on heating, there ensues the common browning, with development of a peculiar odour, likened by Gulielmo to orange flowers, by Dragendorff to the flowers of the Prunus padus, and by Otto to the SpirÆa ulmaria—a sufficient evidence of the untrustworthiness of this as a distinctive test. The odour, indeed, with small quantities, is certainly not powerful, nor is it strongly suggestive of any of the plants mentioned. A far more intense odour is given off if a speck of atropine is evaporated to dryness with a few drops of strong solution of baryta, and heated strongly; the scent is decidedly analogous to that of hawthorn-blossom, and unmistakably agreeable.

By boiling a small quantity of atropine, say 1 mgrm., with 2 mgrms. of calomel and a very little water, the calomel blackens, and crystals may be obtained of a double salt; this reaction is, however, given also by hyoscyamine and homatropine. Mercuric potassium iodide solution, and mercuric bromide solution give amorphous precipitates, which, after a time, become crystalline, and have characteristic forms.

A solution of iodine in potassium iodide gives a precipitate with acidulated solutions of atropine in even a dilution of 1: 10,000. Tannin precipitates, and the precipitate is soluble in excess of the reagent. If atropine be dissolved in dilute hydrochloric acid, and a 5 per cent. of gold chloride solution be added, a precipitate of a gold compound (C₁₇H₂₃NO₃HClAuCl₃) separates. The precipitate is in the form of rosettes or needles; melting-point 137°. On boiling it with water, however, it melts into oily drops, and this peculiar behaviour distinguishes it from the analogous salt of hyoscyamine, which does not melt in boiling water. The percentage of gold left on a combustion of atropine gold chloride is 31·35 per cent. 100 parts of the gold salt are equal to 46·2 of atropine. A platinum salt may also be obtained, (C₁₇H₂₃NO₃HCl)₂,PtCl₄, containing 29·5 per cent. of platinum.

Vitali’s test is important; it consists in the production of a violet colour with alcoholic potash after oxidation.

The test may be applied as follows:—Equal parts, say 1 mgrm., of nitrate of sodium and of the substance to be tested, are rubbed together with a glass rod on a porcelain slab, and to this mixture 1 drop of sulphuric acid is added; the mixture is spread out in a thin film; upon this is strewn a little powdered potassium hydrate, and finally 1 drop of alcohol added; a violet colour is produced which passes into a fine red; according to the author of the test, 0·001 mgrm. of atropine sulphate can by this test be detected. Strychnine obscures this reaction.

Atropine, homatropine, and hyoscyamine show an alkaline reaction with phenolphthalein: atropine and homatropine give a precipitate with HgCl₂. Hyoscyamine, not cocaine, precipitates HgCl₂, and is alkaline to litmus, but not to phenolphthalein. Atropine behaves as follows:—(1) Sodium nitrate, sulphuric acid, and afterwards sodium hydroxide, gives a violet colour; (2) the test as before, but with nitrite instead of nitrate, gives orange colour, which, on dilution with sodium hydroxide solution, changes to red, violet, or lilac; (3) when heated with glacial acetic acid and sulphuric acid for a sufficient time, a greenish-yellow fluorescence is produced.—FlÜckiger, Pharm. Journ. Trans. (3), vol. xvi. p. 601-602.

The two alkaloids, strychnine and atropine, are not likely to be often together in the human body, but that it may sometimes occur is shown by a case recorded by L. Fabris.[488] A patient in the hospital at Padua had for some time been treated with daily injections of 3 mgrms. of strychnine nitrate; unfortunately, one day, instead of the 3 mgrms. of strychnine, the same quantity of atropine sulphate was injected, and the patient died after a few hours, with symptoms of atropine poisoning.

On chemical treatment of the viscera, a mixture of alkaloids was obtained which did not give either the reactions of strychnine or of atropine. To test the possibility of these alkaloids obscuring each other’s reactions, mixtures of 3 per cent. solutions (the strength of the injections) of atropine sulphate and strychnine nitrate were mixed together, and strychnine tested for by the dichromate and sulphuric acid test.

A mixture of equal parts gave the strychnine reaction very clearly, but the atropine reaction not at all; 1 strychnine with 3 of atropine gave strychnine reaction, but not that of atropine; 1 strychnine with 4 atropine gave indistinct reaction for both alkaloids; 1 of strychnine with 5 of atropine gave a momentary atropine reaction, the violet was, however, almost immediately replaced by a red colour. Vitali’s reaction was not clearly shown until the mixture was in the proportion of 9 of atropine to 1 of strychnine, but mixtures in the proportion of 3 strychnine and 1 atropine will give distinct mydriasis.

In such a case, of course, the strychnine should be separated from the atropine; this can be effected by precipitating the strychnine as chromate, filtering and recovering from the filter the atropine by alkalising and shaking it out with ether.

The atropine may be farther purified by converting it into oxalate, dissolving the oxalate in as small a quantity of alcohol as possible, and precipitating the oxalate out with ether; the precipitate is collected, dissolved in as small a quantity of water as possible, the water made alkaline, and the base shaken out with ether.

The most reliable test for atropine, or one of the mydriatic alkaloids, is its action on the iris; a solution of atropine, even so weak as 1: 130,000, causing dilatation.[489] This action on the iris has been studied by Ruyter,[490] Donders, and von Graefe.

The action is local, taking effect when in dilute solution only on the eye to which it has been applied; and it has been produced on the eyes of frogs, not only in the living subject, but after the head has been severed from the body and deprived of brain. The thinner the cornea, the quicker the dilatation; therefore, the younger the person or animal, the more suitable for experiment. In frogs, with a solution of 1: 250, dilatation commences in about five minutes; in pigeons, seven minutes; and in rabbits, ten minutes. In man, a solution of 1: 120 commences to act in about six to seven minutes, reaches its highest point in from ten to fifteen minutes, and persists more or less for six to eight days. A solution of 1: 480 acts first in fifteen to twenty minutes, and reaches its greatest point in twenty minutes; a solution of 1: 48,000 requires from three-quarters of an hour to an hour to show its effect. Dogs and cats are far more sensible to its influence than man, and therefore more suitable for experiment. If the expert chooses, he may essay the proof upon himself, controlling the dilatation by Calabar bean; but it is seldom necessary or advisable to make personal trials of this nature.[491]

[491] A. Ladenburg (Compt. Rend., xc. 92), having succeeded in reproducing atropine by heating tropine and tropic acid with hydrochloric acid, by substituting various organic acids for the tropic acid, has obtained a whole series of compounds to which he has given the name of tropeines. One of these, hydroxytoluol (amygdalic) tropeine, he has named homatropine. It dilates the pupil, but is less poisonous than atropine.

§ 446. Statistics of Atropine Poisoning.—Since atropine is the active principle of belladonna and datura plants, and every portion of these—root, seeds, leaves, and fruit—has caused toxic symptoms, poisoning by any part of these plants, or by their pharmaceutical or other preparations, may be considered with strict propriety as atropine poisoning. Our English death statistics for the ten years ending 1892, record 79 deaths (50 males and 29 females) from atropine (for the most part registered under the head of belladonna); 29 (or 36·7 per cent.) were suicidal, the rest accidental.

The greatest number of the accidental cases arise from mistakes in pharmacy; thus, belladonna leaves have been supplied for ash leaves; the extract of belladonna has been given instead of extract of juniper; the alkaloid itself has been dispensed in mistake for theine;[492] a more curious and marvellously stupid mistake is one in which it was dispensed instead of assafoetida (Schauenstein, op. cit., p. 652). Further, valerianate of atropine has been accidentally substituted for quinine valerianate, and Schauenstein relates a case in which atropine sulphate was administered subcutaneously instead of morphine sulphate; but the result was not lethal. Many other instances might be cited. The extended use of atropine as an external application to the eye naturally gives rise to a few direct and indirect accidents. Serious symptoms have arisen from the solution reaching the pharynx through the lachrymal duct and nose. A curious indirect poisoning, caused by the use of atropine as a collyrium, is related by Schauenstein.[493] A person suffered from all the symptoms of atropine poisoning; but the channel by which it had obtained access to the system was a great mystery, until it was traced to some coffee, and it was then found that the cook had strained this coffee through a certain piece of linen, which had been used months before, soaked in atropine solution, as a collyrium, and had been cast aside as of no value.

§ 447. Accidental and Criminal Poisoning by Atropine.—External applications of atropine are rapidly absorbed, e.g., if the foot of a rat be steeped for a little while in a solution of the alkaloid, and the eyes watched, dilatation of the pupils will soon be observed. If the skin is broken, enough may be absorbed to cause death. A case is on record in which ·21 grm. of atropine sulphate, applied as an ointment to the abraded skin, was fatal.[494] Atropine has also been absorbed from the bowel; in one case, a clyster containing the active principles of 5·2 grms. (80 grains) of belladonna root was administered to a woman twenty-seven years of age, and caused death. Allowing the root to have been carefully dried, and to contain ·21 per cent. of alkaloid, it would seem that so little as 10·9 mgrms. (·16 grain) may even prove fatal, if left in contact with the intestinal mucous membrane. Belladonna berries and stramonium leaves and seeds are eaten occasionally by children. A remarkable series of poisonings by belladonna berries occurred in London during the autumn of 1846.

Criminal poisoning by atropine in any form is of excessive rarity in Europe and America, but in India it has been frightfully prevalent. In all the Asiatic cases the substance used has been one of the various species of datura, and mostly the bruised or ground seeds, or a decoction of the seeds. In 120 cases recorded in papers and works on Indian toxicology, I find no less than 63 per cent. of the cases criminal, 19 per cent. suicidal, and 18 per cent. accidental. In noting these figures, however, it must be borne in mind that known criminal cases are more certain to be recorded than any other cases. The drug has been known under the Sanscrit name of dhatoora by the Hindoos from most remote times. It was largely used by the Thugs, either for the purpose of stupefying their victim or for killing him; by loose wives to ensure for a time the fatuity of their husbands; and, lastly, it seems in Indian history to have played the peculiar rÔle of a state agent, and to have been used to induce the idiocy or insanity of persons of high rank, whose mental integrity was considered dangerous by the despot in power. The Hindoos, by centuries of practice, have attained such dexterity in the use of the “datura” as to raise that kind of poisoning to an art, so that Dr. Chevers, in his Medical Jurisprudence for India,[495] declares that “there appears to be no drug known in the present day which represents in its effects so close an approach to the system of slow poisoning, believed by many to have been practised in the Middle Ages, as does the datura.”

§ 448. Fatal Dose.—It is impossible to state with precision the exact quantity which may cause death, atropine being one of those substances whose effect, varying in different cases, seems to depend on special constitutional tendencies or idiosyncracies of the individual. Some persons take a comparatively large amount with impunity, while others scarcely bear a very moderate dose without exhibiting unpleasant symptoms. Eight mgrms. (¹/₈ grain) have been known to produce poisonous symptoms, and ·129 grm. (2 grains) death. We may, therefore, infer that about ·0648 grm. (1 grain) would, unchecked by remedies, probably act fatally; but very large doses have been recovered from, especially when treatment has been prompt.

Atropine is used in veterinary practice, from 32·4 to 64·8 mgrms. (¹/₂ to 1 grain) and more being administered subcutaneously to horses; but the extent to which this may be done with safety is not yet established.§ 449. Action on Animals.—The action of atropine has been studied on certain beetles, on reptiles (such as the salamander, triton, frogs, and others), on guinea-pigs, hedgehogs, rats, rabbits, fowls, pigeons, dogs, and cats. Among the mammalia there is no essential difference in the symptoms, but great variation in the relative sensibility; man seems the most sensitive of all, next to man come the carnivora, while the herbivora, and especially the rodents, offer a considerable resistance. According to Falck the lethal dose for a rabbit is at least ·79 mgrm. per kilo. It is the general opinion that rabbits may eat sufficient of the belladonna plant to render their flesh poisonous, and yet the animals themselves may show no disturbance in health; but this must not be considered adequately established. Speaking very generally, the higher the animal organisation the greater the sensibility to atropine. Frogs are affected in a peculiar manner. According to the researches of Fraser,[496] the animal is first paralysed, and some hours after the administration of the poison lies motionless, the only signs of life being the existence of a slight movement of the heart and muscular irritability. After a period of from forty-eight to seventy-two hours, the fore limbs are seized with tetanic spasms, which develop into a strychnine-like tetanus.

§ 450. Action on Man.—When atropine is injected subcutaneously, the symptoms, as is usually the case with drugs administered in this manner, may come on immediately, the pupil not unfrequently dilating almost before the injection is finished. This is in no way surprising; but there are instances in which decoctions of datura seeds have been administered by the stomach, and the commencement of symptoms has been as rapid as in poisoning by oxalic or even prussic acid. In a case tried in India in July 1852, the prosecutor declared that, while a person was handing him a lota of water, the prisoner snatched it away on pretence of freeing the water from dirt or straws, and then gave it to him. He then drank only two mouthfuls, and, complaining of the bitter taste, fell down insensible within forty yards of the spot where he had drunk, and did not recover his senses until the third day after. In another case, a man was struck down so suddenly that his feet were scalded by some hot water which he was carrying.—Chevers.

When the seeds, leaves, or fruit of atropine-holding plants are eaten, there is, however, a very appreciable period before the symptoms commence, and, as in the case of opium poisoning, no very definite rule can be laid down, but usually the effects are experienced within half an hour. The first sensation is dryness of the mouth and throat; this continues increasing, and may rise to such a degree that the swallowing of liquids is an impossibility. The difficulty in swallowing does not seem to be entirely dependent on the dry state of the throat, but is also due to a spasmodic contraction of the pharyngeal muscles. Tissore[497] found in one case such constriction that he could only introduce emetics by passing a catheter of small diameter. The mucous membrane is reddened, and the voice hoarse.[498] The inability to swallow, and the changed voice, bear some little resemblance to hydrophobia—a resemblance heightened to the popular mind by an inclination to bite, which seems to have been occasionally observed; the pupils are early dilated, and the dilatation may be marked and extreme; the vision is deranged, letters and figures often appear duplicated; the eyeballs are occasionally remarkably prominent, and generally congested; the skin is dry, even very small quantities of atropine arresting the cutaneous secretion; in this respect atropine and pilocarpine are perfect examples of antagonism. With the dryness of skin, in a large percentage of cases, occurs a scarlet rash over most of the body. This is generally the case after large doses, but Stadler saw the rash produced on a child three months old by ·3 mgrm. of atropine sulphate. It appeared three minutes after the dose, lasted five hours, and was reproduced by a renewed dose.[499] The temperature of the body with large doses is raised; with small, somewhat lowered. The pulse is increased in frequency, and is always above 100—mostly from 115 to 120, or even 150, in the minute. The breathing is at first a little slowed, and then very rapid. Vomiting is not common; the sphincters may be paralysed so that the evacuations are involuntary, and there may be also spasmodic contractions of the urinary bladder. The nervous system is profoundly affected; in one case there were clonic spasms,[500] in another,[501] such muscular rigidity, that the patient could with difficulty be placed on a chair. The lower extremities are often partly paralysed, there is a want of co-ordination, the person reels like a drunken man, or there may be general jactitation. The disturbance of the brain functions is very marked; in about 4 per cent. only of the recorded cases has there been no delirium, or very little—in the majority delirium is present. In adults this generally takes a garrulous, pleasing form, but every variety has been witnessed. Dr. H. Giraud describes the delirium from datura (which it may be necessary to again repeat is atropine delirium) as follows:—“He either vociferates loudly or is garrulous, and talks incoherently; sometimes he is mirthful, and laughs wildly, or is sad and moans, as if in great distress; generally he is observed to be very timid, and, when most troublesome and unruly, can always be cowed by an angry word, frequently putting up his hands in a supplicating posture. When approached he suddenly shrinks back as if apprehensive of being struck, and frequently he moves about as if to avoid spectra. But the most invariable accompaniment of the final stage of delirium, and frequently also that of sopor, is in the incessant picking at real or imaginary objects. At one time the patient seizes hold of parts of his clothes or bedding, pulls at his fingers and toes, takes up dirt and stones from the ground, or as often snatches at imaginary objects in the air, on his body, or anything near him. Very frequently he appears as if amusing himself by drawing out imaginary threads from the ends of his fingers, and occasionally his antics are so varied and ridiculous, that I have seen his near relatives, although apprehensive of danger, unable to restrain their laughter.”[502] This active delirium passes into a somnolent state with muttering, catching at the bedclothes, or at floating spectra, and in fatal cases the patient dies in this stage. As a rule, the sleep is not like opium coma; there is complete insensibility in both, but in the one the sleep is deep, without muttering, in the other, from atropine, it is more like the stupor of a fever. The course in fatal cases is rapid, death generally taking place within six hours. If a person live over seven or eight hours, he usually recovers, however serious the symptoms may appear. On waking, the patient remembers nothing of his illness; mydriasis remains some time, and there may be abnormality of speech and weakness of the limbs, but within four days health is re-established. In cases where the seeds have been swallowed, the symptoms may be much prolonged, and they seem to continue until all the seeds have been voided—perhaps this is due to the imperfect but continuous extraction of atropine by the intestinal juices.

Chronic poisoning by atropine may, from what has been stated, be of great importance in India. It is probable that its continuous effect would tend to weaken the intellect, and there is no reason for any incredulity with regard to its power as a factor of insanity. Rossbach has ascertained that if dogs are, day after day, dosed with atropine, they become emaciated; but a certain tolerance is established, and the dose has to be raised considerably after a time to produce any marked physiological effect.§ 451. Physiological Action of Atropine.—From the numerous experiments on animals which have been performed for the purpose of elucidating the action of atropine, it is clear that the terminations of the vagus in the heart muscle are first excited, and then paralysed. The excitor-motor ganglion is also paralysed, and finally the heart itself; death resulting from heart paralysis. The respiratory disturbance is also to be ascribed to the vagus; the terminations in the lung are paralysed, and, at the same time, the poison circulating through the respiratory nervous centre stimulates it first, and then it also becomes finally paralysed. The small vessels are generally widened after a previous transitory narrowing. Organs containing unstriped muscular fibre are generally paralysed, as well as the ends of the nerves regulating secretion—hence the dryness of the skin. The action on the iris is not thoroughly elucidated.§ 452. The diagnosis of atropine poisoning may be very difficult unless the attention of the medical man be excited by some suspicious circumstance. A child suffering from belladonna rash, with hot dry skin, quick pulse, and reddened fauces, looks not unlike one under an attack of scarlet fever. Further, as before mentioned, some cases are similar to rabies; and again, the garrulous delirium and the hallucinations of an adult are often very similar to those of delirium tremens, as well as tomania.§ 453. Post-mortem Appearances.—The post-mortem appearances do not seem to be characteristic, save in the fact that the pupils remain dilated. The brain is usually hyperÆmic, and in one case the absence of moisture seems to have been remarkable. The stomach and intestines may be somewhat irritated if the seeds, leaves, or other parts of the plant have been eaten; but the irritation is not constant if the poisoning has been by pure atropine, and still less is it likely to be present if atropine has been administered subcutaneously.§ 454. Treatment.—The great majority of cases recover under treatment. In 112 cases collected by F. A. Falck, 13 only were fatal (11·6 per cent.). The greater portion of the deaths in India are those of children and old people—persons of feeble vitality. The Asiatic treatment, which has been handed down by tradition, is the application of cold water to the feet; but the method which has found most favour in England is treatment by pilocarpine, a fifth of a grain or more being injected from time to time. Pilocarpine shows as perfect antagonism as possible; atropine dries, pilocarpine moistens the skin; atropine accelerates, pilocarpine slows the respiration. Dr. Sydney Ringer and others have published a remarkable series of cases showing the efficacy of this treatment, which, of course, is to be combined where necessary with emetics, the use of the stomach-pump, &c.[503]

§ 455. Separation of Atropine from Organic Tissues, &c.—From the contents of the stomach, atropine may be separated by acidulating strongly with sulphuric acid (15 to 20 c.c. of dilute H₂SO₄ to 100 c.c.), digesting for some time at a temperature not exceeding 70°, and then reducing any solid matter to a pulp by friction, and filtering, which can generally be effected by the aid of a filter-pump. The liver, muscles,[504] and coagulated blood, &c., may also be treated in a precisely similar way. The acid liquid thus obtained, is first, to remove impurities, shaken up with amyl alcohol, and after the separation of the latter in the usual manner, it is agitated with chloroform, which will take up any of the remaining amyl alcohol,[505] and also serve to purify further. The chloroform is then removed by a pipette (or the separating flask before described), and the fluid made alkaline, and shaken up with ether, which, on removal, is allowed to evaporate spontaneously. The residue will contain atropine, and this may be farther purified by converting it into oxalate, as suggested, page 374.

From the urine,[506] atropine may be extracted by acidifying with sulphuric acid, and agitation with the same series of solvents. Atropine has been separated from putrid matters long after death, nor does it appear to suffer any decomposition by the ordinary analytical operations of evaporating solutions to dryness at 100°. In other words, there seems to be no necessity for operations in vacuo, in attempts at separating atropine.

TABLE SHOWING THE ALKALOIDAL CONTENT OF VARIOUS PARTS OF THE HENBANE PLANT.

2. HYOSCYAMINE.

§ 456. This powerful alkaloid is contained in small quantities in datura and belladonna, and also is found in the common lettuce (·001 per cent.),[507] and in Scopola carmolica, a solanaceous plant indigenous to Austria and Hungary[508]; but its chief source is the Hyoscyamus niger and Hyoscyamus alba (black and white henbane): it is also found in the Duboisia myoporoides. The latter plant was considered to contain a new alkaloid, “Duboisine,” but duboisine is a mixture of hyoscyamine and hyoscine. Ladenburg’s hyoscine accompanies hyoscyamine, and is an isomeride of both atropine and hyoscyamine; its chemical reactions are similar to those of hyoscyamine, as well as its physiological effects.[509]

Hyoscyamine (C₁₇H₂₃NO₃), as separated in the course of analysis, is a resinoid, sticky, amorphous mass, difficult to dry, and possessing a tobacco-like odour. It can, however, be obtained in well-marked odourless crystals, which melt at 108°-109°, a portion subliming unchanged. It liquefies under boiling water without crystallisation. According to Thorey,[510] hyoscyamine crystallises out of chloroform in rhombic tables, and out of benzene in fine needles; but out of ether or amyl alcohol it remains amorphous. When perfectly pure, it dissolves with difficulty in cold, but more readily in hot, water; if impure, it is hygroscopic, and its solubility is much increased. In any case, it dissolves easily in alcohol, ether, chloroform, amyl alcohol, benzene, and dilute acids. Hyoscyamine neutralises acids fully, and forms crystallisable salts, which assume for the most part the form of needles. It is isomeric with atropine, and is converted into atropine by heating to 110°, or warming with alcoholic potash. The gold salt melts at 159°, and does not melt in boiling water like the atropine gold salt.

§ 457. Pharmaceutical and other Preparations of Henbane.—The leaves are alone officinal in the European pharmacopoeias; but the seeds and the root, or the flowers, may be met with occasionally, especially among herbalists. The table[511] (p. 382) will give an idea of the alkaloidal content of the different parts of the plant.

In order to ascertain the percentage of the alkaloid in any part of the plant, the process followed by Thorey has the merit of simplicity. The substance is first exhausted by petroleum ether, which frees it from fat; after drying, it is extracted with 85 per cent. alcohol at a temperature not exceeding 40°. The alcoholic extracts are then united, the alcohol distilled off, and the residue filtered. The filtrate is now first purified by agitation with petroleum ether, then saturated by ammonia, and shaken up with chloroform. The latter, on evaporation, leaves the alkaloid only slightly impure, and, after washing with distilled water, if dissolved in dilute sulphuric acid, a crystalline sulphate may be readily obtained.

A tincture and an extract of henbane leaves and flowering tops are officinal in most pharmacopoeias; an extract of the seeds in that of France.

An oil of hyoscyamus is officinal in all the Continental pharmacopoeias, but not in the British.

Henbane juice is recognised by the British pharmacopoeia; it is about the same strength as the tincture.

An ointment, made of one part of the extract to nine of simple ointment, is officinal in the German pharmacopoeia.

The tincture (after distilling off the spirit) and the extracts (on proper solution) may be conveniently titrated by Mayer’s reagent (p. 263), which, for this purpose, should be diluted one-half; each c.c. then, according to Dragendorff, equalling 6·98 mgrms. of hyoscyamine. Kruse found 0·042 per cent. of hyoscyamine in a Russian tincture, and ·28 per cent. in a Russian extract. Any preparation made with extract of henbane will be found to contain nitrate of potash, for Attfield has shown the extract to be rich in this substance. The ointment will require extraction of the fat by petroleum ether; this accomplished, the determination of its strength is easy.

The oil of hyoscyamus is poisonous, and contains the alkaloid. An exact quantitative research is difficult; but if 20 grms. of the oil are shaken up for some time with water acidified by sulphuric acid, the fluid separated from the oil, made alkaline, shaken up with chloroform, and the latter removed and evaporated, sufficient will be obtained to test successfully for the presence of the alkaloid, by its action on the pupil of the eye.§ 458. Dose and Effects.—The dose of the uncrystalline hyoscyamine is 6 mgrms. (¹/₁₀ grain), carefully increased. I have seen it extensively used in asylums to calm violent or troublesome maniacs. Thirty-two mgrms. (¹/₂ grain) begin to act within a quarter of an hour; the face flushes, the pupils dilate, there is no excitement, all muscular motion is enfeebled, and the patient remains quiet for many hours, the effects from a single dose not uncommonly lasting two days. 64·8 mgrms. (1 grain) would be a very large, and possibly fatal, dose. The absence of delirium or excitement, with full doses of hyoscyamine, is a striking contrast to the action of atropine, in every other respect so closely allied; yet there are cases on record showing that the henbane root itself has an action similar to that of belladonna, unless indeed one root has been mistaken for another; e.g., Sonnenschein relates the following ancient case of poisoning:—In a certain cloister the monks ate by error the root of henbane. In the night they were all taken with hallucinations, so that the pious convent was like a madhouse. One monk sounded at midnight the matins, some who thereupon came into chapel could not read, others read what was not in the book, others sang drinking songs—in short, there was the greatest disturbance.§ 459. Separation of Hyoscyamine from Organic Matters.—The isolation of the alkaloid from organic tissues or fluids, in cases where a medicinal preparation of henbane, or of the leaves, root, &c., has been taken, is possible, and should be carried out on the principles already detailed. Hyoscyamine is mainly identified by its power of dilating the pupil of the eye. It is said that so small a quantity as ·0083 mgrm. (¹/₄₀₀₀ grain) will in fifteen minutes dilate the eye of a rabbit. It is true that atropine also dilates the pupil; but if sufficient of the substance should have been isolated to apply other tests, it can be distinguished from atropine by the fact that the latter gives no immediate precipitate with platinic chloride, whilst hyoscyamine is precipitated by a small quantity of platinic chloride, and dissolved by a larger amount, and also by the characters of the gold salt.

3. HYOSCINE.

4. SOLANINE.

[517] See “Death of Three Children by S. nigrum”; Hirtz., Gaz. Med. de Strasbourg, 1842; Maury, Gaz. des HÔp., 1864; J. B. Montane, Chim. Med., 1862; Magne, Gaz. des HÔp., 1869; Manners, Edin. Med. Journ., 1867. Cases of poisoning by bitter-sweet berries are recorded in Lancet, 1856; C. Bourdin, Gaz des HÔpitaux, 1864; Bourneville, the berries of S. tuberosum, Brit. Med. Journ., 1859.

5. CYTISINE.

§ 466. The Cytisus Laburnum.—The laburnum tree, Cytisus laburnum, so common in shrubberies, is intensely poisonous. The flowers, bark, wood, seeds, and the root have all caused serious symptoms. The active principle is an alkaloid, to which the name of Cytisine has been given. The best source is the seeds. The seeds are powdered and extracted with alcohol containing hydrochloric acid, the alcohol distilled off, the residue treated with water and filtered through a wet filter to remove any fatty oil, the filtrate treated with lead acetate; and, after separating the precipitated colouring matter, made alkaline with caustic potash, and shaken with amyl alcohol. The amyl alcohol is shaken with dilute hydrochloric acid, the solution evaporated, the crude crystals of hydrochloride thus obtained treated with alcohol to remove colouring matters, and recrystallised several times from water; it then forms well-developed, colourless, transparent prisms. From the hydrochloride the free base is readily obtained.

Cytisine, C₁₁H₁₄N₂O.—To cytisine used to be ascribed the formula C₂₀H₂₇N₃O, but a study of the salt and new determinations appear to prove that it is identical with ulexine.[518] Cytisine is in the form of white radiating crystals, consisting, when deposited from absolute alcohol, of anhydrous prisms, which melt at from 152° to 153°. Cytisine has a strong alkaline reaction; it is soluble in water, alcohol, and chloroform, less so in benzene and amyl alcohol, almost insoluble in cold light petroleum, and insoluble in pure ether. The specific rotatory power in solution is [a]_D17° = -119·57.

It is capable of sublimation in a current of hydrogen at 154·5°; the sublimate is in the form of very long needles and small leaflets; at higher temperatures it melts to a yellow oily fluid, again becoming crystalline on cooling. Cytisine is a strong base; it precipitates the earths and oxides of the heavy metals from solutions of the chlorides, and, even in the cold, expels ammonia from its combinations.

Cytisine forms numerous crystalline salts, among which may be mentioned two platinochlorides, C₁₁H₁₄N₂OH₂PtCl₆ + 2¹/₂H₂O and (C₁₁H₁₄N₂O)₂H₂PtCl₆, crystallising in golden yellow needles, which are tolerably soluble in water; and the aurochloride, C₁₁H₁₄N₂OHAuCl₄, crystallising in short, red-brown, hook-shaped needles; m.p. 212° to 213°, without evolution of gas.§ 467. Reactions of Cytisine.—Concentrated sulphuric acid dissolves cytisine without colour; if to the solution is added a drop of nitric acid, it becomes orange-yellow, and on addition of a crystal of potassic bichromate, first yellow, then dirty brown, and lastly green. Concentrated nitric acid dissolves the base in the cold without colour, but, on warming, it becomes orange-yellow. Picric, tannic, and phosphomolybdic acids, potassic, mercuric, and potass. cadmium iodides, and iodine with potassic iodide, all give precipitates. Neither potassic bichromate nor mercuric chloride precipitates cytisine, even though the solution be concentrated. The best single test appears to be the reaction discovered by Magelhaes; this consists in adding thymol to a solution of cytisine in concentrated sulphuric acid, when a yellow colour, finally passing into an intense red, is produced.§ 468. Effects on Animals.—W. MarmÉ found subcutaneous doses of from 30 to 40 mgrms. fatal to cats; death was from paralysis of the respiration, and could be avoided by artificial respiration. Cattle are sometimes accidentally poisoned by laburnum. An instance of this is recorded in the Veterinarian (vol. lv. p. 92). In Lanark a storm had blown a large laburnum tree down to the ground; it fell into a field in which some young heifers were grazing, and they began to feed on the leaves and pods. Two or three died, and three more were ill for some time, but ultimately recovered.

The laburnum, however, does not always have this effect, for there is a case related in the Gardeners’ Chronicle, in which five cows browsed for some time on the branches and pods of an old laburnum tree that had been thrown aside. Rabbits and hares are said to feed eagerly, and without injury, on the pods and branches.§ 469. Effects on Man.—The sweet taste of many portions of the laburnum tree, as well as its attractive appearance, has been the cause of many accidents. F. A. Falck has been able to collect from medical literature no less than 155 cases—120 of which were those of the accidental poisoning of children: only 4 (or 2·6 per cent.), however, died, so that the poison is not of a very deadly character.

One of the earliest recorded cases is by Christison.[519] A servant-girl of Inverness, in order to excite vomiting in her fellow-servant (the cook), boiled some laburnum bark in soup; very soon after partaking of this soup, the cook experienced violent vomiting, which lasted for thirty-six hours; she had intense pain in the stomach, much diarrhoea, and great muscular weakness; she appears to have suffered from gastro-intestinal catarrh for some time, but ultimately recovered.

Vallance[520] has described the symptoms observed in the poisoning of fifty-eight boys, who ate the root of an old laburnum tree, being allured by its sweet taste. All were taken ill with similar symptoms, differing only in severity; two who had eaten half an ounce (nearly 8 grms.) suffered with especial severity. The symptoms were first vomiting, then narcosis, with convulsive movements of the legs and strange movements of the arms: the pupils were dilated. This dilatation of the pupil Sedgwick also saw in the poisoning of two children who ate the root. On the other hand, when the flower, seeds, or other portions of the laburnum have been eaten, the symptoms are mainly referable to the gastro-intestinal tract, consisting of acute pain in the stomach, vomiting, and diarrhoea. On these grounds it is therefore more than probable that there is another active principle in the root, differing from that which is in those portions of the tree exposed to the influence of sunlight.[521]

The post-mortem appearances are, so far as known, in no way characteristic.

VII.—The Alkaloids of the Veratrums.

§ 470. The alkaloids of the veratrums have been investigated by Dr. Alder Wright, Dr. A. P. Luff, and several other chemists.[522]

The method which Wright and Luff adopted to extract and separate these alkaloids from the root of V. album and V. viride, essentially consisted in exhausting with alcohol, to which a little tartaric acid has been added, filtering, distilling off the alcohol, dissolving the residue in water, alkalising with caustic soda, and shaking up with ether. The ethereal solution was next separated, and then washed with water containing tartaric acid, so as to obtain a solution of the bases as tartrates: in this way the same ether could be used over and over again. Ultimately a rough separation was made by means of the different solubilities in ether, pseudo-jervine being scarcely soluble in this medium, whilst jervine, veratralbine, veratrine, and cevadine are very soluble in it.

The yield of Wright and Luff’s alkaloids was as follows:—

TABLE SHOWING THE ALKALOIDS IN THE VERATRUMS.

From whence it appears that V. album has only a very small quantity of veratrine, that it is almost absent in V. viride; on the other hand, V. viride contains a fair quantity of cevadine, an alkaloid absent in V. album.

Besides the six principles enumerated, G. Salzberger has recently separated two other crystalline substances, to which he has given the names of protoveratrine and protoveratridine, and Pehkschen has also separated a ninth substance, to which he has given the name of veratroidine.

The formulÆ of the nine bodies which have been separated from hellebore root are as follows:—

Three of these alkaloids possess powerful sternutatory properties, the least quantity applied to the nostrils exciting sneezing; the three are veratrine, cevadine, and protoveratrine.

Protoveratrine, C₃₂H₅₁NO₁₁, has been obtained by G. Salzberger[523] from powdered hellebore root, by the following process:—

The powdered root is first freed from fatty and resinous matters by treatment with ether, and then the fat-free powder is exhausted with alcohol. The alcohol is evaporated off in a vacuum, the extract mixed with much acetic acid water, filtered from the insoluble residue, and treated with metaphosphoric acid; the voluminous precipitate contains much amorphous matter, with insoluble compounds of jervine and rubi-jervine. The precipitate is filtered off, and the filtrate treated with excess of ammonia and shaken up with ether. On separating the ether and distilling, protoveratrine crystallises out, and can be obtained pure by recrystallisation from strong alcohol.

Protoveratrine crystallises in four-sided plates, which melt with charring at 245° to 250°. The base is insoluble in water, benzene, and light petroleum; chloroform and boiling 96 per cent. alcohol dissolve it somewhat; cold ether scarcely touches it, boiling ether dissolves it a little.

Concentrated sulphuric acid dissolves the alkaloid slowly with the production of a greenish colour, which passes to cornflower blue, and, after some hours, becomes violet. Sulphuric acid and sugar gives a different colour to that produced by commercial veratrine. There is first a green colour which darkens into olive green, then becomes dirty green, and finally dark brown. When warmed with strong sulphuric, hydrochloric, or phosphoric acids, there is a strong odour of isobutyric acid developed. Dilute solutions of the salts are precipitated by ammonia, Nessler’s reagent, gold chloride, potassium mercury iodide, cadmium iodide, phosphotungstic acid, and picric acid; no precipitate is produced by tannin, platinum chloride, or mercuric chloride.§ 471. Veratrine (C₃₇H₅₃NO₁₁) is a crystallisable alkaloid, which is a powerful irritant of the sensory nerves of the mucous membrane, and excites violent sneezing. Treated with concentrated sulphuric acid, it dissolves with a yellow colour, deepening into orange, then into blood-red, and finally passing into carmine-red. If the freshly-prepared sulphuric acid solution is now treated with bromine water, a beautiful purple colour is produced. Concentrated hydrochloric acid dissolves veratrine without the production of colour, but, with careful warming, it becomes beautifully red. This reaction is very delicate, occurring with ·17 mgrm. On saponification veratrine yields veratric acid.

Veratric acid is procatechu-dimethylether acid, and has the constitutional formula,

Veratric acid forms colourless needles and four-sided prisms which have a marked acid reaction; it melts on heating to a colourless fluid, and sublimes without decomposition; it is easily soluble in hot alcohol, but insoluble in ether. If dissolved in nitric acid, water separates nitro-veratric acid, C₉H₉(NO₂)O₄ which crystallises out of alcohol in small yellow scales. Veratric acid unites with bases forming crystalline salts; the silver salt has the composition of C₉H₉AgO₄ = 37·37 per cent. silver, and may assist in identification. It is crystalline with a melting point of 205° to 206°.

Cevadine, C₃₂H₄₉NO₉ (Merck’s veratrine).—It has powerful sternutatory properties, and, under the influence of alcoholic potash, yields tiglic[524] acid and cevine, C₂₇H₄₃NO₈.

According to Ahrens, angelic acid is first formed, and then converted into tiglic acid. When the alkaloid is boiled with hydrochloric acid, tiglic acid is formed, and a ruby red mass. Nitric acid oxidises cevadine completely; with potassic permanganate it yields acetic and oxalic acids; with chromic acid it forms acetaldehyde and carbon dioxide.[525]

The Continental authorities always give to cevadine the name of veratrine. Cevadine forms a crystalline aurochloride, a crystalline mercurochloride, C₃₂H₄₉NO₉HHgCl₃, and a crystalline picrate, C₃₂H₄₉NO₉C₆H₃N₈O₇. The mercury salt crystallises in small silvery plates, and melts with decomposition at 172°. The picrate forms stable crystals blackening at 225°; both of the latter salts are but little soluble in water, but are soluble in alcohol. Cevadine also unites with bromine, forming a tetrabromide, an amorphous yellow powder insoluble in water, but readily soluble in alcohol, ether, and chloroform.§ 472. Jervine, (C₂₆H₃₇NO₃2H₂O) (Wright and Luff), C₁₄H₂₂NO₂ (Pehkschen),[526] crystallises in white needles, and, when anhydrous, melts at 237·7°. It is slightly lÆvorotatory. At 25° one part of the base dissolves in 1658 benzene, 268 ether, 60 chloroform, and 16·8 absolute alcohol. It is insoluble in light petroleum, and but slightly soluble in ethyl acetate, water, or carbon bisulphide. It forms a very insoluble sulphate, and a sparingly soluble nitrate and hydrochloride. Jervine gives, with sulphuric acid and sugar, a violet colour, passing to blue. Treated with strong sulphuric acid it dissolves to a yellow fluid, which becomes successively dark yellow, brownish yellow, and then greenish. The green shade is immediately developed by diluting with water. Jervine does not produce sneezing.

§ 473. Pseudo-jervine, C₂₉H₄₃NO₇ (Wright), m.p. 299°; C₂₉H₄₉NO₁₂, m.p. 259° (Pehkschen), may be obtained in a crystalline state. One part is soluble in 10·9 parts of light petroleum, 372 parts of benzene, 1021 parts of ether, 4 of chloroform, and 185 of absolute alcohol. The pure base gives no colour with sulphuric, nitric, or hydrochloric acids. It does not produce sneezing.§ 474. Protoveratridine, C₂₆H₄₅NO₈, is probably derived from protoveratrine. Salzberger[527] isolated it from powdered hellebore roots by treating the powder with barium hydroxide and water, and extracting with ether. The ether extract was separated and freed from ether in a current of hydrogen at a low temperature.

From the dark green syrup obtained jervine crystallised out, and from the mother liquor ultimately protoveratridine was separated.

Protoveratridine crystallises in colourless four-sided plates, which melt at 265°. It is almost insoluble in alcohol, chloroform, methyl alcohol, and acetone, and insoluble in benzene, light petroleum, and ether. Concentrated sulphuric acid gives a violet, then a cherry-red colour. Its solution in concentrated hydrochloric acid becomes light red on warming, and there is an odour of isobutyric acid. It is readily soluble in dilute mineral acids, and the solution, on the addition of ammonia, yields the alkaloid in a crystalline condition. The sulphuric acid solution gives precipitates with phosphotungstic, picric, and tannic acids, and with potassium mercury iodide; but gives no precipitate with platinum chloride, potassium-cadmium iodide, or with Millon’s reagent.

It forms a platinum salt, (C₂₆H₄₅NO₈)₂H₂PtCl₆ + 6H₂O, which is precipitated in large six-sided plates on adding alcohol to a mixed solution of platinum chloride and a salt of the base.