The Toxicity of Caffein: An experimental study on different species of animals

EXPERIMENTS ON CATS. All the guinea pigs in these experiments were kept on a diet of hay and oats and were of large size. The tests were made with different doses of caffein in order to determine the limits of toxicity when the drug was administered by mouth. Guinea pig 129. White and black male. Weight, 855 grams. Diet, oats and hay. June 6: 2.20 p. m., 12 cc of 2 per cent caffein (0.28 gram per kilo) by mouth; 3 p. m., reflexes increased; 5 p. m., reflexes still more increased; no other symptoms. June 7: 9 a. m., found dead; guinea pig passed 75 cc urine, which was almost colorless. Autopsy : Heart and blood vessels injected; lungs congested; small intestines congested; other organs apparently normal. Guinea pig 130. Black and brown male. Weight, 800 grams. Diet, oats and hay. June 6: 2.30 p. m., 12 cc of 2 per cent caffein (0.3 gram per kilo) administered by mouth; 3 p. m., reflexes increased; 5 p. m., increase of reflexes greater than at 3 p. m. June 7: 9 a. m., found dead; only a few cubic centimeters of urine passed since 4 p. m. Autopsy : Heart and blood vessels injected; lungs congested; small intestines congested slightly. Guinea pig 181. White and yellow male. Weight, 860 grams. Diet, oats and hay. June 6: 2.40 p. m., 12 cc 2 per cent caffein administered by mouth; 3 p. m., reflexes increased; 5 p. m., reflexes still more marked. June 7: 9 a. m., found dead, pig passed about 5 cc urine since 4 p. m. of previous day. Autopsy : Same as in No. 130. Guinea pig 136. White and black male. Weight, 1,000 grams. Diet, oats and hay. June 9: 4 p. m., 7.5 cc 2 per cent caffein solution injected subcutaneously into the back; 4.50 p. m., reflexes increased. June 10: 9.30 a. m., more sensitive than normal guinea pigs, but reflexes not quite so marked as at 5 p. m. previous day, about 15 cc urine passed since caffein was injected, reduction of Fehling's solution considerable, no albumin. June 13: Alive and in good condition. Appetite good. ( Note. —Parallel test with urine from two guinea pigs which did not receive caffein failed to show reduction of Fehling's solution.) Guinea pig 137. White and brown male. Weight, 925 grams. Diet, oats and hay. June 9: 4 p. m., 7 cc 2 per cent solution caffein injected subcutaneously; 4.50 p. m., reflexes increased. June 10: Reflexes less marked than at 5 p. m. previous day, but is more sensitive than normal guinea pig, about 10 cc urine passed since injection of caffein, moderate amount of reduction of Fehling's solution. June 13: Guinea pig alive, appetite good, condition good. June 16: 9 a. m., found dead. Guinea pig 135. White and black male. Weight, 955 grams. Diet, hay and oats. June 9: 3 p. m., 7.5 cc 2 per cent caffein solution given by mouth through stomach tube; 4.50 p. m., reflexes increased. June 10: Reflexes less than on previous day and less marked than in No. 136, a few cubic centimeters dirty brown urine collected but could not be tested for reduction. June 13: Condition good, appetite good. June 16: 9 a. m., found dead. Guinea pig 134. White and brown male. Weight, 740 grams. Diet, hay and oats. June 9: 2.55 p. m., 6 cc warm 2 per cent caffein solution given by mouth through stomach tube; 4.50 p. m., reflexes increased. June 10: 9.30 a. m., reflexes much less than day before, increase slight, a few cubic centimeters of urine passed since injection of caffein, looked brown and dirty, could not be tested for reducing substances. June 13: Guinea pig alive, appetite good, condition good. June 14: 9 a. m., found dead. Guinea pig 128. White and black male. Weight, 1,075 grams. Diet, hay and oats. June 7: 10 a. m., 11 cc 2 per cent caffein by mouth through stomach tube; 11.10 a. m., no symptoms, no urine passed; 1 p. m., increased reflexes, about 15 cc (estimated) urine passed; 4 p. m., reflexes increased, still more urine passed (about 20 cc); 4.50 p. m., tetanus, frequent attacks, then paralysis and death at 4.58 p. m. Autopsy : Lungs congested; blood vessels of heart injected; intestines slightly congested; fatty liver. Guinea pig 126. White and gray male. Weight, 980 grams. Diet, oats and hay. June 7: 9.40 a. m., 9.8 cc 2 per cent caffein given by mouth through stomach tube; 10 a. m., no symptoms; 11.10 a. m., no urine passed, reflexes increased; 1 p. m., more sensitive than before; 4 p. m., increase of reflexes more marked, no urine passed; 4.45 p. m., about 15 cc urine collected; 5 p. m., no change. June 8: 9 a. m., reflexes about the same as 5 p. m. previous day, no urine passed since 4.45 p. m. previous day, considerable reduction of Fehling's solution, much more than urine of guinea pig No. 127; 11.05 a. m., convulsions; 12 noon, still alive and stretched out on abdomen; died at 1 p. m. Autopsy : Lungs badly congested; heart and blood vessels injected; blood vessels of kidney and of small intestines injected; liver engorged with blood; a few necrotic spots in stomach. Guinea pig 127. White, black, and brown male. Weight, 760 grams. Diet, oats and hay. June 7: 9.50 a. m., 7.6 cc 2 per cent caffein by mouth through stomach tube; 10 a. m., no symptoms; 11.10 a. m., reflexes increased, no urine passed; 1 p. m., very sensitive; 4 p. m., sensitiveness increased, about 20 cc urine passed; 5 p. m., no change. June 8: 9 a. m., reflexes about the same as 5 p. m. previous day; 9.30 a. m., guinea pig passed 30 cc urine since he received caffein, urine showed a moderate amount of reduction; 12 noon, convulsions; died at 2.30 p. m. Autopsy : Lungs congested; blood vessels of heart and of intestines injected; numerous necrotic spots in stomach; other organs apparently normal. Examination of the protocols shows that the absorption of caffein from the gastro-intestinal canal was quite rapid, symptoms having been observed as early as 20 minutes after its introduction. The duration of life, it will be remarked, varied with the size of the dose. When approximately 3 decigrams per kilo were fed, all the animals died in the night. They lived, therefore, less than 18 hours. Two decigrams per kilo were likewise fatal, but the duration of life was longer. To decide whether or not this is the smallest fatal dose, smaller amounts were fed. It seemed at first that about 150 mg per kilo was the smallest toxic dose, and about 200 mg per kilo the minimum fatal dose. Macroscopic examination of the organs, however, threw some doubt on this supposition, for well-marked lesions were noticed in all of the guinea pigs which received 0.2 gram per kilo. It is quite possible, therefore, that the minimum fatal dose may be somewhat higher, as we have reason to believe that, at least in some pathologic conditions, the susceptibility to caffein is increased. The presence of fatty changes in the liver of No. 128 and the rapid death in this case lends especial support to this view. Hence, the minimum fatal dose is probably greater than 0.2 gram per kilo for the normal guinea pig. The doses employed for the tests on guinea pigs Nos. 129, 130, and 131 may be considered therefore the minimum fatal dose for these animals. It will be also remarked that macroscopical examination of the organs of these animals failed to reveal the presence of severe lesions. That the minimum toxic dose is probably much smaller than 0.28 gram per kilo is indicated by the experiments on guinea pigs Nos. 135 and 134, in which 0.15 gram caffein per kilo induced mild symptoms in from two to three hours. Both of these, however, and also No. 137 died four to six days after the drug was fed. As already pointed out, caffein may be a factor in the delayed death of guinea pigs which received moderate doses of it. That this supposition may also be true for guinea pigs Nos. 134, 135, and 137 is indeed made probable by the observation that after moderate amounts of caffein symptoms may persist in the guinea pig for about 24 hours, and also by the fact that the secretion of urine in these animals was very scanty, as shown in the preceding record of the experiments; this means slow elimination of caffein and its products of decomposition. It is conceivable that the presence of toxic amounts of caffein in the body for a considerable length of time would induce changes that ultimately lead to the death of the animal or that morbid processes are set up by the combined action of caffein and some preexisting poison. Since some guinea pigs, however, survived the doses indicated, it is more probable that such changes would be brought about by caffein in the presence of a preexisting poison. The death of these pigs, and also of No. 137 several days later, is difficult to account for on any other theory than the one suggested. Were it not for the fact that controls, that is, animals of the same lot which had not received caffein survived all of the experimental animals, changed conditions of environment or accident might be considered the cause of death in the guinea pigs of the last series. Table 6. — Subcutaneous injection of guinea pigs. SERIES A. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Duration of life. Diet. Month. Remarks. Grams. Mg. 18 500 0.300 2 minutes 2 hours 40 minutes Carrots March Female. 15 548 .290 30 minutes Oats do. Do. 14 442 .360 15 minutes do. do. do. Do. SERIES B. 20 497 0.200 2 hours 20 minutes 3 hours 30 minutes Oats April Female. 38 570 .210 25 minutes 2 hours 15 minutes Carrots February Male. 37 820 .200 1 hour 25 minutes Less than 18 hours Carrots and oats. do. Do. 13 618 .194 25 hours Oats March Female. 36 850 .200 1 hour 30 minutes 18 hours Carrots and oats. February Male. SERIES C. 66 510 0.200 None 5 days Oats October Male. 65 510 .200 do. Survived do. do. do. 60 320 .219 1 hour 15 minutes Within 18 hours do. do. Female. 57 350 .200 do. About 2½ days do. do. Do. 68 785 .200 25 minutes Less than 22 hours do. do. Male. 69 585 .200 20 minutes 9 days do. do. Do. 61 330 .240 1 hour 30 minutes Less than 24 hours do. do. Female. 62 335 .238 1 hour do. do. do. Do. 70 545 .238 50 minutes About 2 days do. do. Male. 71 540 .240 45 minutes do. do. do. Do. 72 560 .232 35 minutes About 3 days do. do. Do. SERIES D. 49 510 0.160 1 hour 40 minutes Less than 18 hours Oats March Male. 40 630 .158 Less than 2 days Oats and carrots. February Do. 45 435 .160 None Survived Oats March Female. 39 820 .150 2 days Oats and carrots. February Male. 41 660 .150 Survived do. do. 46 470 .170 1 hour 20 minutes do. Oats (?) March Female. SERIES E. 19 556 0.100 Survived Oats April 42 490 .120 None do. do. February 43 430 .116 do. do. do. do. 44 535 .112 do. do. do. do. 97 330 .100 do. do. do. November 98 520 .100 do. About 3 days Carrots do. SERIES A. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 18 500 0.300 2 minutes 15 548 .290 14 442 .360 15 minutes Number of pig. Duration of life. Diet. Month. Remarks. 18 2 hours 40 minutes Carrots March Female. 15 30 minutes Oats do. Do. 14 do. do. do. Do. SERIES B. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 20 497 0.200 2 hours 20 minutes 38 570 .210 25 minutes 37 820 .200 1 hour 25 minutes 13 618 .194 25 hours 36 850 .200 1 hour 30 minutes Number of pig. Duration of life. Diet. Month. Remarks. 20 3 hours 30 minutes Oats April Female. 38 2 hours 15 minutes Carrots February Male. 37 Less than 18 hours Carrots and oats. do. Do. 13 Oats March Female. 36 18 hours Carrots and oats. February Male. SERIES C. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 66 510 0.200 None 65 510 .200 do. 60 320 .219 1 hour 15 minutes 57 350 .200 do. 68 785 .200 25 minutes 69 585 .200 20 minutes 61 330 .240 1 hour 30 minutes 62 335 .238 1 hour 70 545 .238 50 minutes 71 540 .240 45 minutes 72 560 .232 35 minutes Number of pig. Duration of life. Diet. Month. Remarks. 66 5 days Oats October Male. 65 Survived do. do. do. 60 Within 18 hours do. do. Female. 57 About 2½ days do. do. Do. 68 Less than 22 hours do. do. Male. 69 9 days do. do. Do. 61 Less than 24 hours do. do. Female. 62 do. do. do. Do. 70 About 2 days do. do. Male. 71 do. do. do. Do. 72 About 3 days do. do. Do. SERIES D. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 49 510 0.160 1 hour 40 minutes 40 630 .158 45 435 .160 None 39 820 .150 41 660 .150 46 470 .170 1 hour 20 minutes Number of pig. Duration of life. Diet. Month. Remarks. 49 Less than 18 hours Oats March Male. 40 Less than 2 days Oats and carrots. February Do. 45 Survived Oats March Female. 39 2 days Oats and carrots. February Male. 41 Survived do. do. 46 do. Oats (?) March Female. SERIES E. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 19 556 0.100 42 490 .120 None 43 430 .116 do. 44 535 .112 do. 97 330 .100 do. 98 520 .100 do. Number of pig. Duration of life. Diet. Month. Remarks. 19 Survived Oats April 42 do. do. February 43 do. do. do. 44 do. do. do. 97 do. do. November 98 About 3 days Carrots do. Table 7.— Injection into peritoneal cavity; guinea pigs. SERIES A. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Duration of life. Diet. Month. Remarks. Grams. Mg. 41 700 0.130 2 hours 15 minutes 22 hours Oats April Male. 49 370 .135 2 hours Survived do. do. Do. 47 550 .127 1 hour do. do. March Female. 50 290 .138 2 hours do. do. April Do. SERIES B. 51 415 0.144 None Survived Oats October Female. 52 450 .155 do. do. do. do. Male. 53 490 .163 do. do. do. do. Do. SERIES C. 59 375 0.200 15 minutes Survived Oats October Gray and white. 58 380 .200 10 minutes do. do. do. 56 440 .200 15 minutes 14 days do. do. Male. 55 690 .188 1 hour 3 hours 30 minutes do. do. Do. SERIES D. 67 330 0.240 5 minutes 30 minutes Oats October Male. 63 340 .235 Survived do. do. Do. 64 305 .250 25 minutes 4 hours 40 minutes do. do. Female. SERIES A. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 41 700 0.130 2 hours 15 minutes 49 370 .135 2 hours 47 550 .127 1 hour 50 290 .138 2 hours Number of pig. Duration of life. Diet. Month. Remarks. 41 22 hours Oats April Male. 49 Survived do. do. Do. 47 do. do. March Female. 50 do. do. April Do. SERIES B. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 51 415 0.144 None 52 450 .155 do. 53 490 .163 do. Number of pig. Duration of life. Diet. Month. Remarks. 51 Survived Oats October Female. 52 do. do. do. Male. 53 do. do. do. Do. SERIES C. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 59 375 0.200 15 minutes 58 380 .200 10 minutes 56 440 .200 15 minutes 55 690 .188 1 hour Number of pig. Duration of life. Diet. Month. Remarks. 59 Survived Oats October Gray and white. 58 do. do. do. SERIES D. 56 14 days do. do. Male. 55 3 hours 30 minutes do. do. Do. SERIES D. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 67 330 0.240 5 minutes 63 340 .235 64 305 .250 25 minutes Number of pig. Duration of life. Diet. Month. Remarks. 67 30 minutes Oats October Male. 63 Survived do. do. Do. 64 4 hours 40 minutes do. do. Female. Table 8.— Caffein by mouth; guinea pigs. SERIES A. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Grams. Mg. 129 855 0.280 40 minutes 130 800 .300 30 minutes 131 860 .280 20 minutes 135 955 .150 1 hour 50 minutes 134 740 .160 3 hours 1 137 925 .150 50 minutes 1 136 1,000 .150 do. 126 980 .200 20 minutes 127 760 .200 1 hour 128 1,075 .200 3 hours Number of pig. Duration of life. Diet. Month. Remarks. 129 Less than 8 hours Hay and oats June Male. 130 Less than 18 hours do. do. Do. 131 do. do. do. Do. 135 6 days do. do. Do. 134 4 days do. do. Do. 1 137 6 days do. do. Do. 1 136 Survived do. do. Do. 126 27 hours do. do. Do. 127 28 hours do. do. Do. 128 7 hours do. do. Do. 1 Subcutaneous injection for comparison. SERIES A. Number of pig. Weight. Caffein per kilo Appearance of symptoms in Duration of life. Diet. Month. Remarks. Grams. Mg. 129 855 0.280 40 minutes Less than 8 hours Hay and oats June Male. 130 800 .300 30 minutes Less than 18 hours do. do. Do. 131 860 .280 20 minutes do. do. do. Do. 135 955 .150 1 hour 50 minutes 6 days do. do. Do. 134 740 .160 3 hours 4 days do. do. Do. 1 137 925 .150 50 minutes 6 days do. do. Do. 1 136 1,000 .150 do. Survived do. do. Do. 126 980 .200 20 minutes 27 hours do. do. Do. 127 760 .200 1 hour 28 hours do. do. Do. 128 1,075 .200 3 hours 7 hours do. do. Do. 1 Subcutaneous injection for comparison. SUMMARY. A survey of the results obtained in experiments on guinea pigs shows that the mode of introduction of caffein exerts but little influence on its toxicity. On careful analysis it will be observed that the rate of absorption after the administration of caffein by mouth, subcutaneously, or intraperitoneally is about the same for the time of appearance of symptoms. The persistence of the symptoms of caffein intoxication observed in these experiments for 24 hours after administration points to slow elimination, which may be expected, owing to the fact that the guinea pigs passed but little urine and caffein is not diuretic for these animals. The prolonged presence of caffein in the body probably exerts a harmful influence or after effect, which may account for the delayed death of some animals many days after a single dose of caffein was given. Among the factors which undoubtedly influence toxicity, season should be considered, while the presence of a diseased condition undoubtedly tends to decrease the resistance of the guinea pig to caffein. Diet was without any influence on the toxicity of the single dose of caffein. EXPERIMENTS ON CATS. These experiments were performed on well-fed animals which were kept under observation for several days before the tests with caffein were made. The diet consisted of meat exclusively. In some cases the urine was examined for albumin and sugar before caffein was given. No tests with caffein were made if large amounts of albumin were found. It may be remarked that sugar was never found in cats before the administration of caffein, but that considerable amounts of it were found in some cases after it was given. Studies by various modes of administration were made, by subcutaneous injection, intraperitoneally, or by mouth. Attention was also directed to the resistance to caffein in young cats, several experiments on kittens being made with this object in view. SUBCUTANEOUS INJECTION. Rost stated that caffein is eliminated in the urine unchanged after its introduction into the body and that the amounts found varied with different species of animals. In the rabbit the amount eliminated was about 21 per cent; in the dog about 8 per cent; and in the cat somewhat less than 2.5 per cent. It would appear, therefore, that the cat decomposes caffein more readily than the rabbit or dog; its resistance consequently ought to be greater than that of the other animals. Moderately large doses were accordingly employed in the preliminary experiments (series A), but the results obtained, as shown in the protocols, indicated that caffein is fully as toxic for the cat as for the rabbit or dog. The doses were then decreased and experiments were performed in order to ascertain the smallest toxic as well as the smallest fatal dose. Series A. Three decigrams of caffein per kilo were administered in these experiments. The results are shown in the following protocols: Cat 4. Black and white. Weight, 1,440 grams. May 26: 10.05 a. m., 22 cc 2 per cent caffein (0.3 gram per kilo) injected subcutaneously; 11.10 a. m., copious salivation, cat irritable, muscular stiffness present, but no tetanus; 11.45 a. m., cat restless, convulsions, attacks of short duration, no paralysis observed after the convulsions, pupils dilated; 4.45 p. m., cat quiet, slight paralysis present. May 27: Cat exhausted. May 28: Found dead. Cat 5. Black and white male. Weight, 1,396 grams. June 3: 10 a. m. 21 cc of 2 per cent caffein (0.3 gram per kilo) injected subcutaneously; 12 noon, found dead. Although there was considerable difference in the duration of life following the injection of the same dose of caffein per kilo, the final outcome was the same, as both cats died from the effects of the drug. One died within 2 hours and the other lived more than 30 hours after its administration. Three decigrams of caffein per kilo is, therefore, surely fatal to these animals. Tests made with smaller doses are shown in the following experiments: Series B. In these experiments the doses employed ranged between 0.20 and 0.25 gram caffein per kilo. Cat 3. Black and white female. Weight, 2,854 grams. Well fed. June 4: 10.30 a. m., 35 cc 2 per cent caffein (0.25 gram per kilo) injected subcutaneously; 11 a. m., found dead. Cat 6. Black and white. Weight, 1,645 grams. June 3: 20 cc 2 per cent caffein (0.243 gram per kilo) injected subcutaneously at 3 p. m., cat grew very irritable in a few minutes; about 4 p. m. reflexes decidedly increased; 5 p. m., cat paralyzed. June 4: Cat found dead. Cat 8. Weight, 1,735 grams. October 7: 4 p. m., 22 cc 2 per cent caffein (0.25 gram per kilo) injected subcutaneously in the back; 4.30 p. m., cat irritable, salivation profuse, convulsions; died at 5.30 p. m.; no urine passed after caffein was given. Cat 9. Weight, 1,960 grams. October 7: 3.45 p. m., 25 cc 2 per cent caffein (0.25 gram per kilo) injected subcutaneously in the back; 4.45 p. m., cat very irritable, repeated attacks of convulsions, salivation copious; died at 5.30 p. m.; cat did not urinate after injection of caffein. Cat 12. Striped kitten. Weight, 1,185 grams. October 9: Urine examined, no albumin, no sugar; 1.45 p. m., 12 cc 2 per cent caffein administered; 5 p. m., cat alive, no symptoms except salivation and general irritability. October 10: 10.30 a. m., found dead. About 15 cc urine collected, but no examination made. Cat 14. Black. Weight, 1,855 grams. October 8: 1.40 p. m., 18.5 cc 2 per cent caffein (0.2 gram per kilo); 3 p. m., cat became restless about 10 minutes after caffein was injected; cried persistently and moved about in cage, no convulsions, cat urinated about 15 cc, cat defecated. October 9: 9 a. m., cat found dead in cage. Urine gave very heavy reduction of Fehling's solution (much more than was obtained from urine of rabbits); 20 cc urine analyzed contained 4.65 per cent sugar. Autopsy : Lungs deeply congested; liver marked fatty infiltration and degeneration; spleen normal; kidneys pale and anemic; intestines normal; stomach normal. Cat 15. Striped. Weight, 2,145 grams. October 8: 2 p. m., 22 cc (0.2 gram per kilo) 2 per cent caffein injected subcutaneously; 2.30 p. m., cat irritable, restless, trying to get out of cage, crying persistently; 2.40, convulsions lasting about two minutes, then cat raised itself and made attempts to get out of cage, no salivation, cat urinated about 10 cc and defecated. October 9: 9 a. m., cat found dead in cage, about 10 cc of urine contained enormous quantities of sugar. Autopsy : Lungs severely congested; liver showed marked fatty degeneration; spleen normal; kidneys slightly pale and anemic; intestines mildly congested; stomach normal. Cat 19. White. Weight, 1,100 grams. October 20: 13 cc of 2 per cent caffein (0.236 gram per kilo). About 15 minutes later cat became irritable, reflexes increased, persistent crying, stiffness of extremities, diarrhea present; 4.30 p. m., stiffness of muscles, coordination much disturbed, walked with great difficulty; 4.30 p. m., no new symptoms, persistent crying continued. October 21: Found dead. Cat 20. White kitten. Weight, 790 grams. October 20: 11.35 a. m., 10 cc 2 per cent caffein (0.25 gram per kilo) given subcutaneously; 12 noon, convulsions followed by paralysis; 1.30 p. m., still breathing, apparently in comatose condition, lay on its side, dyspnœa, profuse salivation; 4 p. m., convulsions and death. The results of the experiments of series B show that a dose of even 0.2 caffein per kilo is very toxic for the cat. Symptoms appeared in one animal 40 minutes after the injection of caffein. Some of them were found dead 18 hours after injection, which means that the duration of life was probably a great deal less since there was evidence that they had been dead for some time. Death occurred quite soon after larger doses were injected. Cat No. 3 died 30 minutes after it received caffein. The amounts employed in these experiments can not be considered therefore as the minimum fatal doses. Smaller doses were then tried, as shown in the experiments of the next series. Series C. Experiments were performed on five cats which received from 140 to 155 mg per kilo, as follows: Cat 24. Striped. Weight, 1,300 grams. October 25: 10 a. m., 50 cc urine, albumin moderate amount—no sugar; 10 cc caffein injected subcutaneously at 12 noon; 12.30, irritable, cried persistently, no appetite; 4 p. m., no convulsions, but persistent crying. October 27: Cat was still alive. Cat 17. Weight, 2,620 grams. October 12: 9.30 a. m., 65 cc urine collected; more than a trace of albumin present, no reduction of Fehling's solution; 3 p. m., 20 cc 2 per cent caffein (150 mg per kilo) injected subcutaneously; 3.15 p. m., irritable and restless. October 13: 9 a. m., about 15 cc urine collected, reduction of Fehling's solution marked; osazone test also positive. Cat 23. Black and white. Weight, 1,645 grams. October 25: 10 a. m., 140 cc urine collected (since October 23), small amount of albumin present, no sugar. October 27: 9 a. m., no albumin; no sugar in urine; 11.50 a. m., 12.5 cc caffein injected subcutaneously (0.15 gram per kilo); 1 p. m., convulsions and death. Cat 7. Striped kitten. Weight, 1,285 grams. October 11: Urine collected, no albumin, no sugar; 9.50 a. m., 10 cc 2 per cent caffein injected subcutaneously in the back; 10.10, violent convulsions lasting about 30 seconds; 10.20, convulsions of shorter duration; 10.30 convulsions; 10.35, convulsions lasting a few seconds; urine passed about 10.20, contained a moderate amount of albumin, but there was no reduction of Fehling's solution; 10.45, profuse salivation and paralysis; died about 10.50. Cat 39. Yellow. Weight, 2,285 grams. April 13: 2.40 p. m., 16 cc 2 per cent caffein (0.14 gram per kilo) injected subcutaneously in the back; 3.45 p. m., cat died. Of the five experiments of this series three died after doses of 140, 150, and 155 mg per kilo. The other two showed symptoms of toxicity, but survived a dose of 150 mg per kilo which indicated that the minimum fatal dose was probably reached. To test this supposition smaller doses were administered, as shown in the following experiments. Series D. Ten cats were used for this series of experiments, and the doses administered varied between 103 and 139 mg per kilo. The results shown in the appended table ( p.58 ) indicate that about 120 to 140 mg of caffein per kilo may induce mild symptoms in some cases. The conclusion may be safely drawn therefore that 150 mg per kilo is approximately the minimum fatal dose for the cat when the drug is given subcutaneously. That smaller doses are, however, by no means to be regarded as always safe is shown in the following experiments. Series E. Cat 43. Weight, 3,225 grams. [D] September 14: 10.20 a. m., 20 cc 2 per cent caffein (0.124 gram per kilo) injected into the back; 11 a. m., tetanus and death. Autopsy : Lungs congested; liver congested and showed hemorrhagic spots in capsules and fatty degeneration; kidneys slightly congested; other organs normal. Cat 48. Black female. Weight, 3,050 grams. September 14: 18 cc 2 per cent caffein (0.118 gram per kilo) injected subcutaneously in the back; 10.30 a. m., violent convulsions and death. Autopsy : Lungs congested in spots showing numerous petechia; liver congested; spleen congested; other organs normal. The diminished resistance to caffein of cats Nos. 43 and 48 might be due to the pathologic changes found on autopsy, for evidence is not wanting that the toxicity of drugs might be greatly altered under pathological conditions. Hunt 40 has shown that resistance to acetonitril is considerably diminished in chronic alcoholism. This seems to be true also of other drugs under abnormal conditions. Smaller doses of atropin 78 are required in lead poisoning than under normal conditions to produce the same results. The following experiment is of interest in this connection, for in this case a much smaller dose than was given in experiments Nos. 43 and 48 produced the typical symptoms of caffein poisoning and proved to be fatal. Cat 47, black and white male. Weight, 4,220 grams. September 15: Received subcutaneously 18 cc 2 per cent caffein (0.084 gram per kilo); no symptoms observed for about six hours. September 16: No symptoms. September 17: Weight, 4,250 grams; injected 18 cc 2 per cent caffein (0.084 gram per kilo); tetanus and death after two hours. Autopsy : Severe hemorrhagic pneumonia; kidneys pale, other organs normal. Since two controls survived the same dose in proportion to the body weight of the animal without showing any symptoms, the assumption is justified that the lower resistance to caffein was due to the presence of pneumonia, thus affording additional support to the view that the toxicity of caffein may be increased in disease. INJECTION INTO THE PERITONEAL CAVITY. These experiments were carried out on full-grown and on young subjects. As in previous experiments, doses of different sizes were employed. A dose of 0.2 gram per kilo was tried first and then reduced gradually to 0.1 gram per kilo. Cat 10. Female. Weight, 2,970 grams. October 9, 1909: 1.30 p. m., 30 cc 2 per cent caffein (0.2 gram per kilo) injected into the peritoneal cavity; urine examined for albumin and sugar, negative; cat found dead at 2.30 p. m. No urine in the bladder. Cat 16. Black female. Weight, 2,420 grams. October 9, 1910: Urine examined for albumin and sugar, negative; 2.30 p. m., 22 cc 2 per cent caffein (0.183 gram per kilo) injected into the peritoneal cavity; found dead at 3 p. m. Cat 99. Well-fed gray female. Weight, 3 kilos. June 22, 1911: 3.40 p. m., 15 cc 2 per cent caffein injected into peritoneal cavity; salivation and marked irritability within one hour after injection. June 24: Alive, appetite good. Cat 98. Well-fed black male. Weight, 4,100 grams. June 22: 3.45 p. m., 20.5 cc 2 per cent caffein (0.1 gram per kilo) injected into peritoneal cavity; very irritable a few minutes after injection, no other symptoms. June 24: No symptoms, appetite good. Cat 93. Black and white. Weight, 1,450 grams. June 22: 3 p. m., 30 cc 2 per cent caffein (0.137 gram per kilo) injected into peritoneal cavity; salivation, no other symptoms; under observation until 6 p. m. June 23: 9 a. m., no urine, cat showed no symptoms. June 24: 9 a. m., no symptoms, took nourishment as usual. Cat 87. Well-fed white female. Weight, 2,615 grams. June 23: 2.45 p. m., 19 cc 2 per cent caffein (0.145 gram per kilo) injected into peritoneal cavity; became irritable and restless. June 24: 9 a. m., no symptoms, took nourishment as usual. Cat 97. Gray. Age, 3 months. Weight, 500 grams. Diet, meat. June 24: 2.25 p. m., 5 cc 2 per cent caffein (0.2 gram per kilo) injected into peritoneal cavity; 4 p. m., no symptoms. June 29: Died. Cat 96. Gray and white. Age, 3 months. Weight, 575 grams. Diet, meat. June 24: 2.20 p. m., 4 cc 2 per cent caffein (0.139 gram per kilo) injected into peritoneal cavity; 3.55 p. m., no symptoms. June 30: Died. Cat 95. Black. Age, about 3 months. Weight, 860 grams. Diet, meat. June 24: 10.15 a. m., 8.6 cc 2 per cent caffein injected into peritoneal cavity, salivation immediately after injection; 10.25, convulsions and paralysis; died 10.45 a. m. Autopsy : Macroscopical examination of the organs, negative. Cat 94. Black and white. Weight, 790 grams. Age, about 3 months. Diet, meat. June 24: 10 a. m., 8 cc 2 per cent caffein injected into peritoneal cavity; 4 p. m. under continual observation since injection, cat very irritable, respiration more rapid than normal, diarrhea present. Examination of the above protocols show that a dose of 2 decigrams per kilo was fatal within one hour to one cat and that a somewhat smaller dose killed another individual in 30 minutes. Amounts under 0.15 gram per kilo were just sufficient to induce mild symptoms, such as increased irritability and salivation, which disappeared within a few hours. In no case were the effects noticeable on the following day. The experiments on young kittens are especially interesting, as they proved, contrary to expectation, to be distinctly more resistant than full grown individuals. The death of Nos. 97 and 96 within five and six days, respectively, can not be ascribed to caffein, since some of the controls also died. Moreover, it will be remarked in this connection that no symptoms appeared in three of the four young kittens after the administration of a dose which was rapidly fatal to adult cats. The rapid death of No. 95 after the same dose forms an exception which can not be accounted for, as macroscopical examination at autopsy proved negative. ADMINISTRATION BY MOUTH. Two decigrams per kilo were given at first, but it was found that this amount was surely fatal. The dose was therefore reduced to 0.125 gram per kilo. In all of these experiments caffein was given by means of a soft rubber catheter slipped over the stem of a funnel which served as a stomach tube. A 2 per cent aqueous solution was used throughout these tests except in one case in which caffein was given mixed with the food. Cat 92. Black and white female. Weight, 1,750 grams. June 10: 12.05 p. m., 14 cc 2 per cent caffein (0.16 gram per kilo) given by mouth; cat was quiet when tied on holder, struggled only a little when tube was put into stomach; 12.30 p. m., cat vomited, no other symptoms. June 13: Condition good, appetite good. Cat 87. White female. Weight, 2,620 grams. Diet, meat. June 5: 2.15 p. m., 20 cc 2 per cent caffein (0.15 gram per kilo) solution administered by mouth through stomach tube; 2.30 p. m., cat irritable, but no other symptoms; 5 p. m., condition about the same, except that it was more irritable and showed some stiffness of the extremities. June 13: Alive and in good condition, appetite good, not irritable. Cat 91. White female. Weight, 3,050 grams. June 10: 12 noon, 23 cc (0.15 gram per kilo) of 2 per cent caffein administered by mouth, cat struggled violently; 1.30, salivation; 1.40 p. m., convulsions; died at 2 p. m. Autopsy : Congestion of lungs, liver, and spleen; heart vessels injected; other organs normal. Cat 88. Black and white female. Weight, 3,260 grams. Diet, meat. June 5: 2.20 p. m., 25 cc of 2 per cent caffein (0.15 gram per kilo) given by mouth; 2.45 p. m., cat irritable, no other symptoms (cat did not vomit after the administration of caffein); 4 p. m., cat found dead. Autopsy : Liver very much congested; heart contracted; body was still warm at the time of autopsy. Cat 90. White and yellow female. Weight, 2,685 grams. Diet, meat.

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