The Active Principle of Indian Hemp.
(From the Indian Medical Gazette)
By SURGEONS WARDEN AND WADDLE, Bengal Medical Service.
One of the most serious drawbacks to the medicinal use of this powerful drug (Cannabis Indica) is that we cannot depend upon its preparations being possessed of activity; moreover, the large amount of resin in each dose is often productive of gastric disturbance. These objections would at once be overcome were we able to extract from the resin its active principle.
Since 1839, when Sir W. O'Shaughnessy, of Calcutta, brought the peculiar properties of Indian hemp prominently to the notice of the medical world, ("On Indian Hemp or Gunjah," Calcutta, 1839; also "Bengal Dispensatory," Calcutta, 1842, pp. 579-601.) several attempts have been made to isolate the active principle of the plant with remarkably conflicting results.
In 1846, Smith (Pharm. Journ., vol. vi., p. 171. In Ph. Jour. April 18,1885, Thos. Smith describes the effects upon himself of his cannabin, and states that it was not a simple principle and after keeping for three years, had become inert.) separated a resin which he called "cannabin," and which he believed to be the active principle; and said that it possessed much narcotic activity. No subsequent observers, however, have been able to obtain by the process employed by Smith, any body which fully answers to the description of Smith's "cannabin."
In 1857, Personn (Journal de Pharm., xxxix., p. 48.) resolved the volatile oil, obtained by distillation of the plant, with water, into cannabene (C18H20) a light hydrocarbon, and a solid crystalline hydride of cannabene (C18H22). He states that inhalation of the vapor of cannabene produces a powerful physiological effect, and he claims it as being the sole active principle of Indian hemp.
In 1876, Preobraschensky, (Pharm. Zeitsch. f. Russland, p. 705.) operating on "hashish" got from Turkestan, asserted that the active principle was not a resin, but an alkaloidal body, which he recognized as nicotine, the volatile liquid alkaloid of tobacco. It has been suggested that the presence of nicotine might be due to the hemp having been mixed, as it sometimes is in the bazaars, with tobacco, but Preobraschensky states that he obtained this nicotine from the flowering tops of the plants as well as from the commercial resin.
Merck, of Darmstadt, applies the term "cannabin tannin" to a glucoside contained in Indian hemp which he has combined with tannin. This preparation is not possessed of powerful activity, and frequently is inactive. By treating this tannin compound with zinc oxide Herr Bombelon obtained a substance which he named "cannabinum," as a greenish-brown powder not agglutinating upon exposure to the air and volatilizing without residue on platinum foil. (Pharm. Zeit., May 10, 1884.)
In 1881, Siebold and Bradbury reported to the British Pharmaceutical Conference that Indian hemp does contain a volatile alkaloid which, however, does not possess the characters of nicotine. They called it "cannabinine" and obtained only 2 grains from 10 pounds of hemp. They do not appear to have tested its action physiologically, and so have left it undetermined whether this volatile alkaloid be really the narcotic principle of hemp.
The above chemists thus obtained widely different bodies, yet each individually believed that the substance which he isolated represented the active principle of the drug. With the subject thus involved, and having at hand a supply of fresh and active hemp, we undertook an examination of the plant in the endeavor to isolate its active principle. Since commencing our observations, Dr. Matthew Hay has reported (Pharm. Journ., 1883, p. 998.) that he has isolated an alkaloid in the form of colorless, needle-like crystals, which, however, did not posses the narcotic properties of the plant, but produced tetanus in frogs in exactly the same manner as strychnine-though not chemically identical with it. Dr. Hay, therefore, called this alkaloid "tetano-cannabin." It must exist in the plant in exceedingly minute traces, for only a few grains were obtained from 1 kilogramme of hemp. He considers it a secondary alkaloid of the plant, and not the chief active principle. We have specially investigated this point as to whether the plant contains an alkaloid with tetanizing properties.
The following is a preliminary note of some of our results: One thousand grams of the flowering tops and leaves of Indian hemp of ascertained activity were roughly powdered and then moistened with 1 litre of a 5 per cent. solution of sulphuric acid and allowed to digest at a temperature of 68°F. This mixture was then packed in a percolator and percolated with about 1 litre of distilled water till the fluid which passed through was colorless.
This fluid, after filtration, measured 11 litres, and was of a dark sherry color, smelling very strongly of the characteristic odor of the plant. Carbonate of lime was added to neutralize the free acid, and carbonate of soda solution to render it alkaline. On the addition of the soda a copious precipitate fell down. The unfiltered mixture was then well agitated with ether; and this ethereal layer, which ought to contain any alkaloidal body soluble in ether, was afterwards drawn off and allowed to evaporate spontaneously.
The subjacent liquid which remained after removal of the ethereal layer was evaporated on the water-bath to dryness and then boiled with absolute alcohol and filtered, and the filtrate evaporated on the water-bath. This ought to contain Hay's tetano-cannabin, which is freely soluble in alcohol, but sparingly so in ether.
The ethereal layer, yielded on evaporation about half a gram of a yellowish-brown extract which was insoluble in water, but soluble in a weak solution of carbonate of soda. Of this extract 0.25 grain was injected into the stomach of a young cat without the slightest effect.
The alcoholic solution yielded about 3 grams of a dark greenish-brown extract with a very fragrant aromatic odor. The whole of this was rubbed up well with water and carbonate of soda solution (Hay's alkaloid is "easily soluble in water"); and frequently shaken tip with ether. The ethereal layer was then siphoned off and the ether driven off by evaporation on the water-bath, giving about .2 of a grain of an amorphous light brown substance, which was soluble in about twenty times its weight of distilled water. This watery solution was neutral in reaction. Half of it was injected hypodermically into the thigh of a, cat without any positive result.
It will thus be seen that although operating on so large a quantity of the plant of ascertained activity, we were unable to find any evidence of the existence of such a principle as Dr. Hay describes.
As many of those addicted to the hashish form of intemperance obtain the intoxi-cating effects by smoking the plant in a pipe, it is to be expected that destructive distillation of the freshly prepared resin might yield up the active principle. This process was, therefore, resorted to. By the destructive distillation of the freshly prepared alcoholic extract of the plant to which an excess of caustic potash solution had been added, an amber colored oil was obtained, which, by exposure to the air or the action of alkalies, rapidly became of a dark reddish-brown color. This oil had a mildly empyreumatic odor which was distinctly tobacco-like. Its taste was warm, aromatic and somewhat terebinthinate. The oil contained phenol, ammonia and several other of the usual products of destructive distillation.
The nicotine-like principle contained in this oil appeared to be alkaloid. It formed salts which evolved a strong nicotine-like odor when acted on by alkalies. But physiologically it was found to be inert, and, therefore, was evidently not identical with nicotine.
The oil as a whole was also found to be devoid of any narcotic or irritant qualities. About one-eighth of an ounce was introduced into the stomach of a cat without producing any sensible effect. These results do not coincide with those of Personne, who asserted that the active principle of the plant resided in the volatile oil. It is just possible that the active principle was decomposed by the high temperature necessary for destructive distillation.
The principle which represents the full activity of the plant has yet to be isolated. If the active principle be a body which is actually distinct from the resin, the fact of its being so intimately associated with the resin renders its separation a matter of peculiar difficulty, for it is remarkably difficult to deal chemically with resinous compounds.—Phar. Jour. and Trans., January 17, 1885, p. 574.