12 THE TOXICITY OF CAFFEIN. 



being specific on voluntary muscle fiber, contractions of which he 

 observed under the microscope, thus differing completely from strych- 

 nin, which is a nerve poison. 



These observations seemed to be confirmed by Pratt 74 (1868), who 

 reported that the isolated posterior extremities and muscle fibers of 

 the toad placed in a solution of caffein (1 grain to a wineglassful of 

 water) for three minutes were contracted, while controls placed in 

 distilled water were relaxed. This experiment is, of course, defective, 

 as normal salt solution should have been used in both cases. When 

 the muscular fibers previously immersed in caffein solution were 

 placed under the microscope violent contractions were observed. 

 The same author administered from 2 to 18 grains at a dose to five 

 healthy young men. After the administration of 12 grains he noticed 

 mental anguish, tremors of the hands and arms, and insomnia. 

 Doses under 5 grains had no marked effect except a diminution in the 

 frequency of the pulse and wakefulness. 



About the same time Amory 4 ( 1868) published the results of his 

 studies on the toxicity of caffein in cats, dogs, rabbits, and pigeons. 

 In all cases very large doses were introduced directly into the stomach 

 by means of a temporary gastric fistula. Ten grains given in meat 

 to a dog caused restlessness, but no other symptoms. Doses of 30 

 grains and above were invariably fatal. Seventy- three grains given 

 to a cat caused death within 20 minutes. 



From observations on frogs, guinea pigs, rabbits, and on one dog, 

 Leven 53 (1868) concluded that caffein which he gave in the form of 

 the citrate in doses of 10 mg to frogs, from 150 to 200 mg to guinea 

 pigs, and three to four times the latter amount to rabbits, stimulates 

 the central nervous system and the voluntary, cardiac, and smooth 

 muscles. He found that 0.9 gram caffein was fatal for a rabbit when 

 injected subcutaneously, while 1 gram of the citrate was not toxic 

 for a dog of medium size. Caffein applied directly to muscle fiber 

 causes tetanus and destroys muscular contractility, while a nerve 

 fiber similarly treated loses its irritability. 



According to Johansen 44 (1869), caffein acts directly on the mus- 

 cular fiber. After the subcutaneous injection of 0.02 gram of caffein 

 into frogs, he observed contraction of the muscles at the site of injec- 

 tion, then contraction of the anterior extremities, and finally the 

 posterior extremities become rigid and extended. Johansen observed 

 muscular rigidity after caffein, even after curara was injected, or after 

 ligating the vessels, or cutting the nerves which supply the muscles. 

 He also observed that large doses of caffein diminish muscular irrita- 

 bility. When cardiac muscle was poisoned with caffein, microscopical 

 examination showed that the striations disappeared. Johansen also 

 states that reflexes disappear after caffein poisoning. He never 

 observed tetanus in frogs, but reported tonic and clonic convulsions as 



