Conium. N. F. IV (U. S. P. VIII). Hemlock. Poison Hemlock. Spotted Hemlock or Parsley. Fool's Parsley. St. Bennett's Herb. Spotted Cowbane. Herba Cicutae (Majoris). Cigue officinale, ou Grande Cigue (Feuille), Fr. Cod. Feuilles de grande Cigue, Fr. Herba Conii, P. G. Schierlingskraut, Schierlingsblätter, Schierling, Gefleckter Schlierling, G. Foglie di cicuta maggiore, It. Cicuta major, Sp.—Formerly the fruit of the Conium maculatum was official in both the United States and British Pharmacopoeias and the leaves in the British Pharmacopoeia. The fruit has now been introduced into the National Formulary IV, where it is described as "the full grown, but unripe fruit of Conium maculatum Linne (Fam. Umbelliferae), carefully dried and preserved, and yielding not less than 0.5 per cent. of confine. After being kept for more than two years, Conium is unfit for use. Broadly ovoid, greenish-gray, the two mericarps of most of the fruits separated, each about 3 mm. in length and about 1.5 mm. in diameter, ovoid, somewhat curved, the inner, flattened side marked by a deep longitudinal groove, the outer, convex side with five, pale yellow, somewhat crenate ribs, the intervening surfaces wrinkled but otherwise smooth; pericarp without oil tubes. Odor slight, but when triturated with a solution of potassium hydroxide, strong, disagreeable, and mouse-like; taste characteristic, disagreeable, afterwards somewhat acrid. Transverse sections of the mericarp, when examined under the microscope, exhibit a pentangular outline, the angles projecting and forming the ribs, four of the sides being almost equal in length, the fifth or commissural side being about twice as long as one of the dorsal sides and usually concave near the middle; a distinct fibro-vascular bundle at each angle composed of thick-walled fibers about 0.013 mm. in diameter and a few tracheae; epidermis consisting of one layer of cells which are sometimes slightly centrifugally developed, hairs are absent; pericarp thin, without vittae, enclosing a single seed and extending inwardly on the commissural side for about one-third the diameter of the section; the inner epidermis of the pericarp composed of two layers of cells with yellowish-brown walls, the outer layer with cells from 0.06 mm. to 0.12 mm. in tangential length and with thickened radial and inner walls, the inner layer with thin-walled cells from 0.03 to 0.06 mm. in tangential length and about 0.03 mm. in radial diameter; the seed coat composed of small, thick-walled cells about 0.015 mm. in radial diameter; often obliterated; a large endosperm or central portion being somewhat pentangular-rounded in outline, with a deep channel on the commissural side and composed of polygonal parenchyma cells; the latter contain globules of fixed oil and aleurone grains with rosette aggregates of calcium oxalate. The powdered drug is greenish-gray and, when examined under the microscope, exhibits numerous angular or rounded, light colored fragments of endosperm tissue, composed of parenchyma cells containing fixed oil, aleurone grains and rosette aggregates of calcium oxalate, the latter from 0.002 to 0.006 mm. in diameter; a few more or less curved groups of lignified fibers; fragments of the seed coat with yellowish-brown walls; a few rounded starch grains about 0.005 mm. in diameter; spiral or annular tracheae few; numerous oil globules on mounting the powder in hydrated chloral T.S. Conium yields not more than 8 per cent. of ash." N. F. Conium fruit (Conii fructus) is sometimes incorrectly called conium seed. The hemlock leaves (Conii folia) were described as "the fresh leaves and young branches of Conium maculatum Linn., collected when the fruit begins to form." Br., 1898.
Conium maculatum is an umbelliferous plant, having a biennial spindle-shaped whitish root, and an herbaceous branching stem, from three to six feet high, round, hollow, smooth, shining, slightly striated, and marked with brownish-purple spots. The lower leaves are tripinnate, more than a foot in length, shining, and attached to the joints of the stem by sheathing petioles; the upper are smaller, bipinnate, and inserted at the division of the branches; both have channelled footstalks, and incised leaflets, which are deep green on their upper surface and paler beneath. The flowers are very small, white, and disposed in compound terminal umbels. The general involucre consists of from three to seven lanceolate, reflected leaflets, whitish at their edges; the partial involucre of three or four leaflets, oval, pointed, spreading, and on one side only. There are five petals, cordate, with their summits inflected, and nearly equal. The stamens are spreading, and about as long as the corolla; the styles diverging.
Conium is a native of Europe, and has become naturalized in America from Quebec to Pennsylvania, where it is also cultivated for medicinal purposes. The term cicuta, which has often been applied to this plant, belongs to a different genus. It grows usually in clusters along the roadsides or in waste grounds, and is found most abundantly near old settlements. It flowers in June and July. The whole plant, especially at this period, exhales a fetid odor, compared by some to that of mice, by others to that of the urine of cats, and narcotic effects result from breathing for a long time air loaded with the effluvia. The plant varies in narcotic power according to the weather and climate, being most active in hot and dry seasons and in warm countries. The hemlock of Greece, Italy, and Spain is said to be much more energetic than that of the north of Europe. As a rule, those plants are most active which grow in a sunny exposure. The proper season for gathering the leaves is when the plant is in flower, and Fothergill asserts, from experiment, that they are most active about the time that the flowers begin to fade. The footstalks should be rejected, and the leaflets quickly dried, either in the hot sun, or on tin plates before a fire, or by a stove-heat not exceeding 48.8° C. (120° F.). They should be kept in boxes or tin cases, excluded from the air and light, by exposure to which they lose their fine green color and become deteriorated. The same end is answered by pulverizing them, and preserving the powder in opaque and well-stoppered bottles. But little reliance can be placed on the dried leaves, as, even when possessed of a strong odor and a fine green color, they may be destitute of the narcotic principle. When rubbed with potassium hydroxide they should exhale the odor of coniine. The fruit retains its activity much longer than the leaves. Commercial conium occasionally contains other umbelliferous plants, or it may be almost wholly composed of such plants, and even anise has been used as an adulterant to the fruit. (See Anise.)
The dried leaves of conium have a strong, heavy, narcotic odor, less disagreeable than that of the recent plant. Their taste is bitterish and nauseous; their color a dark green, which is retained in the powder. A slight degree of acridity possessed by the fresh leaves is said to be dissipated by drying. Water distilled from the fresh leaves has the odor of conium, and a nauseous taste, but does not produce narcotic effects. Upon destructive distillation, the leaves yield a very poisonous empyreumatic oil. Geiger first obtained the active principle in a separate state, the volatile alkaloid coniine or conine. As it exists in the plant in combination with an acid it is not readily volatilized, but it freely comes over with the distillate when an alkali has been previously added. The acid of conium, Peschier believed to be peculiar, and named coniic acid, but other observers assert that it is malic acid. For methods of isolating conium, see U. S. D., 19th ed., p. 393. The seeds contain most of this principle; but even in these it exists in very small proportion. From six pounds of the fresh or nine of the dried seeds, Geiger obtained about an ounce of coniine, while from 100 pounds of the fresh herb only a drachm, and from the dried leaves none. Farr and Wright (P. J., 1896, 273) confirm the views of Harley and Manlius Smith and affirm that green fruits are alone reliable. The volatility and tendency to undergo decomposition of coniine probably has its effect even in the dried unripe seed, otherwise it is difficult to explain the fact that in thirteen analyses of commercial conium fruit made by Fan-and Wright, the average alkaloidal contents were 0.674; while the average of sixteen analyses of samples collected by themselves was 2.13. (P. J., Feb., 1904.) For a method of assaying conium fruit, by Schwickerath, see Ph. Rec., 1893, 282. The N. F. IV adopted the following assay process, requiring that conium should yield not less than 0.5 per cent. of coniine:
Assay.—"Place 15 Gm. of Conium, in No. 40 powder, in a 250 mil Erlenmeyer flask, add 150 mils of purified petroleum benzin and then 15 mils of solution of sodium hydroxide, insert the stopper securely, and shake the flask vigorously at frequent intervals during six hours. Allow the mixture to settle and decant 100 mils of the clear benzin solution (representing 10 Gm. of the drug) into a separator; extract the alkaloid by shaking with successive portions of weak hydrochloric acid until a few drops of the last washing gives no precipitate with iodine T.S. Collect the acid washings and concentrate by evaporation on a water bath to 10 mils, cool and transfer the liquid to a separator, then cautiously add sodium carbonate in excess. Extract the alkaloid by shaking out with successive portions of 15 mils each of purified petroleum benzin. Separate the benzin washings and filter into a beaker. Then add exactly 10 mils of tenth-normal sulphuric acid V.S. and stir thoroughly for two minutes so as to mix the acid and benzin solution. Evaporate the benzin layer in a current of warm air, at a temperature not exceeding 60° C. (140° F.), and as soon as the benzin has disappeared, cool, add five drops of cochineal T.S. or methyl red T.S. and titrate the acid solution with fiftieth-normal potassium hydroxide V.S. Each mil of tenth-normal sulphuric acid V.S. consumed corresponds to 0.0126 Gm. of coniine. Calculate the amount of coniine neutralized by the acid, and multiply the result by ten to obtain the percentage of coniine in the drug." N. F.
Harley has found in the root three proximate principles, one a very bitter resin, which he names conamarine, and the two others crystallizable bodies, named respectively rhizoconin, and rhizo-conolein. They are all neutral, and, so far as known, medicinally inert. (See P. J., Aug., 1867.)
Coniine, C8H17N, has been thoroughly studied by Hofmann (1881), who established the correct formula as given, instead of C8H15N, as it was formerly assumed, and Ladenburg (1886) effected its synthesis from allyl pyridine by reduction with sodium in alcoholic solution: C5H4(C3H5)N+8H = C5H10(C3H7)N.
This reaction gives a-normal propyl piperidine, which is optically inactive, but by the crystallization of its tartrate splits into coniine (dextrorotatory) and a very similar laevorotatory coniine, just as racemic acid splits into dextrorotatory and laevorotatory tartaric acid.
Coniine is in the form of a yellowish oily liquid, of sp. gr. 0.862, of a very acrid taste, and a strong penetrating odor, compared to that of the urine of mice, and recalling the odor of fresh hemlock, though not identical with it. In volatility it resembles the essential oils, readily rising with the vapor of boiling water, -but when unmixed requiring for ebullition a temperature of 166° C. (330.8° F.). It is freely soluble in alcohol, ether, and the fixed and volatile oils, and slightly so in water. It unites with about one-fourth of its weight of water to form a hydroxide. It reddens turmeric, and neutralizes the acids, forming with them soluble salts, some of which are crystallizable. With tannic acid it forms an insoluble compound. Like ammonia, it occasions a white cloud when approached by a rod moistened with hydrochloric acid; and the resulting hydrochloride is crystallizable, and not in the least deliquescent. The hydrochloride may also be obtained as a brilliant crystalline mass by dissolving coniine in anhydrous ether and passing dry hydrochloric acid gas through the solution. The salt is very soluble in water and alcohol, but insoluble in ether. It can be heated to 90° C. (194° F.) without decomposition, and melts at 218° C. (424.4° F.). Coniine coagulates albumin, and precipitates the salts of aluminum, copper, zinc, manganese, and iron. It also precipitates silver nitrate, but in excess redissolves the precipitate. Most of its salts are decomposed by evaporation. When exposed to tlie air, it speedily assumes a deep brown color, and is ultimately converted into a resinous matter, and into ammonia, which escapes. Under the influence of heat this change takes place with much greater rapidity. The presence of coniine may be detected in an extract or other preparation of hemlock by rubbing it with potassium hydroxide, which instantly develops its peculiar odor. It is a most energetic poison.
In association with coniine in the hemlock are found also the following bases: Ethyl-piperidine, C7H15N or C5H10(C2H2)N; Methyl-coniine, C9H12N or C5H9(C3H7)N(CH3); Conhydrine, C8H17NO or C5H9 (CHOH.CH2CH3)NH; Pseudo-conhydrine, C8H17NO or C5H9(CH3.CH2OH.CH)NH. Methyl-coniine, first obtained by Kekule and von Planta in commercial coniine, is of minor importance.
Conhydrine is crystallizable, fusible below 100° C. (212° F.), and volatilizable at a higher temperature, diffusing an odor much like that of coniine. Water dissolves it considerably, ether and alcohol freely; and the solution has a strong alkaline reaction. Its formula is given as C8H17NO. By the action of P2O5.or fuming hydrochloric acid upon conhydrine, is obtained coniceine, C8H15N, and water. It may be separated from coniine by exposing the mixed alkaloids to a freezing mixture, expressing, and then repeatedly crystallizing from ether. (Gmelin, xiii, 169.) E. Merck obtained a small quantity of a new alkaloid from the high boiling portion of crude coniine. The isolation was accomplished by fractional distillation in vacuo and recrystallization. The alkaloid crystallizes in needles, is easily soluble in water, alcohol, ether, benzene, and chloroform, fuses at about 98° C. (208.4° F.), and boils at 230° to 232° C. (446°-449.6° F.). According to Ladenburg, the alkaloid is an isomer of conhydrine, having the formula C8H27NO, and for this reason the name pseudo-conhydrine was selected. (Chem. Cb., 1891, 414; see also P. J., 1891, 1170.)
Paraconiine.—Coniine was supposed to have been artificially produced by Hugo Schiff. From the reaction of butyric aldehyde with an alcoholic solution of ammonia, he obtained two bases, one of which, dibutyraldine, yielded, on distillation, first a neutral oily substance, and afterwards a strong alkaline base, which proved to have the physiological properties of natural coniine, but was optically inactive, while true coniine is dextrorotatory. Since the change in the formula of true coniine it will be seen that the base paraconiine, which is C8H15N, is not even isomeric with coniine.
Uses.—Hemlock or conium is supposed to be the narcotic used by the Athenians to destroy the life of condemned individuals, and by which Socrates and Phocion died. It was also used by the ancients as a medicine, but fell into entire neglect until Storck employed and extravagantly praised it. Though fatal to some animals, hemlock is eaten with impunity by others, as horses, goats, and sheep.
The alkaloids of conium all have the same physiological properties, although there is a difference in the degree of their power. Their most important effect is a paralysis of the peripheral endings of the motor nerves. In the account of the death of Socrates reference is made to loss of sensation as one of the prominent symptoms of his poisoning and there is evidence that the drug has an effect upon the sensory as well as upon the motor nerves, but the dominant action is certainly upon the motor system. Hayashi and Muto (A. E. P. P., 1901, xlviii) have shown that the phrenic nerve is more susceptible to the drug than the other motor nerves of the body. It is evident, therefore, that if given in sufficient dose to control spasms, conium would stop the movements of the diaphragm and therefore cause death through asphyxia.
The drug has, however, been used in spasmodic disorders, such as whooping cough, paralysis agitans, and acute mania and by some with asserted good results. It was in the days of superstitious medicine believed to exercise an alterative effect in scrofulous and similar diatheses, but was long ago abandoned for this purpose.
Coniine acts precisely as does hemlock, and may be used for the same purposes. The dose is from one-fortieth to one-twelfth of a grain (0.0015-0.005 Gm.). Its solution has been used locally in the spasmodic contraction of the orbicularis oculi and ophthalmia, with photophobia in scrofulous children. For these purposes from one-half to one per cent. may be employed.
Various salts, including the hydrochloride and the benzoate have been prepared, but the hydro-bromide is the one most frequently used. This occurs in colorless prismatic needles, soluble in water and alcohol, less so in ether and chloroform, inodorous and almost tasteless, and are not deliquescent. It should, be kept in the dark, otherwise it assumes a red tint. The salt has been used in the treatment of whooping cough. The usual dose of this salt is from one-sixtieth to one-twelfth of a grain, but in tetanus as high as. one-sixth of a grain (0.01 Gm.) has been given. In sciatica- it has been employed hypodermically in quantities of one-twelfth of a grain (0.005 Gm.) with good results. (Report, de Pharm., 1876, p. 369; 2v. R., 1876, 1879, pp. 18, 178.) For an account of Harley's experiments to determine the relative value of different preparations of conium, see U. S. D., 18th ed., p. 451. He concluded that the green fruit, as the basis of tinctures and extracts, is superior to any other part of the plant, and the spirituous extract of the green fruit should be substituted for the almost worthless extract of the former Br. Pharm. (P. J., 1871, p. 585.)
Dose, of conium, three to five grains (0.2 to 0.32 Gm.).