its toxicity is shown by the evidence obtained in experiments on tolerance and cumulative action of drugs; for the toxicity of a substance may diminish when the substance is given steadily for a long time if the body acquires tolerance for it. Arsenic, morphin, and cannabis indica may be cited as illustrations of drugs, the toxicity of which decreases with repeated doses, while digitalis and lead show a tendency to increased toxicity when similarly administered. Moreover the acute and chronic effects are sometimes qualitatively different. According to Igersheimer⁴¹ the symptoms in acute atoxyl intoxication are nausea, vomiting, and diarrhea. These symptoms are absent in chronic intoxication, in which trophic disturbances of the skin and inflammation of the mucous membranes were the effects produced. That the acute action of atoxyl differs from the chronic effects was likewise shown by experiments on animals. The studies of von Anrep⁵ on chronic atropin intoxication are of interest in this connection, as he found that after 10 to 15 injections of atropin there is no manifestation of symptoms such as is observed in acute intoxication, while the effects on the circulation are also less marked, the acceleration of the pulse being less than after the same dose in a normal subject not accustomed to its use. When the administration of atropin is continued for a longer time its usual effects on the pulse disappear altogether; there is, on the contrary a decreased frequency of the pulse. If atropin has been administered for from two to three weeks, respiration is likewise affected.

HISTORICAL REVIEW OF THE LITERATURE ON THE TOXICITY OF CAFFEIN.

Caffein was discovered in 1820 by Runge,⁷⁷ Pelletier,⁶⁰ and Robiquet⁷⁵ and was first analyzed by Dumas and Pelletier,²⁰ but its exact percentage composition was determined by Pfaff and Liebig,^{71, 72} while to Herzog ^{13, 18} belongs the credit of having established that it is basic. Strecker⁸² prepared caffein synthetically by heating theobromin silver and methyl iodid in a closed tube for 24 hours. Soon after its discovery in coffee Oudry⁶⁷ reported the presence of a substance in tea which he called "thein." Its identity with caffein was established 15 years later by Jobst⁴³ and also by Mulder.^{62, 63} According to Brill,¹³ Mulder (1838) was also the first to perform experiments with caffein on animals. After the administration of one-half grain to a pregnant rabbit he observed loss of appetite and kyphosis. The rabbit aborted but recovered from the effects of caffein. It has since been made the subject of numerous investigations which were carried out on a variety of animals. Observations with caffein were also made on the human subject. About four years after Mulder published his results, Lehmann⁵¹ (1842) reported experiments on a number of people who were given caffein. The administration of from 2 to 10 grains of the alkaloid was followed by headache, palpitation of the heart, increased frequency and irregularity of the pulse, tinnitus aurium, photopsia, insomnia, and even delirium. Similar experiments reported by Frerichs²⁵ (1846) indicate that in doses of 25 grains it may induce severe symptoms about 15 minutes after its administration. He also observed circulatory as well as nervous symptoms and vomiting.

According to Albers² (1852), 4.5 grains of caffein citrate injected subcutaneously into the thigh of a rabbit was soon followed by diminished motion and tremors of the operated thigh. Other symptoms reported were spasms of the facial muscles, increased respiratory movements, and mental confusion. Of interest in this connection are the experiments of Cogswell¹⁷ (1852) on frogs. He concluded that in point of destructive action on the tissues, caffein is far superior to morphin and may be compared to strychnin and coniin, its action on the nervous system he believed to be principally confined to the effect on the brain and spinal cord.

Lehmann⁵² (1853) observed increased frequency of heart action after the administration of 4 grains, which were given with a normal diet to an adult man. When the dose was doubled the frequency of the pulse was still more increased, heart action became stronger, and tremors and confusion of thought with excitement of the imagination made their appearance. There was also an increased desire to micturate.

Stuhlmann and Falck⁸³ (1857) were the first to make a study of the toxicity of caffein on animals