introduced directly into the stomach by means of a temporary gastric fistula. Ten grains given in meat to a dog caused restlessness, but no other symptoms. Doses of 30 grains and above were invariably fatal. Seventy-three grains given to a cat caused death within 20 minutes.

From observations on frogs, guinea pigs, rabbits, and on one dog, Leven⁵³ (1868) concluded that caffein which he gave in the form of the citrate in doses of 10 mg to frogs, from 150 to 200 mg to guinea pigs, and three to four times the latter amount to rabbits, stimulates the central nervous system and the voluntary, cardiac, and smooth muscles. He found that 0.9 gram caffein was fatal for a rabbit when injected subcutaneously, while 1 gram of the citrate was not toxic for a dog of medium size. Caffein applied directly to muscle fiber causes tetanus and destroys muscular contractility, while a nerve fiber similarly treated loses its irritability.

According to Johansen⁴⁴ (1869), caffein acts directly on the muscular fiber. After the subcutaneous injection of 0.02 gram of caffein into frogs, he observed contraction of the muscles at the site of injection, then contraction of the anterior extremities, and finally the posterior extremities become rigid and extended. Johansen observed muscular rigidity after caffein, even after curara was injected, or after ligating the vessels, or cutting the nerves which supply the muscles. He also observed that large doses of caffein diminish muscular irritability. When cardiac muscle was poisoned with caffein, microscopical examination showed that the striations disappeared. Johansen also states that reflexes disappear after caffein poisoning. He never observed tetanus in frogs, but reported tonic and clonic convulsions as a result of caffein poisoning in mammals. Somewhat different effects of caffein in frogs were observed by Buchheim and Eisenmenger¹⁴ (1870). After the injection of 2 per cent of the citrate the frogs soon become inactive. He also observed muscular twitching of the extremities, which gradually increased, with rigidity of the muscles and opisthotonos, while respiration became slow and superficial, finally stopping altogether.

Aubert⁶ (1872) studied the toxicity of caffein in man and other animals. After the ingestion of 0.36 gram, he observed dizziness, but doses of 0.12 and 0.24 gram were without any apparent effect. On the other hand, a dose of 0.5 gram of caffein was followed by increased frequency of the pulse, which soon disappeared. After one hour he noticed dizziness and trembling of the hands, which likewise passed away soon. The injection of 0.16 gram of a 2 per cent solution of caffein into the jugular vein of a rabbit weighing 1,090 grams caused tetanus and death in two and one-half minutes, and 0.12 gram injected into a rabbit weighing 980 grams caused death in one minute. Much larger doses could be borne, however, when artificial respiration was resorted to. A dog which was given 3 grams of caffein survived when artificial respiration was performed. Aubert reports, on the other hand, a similar experiment with 0.25 gram of caffein which terminated fatally.

That caffein may give rise to different effects in various species of animals was observed for the first time by Bennett.⁹ He studied its action on frogs, mice, rabbits, and cats, and attempted to determine the minimum fatal dose in rabbits and cats. He also reported experiments with thein. In his first communication on the subject he states that the administration of thein to rabbits first increased and then diminished the frequency of respiration, while the pulse was decreased in frequency. Caffein, which he apparently thought was different from thein, caused increased frequency of respiration, while the pulse was markedly retarded after a preliminary acceleration. He also noticed congestion of the ears, muscular incoordination, tetanus, paralysis, diminished reflexes, and contraction of the pupils. Bennett reported the minimum fatal dose of caffein for a rabbit weighing 3.25 pounds as being 5.25-5.5 grains. The symptoms in cats after the administration of toxic doses of thein or of caffein were great excitement, paralysis alternating with convulsions, and profuse salivation. The minimum fatal dose for a cat weighing 5 pounds was, according to Bennett, 6 grains of caffein and 5.5 grains of thein. Only one experiment on a mouse is reported; the administration of 0.1 grain proved fatal. The symptoms were the same as those observed in cats and rabbits after the administration of caffein. The experiments on frogs indicate that the symptoms were about the same as those previously described in the case of warm-blooded animals except that the reflexes are almost completely lost after the subcutaneous injection of doses of one-sixteenth to one-twelfth of a grain. The latter dose was fatal for frogs. It would be of interest to know the comparative toxicity of caffein to frogs and mammals, but unfortunately the weights were not reported.

Schmiedeberg⁷⁹ (1874) noticed that the administration of 20 mg of caffein to frogs weighing about 45 grams was followed, in Rana esculenta, in about 25 minutes, by increased reflexes, 7 minutes later by tetanus. Several attacks occurred, but tonic spasms were never observed. On the contrary, when the same amount of caffein was given to Rana temporaria weighing 45 grams he noticed a marked diminution of the reflexes and tonic rigidity of the muscles after 23 minutes; the reflexes were greatly increased, however, about 24 hours later. The frogs were under observation for three days, and although symptoms were still present at the end of this time in the subjects of both species tetanus was never observed in Rana temporaria.

Peretti's⁷⁰ (1875) studies on the effects of caffein were confined chiefly to observations on dogs. He also made observations on a few rabbits and reported an experiment on one cat to which he administered, by subcutaneous injection, 0.18 gram of caffein per kilo and noticed increased frequency in lachrymation and crying. The cat was found dead the next day. The subcutaneous injection of a rabbit in which artificial respiration was instituted with 0.36 gram of caffein per kilo proved fatal soon after the injection without any manifestation of symptoms. Small doses of caffein, 0.1 gram, given to a rabbit weighing 3,670 grams, failed to produce any visible effects. Doses under 0.1 gram per kilo likewise failed to induce any symptoms in dogs. When 0.1 gram of caffein per kilo was given by mouth or subcutaneously it was followed by restlessness, salivation, rigidity of hind legs, and vomiting. In both instances the dogs recovered. The symptoms were more severe when the dose was increased to 0.185 gram per kilo, but even in this case the dog recovered. A dose of 0.2 gram per kilo, however, proved fatal.

Henneguy