18 THE TOXICITY OF CAFFEIN. 



This review of the literature on the toxicity of caffein, although 

 bearing evidence of considerable investigation and extending over 

 three-quarters of a century, is largely qualitative in character. It 

 appears from the experiments that the main object of the investiga- 

 tions was to ascertain the nature of the action of caffein, whether it 

 is a muscle or a nerve poison. The comparative toxicity in different 

 species of animals by the accurate determination of the toxic and 

 fatal doses received but little attention. To fill the gap in our 

 knowledge of the toxic effects of caffein, the present investigation 

 was undertaken. This, it will be seen, proved to be a most laborious 

 task, because in the large number of experiments careful observations 

 showed that individuals of the same species varied considerably in 

 their reaction to the drug. Numerous other factors, as will be shown, 

 were also found to play an important part in the determination of the 

 toxicity of caffein. 



ACUTE CAFFEIN INTOXICATION. 



The object of these experiments was to determine the resistance 

 to caffein in various species of animals and by various methods of 

 administration. Caffein was therefore given by mouth and injected 

 subcutaneously into the peritoneal cavity, into the muscles, and in- 

 travenously. As far as could be judged by appearance, healthy ani- 

 mals were selected for the subjects of the experiments, but as it is 

 impossible to diagnose with any degree of accuracy the condition of 

 the animal while it is alive, post mortem examinations were resorted 

 to in many cases in which the issue of the experiment was fatal. 

 Since the age of the animal may modify toxicity full grown, as well 

 as young, animals were employed for these experiments; diet, race, 

 and season also play an important part in determining the toxicity 

 of a drug and these factors were also taken into account in the present 

 investigation. 



EXPERIMENTS ON BABBITS. 



Animals of different varieties were used and were given caffein by all of the methods 

 indicated in the preceding paragraph. Some of the rabbits employed in these experi- 

 ments received oats, others received a diet exclusively of carrots for several days or weeks 

 previous to the administration of caffein. The experiments were conducted at all sea- 

 sons of the year. 



SUBCUTANEOUS INJECTION. 



From a study of the literature on the toxicity of caffein it seemed that about 150 mg 

 per kilo is probably the lethal dose for the rabbit when the drug is injected subcuta- 

 neously. Preliminary observations were therefore carried out with such a dose, but 

 it was found, on the contrary, that this amount per kilo was hardly sufficient to induce 

 symptoms in the great majority of cases. 



