The evidence brought forth in the preceding pages regarding cumulation
of caffein naturally suggests the question whether or not the body
acquires a tolerance for it. This question has already been answered in
the affirmative by Gourewitch,(28) but owing to the method he used for
the identification of caffein and the few experiments made his results
are not conclusive. The experiments of series A, B, and C might be
regarded as indicating that tolerance for caffein is not acquired by
the rabbit. It was noticed, however, that the rabbit apparently does
tolerate increasingly larger doses under certain conditions, as the
following experiments show:
_Rabbit 223._ _Belgian hare, male._
October 22: Weight, 1,520 grams; 15 cc 2 per cent caffein injected
subcutaneously at 2 p. m.
November 1: 10.30 a. m., weight, 1,510 grams; 17 cc 2 per cent caffein
injected subcutaneously (225 mg per kilo), reflexes observed, but no
tetanus.
November 4: 10.30 a. m., weight 1,535 grams; 19 cc 2 per cent caffein
injected subcutaneously at 2.40 p. m.; 4.40 p. m., no symptoms.
November 8: Weight, 1,425 grams; 20 cc 2 per cent caffein (285 mg per
kilo) injected at 11.45 p. m.; 5 p. m., no symptoms.
November 17: Weight, 1,325 grams; 22 cc 2 per cent caffein injected at
2.55 p. m. (329 mg per kilo), no symptoms.
November 18: Rabbit in good condition.
_Rabbit 224. Belgian hare, female. Diet, carrots._
October 18: Weight, 1,935 grams; 11.20 a. m., 15 cc 2 per cent caffein
(155 mg per kilo) injected.
November 1: Weight, 1,780 grams; 20 cc 2 per cent caffein (224 mg per
kilo) injected subcutaneously, reflexes increased, muscle tremors
present, but no other symptoms.
November 4: Weight, 1,710 grams; 21.5 cc 2 per cent caffein (252 mg per
kilo) injected.
November 8: Weight, 1,435 grams; 22.5 cc 2 per cent caffein or 314 mg
per kilo injected at 11.40 p. m.; 5 a. m., no symptoms.
November 17: Weight, 1,340 grams; 24 cc 2 per cent caffein (358 mg per
kilo) injected subcutaneously.
November 18: 9 a. m., rabbit died.
_Rabbit 226. Gray male. Diet, carrots._
October 28: Weight, 1,045 grams; 10 cc 2 per cent caffein injected
subcutaneously at 1.50 p. m.; 4.30 p. m., tremors observed, but no
other symptoms.
October 29: Rabbit in good condition.
November 1: Weight, 950 grams; 10.55 a. m., 11 cc 2 per cent caffein
injected subcutaneously (231 mg per kilo).
November 4: Weight, 930 grams; 2.50 p. m., 12 cc 2 per cent caffein
injected subcutaneously (258 mg caffein per kilo).
November 6: Weight, 945 grams; 11.45 a. m., 15 cc 2 per cent caffein
(313 mg per kilo) injected subcutaneously.
November 17: Rabbit still alive; weight, 890 grams.
The results of these experiments indicate that when sufficient time is
allowed between two successive injections, susceptibility to caffein
is not increased. The rabbit, on the contrary, seems to acquire a
tolerance for the drug, for the fourth dose was 15 per cent larger than
the minimum fatal dose of caffein. This is in all probability due to
the better elimination of caffein and its products of decomposition and
to recovery from the deleterious effects of each dose, made possible by
long intervals between injections.
The results of these experiments may be briefly summed up by stating
that subminimum doses of caffein given to the rabbit daily or at
intervals (not too long) do not produce any symptoms such as were
observed in acute caffein intoxication, namely, increased reflexes
and convulsions, or increased rate of respiration, thus showing that
it is not cumulative. But evidence of undoubted summation of effect
was adduced to show that if the administration of subminimum doses of
caffein be continued daily for a period of 11 to 18 days the result
is fatal. Tolerance, however, may be acquired, although to a limited
extent only, provided sufficiently long intervals between injections
are allowed to give time for repair of the injury done by the drug and
to develop a mechanism for its better decomposition and elimination.
Furthermore, the evidence just given indicates that the elimination
of subminimum doses of caffein and its products of decomposition
is probably accomplished within 24 hours or thereabouts. That the
elimination of larger doses is not accomplished in this interval is
made probable by the following experiment:
_Gray rabbit 455. Female. Diet, oats._
October 12: Weight, 1,185 grams; 3.30 p. m., 11.5 cc 2 of per cent
caffein injected into the lumbar muscles; 3 p. m., reflexes increased.
October 13: 10 a. m., rabbit weighed 1,070 grams; no symptoms of
caffein poisoning, reflexes normal; 10.30 a. m., 10 cc 2 per cent
caffein injected into the lumbar muscles; 11.30 a. m., rabbit jumped
off the table, had convulsions, and died.