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 investigations 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 intravenously. As far as could be judged by appearance, healthy animals 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 RABBITS.
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 experiments 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 seasons 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 subcutaneously. 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.
Series A.